Evidence Report/Technology Assessment

Number 198 

Management of Acute Otitis Media: Update

Prepared for: 

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. HHSA 290-2007-10056-I 

Prepared by: 

RAND Corporation, Santa Monica, CA 90407 

 

Investigators 

Paul G. Shekelle, M.D., Ph.D.

Glenn Takata, M.D., M.S. 

Sydne J. Newberry, Ph.D. 

Tumaini Coker, M.D. 

Mary Ann Limbos, M.D., M.P.H. 

Linda S. Chan, Ph.D. 

Martha M. Timmer, M.S.

Marika J. Suttorp, M.S. 

Jason Carter, B.A. 

Aneesa Motala, B.A.

Di Valentine, J.D. 

Breanne Johnsen, B.A. 

Roberta Shanman, M.L.S. 

AHRQ Publication No. 11-E004 

November 2010
This report is based on research conducted by the RAND Evidence-based Practice Center 

(EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, 

MD (Contract No. HHSA 290-2007-10056-I). The findings and conclusions in this document 

are those of the author(s), who are responsible for its content, and do not necessarily represent 

the views of AHRQ. No statement in this report should be construed as an official position of 

AHRQ or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and 

others make informed decisions about the provision of health care services. This report is

intended as a reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical 

practice guidelines and other quality enhancement tools, or as a basis for reimbursement and 

coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of 

such derivative products may not be stated or implied. 

 
ii 

This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: Shekelle PG, Takata G, Newberry SJ, Coker T, Limbos M, Chan LS, 

Timmer M, Suttorp M, Carter J, Motala A, Valentine D, Johnsen B, Shanman R. Management of 

Acute Otitis Media: Update. Evidence Report/Technology Assessment No. 198. (Prepared by the 

RAND Evidence-Based Practice Center under Contract No. 290 2007 10056 I). Rockville, MD: 

Agency for Healthcare Research and Quality. November 2010. 

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, 

honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) 

that conflict with material presented in this report. 
Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. This report was requested by the American Academy 

of Pediatrics (AAP). The reports and assessments provide organizations with comprehensive, 

science-based information on common, costly medical conditions and new health care 

technologies. The EPCs systematically review the relevant scientific literature on topics assigned 

to them by AHRQ and conduct additional analyses when appropriate prior to developing their 

reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Stephanie Chang, M.D., M.P.H. CAPT Ernestine Murray, R.N., B.S.N., M.A.S. 

Director, EPC Program EPC Program Task Order Officer 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

iii 
Acknowledgments 

We wish to acknowledge the invaluable guidance and expertise contributed to this project by the 

Technical Expert Panel members who are listed in Appendix F. We also thank CAPT Ernestine 

(Tina) Murray (AHRQ) for her patience, guidance, and input, and the Oregon Evidence-based 

Practice Center, Rose Relevo, for assistance with research on drug safety, and the administrative 

staff for assistance with preparation of the report. 

iv 
Structured Abstract 

Context: Acute Otitis Media (AOM), a viral or bacterial infection of the ear, is the most 

common childhood infection for which antibiotics are prescribed in the United States. In 2001, 

the Southern California Evidence-based Practice Center conducted a systematic review of the 

evidence comparing treatments of AOM. 

Objectives: This review updates the 2001 review findings on diagnosis and treatment of 

uncomplicated AOM, assesses the evidence for treatment of recurrent AOM, and assesses the 

impact of the heptavalent pneumococcal conjugate (PCV7) vaccine on the microbiology of 

AOM. 

Data Sources and Study Selection: Searches of PubMed and the Cochrane databases were 

conducted from January 1998 July 2010 using the same search strategies used for the 2001 

report, with the addition of terms not considered in the 2001 review. The Web of Science was 

also searched for citations of the 2001 report and its peer-reviewed publications. 

Data Extraction: After review by two investigators against pre-determined inclusion/exclusion 

criteria, we included existing systematic reviews and randomized controlled clinical trials for 

assessment of treatment efficacy and safety. Pooled analysis was performed for comparisons 

with three or more trials. 

Results and Conclusions: Few studies were found that examined the accuracy and precision of 

the diagnosis of AOM. Since PCV7’s introduction, AOM microbiology has shifted significantly, 

with Streptococcus pneumoniae becoming less prevalent and Haemophilus influenzae (HF) 

increasing in importance. For uncomplicated AOM, pooled analysis indicates that nine children 

(95% CI: 6, 20) would need to be treated with ampicillin or amoxicillin rather than placebo to 

note a difference in the rate of clinical success. However, in four studies of delayed treatment 

approaches for uncomplicated AOM, two had higher rates of clinical success with immediate 

antibiotic therapy while two did not, and in three studies, a marked decrease in antibiotic 

utilization was noted. We are unable to draw definitive conclusions regarding the comparative 

effectiveness of different antibiotics for AOM in children with recurrent otitis media (ROM). For 

ROM, long-term antibiotic administration will decrease AOM episodes from 3 to 1.5 for every 

12 months of treatment per otitis prone child during active treatment (95% CI: 1.2, 2.1); 

however, potential consequences of long-term treatment need to be considered. Data were 

insufficient to draw conclusions about comparative effectiveness of different treatment strategies 

in subgroups of children with uncomplicated AOM. Adverse events were generally more 

frequent for amoxicillin-clavulanate than for cefdinir, ceftriaxone, or azithromycin. Higher 

quality studies and improved reporting of study characteristics related to quality are needed to 

provide definitive conclusions for AOM and ROM treatment options. 

v 
vi
 
Contents 

Executive Summary.........................................................................................................................1
 

Evidence Report.............................................................................................................................19
 

Chapter 1. Introduction ..................................................................................................................21
 

Diagnostic Accuracy..............................................................................................................21
 

Management...........................................................................................................................21
 

Pneumococcal Conjugate Vaccine.........................................................................................22
 

Chapter 2. Methods.......................................................................................................................23
 

Original Proposed Key Questions.............................................................................................23
 

Technical Expert Panel .............................................................................................................24
 

Definitions of Acute Otitis Media.............................................................................................24
 

Literature Search.......................................................................................................................25
 

Article Review ..........................................................................................................................26
 

Study Inclusion ..................................................................................................................... 26
 

Screening............................................................................................................................... 26
 

Data Abstraction & Synethesis of Results............................................................................... 27
 

Review and Assessment of Study Quality............................................................................ 27
 

Data Abstraction ................................................................................................................... 27
 

Supplemental Analysis for Key Question III........................................................................ 27
 

Supplemental Analysis for Key Question IV........................................................................ 29
 

Supplemental Analysis for Key Question V......................................................................... 29
 

Supplemental Analysis for Key Question VI........................................................................ 29
 

Use of Observational Studies to Assess Comparative Effectiveness.................................... 30
 

Rating the Overall Quality of Scientific Evidence ............................................................... 30
 

Peer Review .................................................................................................................................. 33
 

Chapter 3. Results ..........................................................................................................................35
 

Key Question I. Diagnosis of AOM: What are the Operating Characteristics (Sensitivity, 

Specificity, and Likelihood Ratios) of Clinical Symptoms and Otoscopic Findings (Such As 

Bulging Tympanic Membrane) to Diagnose Uncomplicated AOM and to Distinguish It from 

OME? .............................................................................................................................................35
 

Description of the Studies..................................................................................................... 35
 

Findings for Key Question I ................................................................................................. 35
 

Key Question II. What Has Been the Impact of the Pneumococcal Heptavalent Immunization 

(PCV7) on AOM Microbial Epidemiology (Including Acute Mastoiditis and Suppurative
 

Complications)?........................................................................................................................ 44
 

Description of the Studies..................................................................................................... 44
 

Findings for Key Question II ................................................................................................ 44
 

Findings According to Antibiotic History ............................................................................ 56
 

vii 
Key Question III. What is the Comparative Effectiveness of Different Treatment Options for
 

Treating Uncomplicated Acute Otitis Media in Average Risk Children?................................ 56
 

Description of the Studies..................................................................................................... 56
 

Findings for Key Question III............................................................................................... 57
 

Ampicillin or Amoxicillin vs. Placebo ................................................................................. 79
 

Ampicillin or Amoxicillin vs. Ceftriaxone ........................................................................... 88
 

Amoxicillin-Clavulanate (7-10 days) vs. Ceftriaxone (single dose) .................................... 90
 

Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days) ...................................... 93
 

Cefaclor vs. Azithromycin.................................................................................................... 99
 

Antibiotics vs. Wait-and-See/Prescription to Hold............................................................. 101
 

Other Meta-Analyses .......................................................................................................... 105
 

Summary............................................................................................................................. 105
 

Key Question IV. What Is the Comparative Effectiveness of Different Management 

Options for Recurrent Otitis Media (Uncomplicated) and Persistent Otitis Media or Relapse
 

of Acute Otitis Media? ........................................................................................................... 108
 

Description of the Studies................................................................................................... 108
 

Key Question V. Do Treatment Outcomes in Key Questions III and IV Differ by
 

Characteristics of the Condition (AOM), Patient, Environment, and/or Health Care
 

Findings on Treatment of Acute Otitis Media in Children with Recurrent Otitis Media ... 119
 

Findings on Prevention of Acute Otitis Media in Children with Recurrent Otitis Media .. 123
 

Summary............................................................................................................................. 128
 

Delivery System? .................................................................................................................. 129
 

Age Factor in Uncomplicated Acute Otitis Media ............................................................. 130
 

Laterality Factor in Uncomplicated Acute Otitis Media..................................................... 151
 

Childcare Setting Factor in Uncomplicated Otitis Media................................................... 154
 

Other Factors Studied in Uncomplicated Otitis Media....................................................... 157
 

Effectiveness of Treatments in Recurrent Otitis Media, Stratified by Age, Laterality, 

and Severity ........................................................................................................................ 160
 

Summary............................................................................................................................. 164
 

Key Question VI. What Adverse Effects Have Been Observed for the Treatments Whose 

Outcomes Are Addressed in Key Questions 3 and 4? .......................................................... 165
 

Description of the Studies................................................................................................... 165
 

Adverse Effects in Studies of Treatment of Acute Otitis Media in Children with 

Adverse Events Associated with Prevention of Acute Otitis Media in Children with 

Adverse Effects Observed In Treatment of Uncomplicated Acute Otitis Media ............... 165
 

Recurrent Otitis Media or Persistent Acute Otitis Media ................................................... 175
 

Recurrent Otitis Media........................................................................................................ 183
 

Summary............................................................................................................................. 189
 

Chapter 4. Discussion ..................................................................................................................191
 

Limitations ..............................................................................................................................191
 

Publication Bias .................................................................................................................. 191
 

Study Quality ...................................................................................................................... 191
 

Conclusions........................................................................................................................... 191
 

Key Question I. Diagnosis of AOM ................................................................................... 191
 

viii 
Key Question II. The impact of the Pneumococcal Heptavalent Immunization (PCV7)
 

on AOM Microbial Epidemiology...................................................................................... 192
 

Key Question III. Treatment of Uncomplicated AOM

Key Question IV. Prevention or Treatment of Acute Otitis Media in Children with 

....................................................... 197
 

Recurrent Otitis Media........................................................................................................ 193
 

Key Question V................................................................................................................... 194
 

Key Question VI ................................................................................................................. 194
 

Future Research Suggestions .................................................................................................194
 

Key Question I: Diagnostic Criteria for AOM ................................................................... 195
 

Key Question II: Effects of the PCV7 Vaccine .................................................................. 195
 

Key Questions III-VI: Treatment Efficacy and Adverse Effects........................................ 195
 

References....................................................................................................................................199
 

List of Acronyms/Abbreviations..................................................................................................207
 

Figures 

Figure 1. Statistical Inference Using Confidence Interval (CI) and Minimal Clinically
 

Important Difference (MCID)........................................................................................................32
 

Figure 3. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success 

Figure 4. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success 

Figure 5. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success 

Figure 7. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Ceftriaxone (single dose) 

Figure 8. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days) 

Figure 9. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs, Azithromycin 

Figure 2. Shrinkage Plot for Ampicillin/Amoxicillin vs Placebo for Treatment Success .............80
 

(Excluded Halsted 1967 Study) .....................................................................................................82
 

(Included Studies with Quality Score 3, 4, or 5)............................................................................84
 

(Included Studies with Quality Score 3, 4, or 5 (Excluded Halsted 1967 Study)..........................86
 

Figure 6. Shrinkage Plot for Ampicillin/Amoxicillin vs. Ceftriaxone for Treatment Success......90
 

for Treatment Success....................................................................................................................93
 

for Treatment Success....................................................................................................................96
 

(≤ 5 days) for Treatment Success (Excluded Pestalozza 1992 Study)...........................................97
 

Figure 10. Shrinkage Plot for Cefaclor vs. Azithromycin for Treatment Success ......................101
 

Figure 11. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for
 

AGE ≤2 Years..............................................................................................................................146
 

Figure 12. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for
 

AGE>2 Years...............................................................................................................................147
 

Figure 13. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Azithromycin 

(<5 days) for Treatment Success for AGE ≤2 Years ...................................................................148
 

Figure 14. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin 

(<5 days) for Treatment Success for AGE >2 Years ...................................................................149
 

ix 
Tables 

Table S-1. Comparative Effectiveness of Different Treatment Options for Treating
 

Uncomplicated Acute Otitis Media (AOM) in Average Risk Children in the 2001 Report 

and the Present Report .....................................................................................................................6
 

Table S-2 Comparison of Rates of Adverse Events Between Drugs (Significant Differences 

Table 6a. Randomized Controlled Trials from Marcy (2001)13 Addressing Comparative
 

Effectiveness of Different Treatment Options for Treating Uncomplicated Acute Otitis Media
 

Table 6b. Randomized Controlled Trials from Marcy (2001)13 Addressing Other Antibiotic vs. 

Table 6c. Randomized Controlled Trials from Marcy (2001)13 Addressing High-Dose
 

Table 6d. Randomized Controlled Trials from Marcy (2001)13 Addressing Twice a Day
 

Table 6e: Randomized Controlled Trials from Marcy (2001)13 Addressing Short- vs. 

Table 6f. Comparative Effectiveness of Different Treatment Options for Treating
 

Uncomplicated Acute Otitis Media in Average Risk Children in the 2001 Report and the 

Table 7. Review Articles Examining Comparative Effectiveness of Treatment Strategies in 

Table 10. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate 

Table 11. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate 

Table 12. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate
 

Table 13. Ampicillin/Amoxicillin vs. Ceftriaxone; Outcome Indicator: Treatment Success 

Table 14. Amoxicillin-Clavulanate (7-10 Days) vs. Ceftriaxone (single Dose); Outcome
 

Table 15. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (≤5 Days); Outcome
	

Table 16. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (≤5 Days); Outcome
	

Only) ..............................................................................................................................................12
 

Table 1. Evidence for Key Question I (Diagnosis)........................................................................37
 

Table 2. Accuracy of Symptoms....................................................................................................42
 

Table 3. Accuracy of Signs............................................................................................................43
 

Table 4. Overview of Studies that Reported on Microbiology......................................................46
 

Table 5. Studies That Reported on Microbiology, Specific Findings ...........................................49
 

in Average Risk Children...............................................................................................................58
 

Amoxicillin or Trimethoprim-Sulfamethoxazole ..........................................................................59
 

Amoxicillin vs. Standard-Dose Amoxicillin..................................................................................60
 

High-Dose Amoxicillin Therapy vs. Three Time a Day Amoxicillin ...........................................61
 

Long-Term Antibiotic Therapy......................................................................................................62
 

Present Report................................................................................................................................64
 

Uncomplicated Acute Otitis Mediaa ..............................................................................................68
 

Table 8. Listing of Treatment Option Comparisons and Outcomes ..............................................74
 

Table 9. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate........81
 

(Excluded Halsted 1967 Study) .....................................................................................................83
 

(Included Studies with Quality Score 3, 4 or 5).............................................................................85
 

(Included Studies with Quality Score 3, 4 or 5 (Excluded Halsted 1967 Study)...........................87
 

Rate ................................................................................................................................................89
 

Indicator: Treatment Success Rate.................................................................................................92
 

Indicator: Treatment Success Rate.................................................................................................95
 

Indicator: Treatment Success Rate (Excluding Pestalozza 1992 Study) .......................................98
 

Table 17. Cefaclor vs. Azithromycin; Outcome Indicator: Treatment Success Rate ..................100
 

x 
Table 18. Antibiotics vs. Wait-and-See/Prescription Hold..........................................................103
 

Table 19. Treatment Comparisons with Conclusive Evidence in Any Clinical Success 

Table 20 Summary of Findings from Eight Studies on Effectiveness of Treatment of Acute 

Table 21. Summary of Findings from Seven Articles on Effectiveness of Prevention of Acute
 

Table 22. Review Articles Examining Comparative Effectiveness of Treatment Strategies in 

Table 23. Listing of Articles Reported Subgroup Analysis on Effectiveness of Treatment 

Table 24. Summary of Findings from 13 Articles (14 Comparisons) Assessing Clinical 

Table 25. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate 

Outcome in Uncomplicated Otitis Media ....................................................................................106
 

Otitis Media in Recurrent Otitis Media or Persistent Acute Otitis Media...................................109
 

Otitis Media in Recurrent Otitis Media .......................................................................................113
 

Recurrent Acute Otitis Media or Persistent or Relapsing Acute Otitis Mediaa ...........................120
 

Options.........................................................................................................................................129
 

Success Rate of Interventions in Uncomplicated Acute Otitis Media Stratified by Age. ...........131
 

for Age 2 Years..........................................................................................................................141
 

Table 26. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate 

for Age >2 Years..........................................................................................................................142
 

Table 27. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (<5 Days); Outcome
 

Indicator: Treatment Success Rate for Age 2 Years..................................................................143
 

Table 28. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (<5 Days); Outcome
 

Indicator: Treatment Success Rate for Age >2 Years..................................................................144
 

Table 29. Comparison of Treatment Success Rate Between Age ≤2 And Age >2 Years by
	

Table 30. Summary of Findings from Two Articles and One Previous Systematic Review
 

Reporting Effectiveness of Interventions in Uncomplicated Otitis Media Stratified by
 

Table 31. Summary of Findings from 2 Articles Reporting Effectiveness of Interventions in 

Table 32. Summary of Findings from Articles Each Reporting Effectiveness of Interventions 

Table 33. Summary of Findings from Three Articles Reporting Effectiveness of Interventions 

Table 34. Findings of Adverse Events by Treatment Option Comparisons for Uncomplicated 

Table 34a. Comparison of Rates of Adverse Events Between Drugs (Significant Differences 

Table 35. Comparison of Adverse Event Rates Between Treatment Options from Eight
 

Table 36. Findings of Adverse Events from Eight Articles on Effectiveness of Prevention of
 

Table 37. Number of Randomized Controlled Trials in the Original Review by Marcy
 

(2001)13 and the Review Update by Number of AOM Diagnostic Criteria Used and by
 

Treatment Option Based on Pooled Data.....................................................................................145
 

Laterality......................................................................................................................................152
 

Uncomplicated Otitis Media Stratified by Childcare Setting ......................................................156
 

in Uncomplicated Otitis Media Stratified by a Risk Factor.........................................................158
 

in Recurrent Otitis Media Stratified by Age, Laterality, and Severity. .......................................161
 

Otitis Media .................................................................................................................................166
 

Only) ............................................................................................................................................173
 

Comparisions on Effectiveness of Treatment of Acute Otitis Media in Recurrent Otitis Media 177
 

Acute Otitis Media in Recurrent Otitis Media.............................................................................184
 

Number of Jadad Study Quality Criteria Met ..............................................................................201
 

xi 
Appendixes 

Appendix A: Scope, Definitions, and Search Strategies 

Appendix B: Sample Data Abstraction Forms 

Appendix C: Evidence Table 

Appendix D: List of Excluded Studies 

Appendix E: Peer Reviewers 

Appendix F: Technical Expert Panel Members and Meeting Summaries 

Appendix G: Summary Tables for Studies Included in Comparisons 

Appendix H: Conceptual Framework for the Report 

Appendix I: Summary of Systematic Reviews Included in Analyses 

Appendix J: Comparison of Original Research Studies Included in Systematic Reviews 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/downloads/pub/evidence/pdf/otitis/otitisup.pdf. 

xii 
Executive Summary 

Introduction 

Acute Otitis Media (AOM)1 is a viral and/or bacterial infection of the middle ear and 

represents the most common childhood infection for which antibiotics are prescribed in the 

United States. Timely and accurate diagnosis and management of AOM can have significant 

individual and public health consequences. 

The 2001 AHRQ evidence report on the management of AOM analyzed the evidence on the 

initial management of uncomplicated AOM in children, focusing on the natural history of the 

disease and the use of antibiotics in management. Although the 2001 report provided valuable 

analysis of the literature on the management of uncomplicated AOM in children, it did not 

address issues related to diagnostic accuracy and precision, management of AOM in specific 

subgroups of children, or the impact of immunization with Heptavalent Pneumococcal Conjugate 

Vaccine (PCV7) on the microbiology of AOM, recommended for widespread use in 2000. 

Additionally, new trials of treatment continue to be published. The purpose of this current 

AHRQ evidence report is to examine and analyze the evidence on three broad areas of inquiry: 

1) accuracy and consistency of the clinical diagnosis of AOM, 2) the impact of PCV7 on AOM 

microbial epidemiology, and 3) the comparative effectiveness of different treatment options for 

uncomplicated AOM in average risk children and in children with recurrent (defined as three or 

more episodes in six months or four or more episodes within 12 months) or persistent AOM. 

Methods 

Key Questions 

The American Academy of Pediatrics, the nominating organization, proposed six key 

questions aimed at assessing the comparative efficacy of interventions to treat uncomplicated and 

recurrent AOM in terms of treatment success, the safety of such treatments, and the effect on 

children in specific subgroups. In conjunction with a technical expert panel we refined these 

questions: 

I. Diagnosis of AOM: What are the operating characteristics (sensitivity, specificity, and 

likelihood ratios) of clinical symptoms and otoscopic findings (such as bulging tympanic 

membrane), both individual and composite, to diagnose uncomplicated AOM and to distinguish 

it from otitis media with effusion (OME)?2 

II. What has been the impact of the Pneumococcal Heptavalent Immunization (PCV7) on 

AOM microbial epidemiology (including acute mastoiditis and suppurative complications), with 

respect to both the organisms associated with AOM and the patterns of antimicrobial resistance? 

III. What is the comparative effectiveness of different treatment options for treating 

uncomplicated AOM in average risk children? 

1 A diagnosis of AOM requires 1) a history of acute onset of signs and symptoms, 2) the presence of middle ear 

effusion (MEE), and 3) signs and symptoms of middle-ear inflammation. (Marcy, Takata, Shekelle, et al., 2001). 

2 Otitis media with effusion (OME) is defined as fluid in the middle ear without signs or symptoms of acute 

infection. Distinguishing AOM from OME often poses a diagnostic challenge. 

1
 
IV. What is the comparative effectiveness of different management options for recurrent 

otitis media (uncomplicated) and persistent otitis media or relapse of AOM? 

V. Do treatment outcomes in Key Question3 (KQ3) and KQ4 differ by characteristics of the 

condition (AOM), patient, environment, and/or health care delivery system, including but not 

limited to the following: A. Laterality, i.e., unilateral vs. bilateral; B. Otorrhea or perforation; C. 

AOM severity, i.e., as defined as defined by the AAFP/AAP AOM Guideline (2004); D. 

Comorbidities, e.g., asthma; E. Age groups, e.g., <4 weeks, 4weeks to <6 months, 6mos-<2 

years, 2-5 years; F. Race; G. Ethnicity; H. Day care attendance? 

VI. What adverse effects have been observed for the treatments whose outcomes are 

addressed in KQ III and KQ IV? 

Literature Searches 

Searches of PubMed and the Cochrane Databases of Systematic Reviews, Cochrane Central 

Register of Controlled Trials, and Education Resources Information Center were conducted from 

January 1998 through July 2010 using the same search strategies used for the 2001 report, with 

the addition of terms for conditions not considered in the 2001 review (recurrent otitis media), 

new drugs, and the heptavalent vaccine. The Web of Science was also used to search for citations 

of the 2001 report and its peer-reviewed publications. Among the 8, 945 titles identified were a 

number of recent, good-quality systematic reviews, which were included and which were 

examined for references. Titles were screened independently by two pediatricians with 

experience in conducting systematic reviews. For the question pertaining to diagnosis, we 

searched primarily for studies that included an assessment of sensitivity and specificity relative 

to a defined gold standard; we identified one good-quality 2003 meta-analysis and replicated its 

search strategy to obtain subsequent studies not included in their analysis. For the question 

pertaining to the effect of the vaccine on epidemiology and microbiology, we searched for 

studies that compared microbiology in the same populations before and after introduction of the 

vaccine or studies that compared microbiology across vaccinated and unvaccinated populations. 

For the efficacy and safety questions, we searched primarily for controlled trials or large 

observational studies aimed at identifying adverse effects. 

Literature Review, Data Abstraction, and Analysis 

In total, the reviewers examined 8,945 titles for the draft version of this report; 739 titles 

were identified for further review. Of those, 72 articles that met the predetermined inclusion 

criteria were reviewed in detail for efficacy and safety results. Investigators abstracted data into 

standard evidence tables with abstraction checked by a second investigator. Studies were qualityrated by two investigators using established criteria. For randomized controlled trials (RCT), the 

Jadad criteria were used. QUADAS criteria were used to evaluate the studies that pertained to 

diagnosis. Data abstracted included parameters necessary to define study groups, 

inclusion/exclusion criteria, influencing factors, and outcome measures. Data for the analysis 

were abstracted by a biostatistician and checked by a physician reviewer. We used a sequential 

resolution strategy to match and resolve the screening and review results of the two reviewers. 

2
 
For the assessment of treatment efficacy, pooled analysis was performed for comparisons for 

which three or more trials could be identified. The articles eligible for analysis for the key 

questions pertaining to treatment efficacy were grouped according to the specific treatment 

options they compared. Each comparison consisted of articles that were considered 

homogeneous from the standpoint of clinical practice. Since the question of treatment efficacy 

was addressed in the first evidence report published in 2001, we combined the articles identified 

in that report with articles newly identified for this evidence report that addressed the same 

populations and reported the same types of outcomes. We pooled data for comparisons that 

included three or more articles from the old and new searches and performed meta-analyses or 

quantitative syntheses. We used the Der Simonian and Laird random effects model to pool rate 

differences across studies. Among the three effect measures—rate difference, relative risk, and 

odds ratio—the Technical Expert Panel and the project staff chose as most suitable the rate 

difference and its 95 percent confidence interval. We also reported the findings on the success 

rate instead of the failure rate throughout the report as recommended by the Technical Expert 

Panel. A test of heterogeneity was performed using the I2 statistic. GRADE criteria were applied 

to assess the quality of the evidence for each comparison. In addition to the pooled estimate, we 

report the Q statistic and p-value for the Chi-squared test of heterogeneity. 

For the assessment of the adequacy of evidence in arriving at a conclusion on the 

effectiveness of a particular treatment using a particular outcome, we use the concept of the 

―minimal clinically important difference (MCID)‖ against which the location of the 95% 

confidence interval of the pooled outcome was compared. Confidence intervals falling within the 

zone of MCID were considered to establish evidence of no difference, and confidence intervals 

outside the zone of MCID were considered to establish difference. If the confidence intervals 

crossed into the zone of MCID, an effect (positive or negative) of the treatment option on the 

outcome could not be established. While the MCID for treatment of AOM has not been 

empirically determined, we used an MCID of 5%, as this value represents approximately the 

lower limit of what Cohen would classify as a ―small‖ effect size for treatment of AOM. Users of 

this evidence report who consider larger or smaller differences to be the minimum clinically 

important effect may reach different conclusions than we do here. 

Results 

Key Question I. Diagnosis of AOM: What Are the Operating 

Characteristics (Sensitivity, Specificity, and Likelihood Ratios) of 

Clinical Symptoms and Otoscopic Findings (Such As Bulging 

Tympanic Membrane) to Diagnose Uncomplicated AOM and to 

Distinguish It from OME? 

Three clinical criteria are necessary to diagnose AOM: 1. acute symptoms of infection, 2. 

evidence of acute tympanic membrane (TM) inflammation, and 3. presence of middle ear 

effusion (MEE). To address this key question, we searched for studies that examined clinicians‘ 

accuracy and precision in identifying each of these clinical criteria, or their accuracy and 

precision in identifying all three together. A 2003 systematic review and three additional original 

studies met the inclusion criteria for the present review. The systematic review found that among 

3
 
symptoms, only otalgia (ear pain) (sensitivities of 54%, 60%, 100% in three different studies; 

specificities 82%, 92%; positive likelihood ratio [LR] 3.0 [2.1-4.3], 7.3 [4.4-12.1]) and ear 

rubbing (sensitivity 42%; specificity 87%; positive LR 3.3 [2.1-5.1] seemed to predict a clinical 

diagnosis of AOM. An article published subsequent to the 2003 review found that among 469 

children ages 6-36 months with parent-suspected AOM in primary care offices, AOM diagnosis 

was not associated with the occurrence, duration, or severity of parent-reported symptoms (e.g., 

ear pain: sensitivity 92%, specificity 8%, positive LR 1.0 [1.0-1.1]; ear rubbing: sensitivity 70%, 

specificity 22%, positive LR 0.9 [0.8-1.0]; fever: sensitivity 43%, specificity 65%, positive LR 

1.2 [1.0-1.6]).1 

One of the studies examined in this 2003 review assessed the accuracy of individual physical 

exam findings (cloudy, bulging, immobile, or red TM); they found these signs to be positively 

associated with AOM determined by the presence of MEE on tympanocentesis and clinical 

symptoms. 

A study published subsequent to the 2003 review examined the accuracy of otoscopic and 

tympanometric findings compared with tympanocentesis as the criterion standard to determine 

the presence of MEE. The investigators performing otoscopy were not blinded to the 

tympanogram (a tool that evaluates middle ear function) results; further, the criterion standard of 

tympanocentesis was performed only when otoscopic or tympanometric findings suggested 

MEE. Ninety-seven percent of children with MEE on tympanocentesis had “Type B” 

tympanogram findings (abnormal), and all children with MEE on tympanocentesis had an 

otoscopic exam consistent with AOM. However, positive LR estimates are not as useful, since 

all participants had an AOM diagnosis at enrollment. 

The second study published subsequent to the review included 137 eardrums that were either 

assumed to be or were diagnosed as AOM by general practitioners (GP). Of these, 78% were 

confirmed by ear-nose-and-throat (ENT) exam and the remaining were not, because the 

otolaryngologist diagnosed OME, viral otitis, or a normal TM. The ENT exam confirmed the GP 

diagnoses more often when redness and bulging were noted by the GP (83%) than when redness 

only was noted (75%). 

The prior review and three additional studies that we identifieded for this key question did 

not directly or completely answer it; however, the studies do suggest that clinical findings of 

MEE (decreased mobility or abnormal position) and middle ear inflammation (distinctly red 

color of the TM) are positively associated with AOM, defined by positive tympanocentesis and 

acute onset of symptoms. Further, studies comparing diagnostic accuracy between generalist or 

primary care physicians and otolaryngologist suggest that clinicians‘ accuracy in identifying all 

three clinical criteria in one patient is moderate, at best. The overall quality of evidence for this 

Key Question is considered low, meaning that further research is very likely to have an important 

impact on our confidence in the estimate of effect and is likely to change the estimate. 

4
 
Key Question II. What Has Been the Impact of the Pneumococcal 

Heptavalent Immunization (PCV7) on AOM Microbial Epidemiology: 

What Organisms (bacterial and viral) are Associated with AOM Since 

the Introduction of PCV7; and What Are the Patterns of Antimicrobial 

Resistance in AOM Since the Introduction of PCV7? 

Two types of studies could address this question: observational studies that compared the 

types of organisms associated with AOM among children prior to and following introduction of 

the PCV7 vaccine in 2000 and RCTs of vaccine efficacy that compared the causative agents 

between a group of unvaccinated children and those who were vaccinated. Both study types are 

complementary. RCTs provide a better assessment of cause-and-effect for the relationship 

between the vaccine and changes in organisms, but often enroll highly restricted patient 

populations. Observational studies complement RCTs by providing data on more representative 

populations. 

We identified six original studies (four observational studies and two RCTs) that provided 

some information on this question. Since the introduction of PCV7, the observational studies 

generally report that Haemophilus influenzae (HF) has become more prevalent as a causative 

agent of AOM and Streptococcus pneumoniae (SP) has become less prevalent, although SP 

remains an important agent as well. The introduction of the vaccine has also resulted in a greater 

proportion of non-vaccine serotypes and a smaller proportion of the vaccine serotypes. The 

RCTs provided findings consistent with those results. 

We were also asked to assess the evidence for subpopulations of children according to prior 

antibiotic use. However we found no studies that analyzed the effects of the vaccine on causative 

agents according to whether the children had or had not received antibiotics in the past. 

The overall quality of evidence for this Key Question is considered high for the conclusion 

that use of the PCV7 vaccine has resulted in shifts in the prevalence of causative agents, meaning 

further research is very unlikely to change our confidence in the estimate of effect. The quality of 

evidence is very low for the special populations (such as patients with recurrent or persistent 

AOM) since we found fewer studies examining the vaccine‘s effect on these special populations. 

Key Question III. What Is the Comparative Effectiveness of Different 

Treatment Options for Treating Uncomplicated AOM in Average Risk 

Children? 

For the comparison of treatment success for children with uncomplicated AOM, we 

identified 63 comparisons of treatment options for uncomplicated AOM that encompassed 

different antibiotics and regimens. Our analyses yielded inconclusive results for many of these 

comparisons. For 12 comparisons, we reached stronger conclusions. Table S-1 shows key 

comparisons from the first AOM report, the present report, and where possible, combined 

results. 

5
 
Table S-1. Comparative Effectiveness of Different Treatment Options for Treating Uncomplicated Acute Otitis 

Media (AOM) in Average Risk Children in the 2001 Report and the Present Report 

2001 Report 2010 Update 

Comparison Number Success rate Number Total Success Conclusiona 

of trials difference of new number rate 

(95% CI) trials of trials difference 

Drug vs. placebo, wait-and-see, and/or prescription-to-hold 

Ampicillin or 5 12% (3%, 2 7 12%(5%, Ampicillin or 

amoxicillin vs. 22%) 18%) amoxicillin was 

placebo more successful 

than placebo 

Amoxicillin tid (7d) 0 N/A 1 1 16% (6, Amoxicillin was 

vs. prescription-to­ 26) more successful 

hold)2 than prescription-tohold (defined as 

success at day 3) 

Antibiotic vs. 0 N/A 1 1 3% (-8, 14) Inconclusive 

prescription-to­ (defined as otalgia 

hold)2 at day 4-6) 

Amoxicillin 0 N/A 1 1 15% (6, Amoxicillin was 

90mg/kg/d bid 24) more successful 

(10d) vs. wait-and­ (defined as success 

see 3 at day 12) 

PcV vs. wait-and­ 0 N/A 1 1 -3% (-14, Inconclusive 

see 3 8) (defined as success 

at day 14) 

Drug vs. drug 

Ampicillin or 

amoxicillin vs. 

Ceftriaxone 

Amoxicillin 

50mg/kg/d (bid, 

10d) vs. 

erythromycin 

40mg/kg/d (bid, 

10d)4 

Amoxicillinclavulanate vs. 

amoxicillin 

sulbactam 

(80mg/kg/d; bid 

10d 

Amoxicillinclavulanate (>6 yrs 

old: 250 mg tid x 

7d; < 6 yrs old: 125 

mg tid x7d) vs. 

3 3% (-2%, 9%) 1 4 0.1% (-7%, 

7%) 

0 N/A 1 1 0.6% (-3, 

4) 

0 N/A 1 1 0% (-3.3, 

3.3) 

0 N/A 1 1 13% (5, 

21) 

Inconclusive 

Treatments were 

equivalent (when 

success defined as 

freedom from 

recurrence day 31­

40) 

Treatments were 

equivalent (success 

d.12-14) 

Amoxicillinclavulanate was 

more effective than 

cefaclor (success at 

day 28-34, as 

6
 
2001 Report 2010 Update 

Comparison Number 

of trials 

Success rate 

difference 

Number 

of new 

Total 

number 

Success 

rate 

Conclusiona 

cefaclor (125 or 

250 mg tid x 7 d)5 

(95% CI) trials of trials difference 

defined by clinical 

symptoms but not 

by culture) 

Cefaclor vs. 

trimethoprimsulfamethoxazole 

3 -6% (-13, 2) 

(success at 

less than 14 

d) 

0 3 N/A Inconclusive 

(defined as success 

at less than day 14); 

no new data but 

using MCID 

Cefaclor vs. 

Ampicillin or 

amoxicillin 

4 -5% (-15, 6) 

(success at d. 

3-7) 

0 4 N/A Inconclusive 

(defined as success 

at day 3-7); no new 

data; no new data 

but using MCID 

Cefixime vs. 

Ampicillin or 

amoxicillin 

4 0.1% (-3.9, 

4.2) (success 

at d. 10-15) 

0 4 N/A Treatments were 

equivalent; no new 

data 

Penicillin vs. 

ampicillin or 

amoxicillin 

3 -5% (-11, 2) 

(success at d. 

7-14) 

0 3 N/A Inconclusive 

(defined as success 

at day 7-14); no 

new data but using 

MCID 

High vs. Low Dose Treatment 

Amoxicillin­ 1 1.5% (-3, 13) 0 1 N/A Inconclusive 

clavulanate (defined as 

>60mg/kg/d vs. persistent clinical 

amoxicillin­ cure with no 

clavulanate recurrence at follow40mg/kg/d up); no new data 

High-dose 1 -4% (-14, 7) 0 1 N/A Inconclusive 

amoxicillin bid vs. (defined as success 

lower-dose at day 15); no new 

amoxicillin tid data 

Amoxicillin­ 0 N/A 1 1 0.1% (-4.8, Treatments were 

clavulanate 45/64 4.6) equivalent (success 

mg/kg/day / bid for d. 7-12) 

7-10 days vs. 

Amoxicillinclavulanate 40/10 

mg/kg/day / tid for 

7-10 days6 

Short vs. Long Treatment Durationb 

7
 
2001 Report 2010 Update 

Comparison Number 

of trials 

Success rate 

difference 

Number 

of new 

Total 

number 

Success 

rate 

Conclusiona 

Ampicillin or 

amoxicillin (7-10d) 

vs. Ceftriaxone (1 

dose) 

3 

(95% CI) 

3% (-2%, 9%) 

(success rate 

at 5-10d) 

trials 

1 

of trials 

4 

difference 

0% (-7%, 

7%) 

Inconclusive 

AmoxicillinClavulanate (7-10 

d) vs. Ceftriaxone 

(1 dose) 

2 N/A 3 5 3% (-2%, 

7%) 

Inconclusive 

Cefaclor (7-10d) 

vs. Azithromycin 

(<5d) 

1 N/A 2 3 -1% (-4%, 

3%) 

Treatments were 

equivalent 

Amoxicillin (7d) vs. 

Azithromycin (1 

dose) 

0 N/A 1 1 1% (-1%, 

4%) 

Treatments were 

equivalent (defined 

as no new pain 

between day 6 and 

11) 

Amoxicillinclavulanate (7-10d) 

vs. Azithromycin 

(≤5d)

5 2% (1, 5%) 

(success at 

10-14d) 

4 9 -0.3% (­

6%, 6%) 

Inconclusive 

Amoxicillinclavulanate 45/6.4 

mg/kg/d (bid, 10d) 

vs. azithromycin 10 

mg/kg/d (qd for 1 

day), 5 mg/kg/d (qd 

for 4d)7 

0 N/A 1 1 26% (6,36) Longer-term 

amoxicillinclavulanate is more 

successful than 

shorter-term 

azithromycin (at d. 

12-14, when 

pathogen is H. 

influenzae) 

Cefaclor 

50mg/kg/d; bid 5 d) 

vs. cefaclor 

0 N/A 1 1 0.7% (-3.5­

4.9) 

Treatments were 

equivalent 

40mg/kg/d; bid 

10d) 

Table Notes: bid twice a day; CI confidence intervals; d day(s); kg kilograms (body weight); mg milligrams; NNT number 

needed to treat; PcV phenoxymethylpenicillin; qd once a day; 

a Confidence intervals falling within the zone of indifference were considered to establish evidence of no difference, and 

confidence intervals outside the zone of indifference were considered to establish difference. If the confidence intervals crossed 

into the zone of indifference, an effect (positive or negative) of the treatment option on the outcome could not be established 

(inconclusive). For the 2010 systematic review, we used a zone of clinical indifference of +/- 5% for the difference in success 

rate between two treatment options. 

b

Short vs. long term duration refers to the length of treatment from the patient perspective, rather than from the perspective of 

drug action. 

8
 
Meta-analyses of the comparison of ampicillin or amoxicillin vs. placebo indicates that nine 

children (95% CI: 6, 20) with uncomplicated AOM would need to be treated with immediate 

antibiotic therapy rather than placebo to note a difference in the rate of clinical success by day 

14. For the comparison of ampicillin or amoxicillin vs. placebo, the quality of evidence is 

moderate due to heterogeneity in the results of studies, with the higher quality studies reporting 

smaller benefits, meaning that further research is likely to have an important impact on our 

confidence in the estimate of the effect and may change the estimate. In four studies of delayed 

treatment approaches for uncomplicated AOM, (1) two had higher rates of clinical success with 

immediate antibiotic therapy, i.e. Little (2001) and McCormick (2005) individually demonstrated 

higher clinical success rates for amoxicillin than for prescription-to-hold at day 3 (NNT=6; 95% 

CI: 4, 17) and wait-and-see at day 12 (NNT=7; 95% CI: 4, 17) options, respectively, (2) two did 

not demonstrate a difference in clinical success between immediate vs. delayed antibiotics, and 

(3) three studies showed a marked decrease in antibiotic utilization in the delayed antibiotic 

group. 

Four trials, one newly identified for this report and three identified for the original AOM 

report addressed the comparison of ampicillin or amoxicillin vs. ceftriaxone. No difference 

(RD=0%, 95% CI: -7, 7) was found between these treatments for clinical success by day 14 

though this finding was inconclusive utilizing an MCID of 5% (one trial found a slight advantage 

for ceftriaxone, whereas the others found ceftriaxone to be slightly less effective). The quality of 

evidence for this conclusion is moderate, meaning that further research is likely to have an 

important impact on our confidence in the estimate of the effect and may change the estimate. 

Five trials, two newly identified and three identified for the original AOM report, compared 

amoxicillin-clavulanate (7-10 days) with single-dose ceftriaxone. No difference (RD=3%, 95% 

CI: -2, 7) was found between these treatments for clinical success by day 16 though this finding 

was inconclusive utilizing an MCID of 5%. The quality of evidence for this conclusion is 

moderate, meaning that further research is likely to have an important impact on our confidence 

in the estimate of the effect and may change the estimate. 

Meta-analysis of three studies demonstrated equivalence of day-14 clinical success rates 

(RD=-0.7%, 95% CI: -4, 3) between cefaclor (7-10 days) and azithromycin (≤ 5 days) in 

treatment of uncomplicated AOM. In addition, single studies of comparisons (that could not be 

pooled) produced strong results. The quality of evidence for this conclusion is considered high, 

meaning further research is very unlikely to change our confidence in the estimate of effect. 

In pooled analysis, no difference (RD=-0.3%, 95% CI: -7, 6) was noted in clinical success at 

day 14 comparing amoxicillin-clavulanate to azithromycin though this finding was inconclusive 

utilizing an MCID of 5%. In a single study, amoxicillin-clavulanate (for 10 days) was shown to 

have higher clinical success rates than azithromycin (single dose, one day) by day 14 when the 

pathogen was HF (NNT=4, 95% CI: 2, 17) and higher success rates than cefaclor by day 34 

when success was defined by clinical symptoms (NNT=4, 95% CI: 2, 17). The quality of 

evidence for this conclusion is moderate due to heterogeneity in the results of studies, meaning 

that further research is likely to have an important impact on our confidence in the estimate of 

the effect and may change the estimate. 

Equivalent clinical success rates were demonstrated in individual studies of amoxicillin vs. 

azithromycin, amoxicillin vs. erythromycin, amoxicillin-clavulanate vs. amoxicillin-sulbactam, 

cefixime vs. ampicillin or amoxicillin,cefaclor 50 mg/kg/day vs. 40 mg/kg/day, and amoxicillinclavulanate 45/64/mg/kg/day divided into two daily doses vs. 40/10/mg/kg/day divided into three 

9
 
daily doses. In addition, individual studies of amoxicillin-clavulanate >60mg/kg/d vs. 

amoxicillin-clavulanate 40mg/kg/d and high-dose amoxicillin bid vs. lower-dose amoxicillin tid 

that in the 2001 Report were assessed as demonstrating equivalent clinical success rates are now 

assessed as inconclusive utilizing an MCID of 5%. Each of these single study results requires 

replication before strong conclusions can be reached. 

Key Question IV. What Is the Comparative Effectiveness of Different 

Management Options for Recurrent Otitis Media (Uncomplicated) and 

Persistent Otitis Media or Relapse of AOM? 

In approaching this question, studies were divided into those that examined treatment and 

those that examined prevention. 

The available evidence did not allow us to reach strong conclusions regarding the following 

comparisons identified by this study for treatment of AOM in children with ROM, persistent 

AOM, or AOM treatment failure: amoxicillin-clavulanate vs. gatifloxacin, amoxicillinclavulanate vs. levofloxacin, and amoxicillin-clavulanate vs. azithromycin. The overall quality of 

evidence for these comparisons is considered low, meaning that further research is very likely to 

have an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. One systematic review and additional new studies were identified examining otic 

antibiotics for treatment of AOM in children with tympanostomy tubes; however, it was not clear 

from the reports if the tympanostomy tubes were placed for ROM, persistent AOM, or some 

other chronic middle-ear condition, so these results cannot be generalized. 

Several prior systematic reviews addressed the prevention of AOM in children with ROM. 

One review concluded that long-term antibiotics, defined as six weeks or longer, decreased 

episodes of AOM from 3 to 1.5 (95% CI: 1.2, 2.1) for every 12 months of treatment per otitisprone child during active treatment. However data are missing regarding the safety of long-term 

antibiotic administration and the potential consequences on bacterial resistance. The role of 

tympanostomy tube placement was examined in a pooled analysis of two studies. This analysis 

found that tympanostomy tubes played a significant role in maintaining a disease-free state in the 

first six months after tube insertion in children with ROM. This conclusion is qualified by the 

small number of studies included in the analysis. 

The available evidence did not allow for any definitive conclusions about the comparative 

role of amoxicillin vs. azithromycin, amoxicillin vs. sulfisoxazole, amoxicillin vs. placebo, 

sulfisoxazole vs. placebo, ceftibuten five-day vs. 10-day, probiotics vs. placebo, sulfafurazole vs. 

adenoidectomy, adenoidectomy vs. placebo, adenoidectomy vs. adenotonsillectomy, 

adenotonsillectomy vs. placebo, and adenoidectomy plus tympanostomy vs. tympanostomy in 

preventing AOM in children with ROM. The overall quality of evidence for each of these 

comparisons is considered low, meaning that further research is very likely to have an important 

impact on our confidence in the estimate of effect and is likely to change the estimate. 

10
 
Key Question V. Do Treatment Outcomes in Key Question3 (KQ3) and 

KQ4 Differ by Characteristics of the Condition (AOM), Patient, 

Environment, and/or Health Care Delivery System? 

Of the 48 randomized clinical trials newly identified in our review that addressed the 

effectiveness of treatment options in uncomplicated AOM, 15 trials reported analyses for 

subgroups stratified by age, presence of MEE, laterality, parent/caretaker, hearing deficit 

presence/severity, otorrhea, examiner, and pneumococcal vaccine. Of the 10 trials identified in 

our review that addressed the effectiveness of treatment options in ROM, three reported analysis 

by age subgroups, and one reported stratified analysis by laterality and severity of otitis media. 

For uncomplicated AOM, the available evidence indicated that antibiotic effect may be 

modified by age, laterality, and otorrhea. Definitive conclusions could not be made regarding 

subgroup analyses by other characteristics of AOM such as severity, characteristics of the patient 

such as presence of hearing deficit, characteristics of the environment such as the primary 

daytime caretaker, or characteristics of the healthcare delivery system such as the examiner. 

In general, the results of individual trials and of meta-analyses show that children over the 

age of 2 have better outcomes from AOM, regardless of whether they are treated with antibiotics 

or not, compared to children 2 years of age or younger. No differences were seen in our metaanalyses in the rate difference for treatment success between children younger or older than 2 

years when comparing ampicillin/amoxicillin to placebo or when comparing amoxicillin 

clavulanate to azithromycin. Similar conclusions were found in an individual patient metaanalysis. 

In general, the results of individual trials and meta-analyses show that children with bilateral 

disease responded as well to treatment as those with unilateral disease. If left untreated, children 

with unilateral disease did better than those with bilateral disease. Further, the effect of antibiotic 

(compared with placebo) was greater in children with otorrhea than in those without otorrhea. 

Key Question VI. What Adverse Effects Have Been Observed for the 

Treatments Whose Outcomes Are Addressed in KQ3 and KQ4? 

We examined the incidence of adverse events in the RCTs identified for this report that 

compared the effectiveness of one or more treatment options. We also searched the FDA 

MedWatch Database for adverse events associated with use of medications for the treatment of 

AOM; however, none could be identified. 

In general we could not make definitive conclusions regarding differences in adverse event 

rates among antibiotics when taking into account a MCID of 5%. However, Table S-2 shows the 

significant differences in adverse event rates that we noted (Table S-2 also shows the 

comparisons for the original report, those unique to the present report, and those that could be 

combined across both reports). Adverse events were generally more frequent for amoxicillinclavulanate than for cefdinir, ceftriaxone, or azithromycin. 

11
 
Table S-2 Comparison of Rates of Adverse Events Between Drugs (Significant Differences Only) 

2001 Report 2010 Update 

Comparison Number 

of trials 

AE rate 

Difference 

Number 

of new 

Total 

number 

AE rate 

difference 

Conclusion 

(95% CI) trials of trials (95% CI) 

Uncomplicated AOM 

Overall Adverse Events 

Amoxicillinclavulanate (7-10d) 

vs. Azithromycin (5d) 

3 19%( 9%, 

29%) 

0 3 N/A Amoxicillinclavulanate 

associated with 

greater overall 

AE rate 

Amoxicillinclavulanate vs. 

cefdinir (qd) 

0 N/A 1 1 28% (17%, 

39%) 

Amoxicillinclavulanate 

associated with 

greater overall 

AE rate 

Amoxicillinclavulanate vs. 

cefdinir (bid) 

0 N/A 1 1 19% (8%, 

31%) 

Amoxicillinclavulanate 

associated with 

greater overall 

AE rate 

Amoxicillin 

clavulanate vs. 

ceftriaxone 

0 N/A 1 1 16% (9%, 

24%) 

Amoxicillinclavulanate 

associated with 

greater overall 

AE rate 

Gastrointestinal Adverse Events 

Amoxicillin­ 3 18% (8%, 0 0 N/A Amoxicillinclavulanate (7-10d) 28%) clavulanate 

vs. Azithromycin (5d) associated with 

greater rate of 

GI AE 

Diarrhea 

Ampicillin or 

amoxicillin vs. 

5 -8% (-13, -4) 0 0 N/A Cefixime 

associated with 

cefixime greater rate of 

diarrhea 

Amoxicillin 

clavulanate vs. 

cefdinir 

0 1 1 25% (15%, 

35%) in Cef 

QD and 

Amoxicillin 

clavulanate 

associated with 

22% (11%, 

32%)in Cef 

BID 

greater rate of 

diarrhea 

Amoxicillin 

clavulanate vs. 

ceftriaxone 

0 1 1 13% (6%, 

20%) 

Amoxicillin 

clavulanate 

associated with 

greater rate of 

diarrhea 

Recurrent Otitis Media 

Diarrhea 

Amoxicillin­ 0 N/A Greater for 

clavulanate vs. amoxicillin12
 
2001 Report 2010 Update 

Comparison Number AE rate Number Total AE rate Conclusion 

of trials Difference of new number difference 

(95% CI) trials of trials (95% CI) 

ciprofloxacin­ clavulanate in 1 

dexamethasone ear study, but 

drops equivalent in 41; 

no conclusion 

possible in 23 

comparisons 

Table notes: AE adverse event; bid twice a day; CI confidence interval; d day; NNT number needed to treat; qd once a day 

Of the 44 RCTs newly identified for this report that compared the effectiveness of treatment 

options in uncomplicated AOM, there are 61 treatment comparisons. Of the 61 treatment 

comparisons, 42 included comparisons of the percent of cases that had experienced an adverse 

event between two treatment options. For treatment of uncomplicated AOM, five adverse event 

rate comparisons showed a significant difference between two treatment options. Amoxicillinclavulanate was associated with diarrhea more often than was cefdinir (NNT=four) and more 

often than was ceftriaxone (NNT= seven). The adverse event rates ranged from 27% to 35% for 

amoxicillin-clavulanate and from 10% to 14% for the other treatment options. For mention of 

any adverse event, amoxicillin-clavulanate had a higher rate than cefdinir given once or twice 

daily and a higher rate than ceftriaxone. However, in one study, the dose of amoxicillin was 

40mg/kg/day, whereas in the other study, it was 80mg/kg/day (the clavulanate dosage was 

10mg/kg/day in both studies). Equivalence was demonstrated in 29 comparisons, leaving 99 

comparisons inconclusive. 

These findings complement the findings from the first review, which showed that for 

uncomplicated AOM, children treated with amoxicillin-clavulanate for seven to ten days had a 

19% (95% CI: 9, 29; NNT=5) higher rate of overall adverse effects and a 18% (95% CI: 8, 28; 

NNT=6) higher rate of gastrointestinal adverse effects than children treated with five days of 

azithromycin. (Although it was not specified in the studies, the original formulation was 31.25 

mg clavulanate per 125 mg of amoxicillin). Eight children would need to be treated with 

azithromycin rather than amoxicillin-clavulanate to avoid a gastrointestinal adverse event. The 

original review also found that children treated with cefixime had an 8% (95% CI: 4, 13; 

NNT=12) greater rate of diarrhea than children treated with ampicillin or amoxicillin, so 12 

children would need to be treated with ampicillin or amoxicillin rather than cefixime to avoid 

one case of diarrhea. 

We also examined adverse event rates in children with presumed or explicitly defined ROM 

who were being given antibiotics for the treatment or prevention of AOM. Among the fourteen 

studies focused on children with ROM, persistent AOM, or AOM treatment failure, there were 

21 treatment comparisons: eight involving the treatment of AOM in children with presumed or 

explicitly defined recurrent and/or persistent AOM, and/or AOM with treatment failure and the 

remainder in children being given the drugs prophylactically for prevention of AOM. For 

treatment of AOM in children with ROM and/or persistent otitis media, and/or AOM with 

treatment failure, we found one study that identified a significant difference in adverse event 

rates. In that study, amoxicillin-clavulanate (amoxicillin 90mg/kg/day; clavulanate 

6.4mg/kg/day) was associated with diarrhea more often than was ciprofloxacin-dexamethasone 

ear drops (NNT=5). However, in 41 other comparisons, the adverse event rates were equivalent. 

13
 
In 23 comparisons, a definitive conclusion was not possible. For studies that examined 

prevention of AOM in children with ROM, we did not find any significant differences in any of 

the adverse event rate comparisons. 

Conclusions 

This section begins with a brief review of the limitations identified for this review. We then 

present our conclusions and recommendations for future research. 

Limitations 

The conclusions that can be drawn from this review of the evidence are limited by a number 

of factors, some associated with specific questions and some that cross the entire body of 

literature. 

• Assessing the precision of methods used to diagnose AOM is severely limited by the 

continued absence of a true gold standard and the reliance on the clinical definition. Although 

tympanocentesis is employed as the gold standard in some studies, its reliability and validity are 

limited by the need for specially trained operators, and studies that use tympanocentesis rarely 

perform the procedure on asymptomatic ears. 

• Assessing the possible impact of the PCV7 vaccine on AOM microbial epidemiology and 

the development of antibiotic resistance is limited by several factors. First, tympanocentesis is 

not routinely done in children with uncomplicated AOM. Thus, most of the studies that 

compared the microbiology of AOM before and after the introduction and use of PCV7 

examined middle-ear fluid samples for children with complicated, recurrent, or persistent OM. 

Another limitation is that we do not have adequate data to understand the possible impact of 

PCV7 on non-bacterial agents (i.e., viruses). Although the importance of non-bacterial agents has 

been studied for AOM, we were unable to find studies examining the impact of PCV7 on the 

importance of non-bacterial causes of AOM. 

• The assessment of treatment efficacy was limited by the finding that the definitions of 

clinical success were usually not equivalent among studies comparing the same treatments. For 

example, studies used different clinical criteria to define success, and success was often 

measured at different time points. Another limitation to our assessment of treatment efficacy is 

that because we pooled studies across different time periods, we could not take temporal changes 

in microbiology into account, that is older studies might have had a microbiology more (or less) 

responsive to antibiotics than newer studies. 

• The inclusion criteria for participantss also varied widely among studies. Some studies used 

only one of the three criteria included in the definition of AOM for diagnosis, while others 

considered two or all three. It is possible that some studies with less stringent inclusion criteria 

may have included participants who did not have AOM, but rather had OME or no middle ear 

infective process at all. In addition, if the operating characteristics of criteria used to diagnose 

AOM differ by age, then it is possible that treatment outcomes by age may be confounded by a 

differential rate of inclusion of children who actually do not have AOM into a particular age 

group. 

• Few studies assessed the effect of patient characteristics on treatment outcomes, beyond the 

effect of age, laterality, or otorrhea. 

14
 
• Studies that compared adverse effects between treatments almost never explicitly included 

the collection of adverse event information in their designs and were rarely, if ever, powered to 

assess differences in rates of adverse effects between treatments. In addition, differences in the 

ways adverse events were reported and categorized from one study to another made it difficult to 

try to pool these results. 

Discussion 

AOM is a clinical diagnosis with three components: acute signs of infection and evidence of 

middle ear inflammation and effusion.12 Evidence suggests that certain otoscopic findings (i.e., 

a red and immobile or bulging TM) predict AOM, but the accuracy or precision of a clinical 

diagnosis has not been determined. Given the absence of a gold standard for diagnosing AOM, it 

is difficult to draw firm conclusions from existing studies or to design new studies to assess the 

precision of diagnostic methods or criteria for diagnosing AOM. Perhaps the most important way 

to improve diagnosis is to increase clinicians‘ ability to recognize and rely on key otoscopic 

findings. Since the introduction of the PCV7 vaccine, AOM microbiology has shifted 

considerably. Our review indicates that overall, the SP serotype is becoming less prevalent, yet 

still important, while HF is increasing in its importance as an infectious agent of AOM. No 

studies that fit the inclusion criteria for the report examined the impact of the introduction of 

PCV7 on antimicrobial resistance. 

For the treatment of uncomplicated AOM, immediate ampicillin/amoxicillin treatment has a 

modest benefit compared to placebo or delayed antibiotics, but also may be associated with more 

diarrhea and rash. Of 100 average-risk children with AOM, we could expect approximately 80 

to get better within about 10 days without antibiotics. If all were treated with immediate 

ampicillin/amoxicillin, we would expect an additional 12 to improve, but 3 to 10 children would 

develop rash and 5 to 10 would develop diarrhea. Clinicians need to weigh these risks (including 

possible long-term effects on antibiotic resistance) and benefits before prescribing immediate 

antibiotics for uncomplicated AOM. 

In head-to-head comparisons, most antibiotic regimens demonstrated comparable clinical 

success rates. Because of the relatively small number of studies on treatment of AOM in children 

with ROM, we are unable to draw any definitive conclusions regarding the comparative 

effectiveness of different antibiotic treatments. The evidence suggests that long term antibiotics 

decrease episodes of AOM from three to 1.5 for every 12 months of treatment per otitis-prone 

child during active treatment. However, the drawbacks of long-term antibiotics, which include 

adverse effects such as diarrhea, allergic reactions, and emergence of bacterial resistance, must 

be weighed against that of recurrence. Further, we can also conclude that tympanostomy tubes 

can help decrease the likelihood of a repeat infection in a child with a history of ROM within the 

first six months after tube insertion. This conclusion may be tempered by the issue of AOM 

diagnostic accuracy in the presence of tympanostomy tubes possibly confounding these results, 

i.e. the pressure equalization and drainage afforded by the tubes and their physical presence 

decreasing the intensity or visibility of signs and symptoms used to diagnose AOM, leading to 

false negatives. Again, whether or not the benefit of avoiding a repeat episode of AOM over six 

months outweighs the costs of a tympanostomy tube placement will depend on the clinician‘s 

15
 
assessment of the child with AOM, and discussions of advantages and disadvantages with the 

family. 

While the 2001 evidence review identified only sufficient evidence to allow the assessment 

of the effects of age on treatment effectiveness, the current review identified information to 

assess the effect of laterality and otorrhea as well. The current review suggests that overall, 

children over the age of two years had better outcomes with various antibiotic options than 

children under age two and that laterality and otorrhea do have effects as well. These findings 

suggest that clinicians may need to more closely monitor response to treatment and outcomes 

when treating very young children with AOM, in particular those with bilateral AOM and those 

with otorrhea. 

Although the evidence was generally insufficient to allow definitive conclusions regarding 

differences in adverse event rates, the available evidence across all studies did indicate an 

increased rate of gastrointestinal effects and diarrhea specifically with amoxicillin-clavulanate 

(compared with oral cefdinir, oral ceftriaxone, or ciprofloxacin-dexamethasone ear drops) and 

with cefixime (compared with ampicillin or amoxicillin). In addition amoxicillin-clavulanate 

appeared to have a higher overall adverse effect rate than cefdinir, ceftriaxone, or azithromycin. 

Future Research Suggestions 

Based on the findings of this review, we provide the following suggestions for future 

research directions. 

Diagnosis of AOM 

Additional studies are needed to more fully understand the precision of the current diagnostic 

criteria for AOM: acute onset of signs and symptoms, MEE, and middle ear inflammation. For 

example, although it has been determined that all three are necessary for a diagnosis of AOM, 

evidence is insufficient to guide clinicians on the most effective and efficient ways to assess each 

of these elements in the clinical setting. Also needed are more studies that use a reference 

standard that can take into account all three criteria of an AOM diagnosis. Thus, a reference 

standard that takes into account only MEE does not provide sufficient evidence on overall 

diagnostic accuracy for AOM. 

Influence of the PCV7 Vaccine on Microbiology/Epidemiology 

Studies are needed to address the implications of the observed evolution in microbiology 

subsequent to introduction of the PCV7 vaccine. For example, will this shift in microbiology 

translate to a shift in the type and incidence of suppurative and other complications? Further 

research is needed to explore the impact of PCV7 on the clinical progression and outcomes of 

uncomplicated AOM, and of AOM in otitis-prone children with recurrent AOM. 

More inquiry is needed into microbiologic shifts in AOM, especially as it relates to resistance 

patterns of the non-PCV7 serotypes of SP that seem to be increasing since the introduction of 

PCV7. Such research will require continued surveillance of both shifts in the causative 

organisms of AOM and in the antibiotic resistance/susceptibility of these organisms. 

16
 
A recent study of a single pediatric practice, not meeting our inclusion criteria, found 

evidence suggesting that an increase in the proportion of AOM with non-vaccine SP serotypes 

may be leading to another shift in AOM microbiology.8 These new data support the need for 

ongoing surveillance of AOM isolates. 

Continued surveillance will also help us understand the impact of new pneumococcal 

vaccines that include more serotypes than PCV7 currently does, such as the newly-licensed 

PCV13. It will be important to have information to help conduct cost-benefit analysis of vaccines 

that cover more than the current seven serotypes. A growing body of research is assessing the 

efficacy of the vaccine in preventing AOM. Although a review of this literature was beyond the 

scope of this report, such a review may be warranted in the near future. 

Treatment Efficacy and Adverse Effects 

Research issues identified in the original AOM review are still applicable to the review 

update as it relates to treatment of uncomplicated AOM as well as to treatment of ROM, which 

was not previously addressed. Though we report several definitive conclusions, the usefulness of 

these conclusions to the practitioner is limited because of concerns regarding the internal validity 

of some of the source studies and the generalizability of the findings because of differences in 

the definitions of AOM and ROM—as well as treatment outcomes—across studies; the 

variability of study quality; and the relative paucity of evidence related to influencing factors 

such as characteristics of AOM including severity, the patient, the environment, and the 

healthcare delivery system. Standard definitions of AOM and ROM that lead to standard 

diagnostic criteria and that are acceptable to both researchers and practitioners have not been 

developed since the initial review and are still needed. The continued diversity of definitions for 

AOM as well as for ROM and, therefore, the diversity of diagnostic criteria that control entry of 

participants into these treatment trials make it difficult to synthesize and generalize findings, as it 

is unclear if the same condition is being assessed across studies. Greater knowledge regarding 

the effect of children‘s age on the operating characteristics of diagnostic criteria will also help to 

assess results of studies comparing treatment options, e.g., by clarifying whether children of 

different ages who have been diagnosed with and are being treated for AOM truly have the 

condition. In addition, improved knowledge of the effect of tympanostomy tube presence on 

these diagnostic operating characteristics will help to better assess the true impact of 

tympanostomy tubes on prevention of AOM in children with ROM. 

Standard definitions related to the quality of AOM management in terms of specific 

structures, processes, and outcomes are still needed. Differences in terminology and in particular 

outcome choice and definitions between studies make it difficult to synthesize the results across 

studies and to generalize findings. This issue should be addressed in future studies. 

17
 

Evidence Report
 

19
 

Chapter 1. Introduction 

Acute Otitis Media (AOM) is a viral or bacterial infection of the middle ear and represents 

the most common childhood infection for which antibiotics are prescribed in the United States 

(US).9-11A 2009 analysis estimated the annual medical expenditures for treating OM in US 

children (including AOM and OM with effusion) to be approximately $2 billion.12 Timely and 

accurate diagnosis and management of AOM can have significant individual and public health 

consequences. The 2001 AHRQ evidence report on the management of AOM analyzed the 

evidence on the initial management of uncomplicated AOM in children, focusing on the natural 

history of the disease and the use of antibiotics in management. The report concluded that among 

children not treated with antimicrobials, the clinical failure rate was highly variable.13 Antibiotic 

treatment with either ampicillin or amoxicillin did reduce clinical failure rates, and among the 

antibiotic regimens assessed, there were no differences in clinical failure rates; however some 

antibiotic regimens were associated with more adverse events than others. 

Although the 2001 report provided valuable analysis of the literature on the management of 

uncomplicated AOM in children, it did not address issues related to diagnostic accuracy and 

precision, management of AOM in specific subgroups of children, or the impact of immunization 

with Heptavalent Pneumococcal Conjugate Vaccine (PCV7), recommended for widespread use 

in 2000, on the microbiology of AOM. Additionally, new trials of treatment continue to be 

published. The purpose of this current AHRQ evidence report is to examine and analyze the 

evidence on three broad areas of inquiry: 1) the diagnosis of AOM, 2) the impact of PCV7 on 

AOM microbial epidemiology, and 3) the comparative effectiveness and safety of different 

treatment options for uncomplicated AOM in average risk children, and in children with 

recurrent or persistent AOM. 

Diagnostic Accuracy 

Otitis media with effusion (OME) is defined as fluid in the middle ear without signs or 

symptoms of acute infection. Distinguishing AOM from OME often poses a diagnostic 

14, 15 challenge. Key elements of the diagnosis of AOM include the acute onset of symptoms, 

16-18 presence of middle ear effusion (MEE), and signs of middle ear inflammation. Errors often 

occur when the clinician makes a diagnosis of AOM in the absence of MEE.14 At least at the 

time of the first systematic review on management of AOM, diagnostic certainty appeared to be 

linked to patients‘ age: Older children (>30 months) were more likely to have a certain diagnosis 

of AOM than children ≤ 12 months of age.19 Given the uncertainty associated with diagnosis, 

particularly in young children, it is important to continually assess the validity of the clinical 

signs and symptoms used to diagnose AOM. 

Management 

Traditional management approaches have centered on the use of antimicrobials; a 2009 study 

found that prescription of broad-spectrum antibiotics for AOM increased from 34% of doctor 

visits in 1998 to 45% of visits in 2004.20 However, debate is increasing over their benefits. 

Concerns regarding increased antimicrobial resistance and uncertainty about the benefits of 

antibiotic treatments (e.g., AOM may be either bacterial or viral) have resulted in a number of 

16, 21 clinical guidelines proposing more judicious use of antimicrobials. The 2004 guidelines 

released by the American Academy of Pediatrics (AAP) and American Academy of Family 

Practice (AAFP) recommend antibiotics for all children under 6 months and an observation 

21
 
approach for otherwise healthy children ages 6 months to less than 2 years who have BOTH an 

uncertain diagnosis and non-severe disease. Observation is also an option for otherwise healthy 

children 2 years of age or older with either non-severe disease or uncertain diagnosis.16 However, 

the benefits of a watchful waiting approach in young patients with a certain diagnosis of AOM 

are unclear. 

16, 21 Amoxicillin is often recommended as the first-line antibiotic for children. Although 

empiric therapy recommendations vary depending on the local antimicrobial resistance patterns, 

evidence of recent microbiologic shifts and changing resistance patterns associated with PCV7 

warrant determining the effectiveness and safety of the current recommendations and evaluating 

additional antimicrobial agents and other management strategies. 

Recurrent otitis media (ROM), defined as three or more episodes in six months or four or 

more episodes within 12 months, occurs in 20% of children under six months of age.9 Antibiotic 

resistant Streptococcus pneumoniae (SP) is commonly associated with ROM and presents a 

22, 23 significant therapeutic challenge. The choice of antimicrobial is not always clear, and the 

role of prophylactic antibiotics remains uncertain. 

Pneumococcal Conjugate Vaccine 

SP is a common bacterial isolate from the middle ear fluid of children with otitis media.24 In 

February 2000, a heptavalent pneumococcal polysaccharide protein conjugate vaccine (PCV7) 

was recommended for use in children aged 2-23 months and for children aged 24-59 months at 

increased risk for pneumococcal disease.25 These recommendations were expanded in 2007 to 

include all healthy, previously unvaccinated children 24-59 months of age. A question that needs 

to be addressed is whether PCV7 vaccination is associated with a microbiologic shift among 

pathogens commonly responsible for otitis media. 

22
 
Chapter 2. Methods 

Original Proposed Key Questions 

The American Academy of Pediatrics requested that AHRQ commission an update of the 

2001 evidence review, Management of Acute Otitis Media. AHRQ provided an initial list of 

questions. 

1.	 What is the validity of clinical symptoms and otoscopic findings such as a bulging 

tympanic membrane to diagnose AOM? Do these clinical findings aid physicians in 

distinguishing AOM from OME? 

2.	 What organisms (bacterial and viral) are associated with otitis media since the 

introduction of PCV7? 

3.	 What are the patterns of antimicrobial resistance since the introduction of PCV7? 

a.	 New infections 

b.	 Recurrent infections 

4.	 What is the comparative effectiveness of different treatment options (defined below) 

for treating AOM in average risk children ages <2 years, ages 2 years to <5years 

and ages ≥ 5 years? 

a.	 Treatment options include but not limited to: 

i.	 Amoxicillin (including high dose vs. low dose) 

ii.	 Amoxicillin-clavulanate (including high-dose vs. low-dose) 

iii. Cephalosporins (e.g. ceftriaxone, cefdinir, cefixime) 

iv. ―Wait and see approach‖ 

v.	 Placebo 

vi. Duration of treatment 

b.	 Outcomes to consider but not limited to: 

i.	 Parent satisfaction 

ii.	 Duration of symptoms/illness 

iii. Treatment failure, mastoiditis, bacteremia, clinical cure, bacteriologic cure 

iv. Disease recurrence 

5.	 What is the comparative effectiveness of different management options for
 

recurrent otitis media?
 

a.	 Management options include but not limited to: 

i.	 Amoxicillin-clavulanate 

ii.	 Cephalosporins (e.g. ceftriaxone, cefuroxime) 

iii. Quinolones 

iv. Antibiotic prophylaxis 

b.	 Outcomes to consider but not limited to: 

i.	 Parent satisfaction 

ii.	 Duration of symptoms/illness 

iii. Treatment failure, mastoiditis, bacteremia/ Cure rates 

6.	 What is the evidence that the comparative effectiveness of different treatment 

options in KQ 3 differs in subpopulations of patients? 

a.	 Subpopulations to include (but not limited to): 

23
 
i.	 Bilateral disease 

ii.	 Comorbidities (e.g. asthma –will need to define further) 

iii.	 Age groups (e.g. <1 month, 1-<2 months, 2-<6 mos, 6mos-<2 years, 2-5 

years) 

iv.	 Race/Ethnicity 

v.	 Day care attendance 

7.	 What are the comparative harms of different treatment options? 

a.	 Outcomes to consider (but not limited to): 

i.	 Antibiotic resistance 

ii.	 Diarrhea/vomiting 

The final key questions, which were slightly revised in coordination with the technical expert 

panel, appear in Chapter 3 (Results). 

Technical Expert Panel 

Each AHRQ evidence report is guided by a Technical Expert Panel (TEP). We invited a 

distinguished group of scientists and clinicians, including individuals with expertise in 

otolaryngology, audiology, infectious disease, epidemiology, and health services, to participate 

in the TEP for this report. Efforts were made to include the project leader and TEP members 

from the 2001 AHRQ AOM report. The list of TEP members is included in Appendix F. Two 

conference calls were held with the TEP. 

The first call, held on September 25, 2008, reviewed the draft key questions (above) and 

proposed definitions for AOM and ROM (see below). TEP members proposed small revisions to 

the wording of the key questions, definitions, and outcomes and influencing factors to consider. 

A summary of this meeting is provided in Appendix F. The revised key questions appear in 

Chapter 3. The definitions that were accepted appear below and in Appendix A. 

Between the first and second TEP calls, we polled the TEP about several points. In 

November, we polled the panel via email to clarify whether to accept studies that used 

nasopharyngeal cultures for diagnosis and characterization. The consensus was that we should 

not; the summary of responses appears in Appendix F. In February, we provided the TEP with a 

list of the trials included to that point to ascertain whether we had excluded any important 

studies. 

The second call was held on March 10, 2009. During this call, we once again asked the 

TEP‘s help in identifying any studies we had neglected to include. We also reviewed the scope 

of work to assess its completeness and discussed the TEP‘s expectations for reporting of findings 

in the final report. A summary of this call appears in Appendix F. The scope appears in 

Appendix A. 

Definitions of Acute Otitis Media and Recurrent Otitis Media 

Definition of AOM: A diagnosis of AOM requires 1) a history of acute onset of signs and 

symptoms, 2) the presence of MEE, and 3) signs and symptoms of middle-ear inflammation.13 

Elements of the definition of AOM are all of the following: 

1.	 Recent, usually abrupt, onset of signs and symptoms of middle-ear inflammation and 

MEE 

2.	 The presence of MEE that is indicated by any of the following: 

24
 
a. Bulging of the tympanic membrane 

b. Limited or absent mobility of the tympanic membrane 

c. Air-fluid level behind the tympanic membrane 

d. Otorrhea 

3. Signs or symptoms of middle-ear inflammation as indicated by either 

a. Distinct erythema of the tympanic membrane or 

b. Distinct otalgia (discomfort clearly referable to the ear[s] that results in 

interference with or precludes normal activity or sleep) 

Definition of Recurrent AOM (ROM): A diagnosis of ROM requires three or more episodes 

of AOM within six months or four episodes within 12 months, including at least one episode 

26-28 during the preceding six months.

Definition of Persistent Otitis Media: Persistent otitis media is manifested by persistence 

during antimicrobial therapy of symptoms and signs of middle ear infection (treatment failure) 

and/or relapse of AOM within one month of completion of antibiotic therapy. When two 

episodes of otitis media occur within one month, it may be difficult to distinguish recurrence of 

AOM (i.e. a new episode) from persistent otitis media (i.e., relapse).23 

Between the first and second TEP calls, we polled the TEP about several points. In 

November, we polled the panel via email to clarify whether to accept studies that used 

nasopharyngeal cultures for diagnosis and characterization. The consensus was that we should 

not; the summary of responses appears in Appendix F. In February, we provided the TEP with a 

list of the trials included to that point to ascertain whether we had excluded any important 

studies. 

The second call was held on March 10, 2009. During this call, we once again asked the 

TEP‘s help in identifying any studies we had neglected to include. We also reviewed the scope 

of work to assess its completeness and discussed the TEP‘s preferences for the format used to 

describe findings in the final report. A summary of this call appears in Appendix F. The scope 

appears in Appendix A. 

Literature Search 

Our search for studies began in July 2008 with an electronic search of PubMed® for reports 

on AOM diagnosis, treatment outcomes, and the effects of the PCV7 vaccine on the 

microbiology and epidemiology of AOM, using the search strategies designed for the first AOM 

systematic review supplemented with additional key words for newer treatment modalities, 

vaccine outcomes, and recurrent AOM. Separate sets of searches were conducted for Key 

Question I, Key Question II, and Key Questions III through VI (see Chapter 3); these searches 

are described further in Chapter 3 (Appendix A shows our specific search terms and strategies; 

Appendix H shows a conceptual framework that helped guide the searches and approach). 

Simultaneously, we also searched for and identified a number of systematic reviews that 

addressed several of the key questions. 

We also searched the Cochrane Controlled Clinical Trials Register Database and the 

Cochrane Database of Reviews of Effectiveness (DARE). (The Cochrane Collaboration is an 

international organization that helps people make well-informed decisions about health care by 

preparing, maintaining, and promoting the accessibility of systematic reviews on the effects of 

heath care interventions.) Finally, we searched the Web of Science for relevant proceedings. 

Search updates were conducted in January and August 2009, and in August 2010. 

25
 
In addition to the keyword searches, relevant articles were identified by using the Science 

Citation Index to search for articles that cited the 2001 AOM report and its resulting publications 

and by reference mining other relevant systematic reviews as well as the articles accepted for 

inclusion. We also identified several relevant international meeting proceedings and sought 

abstracts that responded to the key questions (the findings reported in most of these abstracts had 

been subsequently published in full-text articles). Finally, as described above, we polled the TEP 

for any studies we had overlooked. 

Article Review 

Study Inclusion 

Although our literature search was unrestricted by study design, the studies included in the 

review are of one of the following types of designs. 

Review articles identified by the search were classified as either systematic (including metaanalyses) or nonsystematic. Systematic reviews were identified by reading the methods section 

of the article to determine whether an acceptable method was employed to identify evidence 

(such as a description of the name of the computerized database searched and the full set of 

search terms used, as well as details about the method for accepting and rejecting identified 

articles). Only systematic reviews were included. 

Randomized controlled trials (RCTs) are studies where the participants are definitely 

assigned prospectively to one of two (or more) alternative forms of intervention, using a process 

of random allocation (e.g., random number generation, coin flips). 

Controlled clinical trials (CCTs) are studies where participants (or other units) are either 

(a) definitely assigned prospectively to one of two (or more) alternative forms of health care 

using a quasi-random allocation method (e.g., alternation, date of birth, patient identifier) 

OR 

(b) possibly assigned prospectively to one of two (or more) alternative forms of health care 

using a process of random or quasi-random allocation. 

Observational studies (such as cohort and cases series) are those where the investigators do 

not control who gets the interventions. The decision was made to exclude observational studies 

unless controlled trials were insufficient to answer the key questions pertaining to treatment. 

To be included, studies had to report on diagnosis or treatment of AOM, primary or 

recurrent; or the effects of the Prevnar® vaccine on bacterial microbiology/epidemiology. 

Screening 

Two reviewers, both pediatricians trained in the critical analysis of scientific literature, 

independently reviewed lists of titles obtained from each search. Abstracts were obtained for all 

potentially relevant titles, and the clinicians independently reviewed the abstracts, resolving 

disagreements by consensus. Using a single-page ―screening form‖ (included in Appendix B), 

they reviewed the abstracts retrieved from the various sources to assess whether they reported 

original data (or appeared to be systematic reviews) and responded to one of the key questions. 

26
 
Full text articles were obtained for all accepted abstracts. Relevant study-level information 

was then abstracted from these articles onto review forms. This information included study 

design, sample size and identity, treatment protocol, types of outcomes reported and by whom, 

potential influencing factors, and study quality. The two reviewers independently reviewed each 

study and resolved disagreements by consensus. The lead investigator resolved any 

disagreements that remained after discussions between the reviewers. 

Data Abstraction & Synthesis of Results 

Review and Assessment of Study Quality 

The criteria for the assessment of study quality were established prior to the review of 

articles. The criteria developed by Jadad, Moore, Carroll et al. (1996) were used to evaluate the 

quality of RCTs.29 For a given study, we awarded one point if the study was described as 

randomized, one point if the study was described as double-blind, and one point if it described 

withdrawals and dropouts. We awarded an extra point if the method of randomization was 

appropriate and another if the method of double-blinding was appropriate; conversely, we 

subtracted one point each if the method of randomization or double-blinding was inappropriate. 

Thus, studies could receive a Jadad score ranging from 0 to 5 points. 

The criteria used to evaluate the quality of cohort studies and case-control studies were based 

30-32 on the work by the McMaster University Group. The quality of cohort studies was evaluated 

against eight components, which included the presence or absence of a clear definition of the 

study cohort, an early inception point, a clear pathway of patient entry, complete follow-up, 

description of dropouts, objective outcome criteria,  ̳blind‘ outcome assessment, and adjustment 

for extraneous factors. The quality of studies that examined diagnostic tests was evaluated using 

QUADAS criteria.33 The quality of systematic reviews was evaluated using the Assessment of 

Multiple Systematic Reviews (AMSTAR) criteria. Quality reviews were carried out in the same 

manner as the screening of articles for inclusion/exclusion. Articles were not masked prior to 

review. Two physician reviewers independently evaluated the quality of the articles and filled 

out the quality review forms. Conferences were held to resolve discrepancies whenever needed. 

Data Abstraction 

For the articles eligible for inclusion in the Evidence Report, data abstraction was carried out 

by two physician reviewers. Data abstracted included parameters necessary to define study 

groups, inclusion/exclusion criteria, influencing factors, and outcome measures. Data for analysis 

were abstracted by a biostatistician and checked by a physician reviewer. We used a sequential 

resolution strategy to match and resolve the screening and review results of the two reviewers. 

The data abstraction form used is included in Appendix B. 

Supplemental Analysis for Key Question III 

Key Question III addresses the comparative effectiveness of different treatment options for 

treating uncomplicated AOM in average risk children for treatment options including but not 

27
 
limited to antibiotics, ―wait-and-see‖ approach, analgesics, and placebo and for outcomes 

including but not limited to treatment failure, invasive infections, bacteriologic cure, disease 

recurrence, quality of life or functional outcome, and parent satisfaction. Among the included 

articles we tabulated the number of articles by treatment options and by outcomes in order to 

assess whether there was an adequate number of articles for pooling analysis. 

Our review of data to address this key question (as well as questions pertaining to prevention 

and treatment of ROM) had several limitations. First, definitions for clinical success were 

usually not equivalent between studies comparing the same treatments. For example, studies 

used different clinical criteria to define success, and success was often measured at different time 

points. Second, the inclusion criteria for participants also varied widely among studies. Some 

studies used only one of the three criteria for AOM diagnosis, while others considered two or all 

three. It is possible that some studies with less stringent inclusion criteria may have included 

participants who did not have AOM, but rather had OME or no middle ear infective process at 

all. Third, the timing of study completion could affect results. In analysis, the articles eligible for 

analysis for the key question were grouped according to the specific treatment options they 

compared. Each comparison consisted of articles that were considered homogeneous from the 

standpoint of clinical practice. 

Since this key question was addressed in the first evidence report published in 2001, we 

combined the articles identified in that report with newly identified articles in this evidence 

report. Comparisons that included three or more articles from the old and new searches were 

subjected to meta-analyses or quantitative syntheses where their data were pooled. 

We used the Der Simonian and Laird random effects model34 to pool rate differences across 

studies. This method produces a summary measure that is a weighted mean. It weights each 

study's measure by the inverse of the sum of the within-study variance and the between-study 

variance. This approach allows both sampling variation and between-study heterogeneity to 

affect the pooled estimate. Among the three effect measures—rate difference, relative risk, and 

odds ratio—the TEP and the project staff chose as most suitable the rate difference and its 95 

percent confidence interval. It should be noted that we have used the absolute rate difference 

rather than the relative rate difference to measure the effect size throughout the report. Further, 

we reported the findings on the success rate instead of the failure rate throughout the report as 

recommended by the TEP. 

In addition to the pooled estimate, we report the Q statistic and p-value for the Chi-squared 

test of heterogeneity, which tests the null hypothesis that the individual study results are 

35 2 36 2 homogeneous. A test of heterogeneity was performed using the I statistic. I values close to 

100% represent very high degrees of heterogeneity. The I2 statistic uses the Q statistic to measure 

the degree of inconsistency (excess variability) across studies: I2=100%x(Q-[k-1])/Q, where k is 

the number of studies included in the analysis. Its advantage is that it can be used for studies with 

different outcomes and it provides an assessment of the degree of heterogeneity. 

For assessment of publication bias, we examined funnel plots and derived the Egger‘s 

asymmetry test. 

We used Stata 10.0 to perform the meta-analyses.37 

28
 
Supplemental Analysis for Key Question IV 

Key Question IV is the same question as Key Question III except that the study population 

comprises children with RECURRENT otitis media. The same analytical approach was taken. 

First we tabulated the number of articles by treatment options and by outcomes in order to assess 

whether the number of articles was adequate for pooled analysis. 

The articles eligible for analysis for the key question were grouped by comparisons of 

treatment options. Each comparison consisted of articles that were considered homogeneous 

from the standpoint of clinical practice. Although this key question was NOT addressed in the 

2001 evidence report, we used the articles identified in that report along with articles newly 

identified for this report. Comparisons that involved three or more articles were subjected to 

meta-analyses or quantitative syntheses where their data were pooled. 

Supplemental Analysis for Key Question V 

Key Question V poses the same question as Key Questions III and IV except that this 

question specifies analysis of the treatment effectiveness by characteristics of the condition 

(AOM), patient, environment, and/or health care delivery system, including but not limited to 

laterality, otorrhea or perforation, AOM severity, comorbidities (e.g. asthma), age group, race, 

ethnicity, and day care attendance. For this key question, we further divided the articles within 

each comparison into subgroups by influencing factors to the extent possible. The same 

analytical approach was taken. Comparisons that involved three or more articles were subjected 

to meta-analyses or quantitative syntheses where their data were pooled. 

Supplemental Analysis for Key Question VI 

Key Question VI addresses the comparative safety of the various treatment options used for 

a) treating uncomplicated AOM, b) preventing AOM in children with ROM, or c) treating AOM 

in children with ROM. Among the included articles, we identified the number of articles by 

treatment options in order to assess whether there were an adequate number of articles for 

pooling analysis. 

Adverse events were recorded onto a spreadsheet that identified each trial arm, the 

description of the adverse event from the original article, the number of participants in each 

group, and the number of participants affected. We counted each event as if it had been 

experienced by a unique individual. However, because a single individual might have 

experienced more than one event, our assumption may have overestimated the actual number of 

people who experienced an adverse event. 

If a trial report mentioned a particular type of adverse event in the discussion but did not 

report data on that adverse event (either that no participants experienced that adverse event or 

some number of participants experienced the adverse event), we excluded that trial from the 

analysis of that particular type of event. In other words, we did not assume an adverse event 

occurred unless the trial report specifically stated that some number of events was observed (at 

the same time, for such studies, we did not assume that NO participants experienced the event). 

29
 
By taking this approach, we may have either overestimated or underestimated the number of 

participants who experienced a particular adverse event, respectively 

After abstracting the data, we identified mutually exclusive groups of similar events, based 

on clinical expertise. For each adverse-event subgroup, we report the number of trials that 

provided data for any event in the subgroup. We also report the total number of individuals in the 

medication groups in the relevant trials who were observed to have experienced the event and the 

total number of patients in the medication groups in those trials. We then report the analogous 

counts for the control groups in the relevant trials. We analyzed and pooled the findings of the 

articles in the same way for this question as for Key Questions III and IV except that the 

outcome measure was the adverse event rate. Comparisons that included three or more articles 

were subjected to meta-analyses or quantitative syntheses where their data were pooled. We used 

the Der Simonian and Laird random effects model34 to pool rate differences across studies. 

Use of Observational Studies to Assess Comparative Effectiveness 

Observational studies can help augment the evidence from trials about the comparative 

effectiveness of treatments. Such studies can provide evidence of benefits and harms in 

populations of patients with less restrictive clinical characteristics than those typically enrolled in 

trials, and large observational studies can provide the statistical power needed to detect rare 

adverse effects. We searched for large observational studies assessing benefits or harms of 

treatment of AOM in children, but found none that addressed the key questions pertaining to 

treatment efficacy or safety. However, a small number of observational studies were included for 

the purpose of responding to Key Question I, on diagnostic criteria, and Key Question II, on the 

impact of the PCV7 vaccine. 

Rating the Overall Quality of Scientific Evidence 

We assessed the overall quality of evidence for outcomes using a method developed by the 

GRADE Working Group, which considers four key elements to classify the quality of evidence: 

study design, study quality, consistency, and directness. 

Study design refers to the basic design of the study (i.e., RCT, observational studies).
 

Study quality refers to the study methods and execution. 

Consistency refers to the similarity of effects estimates across studies. 

Directness refers to the extent to which the study details (participants, interventions, 

outcome measures) are generalizable to those of interest. 

Based on these four criteria, GRADE classifies the quality of evidence as high, moderate, 

low, or very low, where 

High = Further research is very unlikely to change our confidence on the estimate of 

effect. 

Moderate = Further research is likely to have an important impact in our confidence 

in the estimate of effect and may change the estimate. 

Low = Further research is very likely to have an important impact on our confidence 

in the estimate of effect and is likely to change the estimate. 

30
 
Insufficient = Any estimate of effect is very uncertain (this term was modified from 

―Very Low‖ by the EPC).
	

The criteria for consideration when assigning grade of evidence are as follows.
 

Type of evidence:
 

Randomized trial = high 

Observational study = low 

Any other evidence = insufficient 

Decrease grade if: 

Serious (-1) or very serious (-2) limitation to study quality
 

Important inconsistency (-1)
 

Some (-1) or major (-2) uncertainty about directness
 

Imprecise or sparse data (-1)
 

High probability of reporting bias (-1)
 

Increase grade if: 

Strong evidence of association-significant relative risk of > 2 (or < 0.5) based on 

consistent evidence from two or more observational studies, with no plausible 

confounders (+1) 

Very strong evidence of association-significant relative risk of > 5 (or < 0.2) based on 

direct evidence with no major threats to validity (+2) 

Evidence of a dose-response gradient (+1)
 

All plausible confounders would have reduced the effect (+1) 

As part of our consideration in rating the quality of scientific evidence, we also assessed the 

quantitative strength of the evidence, taking into consideration the magnitude of treatment 

effects, the number of studies that have evaluated the given topic, and the overall sample size 

across all included studies. 

When comparing an outcome between two groups, statistical significance is used to answer 

the question ―is there a difference?‖ If there is a difference, the next question is ―is this 

difference clinically important?‖ Not all differences that are statistically significant are clinically 

important. The concept of the ―minimum clinically important difference‖ (MCID) sets a 

threshold for the smallest difference that would be clinically meaningful. Ideally, this would be 

determined empirically, through studies of construct validity of different thresholds for the 

clinical question of interest. Such work has been done in conditions like rheumatoid arthritis and 

back pain. When empirical data are not present, the MCID is often arrived at by using clinical 

judgment or rules of thumb. Cohen first proposed a commonly used classification scheme for 

considering the size of a treatment effect.38 In Cohen‘s classification, effect sizes of 0.20 are 

considered ―small‖ effects. We used this threshold to set the MCID for the treatment of AOM at 

5%. 

Hypothetical examples of the application of the MCID and the statistical significance are 

presented below. Scenario I is a situation where there exists a statistically significant difference 

between AOM outcomes in a trial comparing two treatments, but that difference is only 3%. 

Scenario II is where a trial finds no statistically significant difference in outcomes between 

treatments. In Scenarios I and II, since the 95% confidence intervals lie completely inside the 

zone of MCID, we conclude that there is sufficient evidence that Treatment A and Treatment B 

31
 
%

are not clinically different even though in scenario I the difference between treatments is 

statistically significant. In Scenario III, where the 95% confidence interval lies outside the zone 

of MCID to the right, we conclude that there is sufficient evidence that Treatment A is clinically 

better than Treatment B. In Scenario IV, where the 95% confidence interval lies outside the zone 

of MCID to the left, we can conclude that there is sufficient evidence that Treatment B is 

clinically better than Treatment A. In Scenarios V and VI, the 95% confidence intervals cross 

into the zone of MCID, and we conclude that there is insufficient evidence to make any 

conclusion on the relative effectiveness of Treatments A and B. 

It should be noted that the determination of the size of the zone of MCID must take into 

consideration the topic, the treatment options, the outcome measures, and the balance of proving 

equivalence or significance. The zone of MCID must be the limits within which any difference 

found between two treatment options is considered clinically irrelevant. A narrow zone of MCID 

will allow more differences to be significant but will make it more difficult (require a larger 

sample size) to prove equivalence. A wide zone of MCID will make it easier to prove 

equivalence (i.e., permit a smaller sample size) but more difficult to prove significance (i.e., 

require a larger sample size). 

Readers who believe the MCID should be smaller or larger can adjust their interpretations of 

the evidence to fit their own assumptions. 

Figure 1. Statistical Inference Using Confidence Interval (CI) and Minimal Clinically Important Difference 

(MCID) 

Zone of Minimal 

Clinically 

Important 

Scenario Difference 

I 

II 

III 

IV 

V 

VI 

No difference 

No difference 

Treatment A better 

Treatment B better 

Insufficient evidence 

Insufficient evidence 

-5% +5% 

Difference in success rate (A-B) 

0% 

32
 
Peer Review
 

A draft of this report was prepared in May 2009 and sent to the TEP members and national 

and international experts for review. Peer reviewer comments were considered by the EPC in 

preparation of the final report. Synthesis of the scientific literature presented here does not 

necessarily represent the views of individual reviewers, and service as a peer reviewer or 

member of the TEP cannot be construed as endorsement of the report‘s findings. 

33
 

Chapter 3. Results 

This chapter presents the results of the literature searches, reviews of pertinent systematic 

reviews, the accepted key questions, and the findings and analyses for each key question. 

In total, the reviewers examined 8, 946 titles for the draft version of this report (including 

7,356 from the original searches with three updated searches producing 1, 300 titles (Appendix 

A). 

The reviewers selected 739 titles for further review. Of those 739, four were excluded 

because they were duplicates; 500 were further rejected as they were determined not to be 

relevant to the project, they reported duplicate findings from a study already included; the age of 

the study population was 18 years; or the study population had immunodeficiencies or 

craniofacial deformities or were non-human subjects. 

Screening of the remaining 235 retrieved articles resulted in exclusion of 11 due to 

publication being before 2002; no key question addressed; or for being included as part of a 

diagnostic review article; 67 were excluded for study design, not being a valid pre/post vaccine 

study, or reporting duplicate data. Eighty three observational studies were set aside for possible 

review of efficacy or adverse events at a later time; they were subsequently determined not to 

add further evidence. One RCT was rejected for not addressing the key question, and one article 

for lack of translation resources. The remaining 72 were reviewed in detail. The literature search 

and review flow appear in Appendix A. The list of excluded studies appears in Appendix D. 

Key Question I. 

Diagnosis of AOM: What are the Operating Characteristics 

(Sensitivity, Specificity, and Likelihood Ratios) of Clinical 

Symptoms and Otoscopic Findings (Such As Bulging
 

Tympanic Membrane) to Diagnose Uncomplicated AOM and
 

to Distinguish It from OME?
 

Description of the Studies 

In our initial search, we identified a 2003 systematic review that addressed the question and 

included six original research studies. We requested the search strategy from the principal 

investigator for the review and, using that strategy, re-ran the literature search on PubMed for 

articles published after 2002. This search identified three articles published subsequent to the 

Rothman review. Details of all accepted articles are presented in Tables 1 through 3 below. 

Findings for Key Question I 

A systematic review by Rothman and colleagues15 examined the study question of diagnostic 

operating characteristics for AOM. The authors searched for articles from 1966 through May 

2002 (English language only) that specifically examined the role of any sign or symptom directly 

35
 
related to the diagnosis of AOM. Five studies met the criteria for inclusion in this review; study 

participants ranged in age from birth to 15 years (although the findings were not stratified by 

age). Partly based on the findings of a single study, the authors concluded that the diagnosis of 

AOM was often uncertain; agreement between pediatric residents and otolaryngologists was fair 

for overall diagnosis (kappa statistic 0.30) and slight to fair (Kappa statistics range from 0.16 to 

0.40) for specific TM findings. 

Furthermore, the authors concluded that among symptoms, only otalgia (ear pain) in three 

studies (reported sensitivity/specificity/positive likelihood ratio [95% confidence 

interval]/negative likelihood ratio [95% confidence interval]: 54%/82%/3.0 [2.1-4.3]/0.6 [0.5­

0.7]; 60%/92%/7.3 [4.4-12.1]/0.4[0.4-0.5]; 100%/NA/NA/NA), and ear rubbing in one study 

42%/87%/3.3 [2.1-5.1]/0.7[0.6-0.8]) seemed to predict a clinical diagnosis of AOM. Other 

symptoms, such as fever, did not show much effect, whether present or absent (two studies 

showed no effect, one study showed a slightly increased likelihood ratio [LR]). The major 

drawback to these types of studies examining the accuracy of symptoms in the clinical diagnosis 

of AOM is that the criterion standard is the clinical diagnosis itself, which can include these 

same acute symptoms. 

One of the studies examined in this review assessed the accuracy of individual physical exam 

findings (cloudy, bulging, immobile, or red TM) using tympanocentesis as the criterion standard. 

Otoscopy was performed by an otolaryngologist and a pediatrician. They found these signs to be 

positively associated with AOM (determined by the presence of MEE on tympanocentesis and 

clinical symptoms). Specifically, a TM that was cloudy (adjusted positive LR 34 [28-42]; 

sensitivity and specificity not reported), bulging (adjusted positive LR 51 [37-73]), or distinctly 

immobile (adjusted positive LR 31 [26-37]) greatly increased the likelihood of AOM, and a 

moderately or strongly red TM also increased the likelihood of AOM but with a much lower 

adjusted positive LR (8.4 [6.7-11]). 

Using the same inclusion criteria as this systematic review, we searched for articles published 

after May 2002 and found three additional relevant publications. Similar to the articles in the 

systematic review discussed above, these three additional articles met the 2003 review‘s quality 

criteria for evidence level 4 (on a 1-5 scale, with 1 being the highest and 5 being the lowest, e.g., 

with scores of 1-2 reserved for studies that used an independent blind comparison of 

signs/symptoms against a criterion standard among consecutive patients). We additionally used 

the QUADAS (Quality Assessment of Diagnostic Accuracy of Studies) criteria to assess the 

quality of these two studies; QUADAS is a widely-used quality scale for studies of diagnostic 

accuracy. The total QUADAS scores and the answers for each of the 14 QUADAS questions are 

detailed for each article in Table 1. Tables 2 and 3 present the findings on the accuracy of signs 

and symptoms. 

36
 
Table 1. Evidence for Key Question I (Diagnosis) 

Author, 

Year 

Time/Place/Affiliation 

Inclusion/Exclusion 

Criteria 

Examiner 

Group(s) and Sample 

Size 

Comparison(s) 

Influencing 

factors 

Findings Quality a 

Patient 

Characteristics 

Diagnostic 

Methods (Dx), 

cutpoints 

Gold Standards 

(GS), cutpoints 

Saeed, 

200439 

Time 

Recruitment period: 

Examiner(s) Comparisons Comparisons Study Quality 

Pneumatic otoscopy­ 1. Pneumatic 1. Tympanogram Assessment 

Pediatrician/investigator otoscopy Sensitivity: 97% Rothman scale: 4 

Tympanometry- Dx- : no AOM Specificity: 7% 

research assistant Dx+ : AOM PPV 88% QUADAS: 11 

Tympanostomy- Tympanostomy NPV: 25% y, y, y, y, n, n, y, 

same GS- : no MEE falsely low true y, y, y, n, y, y, y 

Pediatrician/investigator GS+ : MEE present negatives b/c GS test 

as otoscopy examiner not performed on 

Group 2. Tympanogram normal ears 

children with a dx of Dx- :Type A 

AOM and findings from (normal) 2. Pneumatic 

otoscopy, Dx+ Type B otoscopy 

tympanometry, and (abnormal) Sensitivity: 100% 

tympanocentesis Tympanostomy Specificity: 5% 

available GS- : no MEE PPV 86% 

Sample size GS+ :MEE present NPV: 100% 

N=81 participants, 130 falsely low true 

ears negatives b/c GS test 

not performed on 

normal ears 

Sept 1995-May 1998 

Place: pediatric clinics 

Affiliation 

University of Texas 

Medical Branch, 

Galveston 

Inclusion 

Clinical diagnosis of 

AOM by: 

- acute symptoms 

- acute TM 

inflammation 

- evidence of MEE 

by pneumatic 

otoscopy and/or 

tympanometry 

Exclusion 

- ear or 

nasopharynx 

defects 

- tympanostomy 

tubes 

- major medical 

condition 

- antibiotic 

-

treatment w/in 7 

days of enrollment 

treatment of AOM 

37
 
Author, Time/Place/Affiliation Examiner Comparison(s) Findings Quality a 

Year Inclusion/Exclusion Group(s) and Sample Influencing 

Criteria Size factors 

Patient Diagnostic 

Characteristics Methods (Dx), 

cutpoints 

Gold Standards 

(GS), cutpoints 

w/in 30 days 

- allergy to study 

medication 

Patient 

Characteristics 

- mean age 19.2 

months, age 

range 3-72 

months 

- part of clinical trial 

(double blind 

RCT) to evaluate 

adjunctive drugs 

in AOM with AOM 

from pediatric 

clinics 

- all participants 

received IM 

ceftriaxone. 

Legros, 

200740 

Time 

Recruitment period: Examiner(s) 

December 04-March GP clinical exam: 

05 and October 05­ by GP 

January 06 ENT clinical diagnosis: 

Place by ENT 

GP clinics Group 

Affiliation first 6 children either 

Angers Medical suspected or 

School, France diagnosed with AOM by 

Inclusion a GP 

Comparisons 1. GP clinical Study Quality Score 

1. GP clinical diagnosis/ suspicion Rothman scale: 4 

diagnosis/suspicion 137 AOM diagnoses/ QUADAS: 13 

Dx- : no AOM suspicions by GPs of y, y, y, u, y, y, y, 

Dx +: AOM these, 122 based on y, y, y, u, y, y, y 

ENT clinical visible/partially 

diagnosis visible TMs (54 had 

GS- : no AOM redness and bulging 

GS+ : has AOM of TM; 32 had 

redness only), 13 

based on non-visible 

38
 
Author, Time/Place/Affiliation Examiner Comparison(s) Findings Quality a 

Year Inclusion/Exclusion Group(s) and Sample Influencing 

Criteria Size factors 

Patient Diagnostic 

Characteristics Methods (Dx), 

cutpoints 

Gold Standards 

(GS), cutpoints 

- children from 1-4 

years old who had 

been suspected of 

having AOM or 

diagnosed with 

AOM by GP 

- Parents had to 

agree to see ENT 

within 48 hours at 

another location 

Exclusion 

- chronic ear 

pathology 

Patient 

Characteristics 

- mean age 27.1 

months, range 12­

48 months 

Sample Size 

N=104 participants, 137 

ears 

2. GP clinical 

diagnosis/suspicion 

when eardrum only 

partially visible or 

not visible (subset 

of #1) 

Dx- : no AOM 

Dx+ : AOM 

ENT clinical 

diagnosis 

GS- : no AOM 

GS+ : has AOM 

TM, 2 based on 

otorrhea 

Of the 137: 

ENTs diagnosed107 as AOM, and 30 

as not AOM. of these 

30, --- 16 as OME, 4 

as viral otitis, and 10 

as normal 

2. Study also gives 

descriptions of what 

happened with the 

cases based on nonvisible TMs. 19 of the 

24 cases of nonvisible TMs did not 

have a contralateral 

ear w/ AOM. Of 

these, the main signs 

noted by GP for 

diagnosis were night 

cries, irritability, pain, 

ear pulling, and 

fever. 

GP 

diagnoses/suspicions 

based on 42 

visible/partially 

39
 
Author, Time/Place/Affiliation Examiner Comparison(s) Findings Quality a 

Year Inclusion/Exclusion Group(s) and Sample Influencing 

Criteria Size factors 

Patient Diagnostic 

Characteristics Methods (Dx), 

cutpoints 

Gold Standards 

(GS), cutpoints 

Laine, Time: 

1 2010 November 2006­

December 2008 

Place: 

Outpatient setting 

Affiliation: 

Turku University 

Hospital, Finland 

Inclusion: 

Parental suspicion of 

AOM in child based on 

symptoms 

Patient 

Characteristics: 

6-35 months 

Examiner: 

Study physician 

validated to assess TM 

findings 

Group: 

Children presenting to 

an outpatient setting 

with a parental 

suspicion of AOM by 

symptoms 

Sample Size: 

N= 469 children. 

237 with AOM by study 

physician exam and 3 

criteria, 232 without. 

Comparisons: 

1. Parental 

Suspicion 

Dx-: no AOM 

Dx +: AOM 

2. Ear-related 

symptoms 

(pain, rubbing, 

fever, non-specific 

symptoms, 

respiratory 

symptoms) 

visible eardrums: 

24 GP diagnoses/ 

suspicions of AOM 

18/24 were 

confirmed by the 

ENT 

1. Parental suspicion 

was correct for 51% 

of all children, 48% 

of children without a 

previous AOM 

diagnosis, and 52% 

of children with a 

previous AOM 

diagnosis. 

2. The occurrence, 

duration, and 

severity of earrelated symptoms 

were not associated 

with AOM diagnosis 

Rothman scale: 4 

QUADAS: 12 

n,y,y,y,y,y,y, 

y,y,y,n,y,y,y 

Table Notes: B/c: because; Dx: diagnosis; GS: gold standard; MEE: middle ear effusion; NPV: negative predictive value; PPV: positive predictive value; TM: tympanic membrane 

a QUADAS: 1 (y=yes); 2(n=no); 3(u=unclear). Answers to QUADAS questions presented in the following order: 

1. Was the spectrum of patients representative of the patients who will receive the test in practice? 

2. Were selection criteria clearly described? 

3. Is the reference standard likely to correctly classify the target condition? 

4. Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? 

5. Did the whole sample or a random selection of the sample, receive verification using a reference standard? 

6. Did patients receive the same reference standard regardless of the index test result? 

7. Was the reference standard independent of the index test (i.e. the index test did not form part of the reference standard)? 

40
 
8. Was the execution of the index test described in sufficient detail to permit replication of the test? 

9. Was the execution of the reference standard described in sufficient detail to permit its replication? 

10. Were the index test results interpreted without knowledge of the results of the reference standard? 

11. Were the reference standard results interpreted without knowledge of the results of the index test? 

12. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 

13. Were uninterruptible/intermediate test results reported? 

14. Were withdrawals from the study explained? 

41
 
Table 2. Accuracy of Symptoms 

Source and Sensitivity, Specificity, Positive LR Negative LR 

Symptoms % % (95% CI) 95% CI) 

Niemela et al, 

199441 

Ear pain 54 82 3.0 (2.1-4.3) 0.6 (0.5-0.7) 

Ear rubbing 42 87 3.3 (2.1-5.1) 0.7 (0.6-0.8) 

Fever 40 48 0.8 (0.6-1.0) 1.2 (1.0-1.5) 

Cough 47 45 0.9 (0.7-1.1) 1.2 (0.9-1.4) 

Rhinitis 75 43 1.3 (1.1-1.5) 0.6 (0.4-0.8) 

Excessive crying 55 69 1.8 (1.4-2.3) 0.7 (0.5-0.8) 

Poor appetite 36 66 1.1 (0.8-1.4) 1.0 (9.8-1.1) 

Vomiting 11 89 1.0 (0.6-1.8) 1.0 (0.9-1.1) 

Sore throat 13 74 0.5 (0.3-0.8) 1.2 (1.1-1.3) 

Headache 9 76 0.4 (0.2-0.7) 1.2 (1.1-1.3) 

Heikkenen & 

Ruuskannen, 

199542 

Ear pain 60 92 7.3 (4.4-12.1) 0.4 (0.4-0.5) 

Fever 69 23 0.9 (0.8-1.0) 1.4 (0.9-2.0) 

Cough 84 17 1.0 (0.9-1.1) 1.0 (0.6-1.6) 

Rhinitis 96 8 1.0 (1.0-1.1) 0.5 (0.2-1.4) 

Restless sleep 64 51 1.3 (1.1-1.6) 0.7 (0.5-0.9) 

Ingvarsson, 

198243 

Ear pain 100 NA NA NA 

Fever 79 70 2.6 (1.9-3.6) 0.3 (0.2-0.5) 

URI 96 29 1.4 (1.2-1.6) 0.3 (0.2-0.5)_ 

Kontiokari et al, 

199844 

Parental 70 80 3.4 (2.8-4.2) 0.4 (0.3-0.5) 

suspicion of AOM 

Laine et al, 

20101 

Ear pain 92 8 1.0 (1.0-1.1) 0.9 (0.5, 1.7) 

Ear rubbing 70 22 0.9 (0.8-1.0) 1.4 (1.0, 1.8) 

Fever 43 65 1.2 (1.0-1.6) 0.9 (0.8, 1.0) 

Cough 79 26 1.1 (1.0, 1.2) 0.8 (0.6, 1.1) 

Rhinitis 94 95 1.0 (0.9, 1.0) 1.2 (0.6, 2.6) 

Excessive crying 87 88 1.0 (0.9, 1.1) 1.1 (0.7, 1.7) 

Poor appetite 63 64 1.0 (0.9, 1.1) 1.0 (0.8, 1.3) 

Vomiting 1 2 0.6 (0.1, 2.4) 1.0 (1.0, 1.0) 

Table Notes: AOM: acute otitis media; CI: confidence interval; LR: likelihood ratio; URI: upper respiratory infection. 

Adapted from Rothman et al, 200315 

42
 
Table 3. Accuracy of Signs 

ACCURACY OF SIGNS Karma, et al 1989 

Signs Unadjusted Adjusted Positive LR 

Positive LR (95% CI) 

Color 

Cloudy 11 34 (28-42) 

Distinctly red 2.6 8.4 (6.7-11) 

Slightly red 0.4 1.4 (1.1-1.8) 

Normal 0.1 0.2 (0.19-0.21) 

Position 

Bulging 20 51 (36-73) 

Retracted 1.3 3.5 (2.9-4.2) 

Normal 0.4 0.5 (0.49-0.51) 

Mobility 

Distinctly impaired 8.4 31 (26-37) 

Slightly impaired 1.1 4.0 (3.4-4.7) 

Normal .04 0.2 (0.19-0.21) 

Adapted from Rothman et al, 200315 

Saeed examined the accuracy of otoscopic and tympanometric findings compared with 

tympanocentesis as the criterion standard to determine the presence of MEE.39 The investigator 

performing the tympanocentesis was not blinded to the findings of tympanometry (performed by 

a research assistant) or otoscopic exam (performed by an ―experienced‖ physician investigator), 

and only patients whose tympanometry or otoscopic exam suggested MEE received the criterion 

standard of tympanocentesis. Ninety-seven percent of children with MEE on tympanocentesis 

had “Type B” tympanogram findings (abnormal), and all children with MEE on tympanocentesis 

had an otoscopic exam consistent with AOM. However, LR and predictive value estimates are 

not as useful, since all participants had an AOM diagnosis at enrollment. 

The second study (Legros, 2007) examined the diagnostic accuracy of French general 

practitioners (GP) compared with otolaryngologists‘ clinical diagnoses as the criterion 

standard.45 The study used a consecutive sample of patients who had a suspected diagnosis of 

AOM by the GP and received the criterion standard (otolaryngology clinical exam). The study 

included 137 eardrums that were either assumed to be or were diagnosed as AOM by the GP. Of 

these 137, 78% (107) were confirmed by ear-nose-and throat (ENT) exam and the remaining 

were not, because the otolaryngologist diagnosed OME, viral otitis, or a normal TM. The ENT 

exam confirmed the GP diagnoses more often when redness and bulging were noted by the GP 

(83%) than when only redness was noted (75%). One major drawback to this study was that the 

criterion standard was not performed at the time of GP exam; in the majority of cases, the ENT 

exam occurred the following day when it was possible that GP-prescribed antibiotic treatment 

might have already altered the physical signs and clinical symptoms. 

The third study published subsequent to the 2003 review found that among 469 children ages 

6-36 months with parent-suspected AOM in primary care offices, AOM diagnosis was not 

associated with the occurrence, duration, or severity of parent-reported symptoms (e.g., ear pain: 

sensitivity 92%, specificity 8%, positive LR 1.0 [1.0-1.1]; ear rubbing: sensitivity 70%, 

specificity 22%, positive LR 0.9 [0.8-1.0]; fever: sensitivity 43%, specificity 65%, positive LR 

1.2 [1.0-1.6]).1 

43
 
In summary, there is limited evidence on clinicians‘ accuracy and precision in identifying 

each of the three clinical criteria necessary to diagnose AOM, or their accuracy and precision in 

identifying all three together. The prior review and studies examined above do not directly or 

completely answer our key question; however, they do suggest that clinical findings of MEE 

(decreased mobility or abnormal position) and middle ear inflammation (distinctly red color of 

the TM) are positively associated with AOM, defined by positive tympanocentesis and acute 

onset of symptoms. Further, studies comparing diagnostic accuracy between generalist or 

primary care physicians and otolaryngologists suggest that clinicians‘ accuracy in identifying all 

three clinical criteria in one patient is moderate, at best. The overall quality of evidence for this 

Key Question is considered low, meaning that further high-quality research is very likely to have 

an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Key Question II. 

What Has Been the Impact of the Pneumococcal Heptavalent 

Immunization (PCV7) on AOM Microbial Epidemiology 

(Including Acute Mastoiditis and Suppurative 

Complications)? 

Description of the Studies 

The combined searches for titles pertaining to this key question resulted in 1,044 titles. Of 

these 1,044 titles, 73 titles appeared potentially relevant and full-text articles were ordered. A 

second level of screening was conducted to identify only articles that assessed microbiology both 

pre- and post-implementation of the vaccine. Of the 73 articles screened, six were accepted for 

our report and 67 were rejected. Details of all accepted articles are described below and 

presented in Tables 4 and 5. The rejected articles and the reasons for rejection are listed in 

Appendix D. 

Findings for Key Question II 

In order to address this question, we searched for studies and RCTs that compared the 

organisms (bacterial and viral) that caused AOM in children who had received PCV7 to those in 

children who had not received PCV7. Two main types of studies would directly address this 

question: observational studies that take advantage of the time periods both before and after the 

licensure of PCV7 and RCTs of PCV7 efficacy. 

This first group of studies consists of observational studies that either retrospectively or 

prospectively examine two separate cohorts of children, before and after 2000 (PCV7 was 

licensed in February 2000 and recommended for all children aged 2-23 months by the CDC 

Advisory Committee on Immunization Practices (ACIP) in June 2000). 

44
 
We identified four such studies. (Table 4). Casey and Pichichero (2004) reported data 46-49 

based on a prospective study of children diagnosed with AOM with treatment failure (AOMTF) 

and persistent AOM at a suburban pediatric private practice in Rochester, New York. Between 

1995 and 2003, middle ear fluid (MEF) was obtained by tympanocentesis for 551 patients 

(minimum age 2 months) with persistent AOM (otalgia and AOM signs after 48 hours of 

antibiotic treatment) or AOMTF (clinical failure within 30 days of antibiotic completion). None 

of the 195 children in the 1995-1997 cohort had received PCV7, 4% of the 204 children in the 

1998-2000 cohort received at least one dose of PCV7, and 85% of the 152 children in the 2001­

2003 cohort received at least one dose. In each successive cohort, the proportion of all isolates 

that were S. pneumoniae (SP) decreased significantly, with 44% of isolates identified as SP in 

the 1998-2000 cohort and 31% of the 2001-2003 cohort (p<0.017). Conversely, the proportion of 

isolates that were found to be H. influenzae (HF) increased significantly from 43% in the 1998­

2000 cohort to 57% in the 2001-2003 cohort (p<0.012). In addition to the decrease in SP isolates 

and increase in HF isolates from 1998-2000 to 2001-2003, the authors report an increase in the 

proportion of SP that was penicillin-susceptible (58% and 72% p=0.017) and variation in the 

proportion of HF that were B-lactamase-producing (33% and 55%, p=0.44) from 1998-2000 to 

2001-2003. 

45
 
Table 4. Overview of Studies that Reported on Microbiology 

Study Age Setting Study Design Number Patients Number of Inclusive Years 

Casey, 200447 mean age 20­ Pediatric prospective 551 patients with 

Specimens 

551 1995-1997 

22 months practice, US observational cohort AOM treatment 1998-2000 

study failure or 2001-2003 

Block, 200446 7-24 months Pediatric prospective 

persistent AOM 

379 419 1992-1998 

practice, US observational cohort 2000-2003 

study 

Veenhoven, 

200350 

12-84 months, 

median age 2 

2 hospitals in the 

Netherlands 

RCT of vaccine among 

unvaccinated 

383 patients with 

recurrent AOM; 

181 1998-2002 

years toddlers/children with 181 with MEF 

previous AOM) samples 

McEllistrem, 

200548 

not reported 5 hospitals in the 

US 

retrospective 

observational cohort 

not reported 505 1999-2002 

Eskola, 200151 infants enrolled 8 clinics in 

study 

RCT for vaccine 1662 (with 2,596 2,444 episodes of 1995-1999 

<2 months; Finland efficacy episodes of AOM) AOM with cultures 

follow-up 6.5 to (685 with S. 

25 months of pneumoniae) 

Brook, 200949 

age 

1993-1998 Outpatient retrospective 100 patients with 125 1993-1998 

cohort: 5 practice, US observational cohort AOM with a new 2001-2006 

months- 12 study spontaneous 

years, median perforation 

age 3 years, 1 

month 

2001-2006 

cohort: 10 

months – 12 

years, median 

age 3 years, 8 

months 

46
 
The second observational study described in Table 4 by Block (2004)46 reports a similar 

decrease in SP isolates after PCV7 introduction. In this study, 419 MEF specimens from 379 

patients from a pediatric practice in a rural Kentucky area in the U.S. were examined. The 

researchers compared 336 isolates with positive cultures from 1992-1998 with 83 isolates from 

2000-2003 (all had three or more vaccine doses). The proportion of isolates due to SP decreased 

over these two time periods (48% in 1992-1998 and 31% in 2000-2003; p=0.007), while the 

proportion of isolates from HF increased (41% in 1992-1998 and 56% in 2000-2003; p=0.01). In 

addition, among the SP isolates, vaccine serotypes decreased, while vaccine-related and nonvaccine serotypes increased significantly (because of an error in shipping/storage, two serotypes 

could not be analyzed). 

This change over time in the serogroup composition of SP isolates was also found in the third 

observational study (Table 4). This study examined only the MEF specimens that were positive 

for SP among 505 episodes of AOM in children in five hospitals across four states.48 These SPpositive MEF specimens were obtained either from spontaneous otorrhea, myringotomy and/or 

tympanostomy tube placement, or tympanocentesis performed in children with AOMTF or in 

children with AOM in a clinical trial. Comparing specimens from 1999 to 2002, a significant 

decrease was reported in the proportion of SP isolates that were of a vaccine serogroup (76% in 

1999 and 52% in 2002; p<0.01) while isolates from non-vaccine serogroups increased (12% in 

1999; 32% in 2002, p<0.01). The authors of this study recognized a limitation to observational 

studies that retrospectively or prospectively rely on tympanocentesis performed in children with 

AOM for analysis of AOM bacteriology—in most cases, tympanocentesis is not performed in 

uncomplicated, non-recurrent, non-persistent cases of AOM. To address this limitation, the 

authors separately analyzed those AOM cases when tympanocentesis was not performed but 

MEF specimens were obtained by collection of spontaneous otorrhea. Results were similar to the 

entire sample; the proportion of greater SP isolates due to vaccine serotypes decreased and the 

proportion due to non-vaccine serotypes increased over time. Additionally, among the vaccine 

serotype isolates, the proportion that were penicillin non-susceptible increased (60% in 1999 to 

100% in 2002, p<0.01). 

The final observational study examined was smaller; it examined middle ear fluid from 50 

children diagnosed with AOM with perforation (collected by aspiration with a syringe inserted 

through the TM perforation) between 1993 and 1998 with 50 children with the same diagnosis 

between 2001 and 2006. Ninety-two percent of children in the group from 2001-2006 had 

received PCV7. This study did not find changes in microbiology described above; however, the 

authors did find that methicillin-resistant S. aureus (MRSA) was significantly greater in children 

from the later time period. There was no MRSA isolated from middle ear fluid samples during 

1993-1998, but there were five MRSA isolates in middle ear fluid samples collected from 2001­

49 46, 48 2006. The three previous studies described above either did not report S. aureus isolates, or 

did not report on methicillin resistance of S. aureus isolates. 

Two RCTs addressed our study question directly as well (Table 5). Eskola (2001)51 report the 

results of a double-blind RCT of the efficacy of PCV7. In 1,662 children with 2,596 episodes of 

AOM, investigators collected MEF and found that 685 were positive for SP (33% in control 

group; 23% in the PCV7 group). Findings comparing the intervention (PCV7) and control groups 

are similar to the findings in the observational studies described above. Vaccine serotype isolates 

were less prevalent in the intervention group isolates than the control group isolates (40% vs. 

60%), while non-vaccine serotype isolates were more prevalent in the intervention group isolates 

47
 
than in the control group (46% vs. 23%). There were also fewer isolates from vaccine-related 

serotypes in the intervention vs. control group. The proportion of AOM episodes caused by HF 

(27% vs. 23%) was greater for the vaccine group and the proportion of AOM episodes caused by 

M. catarrhalis (MC) (32% vs. 30%) was similar across both groups. 

48
 
Table 5. Studies That Reported on Microbiology, Specific Findings 

Study % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

Intervention/Postvaccine vs. 

Control/Prevaccine 

Casey, 200447 31% vs. 48% 57% vs. 38% 1% vs. 4% no serotype no serotype no serotype S. pyogenes: 

Differences in analysis analysis analysis 1995-1997- 3% 

bold are 1995-1997- 1995-1997: 1995-1997: 1998-2000- 3% 

significant at 48% 38% 4% 2001-2003- 2% 

the p<0.05 level 1998-2000- 1998-2000: 1998-2000: 

44% 43% 5% No growth (not 

2001-2003- 2001-2003: 2001-2003: included in 

31% 57% 1% total): 

a

includes S. 

Proportion by Proportion by epidermidis. S. 

Susceptibility: Susceptibility: aureus and 

Susceptible: B-lactamase diphtheroids 

1995-1997­ positive: were 

54% 1995-1997- considered non1998-2000­ 46% pathogens 

58% 1998-2000-

2001-2003­ 33% 1995-1997­

72% 2001-2003- 47% 

55% 1998-2000­

Intermediate­ 44% 

susceptibility: B-lactamase 2001-2003­

1995-1997­ negative: 42% 

12% 1995-1997­

1998-2000­ 54% 

18% 1998-2000­

2001-2003­ 67% 

14% 2001-2003­

45% 

Resistant: 

1995-1997­

49
 
Study	 % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

34% 

1998-2000­

24% 

2001-2003­

14% 

Block, 200446	 31% vs. 48% 

p=0.007 

Proportion by 

Susceptibility: 

Susceptible: 

12% vs. 23% 

Intermediate: 

13% vs. 16% 

Resistant: 

6% vs. 9% 

PCV7 

Serogroups: 

% of SP 

isolates that 

were 

nonsusceptible 

27% vs. 46% 

Non-PCV7 

Serogroups: 

% of SP 

isolates that 

were 

nonsusceptible 

18% vs. 1% 

PCV7 Related 

56% vs. 41% 11% vs. 9% 36% vs. 70% 32% vs. 22% 32% vs. 8% S. Pyogenes 

p=0.001 (B- p=0.005 1, 11, 15A, p=0.005 2% vs. 2% 

lactamase) 29, and 33F 6A and 19A 

Otitis prone 

Proportion by All SP- 85% vs. 

Susceptibility: 43% 

Non- B PNSP- 81% vs. 

lactamase 53% 

20% vs. 18% Gram Negative78% vs. 45% 

B-lactamase 

36% vs. 23% Antibiotics 

within 30 days 

All SP- 62% vs. 

58% 

PNSP-75% vs. 

70% 

Gram Negative85% vs. 61% 

Antibiotics 

within 3 days 

All SP- 27% vs. 

34% 

PNSP- 38% vs. 

41% 

Gram Negative38% vs. 24% 

50
 
Study % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

Serogroups: 

% of SP 

isolates that 

were 

nonsusceptible 

27% vs. 5% 

Veenhoven, 

200350 

22% vs. 35% 

(re-calculated 

to exclude 

negative 

cultures) 

35% vs. 43% 

PCV7: 21/60 

Control: 

23/54 

13% vs. 11% 

PCV7: 8/60 

Control: 6/54 

31% vs. 42% 

PCV7: 4/13 

Control: 8/19 

vaccine 

serotypes: 4, 

6B, 9V, 14, 

18c, 19F, 

23F 

McEllistrem, 

200548 

All cases were 

SP 

All cases 

were SP 

All cases 

were SP 

52% vs.. 

76%a 

70% vs. 58% 

PCV7: 9/13 

Control: 

11/19 

non-vaccine 

serotypes not 

specified 

32% vs.. 13% vs. 10% 

12% 

1999: 10 

Male
 

All SP- 67% vs. 

59%
 

PNSP- 75% vs. 

60%
 

Gram Negative58% vs. 51%
 

Day-care 

attendees 

All SP-57% vs. 

31% 

PNSP-63% vs. 

40% 

Gram Negative69% vs. 29% 

P. aeruginosa 

10% vs. 17% 

PCV7: 9/60 

Control: 6/54 

S. aureus 

34% vs. 17% 

(p=0.004) 

PCV7: 26/60 

Control: 9/54 

Group A Strep 

10% vs. 7% 

PCV7: 6/60 

Control: 4/54 

Subgroups: 

Antibiotic 

51
 
Study % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

% that were 

PNSP:
 

Overall
 

nonsusceptible
 

1999: 62%
 

2000: 63%
 

2001: 50%
 

2002: 59%; 

p=0.21
 

Intermediate
 

1999: 23% 

2000: 22% 

2001: 19% 

2002: 23%; 

p=0.74 

Resistant 

1999: 39% 

2000: 41% 

2001: 31% 

2002: 35%; 

p=0.32 

By number of 

PCV7 doses: 

2-4 doses vs. 

≤1 dose 

Overall- 56% 

vs. 60% p=.64 

Intermediate22% vs. 22%; 

p=.88 

Resistant 33% 

vs. 37% 

1999: 76% 

2000: 74% 

2001:50% 

2002: 52% 

p<0.01 

By number of 

PCV7 doses: 

2-4 doses vs. 

≤1 dose 

41% vs. 70% 

p<0.01 

1999: 12 

2000: 13 

2001:30 

2002: 32 

p<0.01 

By number of 

PCV7 doses: 

2-4 doses vs. 

≤1 dose 

35% vs. 18% 

p<0.01 

2000: 10 

2001: 13 

2002: 13 

p<0.29 

By number of 

PCV7 doses: 

2-4 doses vs. 

≤1 dose 

19% vs. 10% 

p=0.05 

within 30 days 

% of SP 

isolates that 

were 

nonsusceptible 

1999: 65% 

2000: 65% 

2001: 65% 

2003: 56% 

p=.23 

2-4 doses 67% 

≤1 dose- 63% 

p=.62 

52
 
Study % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

p=.64 

PCV7 

Serogroups: 

% of SP 

isolates that 

were 

nonsusceptible 

1999: 70% 

2000: 71% 

2001: 66% 

2003: 88% 

p=.12 

2-4 doses 89% 

≤1 dose- 70% 

p=.08 

Non-PCV7 

Serogroups: 

% of SP 

isolates that 

were 

nonsusceptible 

1999: 27% 

2000: 12% 

2001: 14% 

2003: 23% 

p=.75 

2-4 doses 24% 

≤1 dose- 28% 

p=.86 

53
 
Study	 % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

Eskola, 200951	 23% vs. 33% 27% vs.. 32% vs.. 40% vs. 60% 46% vs. 23% 15% vs. 20% 

Comparisons in	 (p<0.001) 23% (p=0.02) 30% (p<0.001) p<0.001) Denominator: 

bold are Denominator: Denominator: Denominator: all S.pne 

significant at Denominator: all AOM all S.pne all S.pne isolates 

the p<0.05 level all AOM episodes isolates isolates 

episodes vaccinevaccine non-vaccine related 

serotypes: 4, serotypes: 3, serotypes: 

6B, 9V, 14, 11, 15, 16, 6A, 9N, 18B, 

18c, 19F, 22, 33, 35, 19A, 23A 

23F (also 38, and (also 

separately others separately 

analyzed) combined: 7, analyzed) 

10, 12, 28, 

34, pool G 

Brook, 200949 44% vs. 54% 24% vs. 18% 12% vs. 10% Not reported Not reported S. pyogenes Methicillinsensitive S. 

1993-1998: 10% vs. 14% aureus 

54% Proportion by 

2001-2006: Susceptibility: 1993-1998: 8% 

44% B-lactamase 2001-2006: 8% 

positive: 

Proportion by 1993-1998: MethicillinSusceptibility: 67% resistant S. 

2001-2006: aureus 

Susceptible: 50% 

1993-1998: 1993-1998: 0% 

52% B-lactamase 2001-2008: 

2001-2006: negative: 10% 

73% 1993-1998: p<0.05 

33% 

Intermediate­ 2001-2006: 

Susceptibility 50% 

1993-1998: 

54
 
Study % of all % of all – HF % of all- MC % of SP % of SP % of SP Other bacteria 

specimens (H. (M. AOM AOM vaccine- and subgroup 

caused by SP influenzae) catarrhalis) caused by caused by related analyses 

(S. PCV7 non-vaccine serotypes 

pneumoniae) serotypes serotypes 

33% 

2001-2006: 

23% 

Resistant 

1993-1998: 

15% 

2001-2006: 

4% 

Table Notes : PCV7 : Heptavalent pneumococcal vaccine ; PSSP: Penicillin sensitive SP; PNSP- Penicillin non-susceptible SP ; S. pne : staphylococcus pneumoniae 

a (Vaccine serotype 19F did not decrease; molecular analyses and serologic data suggest that PCV7 may be less protective against 19F compared with other vaccine serotypes) 

55
 
Another RCT for vaccine efficacy studied recurrent AOM in previously unvaccinated 

children with at least two episodes of AOM in the previous year.50 The authors report fewer 

vaccine serotype SP isolates and more non-vaccine serotype SP isolates in the intervention 

(PCV7) group compared with the control group. There were no significant differences in the 

numbers of HF or MC isolates between the two groups; however, the sample size was very 

small, with 60 and 54 positive culture isolates in intervention and control groups, respectively. 

Further, a majority of MEF specimens were obtained from spontaneous otorrhea, calling into 

question the higher rate of S. aureus and P. aeruginosa cultures found in the intervention group. 

Findings According to Antibiotic History 

As part of our review, we were also asked to analyze changes in causative agents among the 

following subpopulations: children who have never had antibiotics for any reason; children who 

have had antibiotics for any reason, including ROM, persistent otitis media or relapse of AOM; 

children with unknown antibiotic history. We found that only a few studies separately analyzed 

data for these subpopulations. 

The observational study by Casey, et al47 specifically examined patients with AOMTF or 

persistent AOM; the study by McEllistrem and colleagues48 performed a subgroup analysis of 

patients with AOM and spontaneous drainage to look for any differences in the microbiology 

patterns for children with uncomplicated AOM; and finally, the study by Block and colleagues46 

examined differences in SP resistance in otitis-prone children before and after the introduction of 

PCV7. 

In summary, these six studies shed some light on the first part of our study question. Since 

the introduction of PCV7, these studies report that HF has become more prevalent as a causative 

agent of AOM, although SP remains an important agent as well. The introduction of the vaccine 

has also resulted in a greater proportion of non-vaccine serotypes and a smaller proportion of the 

vaccine serotypes. The overall quality of evidence for this Key Question is considered high for 

the conclusion that use of PCV7 vaccine has resulted in shifts in the prevalence of causative 

agents, meaning further research is very unlikely to change our confidence in the estimate of 

effect. The quality of evidence is insufficient for the special populations (such as patients with 

recurrent or persistent AOM) since we found virtually no evidence about the vaccine‘s effect on 

these special populations. 

Key Question III. 

What is the Comparative Effectiveness of Different Treatment
 

Options for Treating Uncomplicated Acute Otitis Media in 

Average Risk Children?
 

Description of the Studies 

Initial screening of the titles identified for Key Questions III-VI found 147 studies reporting 

on trials that appeared potentially relevant, and full-text articles were ordered. Of the 147 articles 

56
 
that underwent further screening, 62 were accepted. A total of 85 articles were rejected; these 

articles and the reasons for rejection are listed in Appendix D. The studies that were accepted for 

analysis are described in the Evidence Table in Appendix C. 

Findings for Key Question III 

The present review updates the 2001 AOM systematic review report, which addressed the 

natural history of uncomplicated AOM, the efficacy of antibiotic vs. no antibiotic therapy, and 

the comparative efficacy of various antibiotic regimens, including amoxicillin or trimethoprimsulfamethoxazole vs. other antibiotics, high-dose vs. standard-dose amoxicillin or amoxicillinclavulanate, high-dose amoxicillin twice daily vs. standard-dose amoxicillin three times daily, 

and short-term vs. long-term antibiotic therapy. That review found no significant differences in 

clinical failure rates between the antibiotic regimens that were compared. The findings of that 

review that are relevant to specific treatment regimen comparisons are presented in the relevant 

sections below. Tables 6a-e summarize the studies that addressed the comparative effectiveness 

of different treatment options for uncomplicated AOM in average-risk children that were 

identified in the 2001 report, and further details can be found in the evidence and meta-analysis 

tables in that report.3 Table 6f summarizes key findings of the comparisons in the 2001 report, 

those included only in the present report, and those in both reports. 

57
 
Table 6a. Randomized Controlled Trials from Marcy (2001)13 Addressing Comparative Effectiveness of Different Treatment Options for Treating 

Uncomplicated Acute Otitis Media in Average Risk Children 

Author Year RCT AOM Interventionc Time Place Age 

Qualitya Definitionb 

Appelman, 1991; [1,1,1,1,1] [0,0,1] amox-clav vs. placebo 9/86-4/90 Netherlands 6 mo-<12 yr 

Claessen, 1994 

Burke, 1991 [1,1,0,1,1] [0,0,1] amox vs. control 10/86-4/87; 10/87-4/88; Great Britain 3-<10 yr 

10/88-4/89 

Halsted, 1967; [1,1,1,1,1] [1,0,0] amp vs. pcn G-sulfisoxazole vs. 7/65-3/66 Cleveland, OH 2-66 mo 

1968 placebo 

Howie, 1972 [1,0,0,0,0] [1,0,0] triple sulfa vs. ery vs. amp vs. 12/68-7/70 Alabama <=2.5 yr 

ery-triple sulfa vs. placebo 

Kaleida, 1991 [1,1,0,0,0] [1,0,0] amox vs. myringotomy vs. amox 5/81-8/85 Pittsburgh, PA 7 mo-12 yr 

with myringotomy vs. placebo 

Laxdal, 1970 [1,0,0,1,0] [0,0,0] amp vs. pcn vs. symptomatic 1/66-9/68 Canada <15 yr 

treatment 

Mygind, 1981 [1,1,1,0,0] [0,1,1] pcn V vs. placebo 11/77-4/78 Denmark 1-10 yr 

Thalin, 1985 [1,1,0,1,1] [0,0,0] pcn V vs. placebo 7/84- 6/85 Sweden 2-15 yr 

van Buchem, [1,1,1,0,1] [0,0,0] myringotomy vs. amox vs. amox 1/79-5/79; 10/80-3/81 Netherlands 2-12 yr 

1981 plus myringotomy vs. placebo 

Barnett, 1997 [1,0,1,1,0] [1,0,0] ceftriaxone vs. tmp-smx 2/91-4/94 Boston 3 mo-3 yr 

a Jadad study quality score components (1=present; 0=not present): randomization mentioned; double-blind mentioned; dropouts described; randomization appropriate; doubleblinding appropriate. 

b AOM definition components (1=required; 0=not required): MEE; rapid onset; acute inflammation 

c amox=amoxicillin; clav=clavulanate; amp=ampicillin; pcn=penicillin; triple sulfa=triple sulfonamide; ery=erythromycin; tmp-smx=trimethoprim-sulfamethoxazole 

58
 
Table 6b. Randomized Controlled Trials from Marcy (2001)13 Addressing Other Antibiotic vs. Amoxicillin or Trimethoprim-Sulfamethoxazole 

Author, Year RCT AOM Interventionc Time Place 

Qualitya Definitionb 

Age 

Barnett, 1997 [1,0,1,1,0] [1,0,0] ceftriaxone vs. tmp-smx 2/91-4/94 Boston 3 mo-3 yr 

Bass, 1967 [1,1,0,1,0] [0,0,0] oxytetracycline vs. procaine 1/66-5/66 ? 2 mo-12 yr 

pcn & benzathine pcn G plus 

sulfisoxazole vs. pcn V plus 

sulfisoxazole vs. amp 

Bass, 1973 [1,1,0,1,0] [0,0,0] pcn V vs. pcn V plus sulfa vs. 11/68-8/71 Hawaii 2 mo-12 yr 

ery vs. amp 

Berman, 1983 [1,1,1,0,0] [1,0,0] amox vs. cefaclor 6/80-3/82 Denver, CO <3 mo 

Blumer, 1984 [1,1,1,0,0] [1,0,0] cefaclor vs. tmp-smx ? Cleveland, OH 3 mo-7 yrs 

Brodie, 1990 [1,0,1,0,0] [0,0,0] cefuroxime vs. amox ? United 3 mo-12 yr 

Kingdom 

Coles, 1993 [1,0,1,0,0] [0,0,0] 7/91-1/92 United 1-12yrs 

Kingdom 

Feigin. 1973 [1,0,1,1,0] [0,0,0] clindamycin vs. amp 3/70-12/71 St. Louis, MS 3mo-10yr 

Feldman, 1990 [1,1,1,1,1] [1,0,1] tmp-smx vs. amox-clav 1987-1988 Canada 1-14 yrs 

Foshee, 1992 [1,1,1,0,1] [1,0,1] loracarbef vs. amox 10/88-3/90 Finland; 6m-12y 

Iceland; 

Netherland 

Giebink, 1984 [1,0,1,1,0] [1,0,0] cefaclor vs. amox ? Minneapolis, 3mo-17yrs 

MN 

Green, 1993 [1,1,1,0,1] [0,0,1] ceftriaxone vs. amox 9/90-6/91 California 5mo-5yrs 

Halsted, 1967; [1,1,1,1,1] [1,0,0] amp vs. pcn G-sulfisoxazole 7/65-3/66 Cleveland, OH 2-66 mo 

1968 vs. placebo 

Howie, 1972 [1,0,0,0,0] [1,0,0] triple sulfa vs. ery vs. amp vs. 12/68-7/70 Alabama <=2.5 yr 

ery-triple sulfa vs. placebo 

Jacobson, 1979 [1,1,1,1,1] [1,0,0] Cefaclor vs. amox 5/77-8/78 Utah 1-12yrs 

Johnson, 1991 [1,0,0,0,0] [1,0,1] cefuroxime vs. amox 10/86-6/89 Cleveland, OH 8wk-13yrs 

Kara, 1998 [1,0,0,0,0 amox vs. cefuroxime 9/97 – 5/97 Turkey 6m-6yr 

Laxdal, 1970 [1,0,0,1,0] [0,0,0] amp vs. pcn vs. symptomatic 1/66-9/68 Canada <15 yr 

treatment 

Leigh, 1989 [1,0,1,0,0] [0,0,0] cefixime vs. amox ? United 6mo-16 yrs 

Kingdom 

Lenoski, 1968 [1,0,1,1,0] [0,0,0] ery vs. ery plus triple sulfa vs. 8/66-8/67 Los Angeles, ? 

triple sulfa vs. amp CA 

Marchant, 1984 [1,1,1,1,0] [1,0,1] cefaclor vs. tmp-smx ? Cleveland, OH 2-24months 

McLinn, 1979 [1,0,0,0,0] [1,0,0] cephradine vs. amox ? Pennsylvania 4mo-14yrs 

59
 
Author, Year RCT AOM Interventionc Time Place 

Qualitya Definitionb 

Age 

McLinn, 1980 [1,0,0,1,0] [1,0,0] cefaclor vs. amox ? Pennsylvania 1mo-11yrs 

McLinn, 1987 [1,0,1,1,0] [1,0,1] cefuroxime vs. amox 4/85-9/85 United States 6mo-11yr 

Nassar, 1974 [1,1,0,0,1] [0,0,0] cephalexin vs. amp ? England under 12yrs 

Nilson, 1969 [1,1,1,1,0] [1,0,0] pcn V vs. pcn V plus sulfa vs. 12/66-2/68 Baltimore, MD <3yr 

amp 

Owen, 1993 [1,0,1,0,0] [1,0,1] cefixime vs. amox 10/87-3/88 Texas 2mo-6yrs 

Ploussard, 1984 [1,0,0,1,0] [1,0,0] cefaclor vs. amox ? ? 5mo-5yr 

Principi, 1991 [1,0,0,1,0] [1,0,1] cefixime vs. amox ? Italy <12yr 

Pukander, 1993 [1,0,1,0,0] [1,0,0] clarithromycin vs. amox 12/90-3/92 Finland 1-12yrs 

Rodriguez, 1985 [1,1,1,1,1] [1,0,0] ery vs. amox 2/80 – 5/82 Washington, 2mo-17yr 

DC 

Scholz, 1998 [1,1,1,0,1] [1,0,0] ery vs. amox 5/95-1/96 Germany 6mo-11yr 

Stechenberg, [1,0,1,0,0] [0,0,0] cephalexin vs. amp 7/73-7/75 St. Louis, MS 3mo-11.6yr 

1976 

Varsano, 1988 [1,1,1,0,1] [1,0,1] ceftriaxone vs. amox ? Israel 6mos-8yrs a Jadad study quality score components (1=present; 0=not present): randomization mentioned; double-blind mentioned; dropouts described; randomization appropriate; doubleblinding appropriate. 

b AOM definition components (1=required; 0=not required):MEE; rapid onset; acute inflammation 

c amox=amoxicillin; clav=clavulanate; amp=ampicillin; pcn=penicillin; triple sulfa=triple sulfonamide; ery=erythromycin; tmp-smx=trimethoprim-sulfamethoxazole 

Table 6c. Randomized Controlled Trials from Marcy (2001)13 Addressing High-Dose Amoxicillin vs. Standard-Dose Amoxicillin 

Author Year RCT AOM Interventionc Time Place Age 

Qualitya Definitionb 

Bottenfield, 1998 [1,0,0,0,0] [0,0,0] Amox-clav high dose vs. low dose 12/96-2/97 USA 3mo – 12yr 

a Jadad study quality score components (1=present; 0=not present): randomization mentioned; double-blind mentioned; dropouts described; randomization appropriate; doubleblinding appropriate. 

b AOM definition components (1=required; 0=not required):MEE; rapid onset; acute inflammation 

c amox=amoxicillin; clav=clavulanate; amp=ampicillin; pcn=penicillin; triple sulfa=triple sulfonamide; ery=erythromycin; tmp-smx=trimethoprim-sulfamethoxazole 

60
 
Table 6d. Randomized Controlled Trials from Marcy (2001)13 Addressing Twice a Day High-Dose Amoxicillin Therapy vs. Three Time a Day Amoxicillin 

Author Year RCT AOM Interventionc Time Place Age 

Qualitya Definitionb 

Principi, 1986 [1,0,1,0,0] [1,0,1] amox twice vs. three times daily 10/84-2/85 Italy 6mo-12yrs 

a Jadad study quality score components (1=present; 0=not present): randomization mentioned; double-blind mentioned; dropouts described; randomization appropriate; doubleblinding appropriate. 

b AOM definition components (1=required; 0=not required):MEE; rapid onset; acute inflammation 

c amox=amoxicillin; clav=clavulanate; amp=ampicillin; pcn=penicillin; triple sulfa=triple sulfonamide; ery=erythromycin; tmp-smx=trimethoprim-sulfamethoxazole 

61
 
Table 6e: Randomized Controlled Trials from Marcy (2001)13 Addressing Short- vs. Long-Term Antibiotic Therapy 

Author Year RCT AOM Interventionc Time Place Age 

Qualitya Definitionb 

Adam, 1995 [1,0,1,0,0] [0,0,0] cefpodoxime vs. cefaclor ? Germany 3m-6yr 

Arguedas, 1996 [1,0,1,1,0] [1,0,0] azithromycin vs. amox-clav ? Costa Rica 6m-12y 

Arguedas, 1997 [1,0,1,1,0] [1,0,0] azithromycin vs. clarithromycin ? Costa Rica 6mo-12yrs 

Aronovitz, 1996 [1,0,1,0,0] [1,0,0] azithromycin vs. amox-clav ? USA 2-15yrs 

Bain, 1985 [1,0,1,1,0] [0,0,0] amox 2 day vs. 7 day winter 1983, 1984 ? 3-10 yrs 

Barnett, 1997 [1,0,1,1,0] [1,0,0] ceftriaxone vs. tmp-smx 2/91-4/94 Boston 3 mo-3 yr 

Bauchner, 1996 [1,0,0,1,0] [1,0,0] ceftriaxone vs. amox-clav 10/93-5/94 USA 3mo-6yrs 

Boulesteix, 1995 [1,0,1,0,0] [0,0,0] cefpodoxime vs. cefixime 9/91-3/92 France 6m-6yr 

Chamberlain, [1,0,1,1,0] [1,0,1] ceftriaxone vs. cefaclor ? Washington, 18mo-6yrs 

1994 DC 

Chaput de [1,1,1,0,1] [0,0,0] amox 3 day vs. 10 day Winter 1979, 1980 England 2-10yrs 

Saintongen, 

1982 

Cohen, 1997 [1,0,1,0,0] [0,0,0] cefpodoxime vs. amox-clav 10/93-3/94 France 4mos4.5yrs 

Cohen, 1998 [1,1,1,1,1] [1,0,1] amox-clav 5 day vs. 10 day 11/94-6/96 France 4m-2.5yr 

Daniel, 1993 [1,0,1,0,0] [1,0,1] azithromycin vs. amox-clav ? European 2-8yr 

Gooch, 1996 [1,0,1,0,0] [1,0,1] cefuroxime vs. amox-clav ? USA 3mos12yrs 

Green, 1993 [1,1,1,0,1] [0,0,1] ceftriaxone vs. amox 9/90-6/91 California 5mo-5yrs 

Hendrickse, [1,1,1,1,1] [1,0,1] cefaclor 5 day vs. 10 day ? USA 1mo-12yrs 

1988 

Hoberman, 1997 [1,0,1,0,0] [0,0,0] amox-clav 5 day vs. 10 day 1/94-7/94 USA & 2m-12yr 

Canada 

Ingvarsson, [1,0,0,0,0] [0,0,0] pcn V 5 day vs. 10 day 10/76-12/76; 2/77-4/77 Sweden 6m-7yr 

1982 

Jones, 1986 [1,1,1,0,1] [0,0,0] cefaclor 3 day vs. 7 day Winter 1983 and 1984 Great Britain 3-10yrs 

Kafetzis, 1997 [1,0,1,0,0] [0,0,1] cefprozil 5 day vs. 10 day ? Greece 2m-14.3yr 

Kara, 1998 [1,0,0,0,0] [0,0,0] amox vs. cefuroxime vs. ceftriaxone 9/97 – 5/97 Turkey 6m-6yr 

Khurana, 1996 [1,0,1,0,0] [1,0,0] erythromycin vs. amox-clav ? USA 6mo-12yrs 

Leigh, 1989 [1,0,1,0,0] [0,0,0] cefixime vs. amox ? United 6mo-16 yrs 

Kingdom 

McLinn, 1996 [1,1,1,0,1] [1,0,0] azithromycin vs. amox-clav ? USA 1-15yr 

Meistrup­ [1,1,0,0,1] [0,1,1] pcn 2 day vs. 7 day 11/80-5/81 Denmark 1-10yrs 

Larsen, 1983 

Pestalozza, [1,0,0,0,0] [0,0,1] azithromycin vs. amox-clav ? Italy 11mo-9 yrs 

62
 
Author Year RCT AOM Interventionc Time Place Age 

Qualitya Definitionb 

1992 

Ploussard, 1984 [1,0,1,1,0] [1,0,0] cefaclor vs. amox ? ? 5mo-5yr 

Principi, 1995 [1,0,1,0,0] [1,0,1] azithromycin vs. amox-clav ? Italy <12yr 

Puczynski, 1987 [1,1,1,0,0] [1,0,1] amox vs. placebo 5/84-2/85 Chicago, IL >2yrs 

Rodriguez, 1996 [1,0,1,0,0] [0,0,0] azithromycin vs. cefaclor ? Guatemala 6mo-13yrs 

Rubenstein, [1,0,1,0,0] [0,0,0] benzathine pcn G plus procaine pcn 11/63-4/64 Rochester, <15yr 

1965 vs. benzathine pcn G plus MN 

pseudoephedrine vs. benzathine 

pcn G plus triple sulfa vs. 

benzathine pcn G plus triple sulfa 

plus pseudoephedrine vs. 

tetracycline vs. tetracycline plus 

pseudoephedrine 

Schaad, 1993 [1,0,1,0,0] [0,0,0] azithromycin vs. amox-clav ? Switzerland 0.5-10.2 

yrs 

Simon, 1997 [1,1,0,0,0] [1,0,0] ceftibuten 5 day vs. 10 day ? Kentucky 6m-14yr 

Stickler, 1967 [1,0,1,1,0] [0,0,0] pcn vs. pcn plus antihistamine vs. ? Rochester, <15yr 

pcn plus triple sulfa vs. pcn plus MN 

triple sulfa 

Varsano, 1988 [1,1,1,0,1] [1,0,1] ceftriaxone vs. amox ? Israel 6ms-8yrs 

Varsano, 1997 [1,0,1,1,0] [1,0,1] ceftriaxone vs. amox-clav ? Israel 4mo-6yr a Jadad study quality score components (1=present; 0=not present): randomization mentioned; double-blind mentioned; dropouts described; randomization appropriate; doubleblinding appropriate. 

b AOM definition components (1=required; 0=not required): MEE; rapid onset; acute inflammation 

c amox=amoxicillin; clav=clavulanate; amp=ampicillin; pcn=penicillin; triple sulfa=triple sulfonamide; ery=erythromycin; tmp-smx=trimethoprim-sulfamethoxazole 

63
 
Table 6f. Comparative Effectiveness of Different Treatment Options for Treating Uncomplicated Acute Otitis 

Media in Average Risk Children in the 2001 Report and the Present Report 

2001 Report 2009 Update 

Comparison Number Success Number Total Success Conclusiona 

of trials rate of new number rate 

difference trials of trials difference 

(95% CI) 

Drug vs. placebo, wait-and-see, and/or prescription-to-hold 

Ampicillin or 5 12% (-22%, - 2 7 12%(5%, Ampicillin or 

amoxicillin vs. 3%) 18%) amoxicillin was 

placebo more successful 

than placebo 

Amoxicillin tid (7d) 0 N/A 1 1 16% (6, Amoxicillin is more 

vs. prescription-to- 26) successful than 

hold) 2 prescription-to-hold 

(defined as success 

at day 3) 

Antibiotic vs. 0 N/A 1 1 3% (-8, 14) Inconclusive 

prescription-to- (defined as otalgia 

hold)2 at day 4-6) 

Amoxicillin 0 N/A 1 1 15% (6, Amoxicillin was 

90mg/kg/d bid (10d) 24) more successful 

vs. wait-and-see 3 (defined as success 

at day 12) 

PcV vs. wait-and- 0 N/A 1 1 -3% (-14, Inconclusive 

see 3 8) (defined as success 

at day 14) 

Drug vs. drug 

Ampicillin or 3 3% (-8%, 1 4 0% (-7%, Inconclusive 

amoxicillin vs. 2%) 7%) 

Ceftriaxone 

Amoxicillin 0 N/A 1 1 0.6% (-3, Treatments were 

50mg/kg/d (bid, 4) equivalent (when 

10d) vs. success defined as 

erythromycin freedom from 

40mg/kg/d (bid, recurrence day 31-

10d) 4 40) 

Amoxicillin- 0 N/A 1 1 0% (-3.3, Treatments were 

clavulanate vs. 3.3) equivalent (success 

amoxicillin d.12-14) 

sulbactam 

80mg/kg/d; (bid 

10d) 

Amoxicillin- 0 N/A 1 1 13% (5, Amoxicillinclavulanate (>6 yrs 21) clavulanate was 

old: 250 mg tid x more effective than 

7d; < 6 yrs old: 125 cefaclor (success at 

64
 
2001 Report 2009 Update 

Comparison Number Success Number Total Success Conclusiona 

of trials rate of new number rate 

difference trials of trials difference 

(95% CI) 

mg tid x7d) vs. day 28-34, as 

cefaclor (125 or 250 defined by clinical 

mg tid x 7 d) 5 symptoms but not 

by culture) 

Cefaclor vs. 3 -6% (-13, 2) 0 3 N/A Inconclusive 

trimethoprim- (success at (defined as success 

sulfamethoxazole less than 14 at less than day 14); 

d) no new data but 

using MCID 

Cefaclor vs. 4 -5% (-16, 6) 0 4 N/A Inconclusive 

Ampicillin or (success at (defined as success 

amoxicillin d. 3-7) at day 3-7); no new 

data but using MCID 

Cefixime vs. 4 0.1% (-3.9, 0 4 N/A Treatments were 

Ampicillin or 4.2) equivalent; no new 

amoxicillin (success at data 

d. 10-15) 

Penicillin vs. 3 -5% (-11, 2) 0 3 N/A Inconclusive 

ampicillin or (success at (defined as success 

amoxicillin d. 7-14) at day 7-14); no 

new data but using 

MCID 

High vs. Low Dose Treatment 

Amoxicillinclavulanate 

>60mg/kg/d vs. 

amoxicillinclavulanate 

40mg/kg/d 

1 1.5% (-3, 

13) 

0 1 N/A Inconclusive(defined 

as persistent clinical 

cure with no 

recurrence at followup) 

High-dose 

amoxicillin bid vs. 

lower-dose 

amoxicillin tid 

1 -4% (-14, 7) 0 1 N/A Inconclusive 

(defined as success 

at day 15)t; no new 

data 

Amoxicillinclavulanate 45/64 

mg/kg/day / bid for 

7-10 days vs. 

Amoxicillinclavulanate 40/10 

mg/kg/day / tid for 

7-10 days 6 

0 N/A 1 1 0.1% (-4.8, 

4.6) 

Treatments were 

equivalent (success 

d. 7-12) 

Short vs. Long Treatment Durationb 

Ampicillin or 3 3% (-2%, 1 4 0% (-7%, Inconclusive 

65
 
2001 Report	 2009 Update 

Comparison Number Success Number Total Success Conclusiona 

of trials rate of new number rate 

difference trials of trials difference 

(95% CI) 

Amoxicillin 

(7-10d) vs. 

Ceftriaxone 

(1 dose) 

AmoxicillinClavulanate (7-10d) 

vs. Ceftriaxone (1 

dose) 

Cefaclor (7-10d) vs. 

Azithromycin (<5d) 

Amoxicillin (7d) vs. 

Azithromycin (1 

dose) 

Amoxicillinclavulanate (7-10d) 

vs. Azithromycin 

(<5d) 

Amoxicillinclavulanate 45/6.4 

mg/kg/d (bid, 10d) 

vs. azithromycin 10 

mg/kg/d (qd for 1 

day), 5 mg/kg/d (qd 

for 4d) 7 

Amoxicillinclavulanate 45/6.4 

mg/kg/d (bid, 10d) 

vs. azithromycin 10 

mg/kg/d (qd for 3 

day) 52 

Cefaclor 50mg/kg/d; 

bid 5 d) vs. cefaclor 

40mg/kg/d; bid 10d) 

9%) 

(success 

rate at 5-

10d) 

2	 No meta- 3 

analysis 

1	 N/A 2 

0	 N/A 1 

5	 2% (-1, 5%) 4 

(success at 

10-14d) 

0	 N/A 1 

0	 N/A 1 

0	 N/A 1 

7%) 

5 3% (-2%, Inconclusive 

7%) 

3 -1% (-4%, Treatments were 

3%) equivalent 

1 1% (-1%, Treatments were 

4%) equivalent (defined 

as no new pain 

between day 1 and 

11) 

9	 -0.3% (- Inconclusive 

6%, 6%) 

1 26% (6,36)	 Longer-term 

amoxicillinclavulanate is more 

successful than 

shorter-term 

azithromycin (at d. 

12-14, when 

pathogen is H. 

influenzae) 

1 -20% (-34, Amoxicillin-

-6) clavulanate was 

worse than 

azithromycin (cure 

defined as negative 

culture) 

1 0.7% (-3.5- Treatments were 

4.9) equivalent 

Table Notes: bid twice a day; CI confidence intervals; d day(s); kg kilograms (body weight); mg milligrams; NNT number 

needed to treat; PcV phenoxymethylpenicillin; qd once a day; 

a Confidence intervals falling within the zone of indifference were considered to establish evidence of no difference, and 

confidence intervals outside the zone of indifference were considered to establish difference. If the confidence intervals crossed 

into the zone of indifference, an effect (positive or negative) of the treatment option on the outcome could not be established 

66
 
(inconclusive). For the 2010 systematic review, we used a zone of clinical indifference of +/- 5% for the difference in success
 

rate between two treatment options. 

b

Short vs. long term duration refers to the length of treatment from the patient perspective, rather than from the perspective of
 

drug action.
 

We also identified seven new or updated systematic reviews of the comparative effectiveness 

of different options for treating uncomplicated AOM in average-risk children (Table 7 and 

53-59
 Appendix I), in addition to the four systematic reviews that we reported on in the 2001 

53, 60-64
 report. Table 7 summarizes the key features of these reviews; the findings of these reviews 

are summarized in the relevant sections below or at the end of the descriptions of our pooled 

findings. 

67
 
Table 7. Review Articles Examining Comparative Effectiveness of Treatment Strategies in Uncomplicated Acute Otitis Mediaa 

Author (year) Review Databases Study Target Outcomes Number of Author’s 

(quality) b focus (included design population trials and highlight 

dates) participants conclusion 

Marcy, 200113 c	 natural 

(y,y,y,y,y,y, y,y,y,y,n)	 history 

antibiotics 

(ab) vs. no 

ab 

ab regimen 

Rosenfeld, 199461 ab vs. no ab 

(y,y,n,y,n,y, y,y,y,n,n) ab regimen 

CENTRAL 

(TCL, through 

Mar 1999), 

MEDLINE 

(1966-Mar 

1999), 

HlthSTAR 

(1975-Mar 

1999), IPA 

International 

Pharmaceutical 

Abstracts 

(1970-Mar 

1999), CINAHL 

(1982-Mar 

1999), BIOSIS 

(1970-Mar 

1999), and 

EMBASE 

(1980-Mar 

1999); hand 

search 

MEDLINE (Jan 

1966-Jun 

1992); Current 

Contents (3 

months 

through Jun 

29, 1992); 

hand search 

RCT; AOM Clinical 80 trials total	 Rx with 

Cohort, 4wk-18y failure; amp/amox 

for adverse clinical failure 

natural effects	 by 12% vs. 

history	 no a; 

ab regimen 

outcomes not 

different; 

cefixime & 

amoxicillinclavulanate 

adverse 

effects 

RCT AOM Clinical 33 trials total ab effect 

4wk-18y response; modest but 

MEE significant; 

presence no significant 

difference 

between ab 

regimens 

studied 

68
 
Author (year) Review Databases Study Target Outcomes Number of Author’s 

(quality) b focus (included design population trials and highlight 

dates) participants conclusion 

Damoiseaux, 199862 ab vs. no ab MEDLINE RCT AOM Clinical 4 trials No significant 

(y,n,y,y,n,y, y,y,n,n,n) (1966-Jan <2 years resolution 416 children difference 

1997); old within 7d between ab 

EMBASE and no ab in 

(1974-Jan <2y olds 

1997); hand 

search 

Kozyrskyj, 200053 ab <7d vs. MEDLINE (Jan RCT AOM Clinical 32 trials total ab 

(y,y,y,y,y,y, y,y,y,y,n) 7d 1966-Jul 4wk-18y resolution 5deffective 

1997); 31d & 1-3m; Rx for AOM 

EMBASE (Jan relapse; 

1966-Jul recurrence 

1997); Science 

Citation Index 

(Mar 1998); 

Current 

Contents (Mar 

1998); hand 

search 

Glasziou, 200454 ab vs. no ab CENTRAL RCT AOM Severity and 8 trials total ab of small 

(y,y,y,y,y,y, y,y,y,n,n) (1966-Jan Children, duration of benefit for 

2000; TCL, age not pain; mid- to AOM Rx 

issue 1, 2003); specified long-term 

Current hearing 

Contents problems; 

(1966- Jan adverse 

2000); Index effects; 

Medicus (1958­ recurrent 

1965); attacks 

MEDLINE (Jan 

2000-Mar 

2003); 

EMBASE (Jan 

1990-Mar 

2003); hand 

search 

69
 
Author (year) 

(quality) b 

Review 

focus 

Databases 

(included 

Study 

design 

Target 

population 

Outcomes Number of 

trials and 

Author’s 

highlight 

Foxlee, 200655 topical 

dates) 

CENTRAL RCT or AOM Pain severity 

participants 

4 trials total 

conclusion 

evidence 

(y,y,y,y,y,y, y,y,y,n,n) analgesia (TCL, issue 2, quasi- without and duration; insufficient to 

2006); RCT perforation parental make 

Subgroups: MEDLINE in satisfaction; conclusions 

<2y vs. 2y ; (1966-May Adults and days missed on topical 

concurrent 2006); children from school analgesia 

ab EMBASE or work; effectiveness 

(1990-Dec adverse 

2005); LILACS events 

(1982-Sep 

2005); hand 

search 

Rovers, 200656 ab vs. no ab CENTRAL; RCT AOM Pain &/or 6 trials total ab beneficial 

(y,n/a,n,n,n,y,y,y,y,y,n) PubMed; 0-12 years fever 3-7d for 

Subgroups: EMBASE <2 year old 

<2y vs. 2y; (dates not with bilat 

laterality; specified) AOM & AOM 

otorrhea with otorrhea 

Spurling, 200757 Delayed (>48 CENTRAL RCT Respiratory Clinical 2 trials total immediate 

(y,y,y,n,y,y, y,y,y,y,n) hrs) ab vs. (TCL, issue 1, tract outcomes; ab for AOM in ab

immediate ab 2004; TCL, infections use; patient children improved 

issue 4, 2006); All ages satisfaction; pain and 

MEDLINE (Jan (For health- malaise on 

1966-Jan identified seeking day 3; 

2007); AOM behaviors; delayed 

EMBASE studies alternative abdiarrhea 

(1990-Jan 6m-12y) therapies reduced 

2007); Current (For (thought not 

Contents identified an a priori 

(1998-Jan AOM studies outcome of 

2007) pain, this review) 

malaise, and 

fever) 

70
 
Author (year) 

(quality) b 

Review 

focus 

Databases 

(included 

Study 

design 

Target 

population 

Outcomes Number of 

trials and 

Author’s 

highlight 

Coleman, 200858 decongestant 

dates) 

CENTRAL RCT AOM Clinical 

participants 

15 trials total 

conclusion 

lack of benefit 

(y,y,y,y,y,y, y,y,y,y,n) &/or (TCL, issue 2, <18y resolution at for 

antihista­ 2001; TCL, 2wk, 1wk, decongestant 

mine issue 3, 2003; 4wk; &/or 

TCL, issue 2, symptom antihistamine; 

2007); resolution; increased risk 

MEDLINE (Jan medication of side effects 

1966-May side effects; 

2007); AOM 

EMBASE (Jan complications 

1990-May 

2007); hand 

search 

Thanaviratananich, 

200859 

amox or 

amox-clav 

CENTRAL 

(TCL, issue 1, 

RCT AOM 

12y 

Clinical cure 

at end of 

6 trials total evidence 

appears 

(y,y,y,y,y,y, y,y,y,y,y) once or twice 2008); antibiotic biased so no 

daily vs. MEDLINE (Jan therapy, i.e. data pooling 

three times 1950-Mar 7d and 14 d, performed; 

daily 2008); with respect no firm 

EMBASE to otalgia, conclusions 

(1974-Mar fever, 

2008); Science bacteriologic 

Citation Index cure; also, 

(2001-Mar clinical cure 

2008); NLM during 

Gateway (HSR therapy and 

Project) (Mar post2008); hand treatment, 

search recurrent 

OM, acute 

mastoiditis, 

adverse 

reactions 

a

Abbreviations: ab=antibiotic; amox-clav=amoxicillin-clavulanate; CENTRAL=Cochrane Central Register of Controlled Trials; CINAHL=Cumulative Index to Nursing & Allied 

Health Literature; HlthSTAR=HealthSTAR; IPA=International Pharmaceutical Abstracts; MEE=middle ear effusion; Rx=treatment; TCL=The Cochrane Library 

71 
b

AMSTAR quality criteria (Shea, Grimshaw, Wells, et al., 2007) 

1. Was an  ̳a priori‘ design provided? 

2. Was there duplicate study selection and data extraction? 

3. Was a comprehensive literature search performed? 

4. Was the status of publication (i.e. grey literature) used as an inclusion criteria? 

5. Was a list of studies (included and excluded) provided? 

6. Were the characteristics of the included studies provided? 

7. Was the scientific quality of the included studies assessed and documented? 

8. Was the scientific quality of the included studies used appropriately in formulating conclusions? 

9. Were the methods used to combine the findings of studies appropriate? 

10. Was the likelihood of publication bias assessed? 

11. Was the conflict of interested stated? c

Marcy (2001) is the 2001 AHRQ AOM systematic review that is being updated. 

72
 
A total of 46 RCTs (published since the 2001 AOM report) that compared the effectiveness 

of treatment options in uncomplicated AOM were newly identified for this review update. They 

encompassed different antibiotics, different regimens, and different outcomes. The number of 

articles for each comparison for each reported outcome measure is provided in Table 8. These 46 

trials were added to the trials identified in the 2001 AOM report (Tables showing the numbers of 

articles included from the 2001 AOM report as well as the articles included in these analyses are 

provided in Appendix G). We identified the treatment comparisons that involved three or more 

articles and conducted meta-analysis to pool the data for each. The following comparisons had 

three or more studies on the treatment success rate: 

Ampicillin or amoxicillin vs. placebo
 

Ampicillin or amoxicillin vs. ceftriaxone (single dose)
 

Amoxicillin-clavulanate (7-10 days) vs. ceftriaxone (single dose)
 

Amoxicillin-clavulanate (7-10 days) vs. Azithromycin (≤5 days) 

Azithromycin (<5 days) vs. cefaclor (7-10 days) 

Antibiotics vs. placebo 

Findings for subgroups of patients are reported in the response to Key Question 5. 

73
 
Table 8. Listing of Treatment Option Comparisons and Outcomes 

Comp# Comparison Author, Year Tx success/ 

failurea Invasive infectionb Bacteriologic cure 

Disease 

recurrence 

Adverse 

effects 

Quality 

of life 

Parent 

Satisfacti 

Cost Otherc 

on 

1 Amox vs. Zielnik­ 1 

Amox+Fenspiride Jurkiewicz, 

200565 

2 

3 

Amox vs. 

Azithromycin 

Amox vs. 

Arguedas, 

200566 

Morris, 201067 

1 

1 

1 1 

1 

4 

Azithromycin 

Amox vs. 

Ceftriaxone 

Zhang, 200368 1 

5 Amox-clav vs. 

Amox-sulbactam 

Casellas, 

200569 

1 1 1 1 

6 Amox-clav vs. 

Azithromycin 

Dagan, 20007 1 1 1 

7 Amox-clav vs. Dunne, 200370 1 1 

8 

Azithromycin 

Amox-clav vs. Guven, 200652 1 1 1 1 

9 

Azithromycin 

Amox-clav vs. Biner, 200771 1 1 1 

Azithromycin 

10 Amox-clav vs. 

Cefaclor 

Subba Rao, 

19985 

1 1 1 1 

11 Amox-clav vs. Block, 200072 1 1 1 

Cefdinir 7mg 

12 Amox-clav vs. Block, 200072 1 1 1 

13 

Cefdinir 14mg 

Amox-clav vs. Adler, 200073 1 1 1 

14 

Cefdinir 7mg 

Amox-clav vs. Adler, 200073 1 1 1 

15 

Cefdinir 14mg 

Amox-clav vs. Cifaldi, 200474 1 1 1 

16 

Cefdinir 

Amox-clav vs. Block, 200475 1 1 1 1 1 

Cefdinir 

74
 
Comp# Comparison Author, Year Tx success/ Invasive Bacteriologic Disease Adverse Quality Parent Cost Otherc 

failurea infectionb cure recurrence effects of life Satisfacti 

on 

17 Amox-clav vs. Hedrick, 200176 1 1 

Cefprozil 

18 Amox-clav vs. Cohen, 199977 1 1 1 1 1 

Ceftriaxone 

19 Amox-clav vs. Wang, 200478 1 1 

Ceftriaxone 

20 Amox-clav vs. Biner, 200771 1 1 1 

Ceftriaxone 

21 Amox-clav 40 mg Pessey, 199979 1 1 1 

vs. Cefuroxime 

22 Amox-clav 80 mg Pessey, 199979 1 1 1 

vs. Cefuroxime 

23 Amox-clav vs. Dohar, 200680 1 1 1 

Ciprodex drops 

24 Azithromycin vs. Dagan, 200081 1 1 

Cefaclor 

25 Azithromycin vs. Oguz, 200382 1 1 1 

Cefaclor 

26 Azithromycin vs. Block, 200583 1 1 1 

Cefdinir 

27 Azithromycin vs. Biner, 200771 1 1 1 

Ceftriaxone 

28 Cefaclor vs. Carvalho, 1 1 

Cefprozil 199884 

29 Cefdinir vs. Block, 200085 1 1 

Cefprozil 

30 Cefaclor vs. Tsai, 199886 1 1 1 

Cefpodoxime 

31 Amox vs. Wait- McCormick, 1 1 1 1 1 1 1 1 

and-see 20053 

32 PcV vs. Wait- Neumark, 1 1 1 1 

and-see 200787 

33 Amox vs. Damoiseaux, 1 1 

Placebo 200088 

75
 
Comp# Comparison Author, Year Tx success/ 

failurea Invasive infectionb Bacteriologic cure 

Disease 

recurrence 

Adverse 

effects 

Quality 

of life 

Parent 

Satisfacti 

Cost Otherc 

on 

34 

35 

Amox vs. 

Placebo 

Lidocaine drop 

vs. Placebo 

Le Saux, 

200589 

Bolt, 200890 

1 

1 

1 1 

1 

1 

36 

37 

Probiotic vs. 

Placebo 

Homeopathic vs. 

Placebo 

Hatakka, 

200791 

Jacobs, 200192 

1 

1 

1 

1 

38 Amox vs. Little, 20012 1 1 1 1 

39 

PrescriptionHold 

Amox vs. Little, 200693 1 1 

40 

41 

PrescriptionHold 

Antibiotic vs. 

PrescriptionHold 

PrescriptionHold 

vs. Wait-and-see 

Spiro, 200694 

Chao, 200895 

1 

1 

1 1 

1 

1 1 

1 

42 

43 

Amox high vs. 

low dose 

Amox-clav high 

vs. low dose 

Garrison, 

200496 

Pessey, 199979 

1 

1 1 

1 1 

1 

1 

44 Amox-clav high 

vs. low dose 

Bottenfield, 

199897 

1 1 1 

45 Amox-clav bid vs. 

tid 

Damrikarnlert, 

20006 

1 1 1 1 

46 Cefdinir high vs. 

low dose 

Adler, 200073 1 1 1 

47 Cefdinir high vs. 

low dose 

Block, 200072 1 1 1 

48 

49 

50 

Amox-clav 5-day 

vs. 10-day 

Cefaclor 5-day 

vs. 10-day 

Cefpodoxime 5­

day vs. 10-day 

Cohen, 199898 

Catania, 200499 

Cohen, 2000100 

1 

1 

1 

1 1 1 

1 

1 

1 

1 

1 

76
 
Comp# Comparison Author, Year Tx success/ Invasive Bacteriologic Disease Adverse Quality Parent Cost Otherc 

failurea infectionb cure recurrence effects of life Satisfacti 

on 

51 Ceftriaxone vs. Chonmaitree, 1 1 1 

Ceftriaxone+Pred 2003101 

nisolone 

52 Ceftriaxone vs. Chonmaitree, 1 1 1 

Ceftriaxone+Anti 2003101 

histamine 

53 Ceftriaxone vs. Chonmaitree, 1 1 1 

Ceftriaxone+Pred 2003101 

nisolone+Antihist 

amine 

54 Ceftriaxone+Pred Chonmaitree, 1 1 1 

nisolone vs. 2003101 

Cetriaxone+Antihi 

stamine 

55 Ceftriaxone+Pred Chonmaitree, 1 1 1 

nisolone vs. 2003101 

Ceftriaxone+Pred 

inisolone+Antihist 

amine 

56 Ceftriaxone+Anti Chonmaitree, 1 1 1 

histamine vs. 2003101 

Ceftriaxone+Pred 

inisolone+Antihist 

amine 

57 Otikon drops vs. Sarrell, 2001102 1 1 1 

Topical 

Anesthetic 

58 Anesthetic vs. Sarrell, 2003103 1 1 

Anesthetic+Amox 

59 Anesthetic vs. Sarrell, 2003103 1 1 

NHED 

60 Anesthetic vs. Sarrell, 2003103 1 1 

NHED+Amox 

61 Anesthetic+Amox Sarrell, 2003103 1 1 

vs. NHED 

77
 
Comp# Comparison Author, Year Tx success/ 

failurea Invasive infectionb Bacteriologic cure 

Disease 

recurrence 

Adverse 

effects 

Quality 

of life 

Parent 

Satisfacti 

Cost Otherc 

on 

62 Anesthetic+Amox 

vs. NHED+Amox 

Sarrell, 2003103 1 1 

63 NHED vs. 

NHED+Amox 

Sarrell, 2003103 1 1 

61 5 13 24 47 4 7 6 19 

a Included success/failure defined by improvement of signs and/or symptoms 

b Included otologic complications 

c Included healthcare utilization, compliance, tolerability, PE tube placement, need for change of treatment, duration of AOM 

78
 
Ampicillin or Amoxicillin vs. Placebo 

The 2001 report found a rate difference of -12% (95% CI: -22%, -3; NNT=8, 95% CI: 4, 33) 

(in terms of clinical failure rate) favoring ampicillin/amoxicillin treatment vs. placebo based on 

104-108 five trials.

One new meta-analysis was identified relevant to this comparison. A meta-analysis by 

Glasziou (2004) reported a possible benefit for antibiotics for pain at 2 to 7 days with an odds 

ratio of 0.57 (95% CI: 0.45, 0.73) with a number needed to treat of 15 children, but not for pain 

at 24 hours, abnormal tympanogram at one or three months, perforation, contralateral otitis, or 

late recurrence.109 

88, 89 Two new RCTs were also identified that addressed the comparison of ampicillin or 

amoxicillin vs. placebo. 

The ages of children in these studies ranged from 2 months to 14 years (no two studies 

included the same age range). The outcome assessed in the five older trials was success rate at 

days 2-18, whereas the outcome assessed in the two new trials was success rate at days 11-14. 

We considered the trials sufficiently clinically similar to justify pooling. Sample sizes ranged 

from 30 to 488. The studies reviewed for the initial report varied somewhat in their definitions of 

treatment success (including absence of persistent symptoms [fever, earache, crying, irritability], 

improvement, absence of otorrhea, cumulative clinical resolution); however, we felt these 

outcomes were sufficiently similar to pool. The Jadad quality scores of the five older studies 

were 5,2,1,4, and 2 out of 5; the two newer studies both had scores of 5. 

The random effects pooled rate difference for clinical success by day 14 between 

ampicillin/amoxicillin and placebo was estimated at 12% (95% confidence interval [CI] 5%, 

18%), and the NNT for a clinical success was nine (95% CI: 6, 20) (Figure 2 and Table 9). Using 

an a priori MCID of 5% (as will be used for all remaining comparisons in this report), 

ampicillin/amoxicillin has a significantly higher success rate than placebo. 

79
 
Figure 2. Shrinkage Plot for Ampicillin/Amoxicillin vs Placebo for Treatment Success 

-40 -20 0 20 40 

Study 

Risk difference (%) 

(95% CI) 

Halsted 1967 -8 (-21, 5) 

Laxdal 1970 27 (11, 43) 

Howie 1972 27 (9, 44) 

Burke 1991 13 (6, 19) 

Kaleida 1991 15 (8, 22) 

Damoiseaux 2000 6 (-6, 18) 

Le Saux 2005 9 (3, 14) 

Overall 12 (5, 18) 

Risk difference (%)
 

Favors Placebo Favors Amoxicillin/Ampicillin
 

80
 
Table 9. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Difference Rate Difference 

outcome Sample Size Size Rate (%) Rate (%) In % In % 

Halsted, 1967104 2-66 mos Success at day 30 27 92.0 100.0 -8.0 -20.9, 4.9 

14-18 

Laxdal, 1970105 <15 yrs Success at day 49 48 89.8 62.5 27.3 11.2, 43.4 

7 

Howie, 1972106 <=2.5 yrs Success at day 36 116 47.2 20.7 26.5 8.6, 44.4 

2-7 

Burke, 1991107 3-<10 yrs Success at day 114 118 98.2 85.6 12.7 5.9, 19.4 

7 

Kaleida, 1991108 7 mo-12 yrs No effusion at 401 408 53.1 38.0 15.1 8.3, 21.9 

day 14 

Damoiseaux, 6 mos-2yrs Clinical success 112 120 35.7 30.0 5.7 -6.4, 17.8 

200088 at day 11 

Le Saux, 200589 6 mos-5yrs Clinical 250 240 92.8 84.2 8.6 3.0, 14.3 

resolution at day 

14 

Random effects estimates 987 1071 73.2 60.2 11.5 5.0, 18.0 

Test of heterogeneity Chi-square test value 19.28 

Test of heterogeneity Chi-square test p-value 0.04 

Test of heterogeneity I-squared 68.9% 

Number Needed to Treat (NNT) 9 (6, 20) 

Test of publication bias, Egger’s asymmetry test p-value 0.77 

81
 
The I2 statistic for this analysis was 68.9%, indicating the presence of unexplained 

heterogeneity, which could be due to the differences in the populations studied and/or research 

methods employed. Therefore, caution is advised in interpreting overall summary measures. 

Egger‘s test did not yield evidence suggestive of publication bias (p=0.77). 

As a sensitivity analysis, we excluded the study by Halsted (1967),104since it was clearly an 

outlier, in that the 95% confidence limits favored placebo far more strongly than any other 

88, 89, 105-108 individual study. The pooled analysis with the remaining six articles yielded a rate 

difference of 13% (95% CI: 8%, 19%), with seven children (95% CI: 5, 12) needing treatment 

with ampicillin or amoxicillin to gain a case of clinical success (Figure 3 and Table 10). The I2 

statistic for the pooled analysis excluding the Halsted study was 61.9%. It is not clear why 

Halsted (1967) would introduce heterogeneity as it is from a similar time period as Laxdal 

(1970) and Howie (1972) and was of high quality, as were the studies by Burke (1991), 

88, 89, 104-107 Damoiseaux (2000), and LeSaux (2005).

Figure 3. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success (Excluded Halsted 

1967 Study) 

Study 

Risk difference (%) 

(95% CI) 

Laxdal 1970 

Howie 1972 

Burke 1991 

Kaleida 1991 

Damoiseaux 2000 

Le Saux 2005 

Overall 

27 (11, 43) 

27 (9, 44) 

13 (6, 19) 

15 (8, 22) 

6 (-6, 18) 

9 (3, 14) 

13 (8, 19) 

-40 -20 0 20 40
 

Risk difference (%)
 

Favors Placebo Favors Amoxicillin/Ampicillin
 

82
 
Table 10. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate (Excluded Halsted 1967 Study) 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Differenc Rate Difference 

outcome Sample Size Rate (%) Rate (%) e In % 

Size In % 

Laxdal, 1970105 <15 yrs Success at day 49 48 89.8 62.5 27.3 11.2, 43.4 

7 

Howie, 1972106 <=2.5 yrs Success at day 36 116 47.2 20.7 26.5 8.6, 44.4 

2-7 

Burke, 1991107 3-<10 yrs Success at day 114 118 98.2 85.6 12.7 5.9, 19.4 

7 

Kaleida, 1991108 7 mo-12 yrs No effusion at 401 408 53.1 38.0 15.1 8.3, 21.9 

day 14 

Damoiseaux, 6 mos-2yrs Clinical success 112 120 35.7 30.0 5.7 -6.4, 17.8 

200088 at day 11 

Le Saux, 200589 6 mos-5yrs Clinical 250 240 92.8 84.2 8.6 3.0, 14.3 

resolution at day 

14 

Random effects estimates 962 1050 70.1 53.5 13.4 8.3, 18.6 

Test of heterogeneity Chi-square test value 9.51 

Test of heterogeneity Chi-square test p-value 0.09 

Test of heterogeneity I-squared 47.4% 

Number Needed to Treat (NNT) 7 (5, 12) 

Test of publication bias, Egger’s asymmetry test p-value 0.18 

83
 
As an additional sensitivity analysis, we pooled the four studies with a quality score of at 

88, 89, 104, 107 least 3 of 5 , which yielded a rate difference of 6% (95% CI: -1%, 13%) for a clinical 

success, which was about half that of the primary analysis and no longer met the conventional 

88, 89, 104, 107 levels of statistical significance. (Figure 4 and Table 11) Further excluding the study 

by Halsted (1967) which continued to be an outlier among these four articles, yielded a rate 

difference of 10% (95% CI: 6%, 14%) or a NNT of 10 (95% CI: 7, 18) for a clinical success 

2 88, 89, 107 without apparent heterogeneity (I =0.0%) or publication bias. This sensitivity analysis 

modestly changed the NNT: 10 children needed treatment with ampicillin or amoxicillin to gain 

88, 89, 104-108 a case of clinical success, rather than nine as with the original seven articles. (Figure 5 

and Table 12) 

Figure 4. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success (Included Studies with 

Quality Score 3, 4, or 5) 

Study 

Risk difference (%) 

(95% CI) 

Halsted 1967 

Burke 1991 

Damoiseaux 2000 

Le Saux 2005 

Overall 

-8 (-21, 5) 

13 (6, 19) 

6 (-6, 18) 

9 (3, 14) 

6 (-1, 13) 

-40 -20 0 20 40
 

Risk difference (%)
 

Favors Placebo Favors Amoxicillin/Ampicillin
 

84
 
Table 11. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate (Included Studies with Quality Score 3, 4 or 5) 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Difference Rate Difference 

outcome Size Rate (%) Rate (%) In % In % 

Sample Size 

Halsted, 1967104 2-66 mos Success at day 25 21 92.0 100.0 -8.0 -20.9, 4.9 

14-18 

Burke, 1991107 3-<10 yrs Success at day 7 114 118 98.2 85.6 12.7 5.9, 19.4 

Damoiseaux, 200088 6 mos-2yrs Clinical success 112 120 35.7 30.0 5.7 -6.4, 17.8 

at day 11 

Le Saux, 200589 6 mos-5yrs Clinical resolution 250 240 92.8 84.2 8.6 3.0, 14.3 

at day 14 

Random effects estimates 501 499 80.1. 75.2 6.4 -0.6, 13.4 

Test of heterogeneity Chi-square test value 7.87 

Test of heterogeneity Chi-square test p-value 0.049 

Test of heterogeneity I-squared 61.9% 

Test of publication bias, Egger’s asymmetry test p-value 0.26 

85
 
Figure 5. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success (Included Studies with 

Quality Score 3, 4, or 5 (Excluded Halsted 1967 Study) 

-40 -20 0 20 40 

Study 

Risk difference (%) 

(95% CI) 

Burke 1991 13 (6, 19) 

Damoiseaux 2000 6 (-6, 18) 

Le Saux 2005 9 (3, 14) 

Overall 10 (6, 14) 

Risk difference (%)
 

Favors Amoxicillin/Ampicillin
 

86
 
Table 12. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate (Included Studies with Quality Score 3, 4 or 5 (Excluded 

Halsted 1967 Study) 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Differenc Rate 

outcome Size Rate (%) Rate (%) e Difference 

Sample In % In % 

Size 

Burke, 1991107 3-<10 yrs Success at day 114 118 98.2 85.6 12.7 5.9, 19.4 

7 

Damoiseaux, 6 mos-2yrs Clinical success 112 120 35.7 30.0 5.7 -6.4, 17.8 

200088 at day 11 

Le Saux, 200589 6 mos-5yrs Clinical 250 240 92.8 84.2 8.6 3.0, 14.3 

resolution at day 

14 

Random effects estimates 476 478 76.3 66.7 9.8 5.7, 13.8 

Test of heterogeneity Chi-square test value 4.69 

Test of heterogeneity Chi-square test p-value 0.48 

Test of heterogeneity I-squared 0.0% 

Number Needed to Treat (NNT 10 (7, 18) 

Test of publication bias, Egger’s asymmetry test p-value 0.26 

87
 
The quality of evidence for this conclusion is moderate due to heterogeneity in the results of 

studies, with the higher quality studies reporting smaller benefits, meaning that further high 

quality research is likely to have an important impact on our confidence in the estimate of the 

effect and may change the estimate. 

Ampicillin or Amoxicillin vs. Ceftriaxone 

One new RCT was identified that addressed this comparison.68 The 2001 AOM report 

110-112 identified three trials.

The ages of children in these trials ranged from 5 months to 12 years. Sample sizes ranged 

from 22 to 107. The outcome assessed in these four articles was treatment success rate at days 5­

14. Definitions of treatment success in both the original and the new studies varied somewhat 

(e.g., clinical cure; rate of acute symptom resolution; clinical and tympanometric appearance of 

tympanic membrane); however, we felt these outcomes were sufficiently similar to justify 

pooling. The Jadad quality scores for the three older articles were 4, 4, and 1 out of 5; the newer 

study scored 2 out of 5.68 

The random effects pooled rate difference for clinical success by day 14 between 

ampicillin/amoxicillin and ceftriaxone was estimated at 0% (95% CI:-7%, 7%) for a clinical 

success (Table 13, and Figure 6).Thus, it is not possible to establish an advantage of either 

antibiotic over the other or their equivalence based on the current evidence. In order to show 

equivalence, the 95% confidence interval must lie within the zone of MCID. It is also worth 

noting that Zhang and colleagues reported a negative rate difference favoring ceftriaxone, while 

the other three older articles reported no rate difference; however, Zhang (2003), unlike the other 

three articles, did not report stringent criteria for entry of patients into the study and, like Kara 

68, 112 (1998), had low study quality.

88
 
Table 13. Ampicillin/Amoxicillin vs. Ceftriaxone; Outcome Indicator: Treatment Success Rate 

Amoxicillin/ Ceftriaxon Amoxicillin Ceftriaxone Rate 95% CI of 

Author, Year Age Definition of Ampicillin e Success Success Differenc Rate Difference 

outcome Sample Rate (%) Rate (%) e In % 

Sample Size In % 

Size 

Varsano, 6 mos-8 yrs Success at day 22 22 86.4 81.8 4.5 -17.0, 26.1 

1988110 7 

Green, 5 mos-5 yrs Success at day 107 105 97.2 94.3 2.9 -2.5, 8.3 

1993111 10 

Kara, 6 mos-6 yrs Success at day 25 25 92.0 84.0 8.0 -9.9, 25.9 

1998112 5 

Zhang, 6 mos-12 yrs Success at day 106 106 90.6 97.2 -6.6 -13.0, -0.2 

200368 10-14 

Random effects estimates 260 258 93.1 93.4 0 -6.9, 7.0 

Test of heterogeneity Chi-square test value 6.09 

Test of heterogeneity Chi-square test p-value 0.107 

Test of heterogeneity I-squared 50.7% 

Test of publication bias, Egger’s asymmetry test p-value 0.70 

89
 
Figure 6. Shrinkage Plot for Ampicillin/Amoxicillin vs. Ceftriaxone for Treatment Success 

Study 

Risk difference (%) 

(95% CI) 

Varsano 1988 5 (-17, 26) 

Green 1993 3 (-3, 8) 

Kara 1998 8 (-10, 26) 

Zhang 2003 -7 (-13, 0) 

Overall 0 (-7, 7) 

-40 -20 0 20 40
 

Risk difference (%) 

Favors Ceftriaxone Favors Ampicillin/Amoxicillin 

The I2 statistic for this analysis was 50.7%, indicating the presence of unexplained 

heterogeneity, which could be due to differences in population studied and/or research methods 

employed. Therefore, caution is advised in interpreting overall summary measures. Egger‘s test 

did not yield evidence suggestive of publication bias (p=0.70). The two higher quality studies110, 

111 showed no difference between amoxicillin and ceftriaxone, whereas one of the lower quality 

112 68 studies showed no difference and the other favored ceftriaxone. 

The quality of evidence for this conclusion is moderate, meaning that further high quality 

research is likely to have an important impact on our confidence in the estimate of the effect and 

may change the estimate. 

Amoxicillin-Clavulanate (7-10 days) vs. Ceftriaxone (single dose) 

71, 78 Two new RCTs were identified that addressed this comparison. The 2001 AOM report 

77, 113, 114 identified three.

The ages of the children ranged from 3 months to 10 years. Sample sizes ranged from 32 to 

271. The outcome assessed in these five trials was treatment success rate at days 3-16. The 

definitions of treatment success varied slightly (improvement in clinical signs and symptoms; 

resolution; acute symptom resolution); however, we concluded that these studies were 

90
 
sufficiently clinically similar to justify pooling. The Jadad scores for the two newer trials were 1 

and 2; the Jadad scores for the older trials were 2, 4, and 2 out of 5. 

The random effects pooled rate difference for clinical success by day 16 between 

amoxicillin-clavulanate (7-10 days) and ceftriaxone (single dose) was estimated at 3% (95% CI: 

-2%, 7%) (Table 14 and Figure 7). Thus, the advantage of either antibiotic over the other cannot 

be established based on the current evidence. 

91
 
Table 14. Amoxicillin-Clavulanate (7-10 Days) vs. Ceftriaxone (single Dose); Outcome Indicator: Treatment Success Rate 

Amox-clav Ceftriaxon Amox-clav Ceftriaxone Rate 95% CI of 

Author, Year Age Definition of e Success Success Differenc Rate 

outcome Sample Sample Rate (%) Rate (%) e Difference 

Size Size In % In % 

Bauchner, 3 mos-6 yrs Success at day 271 267 89.7 81.3 8.4 2.5, 14.3 

1996113 14-16 

Varsano, 6 mos-8 yrs Success at day 106 109 95.3 95.4 -0.1 -5.8, 5.5 

1997110 11 

Cohen, 4-30 mos Success at day 228 235 48.2 49.4 -1.1 -10.2, 8.0 

199977 12-14 

Wang, 3 mos-6 yrs Success at day 32 41 78.1 75.6 2.5 -16.9, 22.0 

200478 10 

Biner, 6 mos-10 yrs Success at day 39 34 87.2 85.3 1.9 -14.0, 17.8 

200771 3 

Random effects estimates 676 686 79.8 77.4 2.8 -1.6, 7.2 

Test of heterogeneity Chi-square test value 5.19 

Test of heterogeneity Chi-square test p-value 0.27 

Test of heterogeneity I-squared 22.9% 

Test of publication bias, Egger’s asymmetry test p-value 0.78 

92
 
Figure 7. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Ceftriaxone (single dose) for Treatment 

Success 

Study 

Risk difference (%) 

(95% CI) 

Bauchner 1996 8 (2, 14) 

Varsano 1997 0 (-6, 6) 

Cohen 1999 -1 (-10, 8) 

Wang 2004 3 (-17, 22) 

Biner 2007 2 (-14, 18) 

Overall 3 (-2, 7) 

-40 -20 0 20 40
 

Risk difference (%) 

The I2 statistic for this analysis was 22.9%, indicating no evidence of heterogeneity. Egger‘s 

test did not yield evidence suggestive of publication bias (p=0.78). 

The quality of evidence for this conclusion is moderate, meaning that further high quality 

research is likely to have an important impact on our confidence in the estimate of the effect and 

may change the estimate. 

Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days) 

7, 52, 70, 111 Four new RCTs were identified that addressed this comparison. Five articles were 

115-119 identified in the 2001 report.

The ages of the children in these trials ranged from 6 months to 12 years. Sample sizes 

ranged from 15 to 198 (total pooled sample was 875).The outcome assessed in these nine articles 

was treatment success rate at days 3-14. The definitions of treatment success varied (e.g., followup middle ear fluid culture negative or absent; complete resolution of signs or symptoms; 

bacteriologic cure; a score indicating absence of clinical and bacteriologic signs); however, we 

concluded that these studies were sufficiently clinically similar to justify pooling. The Jadad 

scores for the newer trials were 2, 5, 2, and 1 out of 5; the scores for the older trials were 1, 2, 2, 

2, and 3 out of 5. 

The random effects pooled rate difference for clinical success by day 14 between 

amoxicillin-clavulanate (7-10 days) and azithromycin (≤5 days) was estimated at -0.3% (95% 

CI: -7%, 6%) (Table 15, and Figure 8).Thus, the advantage of one antibiotic over the other or 

93
 
their equivalence cannot be established based on the current evidence. It is worth noting that the 

magnitude of the 1992 Pestalozza study115 result is an outlier compared to the results of the other 

eight studies. However, the only apparent difference is the small size of each treatment group, 

i.e., 15 each, compared with the other studies. 

94
 
Table 15. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (≤5 Days); Outcome Indicator: Treatment Success Rate 

Amox-clav Azithromy Amox-clav Azithromyc Rate 95% CI of 

Author, Year Age Definition of cin Success in Differenc Rate 

outcome Sample Sample Rate (%) Success e Difference 

Size Size Rate (%) In % In % 

Pestalozza, 11 mos-9 yrs Success at day 15 15 40.0 93.3 -53.3 -81.2, -25.5 

1992115 12-14 

Daniel, 2-8 yrs Success at day 54 103 100.0 94.2 5.8 0.5, 11.1 

1993116 10-12 

Schaad, 6 mos-10.2 Success at day 189 192 97.4 93.8 3.6 -0.5, 7.7 

1993117 yrs 7-20 

Principi, 6 mos-12 yrs Success at day 198 215 73.2 85.1 -11.9 -19.7, -4.1 

1995118 10-14 

Arguedas, 6 mos-12 yrs Success at day 45 47 95.6 100.0 -4.4 -11.6, 2.7 

1996119 10-11 

Dagan, 6 mos-9 yrs Success at day 70 73 85.7 69.9 15.9 2.5, 29.2 

20007 12-14 

Dunne, 6 mos-12 yrs Success at day 181 185 87.8 82.7 5.1 -2.1, 12.4 

200370 10 

Guven, 6 mos-12 yrs Success at day 84 90 81.0 77.8 3.2 -8.8, 15.2 

200652 11-13 

Biner, 6 mos-10 yrs Success at day 39 31 87.2 87.1 0.1 -15.7, 15.9 

200771 3 

Random effects estimates 875 951 86.1 86.4 -0.3 -6.5, 5.9 

Test of heterogeneity Chi-square test value 39.8 

Test of heterogeneity Chi-square test p-value <0.001 

Test of heterogeneity I-squared 79.9% 

Test of publication bias, Egger’s asymmetry test p-value 0.28 

95
 
Figure 8. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days) for Treatment 

Success 

Risk difference (%) 

Study (95% CI) 

Pestalozza 1992 -53 (-81,-26) 

Daniel 1993 6 (1, 11) 

Schaad 1993 4 (-1, 8) 

Principi 1995 -12 (-20,-4) 

Arguedas 1996 -4 (-12, 3) 

Dagan 2000 16 (3, 29) 

Dunne 2003 5 (-2, 12) 

Guven 2006 3 (-9, 15) 

Biner 2007 0 (-16, 16) 

Overall 0 (-7, 6) 

-40 -20 0 20 40
 

Risk difference (%) 

Favors Azithromycin Favors Amoxicillin/Clavulanate 

The I2 statistic for this analysis was 79.9%, indicating the presence of unexplained 

heterogeneity, which could be due to the differences in the population studied and/or research 

methods employed. Therefore, caution is advised in interpreting overall summary measures. 

Egger‘s test did not yield evidence suggestive of publication bias (p=0.28). 

As a sensitivity analysis, we excluded the Pestalozza study (1992),115 as it appeared to be an 

52, 70, 71, 81, 116-119 outlier. The pooled analysis with the remaining eight articles yielded a rate 

difference of 2% (95% CI: -3%, 7%), so the advantage of one antibiotic over the other or their 

equivalence still cannot be established, confirming the primary analysis (Figure 9 and Table 16). 

Possible heterogeneity and publication bias were still present among the remaining eight articles 

(I2

=70.6%, Egger‘s test=0.85). Also, the two higher quality studies, Arguedas (1996) and Dunne 

(2003), both individually had insignificant results that could establish neither the advantage of 

70, 119 one antibiotic over the other nor their equivalence. Amoxicillin-clavulanate was shown to 

have higher clinical success rates than azithromycin by day 14 when the pathogen was HF (RD 

=26%, 95% CI: 6, 46; NNT=4, 95% CI: 2, 17) in one study (Dagan, 2000).7 

96
 
Figure 9. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs, Azithromycin (≤ 5 days) for Treatment 

Success (Excluded Pestalozza 1992 Study) 

Risk difference (%) 

Study (95% CI) 

Daniel 1993 6 (1, 11) 

Schaad 1993 4 (-1, 8) 

Principi 1995 -12 (-20,-4) 

Arguedas 1996 -4 (-12, 3) 

Dagan 2000 16 (3, 29) 

Dunne 2003 5 (-2, 12) 

Guven 2006 3 (-9, 15) 

Biner 2007 0 (-16, 16) 

Overall 2 (-3, 7) 

-40 -20 0 20 40
 

Risk difference (%)
 

Favors Azithromycin Favors Amoxicillin/Clavulanate
 

97
 
Table 16. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (≤5 Days); Outcome Indicator: Treatment Success Rate (Excluding Pestalozza 1992 

Study) 

Amox-clav Azithromyci Amox-clav Azithromyci Rate 95% CI of 

Author, Year Age Definition of n Success n Difference Rate 

outcome Sample Size Sample Rate (%) Success In % Difference 

Size Rate (%) In % 

Daniel, 2-8 yrs Success at day 54 103 100.0 94.2 5.8 0.5, 11.1 

1993116 10-12 

Schaad, 6 mos-10.2 yrs Success at day 7­ 189 192 97.4 93.8 3.6 -0.5, 7.7 

1993117 20 

Principi, 6 mos-12 yrs Success at day 198 215 73.2 85.1 -11.9 -19.7, -4.1 

1995118 10-14 

Arguedas, 6 mos-12 yrs Success at day 45 47 95.6 100.0 -4.4 -11.6, 2.7 

1996119 10-11 

Dagan, 6 mos-9 yrs Success at day 70 73 85.7 69.9 15.9 2.5, 29.2 

20007 12-14 

Dunne, 6 mos-12 yrs Success at day 181 185 87.8 82.7 5.1 -2.1, 12.4 

200370 10 

Guven, 6 mos-12 yrs Success at day 84 90 81.0 77.8 3.2 -8.8, 15.2 

200652 11-13 

Biner, 6 mos-10 yrs Success at day 3 39 31 87.2 87.1 0.1 -15.7, 15.9 

200771 

Random effects estimates 860 936 86.9 86.3 1.7 -3.3, 6.7 

Test of heterogeneity Chi-square test value 23.8 

Test of heterogeneity Chi-square test p-value <0.001 

Test of heterogeneity I-squared 70.6% 

Test of publication bias, Egger’s asymmetry test p-value 0.85 

98
 
The quality of evidence for this conclusion is moderate due to heterogeneity in the results of 

studies, meaning that further high quality research is likely to have an important impact on our 

confidence in the estimate of the effect and may change the estimate. 

Cefaclor vs. Azithromycin 

81, 82 Two new RCTs were identified that addressed this comparison. The 2001 report 

identified only one article.120 

The ages of the children included in these trials ranged from 6 months to 13 years. Sample 

size ranged from 33 to 120. The outcome assessed in these three articles was treatment success 

rate at days 10-14; the definition of treatment success varied among the studies (bacteriologic 

cure; a composite score; complete resolution of all clinical and otoscopic findings; disappearance 

or improvement in signs and symptoms). However, we concluded that the definitions were 

sufficiently clinically similar to justify pooling. The Jadad quality score for the article in the 

2001 report was 2 out of 5 and those of the two newer articles were 2 and 3. The random effects 

pooled rate difference for clinical success by day 14 between cefaclor and azithromycin was 

estimated at -0.7% (95% CI: -4%, 3%) (Table 17, and Figure 10).Thus, the two drugs are 

equivalent in efficacy. Amoxicillin-clavulanate was shown to have higher clinical success rates 

than cefaclor by day 34 (RD =26%, 95% CI: 6, 46; NNT=4, 95% CI: 2, 17) in one study (Subba 

Rao, 1998).5 

99
 
Table 17. Cefaclor vs. Azithromycin; Outcome Indicator: Treatment Success Rate 

Cefaclor Azithromyci Cefaclor Azithromyci Rate 95% CI of 

Author, Year Age Definition of n Success n Difference Rate 

outcome Sample Size Sample Rate (%) Success In % Difference 

Size Rate (%) In % 

Rodriguez, 6 mos-13 yrs Success at day 120 114 96.7 98.2 -1.6 -5.6, 2.4 

1996120 10-14 

Dagan, 6 mos-9 yrs Success at day 59 62 84.7 82.3 2.5 -10.7, 15.7 

200081 10 

Oguz, 6 mos-10 yrs Success at day 33 39 97.0 94.9 2.1 -7.0, 11.2 

200382 10 

Random effects estimates 212 215 94.0 93.0 -0.7 -4.3, 2.8 

Test of heterogeneity Chi-square test value 1.03 

Test of heterogeneity Chi-square test p-value 0.60 

Test of heterogeneity I-squared 0.0% 

Test of publication bias, Egger’s asymmetry test p-value 0.18 

100
 
Figure 10. Shrinkage Plot for Cefaclor vs. Azithromycin for Treatment Success 

Risk difference (%) 

Study (95% CI) 

Rodriguez 1996 -2 (-6, 2) 

Dagan 2000 2 (-11, 16) 

Oguz 2003 2 (-7, 11) 

Overall -1 (-4, 3) 

-40 -20 0 20 40
 

Risk difference (%) 

Favors Azithromycin Favors Cefaclor 

The I2 statistic for this analysis was 0.0%, indicating the absence of unexplained 

heterogeneity. Egger‘s test did not yield evidence suggestive of publication bias (p=0.18). 

The quality of evidence for this conclusion is considered high, meaning further high quality 

research is very unlikely to change our confidence in the estimate of effect. 

Antibiotics vs. Wait-and-See/Prescription to Hold 

One relevant meta-analysis was identified that compared the use of any antibiotics to that of 

the wait-and-see approach or the similar approach of prescribing antibiotics if needed. A metaanalysis by Spurling (2007) identified three studies that compared delayed vs. immediate 

2, 93, 94 

Two studies looked at the wait-and-see approach , and two looked at the prescription-toantibiotic therapy. Two new RCTs were identified that addressed these comparisons as 

well.3, 87 

3, 87

2, 93, 94 hold approach. In all four studies, the majority of patients in the immediate antibiotic group 

complied with use of the prescribed antibiotic (range of 83% to 99%), and many of those in the 

wait-and-see and prescription-to-hold groups ultimately used prescribed antibiotics, as well 

3, 87 (range of 1% to 38%).

101
 
Of the four studies in this comparison, one study compared amoxicillin to the wait-and-see 

approach3 and another compared amoxicillin to the prescription-to-hold approach.2 The 

McCormick (2005) article reported a 15% rate difference (95% CI: 6%, 23%; NNT=7, 95% CI: 

4, 17), favoring amoxicillin compared to wait-and-see for success rate at day 12 as perceived by 

the parent. The Little (2001) article reported a 16% rate difference (95% CI: 6%, 26%; NNT=6, 

95% CI: 4, 17), also favoring amoxicillin compared to prescription-to-hold for success at day 3 

as perceived by the parent. We conclude that in both studies, immediate amoxicillin therapy has 

a higher success rate than the ―no immediate treatment‖ approaches, even though 34% in the 

McCormick (2005) and 24% in the Little (2001) wait-and-see and prescription-to-hold groups, 

respectively were on antibiotics later in the course of the disease. (Table 18) 

The Little (2006)93 article reported the long-term outcomes (3-month and 1-year) on the same 

groups of patients whose short-term outcomes were reported in their 2001 article.2 The Spiro 

(2006) article reported the difference between the antibiotic and prescription-to-hold approaches 

(91% of the prescription-to-hold group and 93% of the standard prescription group received 

prescriptions for amoxicillin; the remainder received prescriptions for other antibiotics) on health 

services utilization (filling prescriptions on day 4-6) as the primary outcome measure and 

presence of otalgia and fever at day 4-6 and 11-14 as the secondary outcomes.94The Neumark 

2007 article compared phenoxymethylpenicillin with the wait-and-see approach. The findings 

from these three studies are reported in Table 22.87 

It can be observed from the 95% confidence intervals of these outcome measures that no 

conclusion can be established with respect to the effectiveness of either treatment option in the 

pairs in terms of success rates. Although, the Spiro 2006 article established that those given 

prescriptions for immediate antibiotics filled the prescription more often than those who were 

given prescriptions ―to hold,‖ no differences were seen in absence of otalgia or fever between 

groups at either follow-up point.94 

The quality of evidence for these conclusions is moderate, meaning that further high quality 

research is likely to have an important impact on our confidence in the estimate of the effect and 

may change the estimate. 

102
 
Table 18. Antibiotics vs. Wait-and-See/Prescription Hold 

Wait-and-See (WAS) 

Author, Year Outcome Tx 1 Tx 2 Tx 1 Tx 2 Tx12 Tx22 Tx 1 Tx 2 % RD NNT 

Sample Sample % on % on Outcome Outcome (95% CI) (95% CI) 

Size Size antibiotic antibiotic Rate (%) Rate (%) 

McCormick, 20053 Success day 12 amx WAS 107 107 83 34 95 80 15 7 

(6, 24) (4, 17) 

“ Cure Before day 30 “ “ 109 100 “ “ 77 66 11 n/a 

(-1, 23) 

“ AOM extra office visit “ “ 111 108 “ “ 13 20 -7 n/a 

(-17, 3) 

“ AOM ED visit “ “ 111 108 “ “ 1 4 -3 n/a 

(-7, 1) 

“ AOM extra phone call “ “ 111 108 “ “ 23 24 -1 n/a 

(-12, 10) 

“ Parent missed “ “ 111 108 “ “ 14 9 5 n/a 

school/work (-3.5, 14) 

Neumark, 200787 Success day 14 PcV WAS 87 82 83 1 82 85 -4 n/a 

(-15, 7) 

“ Pain Day 3-7 “ “ 76 87 “ “ 2 5 -3 n/a 

(-9, 3) 

“ Analgesic use Day 3-7 “ “ 76 87 “ “ 3 10 -7 n/a 

(-15, 1) 

“ Fever>38oC Day 3-7 “ “ 76 87 “ “ 3 6 -3 n/a 

(-9, 3) 

“ Success 3 months “ “ 86 75 “ “ 85 84 1 n/a 

(-10, 12) 

“ Perforation 3 months “ “ 86 75 “ “ 0 0 0 n/a 

“ Serous OM 3 months “ “ 86 75 “ “ 12 11 1 n/a 

(-9,11) 

“ Work Loss “ “ 76 87 “ “ 56 53 3 n/a 

(-12, 18) 

103
 
Prescription Outcome Tx 1 Tx 2 Tx 1 Tx 2 Tx 1 Tx 2 % RD NNT 

Hold Sample Sample Outcome Outcome (95% CI) (95% CI) 

(PH)Author, Size Size Tx12 Tx22 Rate (%) Rate (%) 

Year % on % on 

antibiotic antibiotic 

Little, 2001, Success day 3 Amx PH 135 150 99 24 86 70 RD 16 6 

20062, 93 (6, 26) (4, 17) 

“ Parent belief ab “ “ 131 140 “ “ 76 46 RD 31 3 

effective (19, 42) (2, 5) 

“ Parent satisfied “ “ 131 150 “ “ 94 77 RD 17 6 

with treatment (9, 31) (4, 11) 

“ Parent likely to “ “ 132 147 “ “ 83 63 RD 20 5 

consult MD in (9, 31) (3, 11) 

future 

“ Earache 3 “ “ Not Not “ “ Not Not OR 0.89 n/a 

months reported reported reported reported (0.5, 1.7) 

“ Earache 1 year “ “ Not Not “ “ Not Not OR 1.03 n/a 

reported reported reported reported (0.6, 1.8) 

Spiro, 200694 Did not fill Ab PH 133 132 87 38 13 62 RD -49 2 

prescription Day (-59, ­ (2, 3) 

4-6 37) 

“ No analgesic Day “ “ “ “ “ “ 90 93 RD -3 n/a 

4-6 (-10, 4) 

“ No MD visit Day “ “ “ “ “ “ 92 90 RD 2 n/a 

4-6 (-5, 9) 

“ Otalgia Day 4-6 “ “ “ “ “ “ 67 64 RD 3 n/a 

(-8, 14) 

“ Fever Day 4-6 “ “ “ “ “ “ 35 32 RD 3 (­ n/a 

8, 14) 

“ No Analgesic Day “ “ 123 124 “ “ 11 5 RD 6 (­ n/a 

11-14 18, 6) 

“ No MD visit Day “ “ “ “ “ “ 89 85 RD 4 (­ n/a 

11-14 4, 12) 

“ Otalgia Day 11­ “ “ “ “ “ “ 61 67 RD -6 n/a 

14 (-18, 6) 

“ Fever Day 11-14 “ “ “ “ “ “ 31 32 RD -1 n/a 

(-13, 11) 

Abbreviations: amx=amoxicillin; PcV=phenoxymethylpenicillin; NNT=number-to-treat; OR=odds ratio; RD=rate difference; Tx=treatment 2 Estimates of patients in a treatment group on antibiotic are either directly from the study articles or based on information from the study articles for the treatment groups as a 

whole and not for the subgroup analyses within each study. 

104
 
Other Meta-Analyses 

Short duration vs. long duration antibiotic therapy. Kozyrskyj (2000) reported that five 

days of antibiotics were as effective as 10 days of treatment for uncomplicated AOM based on 

signs and symptoms, relapse, or re-infection, with a risk difference of 6% (95% CI: 2%, 10%) at 

8 to 19 days, favoring 10 days treatment with a NNT of 17 children (95% CI: 10, 50) and a risk 

difference of 3% (95% CI: -0.3%, 6%) at 30 days.53 

Amoxicillin or amoxicillin-clavulanate once or twice daily vs. three times daily. 

Thanaviratananich (2008) reported that the available evidence was biased, so no definitive 

conclusions could be drawn.59 

Topical analgesia. A review by Foxlee (2006) concluded that the existing evidence was 

insufficient to make definitive conclusions on the effectiveness of topical analgesia.55 

Decongestant and/or antihistamine treatment. Coleman (2008) reported that despite a 

slight benefit of combined decongestant-antihistamine at two weeks of persistent AOM with a 

fixed relative risk of 0.76 (95% CI: 0.60, 0.96; NNT=10, 95% CI: 8, 13), decongestants and /or 

antihistamines were not beneficial in general and specifically not for early cure rates, symptom 

resolution, prevention of surgery, or other complications, and resulted in an increased risk of 

other side effects (odds ratio 5 [95% CI: 2,14]).58 

Summary 

We identified 63 comparisons of treatment options for uncomplicated AOM that 

encompassed different antibiotics and regimens. Our analyses yielded inconclusive results for 

many of these comparisons. For 12 comparisons, we reached stronger conclusions (Table 19). 

Meta-analyses of ampicillin or amoxicillin vs. placebo (Table 9) demonstrated higher clinical 

success rates for ampicillin or amoxicillin, with nine children needing to be treated for a clinical 

success. Little (2001) and McCormick (2005) individually demonstrated higher clinical success 

rates as perceived by the parent for amoxicillin than for prescription-to-hold at day 3 and waitand-see at day 12 options, respectively; however, these results are tempered by Spiro‘s 

comparison of immediate antibiotic therapy to the prescription-to-hold option (2006) and 

Neumark‘s comparison of immediate antibiotic therapy to the wait-and-see option (2007), which 

had inconclusive results. Meta-analysis of three studies demonstrated equivalence of clinical 

success rates between cefaclor and azithromycin in treatment of uncomplicated AOM (Table 17). 

In addition, single studies of comparisons (that could not be pooled) produced strong results. 

Amoxicillin-clavulanate was shown to have higher clinical success rates than azithromycin by 

day 14 when the pathogen was HF in one study (Dagan, 2000) and higher success rates than 

cefaclor by day 34 in another study (Subba Rao, 1998).5, 7 Equivalent clinical success rates were 

also demonstrated in individual studies of amoxicillin vs. azithromycin for one of many 

outcomes assessed (Morris, 2010)67, amoxicillin vs. erythromycin (Scholz, 1998)4, amoxicillinclavulanate vs. amoxicillin-sulbactam (Casellas, 2005), cefixime vs. ampicillin or amoxicillin 

(Table 36 in Marcy, 2001),cefaclor 50 mg/kg/day vs. 40 mg/kg/day (Catania, 2004), and 

amoxicillin-clavulanate 45/64/mg/kg/day divided into two daily doses vs. 40/10/mg/kg/day 

divided into three daily doses.88 In addition, individual studies of amoxicillin-clavulanate 

105
 
>60mg/kg/d vs. amoxicillin-clavulanate 40mg/kg/d and high-dose amoxicillin bid vs. lower-dose 

amoxicillin tid that in the 2001 report were assessed as demonstrating equivalent clinical success 

rates are now assessed as inconclusive utilizing an MCID of 5%.Each of these single study 

results requires replication before strong conclusions can be reached. 

Table 19. Treatment Comparisons with Conclusive Evidence in Any Clinical Success Outcome in 

Uncomplicated Otitis Media 

Article Treatment Rate for Rate for Rate Conclu 

1 Treatment 1 Treatment 2 Differenc sion 

e (95% 

CI) 

7 studies Ampicillin/ Placebo 69.0% (681/987) 53.1% 12% (5, Amp/Amo 

Table 9 Amoxicillin (569/1071) 18) x better 

(success 

day 2-14) 

3 studies Cefaclor Azithromycin 93.4% (198/212) 93.0% -0.7% (- Equivalen 

Table 17 (200/215) 4.3, 2.8) ce 

(success 

day 10-

14) 

4 Studies Cefixime Ampicillin/Am 90.0% 91.1% 0.1% (- Equivalen 

Table 36 in oxicillin (245/274) (240/265) 3.9, 4.2) ce 

Marcy (2001) (success 

at day 10­

15) 

Casellas Amoxicillin Amoxicillin 98.3% (115/117) 98.3% 0% (-3.3, Equivalen 

200569 - Sulbactam 80 (115/117) 3.3) t 

clavulanat mg/kg/day = (success 

e 80 bid for 10 day 12­

mg/kg/day days 14) 

= bid for 

10 days 

Catania, Cefaclor Cefaclor 40 95.5% (195/204) 94.8% 0.7% (- Equivalen 

200499 50 mg/kg/day = (195/206) 3.5, 4.9) t 

mg/kg/day bid for 10 (cured 

= bid for 5 days end of 

days therapy) 

Dagan, Amoxicillin Azithromycin 90.9% (30/33) 64.7% (22/34) 26% (6, Amox20007 - 10 mg/kg/day 36) clav 

clavulanat = qd for 1 better 

e 45/6.4 day, (success 

mg/kg/day --- 5 day 12-14 

/ bid for 10 mg/kg/day = when 

days qd for 4 days pathogen 

is H. 

Influ). 

106
 
Article Treatment Rate for Rate for Rate Conclu 

1 Treatment 1 Treatment 2 Differenc sion 

e (95% 

CI) 

Damrikarnlert, Amoxicillin Amoxicillin­ 94.0% (187/199) 94.1% 0.1% (- Equivalen 

20006 - clavulanate (175/186) 4.8, 4.6) t 

clavulanat 40/10 (success 

e 45/64 mg/kg/day / day 7-12) 

mg/kg/day tid for 7-10 

/ bid for 7­ days 

10 days 

Little, Amoxicillin Prescription 85.9% (116/135) 70.0% 16% (6, Amox 

20012 tid for 7 to Hold (105/150) 26) better 

days (success 

day 3) 

McCormick, Amoxicillin Wait and see 95.3% (102/107) 80.4% (86/107) 15% (6, Amox 

20053 90 24) better 

mg/kg/day (success 

/ bid for 10 day 0-12) 

days 

Morris, 201067 Amoxicillin Azithromycin 99% 98% 1% (-1, 4) Equivalen 

50 30mg/kg as a (155/156) (144/147) ce (no 

mg/kg/day single dose new pain 

/ bid for 7 between 

days day 6-11) 

Scholz, Amoxicillin Erythromycin 97.8% (136/139) 97.2% 0.6% (-3, Equivalen 

19984 50 40 mg/kg/day (137/141) 4) ce 

mg/kg/day / bid for 10 (free of 

/ bid for 10 days recurrenc 

days e day 31­

40) 

Subba Rao, Amoxicillin Cefaclor 125 97.1% (102/105) 83.9% (94/112) 13% (5.3, Amox19985 - or 250 mg = 21) clav 

clavulanat tid for 7 days better 

e 250 mg (success 

for > 6 y = day 28­

tid for 7 34) 

days, 

--- 125 mg 

for < 6 y = 

tid for 7 

days 

107
 
Key Question IV. 

What Is the Comparative Effectiveness of Different 

Management Options for Recurrent Otitis Media 

(Uncomplicated) and Persistent Otitis Media or Relapse of 

Acute Otitis Media? 

Description of the Studies 

This question was not addressed in the 2001 AOM report. Thus, in order to address this study 

question, we employed several strategies. We began by identifying articles from our searches on 

uncomplicated AOM (Key Question III) that dealt with recurrent, persistent, or relapsing AOM. 

Of the 62 RCTs identified in our review update that addressed the effectiveness of treatment 

options, 14 compared treatment options in children with ROM, persistent AOM, or AOM 

treatment failure. Among these studies are 21 treatment comparisons. Eight studied the treatment 

of AOM in children with presumed or explicitly defined recurrent and/or persistent AOM, and/or 

AOM with treatment failure. Thirteen studied the prevention of AOM in children with ROM. 

The 21 comparisons are listed in Tables 20 and 21 together with a description of the 

characteristics of the study populations and interventions and the main findings. Findings by 

patient subgroups are reported in the findings for Key Question V. 

Also identified were seven systematic reviews that addressed the question of prevention of 

recurrent AOM. We present the results of these reviews below. 

In addition to the literature search described for Key Question III, we also conducted a search 

of the literature from 1966 to the present using the strategy described in Appendix A. This search 

identified some 1400 titles. A screen of a sample of these titles revealed very few actually 

relevant to the topic. We therefore did not pursue this search strategy, which would have added 

mostly older (pre-2001) articles. 

108
 
Table 20. Summary of Findings from Eight Studies on Effectiveness of Treatment of Acute Otitis Media in Recurrent Otitis Media or Persistent Acute 

Otitis Media 

Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

1 Amoxicillin- Saez­ 0.5-7 years Amox-clav Success rate on day 3-10: Not enough 

clavulanate 

(Amox-clav) 

Llorens, 

2005121 

ROM and/or 

AOM 

(45mg/6.4mg/kg/d in 2 

divided doses) 

Amox-clav: 84% (102/121) 

Gatifloxacin: 90% (222/246) 

evidence to 

conclude 

vs. gatifloxacin treatment 

failurea 

Gatifloxacin (10mg/kg, 

qd) 

Mean 

difference 

20 sites non- (95% CI): -5.9% (-12.9%, 

US 1.1%) 

2 Amox-clav vs. 

gatifloxacin 

Sher, 

2005122 

0.5-7 years 

ROM and/or 

Amox-clav 

(90mg/6.4mg/kg/d in 2 

Success rate on day 10: 

Amox-clav: 79% (92/117) 

Not enough 

evidence to 

AOM doses), 10d Gatifloxacin: 85% (105/124) conclude 

treatment 

failurea 

Gatifloxacin (10mg/kg, 

qd) 10d 

Mean 

difference 

26 sites in US (95% CI): -6.1% (-15.9%, 

1 site in Costa 3.7%) 

Rica 

3 Amox-clav vs. 

levofloxacin 

Noel, 

2008123 

0.5-<5 years 

ROM and/or 

Amox-clav (45mg/kg bid, 

10d) 

Success rate on day 2-5: 

Amox-clav: 91% 

Not enough 

evidence to 

persistent 

AOMb 

Levofloxacin (10mg/kg 

bid, 10d) 

Levofloxacin: 94% 

Mean 

conclude 

66 centers in 6 difference 

countries, (95% CI): -3.2% (-6.2%, ­

including US 0.2%) 

4 Amox-clav vs. 

azithromycin 

Arrieta, 

2003124 

0.5-6 years 

ROM and/or 

Amox-clav (95mg/kg, bid, 

10d) 

Success rate on day 12-16: 

Amox-clav: 84% (122/145) 

Not enough 

evidence to 

persistent 

AOMb 

Azithromycin (20mg/kg, 

qd, 3d) 

Azithromycin: 86% (128/149) 

Mean 

conclude 

13 US and 5 difference 

Latin (95% CI): -1.8% (-10.0%, 

American 6.4%) 

centers 

5 Amox-clav vs. 

ciprofloxacin 

0.3%­

dexamethason 

e 0.1% (ciproDohar, 

200680 

0.5-12 years 

with 

tympanostomy 

tubes 

Amox-clav (90mg/kg/d, 

bid, 10d) 

cipro-dex (4 drops, bid, 

7d) 

Success rate on day 18-21: 

Amox-clav: 58.5% (24/41) 

Cipro-dex: 84.6% (33/39) 

Mean 

difference 

Cipro-dex higher 

success rate than 

amox-clav 

dex) otic drops 6 sites in US (95% CI): -26% (-46%, -6%) 

109
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

6 Cefaclor vs. Turik, 3months-12 Cefaclor (40mg/kg/d, bid, Success rate on day 10: Not enough 

cefuroxime 1998125 years 10d) Cefaclor: 93.6% (73/78) evidence to 

AOM Cefuroxime (40mg/kg/d, Cefuroxime: 92.9% (65/70) conclude 

treatment bid, 10d) Mean 

failure difference 

13 sites (95% CI): 0.7% (-7%, 9%) 

Success rate on day 20-26: 

Cefaclor: 85.9% (67/78) 

Cefuroxime: 87.1% (61/70) 

Mean 

difference 

(95% CI): -1.2% (-12%, 10%) 

7 Cipro 0.3% Roland, 0.5-12 years Cipro (3 drops, bid, 7d) Success rate on day 8: Not enough 

otic drops vs. 2003126 with Cipro-dex (3 drops, bid, Cipro: 91.2% (73/80) evidence to 

Cipro 0.3%­ tympanostomy 7d) Cipro-dex: 94.2% (82/87) conclude 

dex 0.1% otic tubes Mean 

drops 18 sites in US difference 

(95% CI): -3% (-11%,4.9%) 

Success rate on day 14: 

Cipro: 93.8% (75/80) 

Cipro-dex: 98.9% (86/87) 

Mean 

difference 

(95% CI): -5% (-11%,0.5%) 

110
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

8 Cipro 0.3%-dex Roland, 0.5-12 years Cipro-dex (4 drops, bid, 7d) Success rate on day 18-21: Cipro-dex higher 

0.1% otic drops 2004127 with Ofloxacin (5 drops, bid, 10d) Cipro-dex: 90% (162/180) success rate than 

vs. ofloxacin 

0.3% otic drops 

tympanostomy 

tubes 

Ofloxacin:78.2% (133/170) 

Mean 

difference 

ofloxacin at day 3 & 

not enough evidence 

39 sites in US (95% CI): 12% (4.2%, 19%) to conclude for days 

11, 18, and 18-21; 

Success rate on day 3: Cipro-dex higher 

Cipro-dex: 93.7% (194/207) otorrhea absence 

Ofloxacin:79.6% (172/216) days 3, 11, and 18 

Mean 

difference 

(95% CI): 14% (7.6%, 21%) 

Success rate on day 11: 

Cipro-dex: 96.1% (199/207) 

Ofloxacin:89.8% (194/216) 

Mean 

difference 

(95% CI): 6% (1.4%, 11%) 

Success rate on day 18: 

Cipro-dex: 93.7% (194/207) 

Ofloxacin:88.4% (191/216) 

Mean 

difference 

(95% CI): 5% (-0.2%, 11%) 

Otorrhea absence on day 3: 

Cipro-dex: 32.2% (62/207) 

Ofloxacin:18.5% (40/216) 

Mean 

difference 

(95% CI): 14% (5.4%, 22%) 

Otorrhea absence on day 11: 

Cipro-dex: 84.6% (176/207) 

Ofloxacin:63.4% (137/216) 

Mean 

difference 

(95% CI): 21% (13%, 30%) 

Otorrhea absence day 18: 

Cipro-dex: 85.0% (176/206) 

Ofloxacin:70.8% (153/216) 

Mean 

difference 

(95% CI): 14% (6%, 22%) 

111
 
a AOM Treatment Failure: infection within 14 days of last antibiotic dose or failure to improve after 48 hours 

b Persistent AOM: signs or symptoms of AOM after 48 hours of treatment 

112
 
Table 21. Summary of Findings from Seven Articles on Effectiveness of Prevention of Acute Otitis Media in Recurrent Otitis Media 

Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

1 Amoxicillin vs. 

azithromycin 

De Diego, 

2001128 

9-120 months 

1 institution in 

Amoxicillin (20mg/kg/d, 

3mos) 

Effective rate (#AOM episodes dropped to 

<50% after prophylaxis) in 6-27 months: 

Not enough 

evidence to 

Spain Azithromycin Amoxicillin: 89% (34/38) conclude 

(10mg/kg/wk, 3mos) Azithromycin: 81% (25/31) 

Mean difference 

(95% CI): 8.9% (-7.8%, 25.6%) 

2 Amoxicillin vs. 

sulfisoxazole 

Teele, 

2000129 

0-1 year 

2 sites in US 

Amoxicillin (20mg/kg/d) 

Sulfisoxazole (50mg/kg/d) 

Success rate (none or 1 AOM episode in 6 

months 

Not enough 

evidence to 

Amoxicillin: 90% (36/40) conclude 

Sulfisoxazole: 78% (28/36) 

Mean difference 

(95% CI): 12.2% (-4.2%, 28.6%) 

Success rate (none or 1 AOM episode in 1 

year 

Amoxicillin: 68% (27/40) 

Sulfisoxazole: 64% (23/36) 

Mean difference 

(95% CI): 3.6% (-17.8%, 25.0%) 

3 Amoxicillin vs. 

placebo 

Teele, 

2000129 

0-1 year 

2 sites in US 

Amoxicillin (20mg/kg/d) 

Placebo 

Success rate (none or 1 AOM episode in 6 

months 

Not enough 

evidence to 

Amoxicillin: 90% (36/40) conclude 

Placebo: 71% (29/41) 

Mean difference 

(95% CI): 19.3% (2%, 36.6%) 

Success rate (none or 1 AOM episode in 1 

year 

Amoxicillin: 68% (27/40) 

Placebo: 66% (27/41) 

Mean difference 

(95% CI): 1.7% (-18.9%, 22.2%) 

113
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

4 Sulfisoxazole vs. Teele, 0-1 year Sulfisoxazole Success rate (none or 1 AOM episode in 6 Not enough 

placebo 2000129 2 sites in US (50mg/kg/d) months evidence to 

Placebo Sulfisoxazole: 78% (28/36) conclude 

Placebo: 71% (29/41) 

Mean difference 

(95% CI): 7.1% (-12.5%, 26.7%) 

Success rate (none or 1 AOM episode in 1 

year 

Sulfisoxazole: 64% (23/36) 

Placebo: 66% (27/41) 

Mean difference 

(95% CI): -1.9% (-23.3%, 19.5%) 

5 Sulfafurazole vs. Koivunen, 10mos-2yrs Sulfafurazole (50mg/kg, Success rate (<=1 in 2 months or <=2 in 6 Not enough 

placebo 2004130 1 hosp in qd, 6mos) months of AOM or <2 months of MEE) at 6 evidence to 

Finland Placebo months conclude 

Sulfafurazole: 63% (29/46) 

Placebo: 45% (21/47) 

Mean difference 

(95% CI): 18.3% (-2.0%, 38.6%) 

Success rate (<=1 in 2 months or <=2 in 6 

months of AOM or <2 months of MEE) at 2 

years 

Sulfafurazole: 34% (14/41) 

Placebo: 22% (10/45) 

Mean difference 

(95% CI): 11.9% (-7.1%, 30.9%) 

114
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

6 Sulfafurazole vs. Koivunen, 10mos-2yrs Sulfafurazole (50mg/kg, 

adenoidectomy 2004130 1 hosp in qd, 6mos) 

Finland Adenoidectomy 

7 Adenoidectomy Koivunen, 10mos-2yrs Adenoidectomy 

vs. placebo 2004130 1 hosp in Placebo 

Finland 

Success rate (<=1 in 2 months or <=2 in 6 

months of AOM or <2 months of MEE) at 6 

months 

Sulfafurazole: 63% (29/46) 

Adenoidectomy:58% (34/59) 

Mean difference 

(95% CI): 5.4% (-13.5%, 24.3%) 

Success rate (<=1 in 2 months or <=2 in 6 

months of AOM or <2 months of MEE) at 2 

years 

Sulfafurazole: 34% (14/41) 

Adenoidectomy:28% (16/58) 

Mean difference 

(95% CI): 6.5% (-11.9%, 24.9%) 

Success rate (<=1 in 2 months or <=2 in 6 

months of AOM or <2 months of MEE) at 6 

months 

Adenoidectomy:58% (34/59) 

Placebo: 45% (21/47) 

Mean difference 

(95% CI): 12.9% (-6.2%, 32.0%) 

Success rate (<=1 in 2 months or <=2 in 6 

months of AOM or <2 months of MEE) at 2 

years 

Adenoidectomy:28% (16/58) 

Placebo: 22% (10/45) 

Mean difference 

(95% CI): 5.4% (-11.5%, 22.3%) 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

115
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

8	 Adenoidectomy Paradise, 3-15yrs Adenoidectomy 

vs. placebo 199926 1 hosp in US Placebo 

9	 Adenoidectomy Paradise, 3-15yrs Adenoidectomy 

vs. 199926 1 hosp in US Adenotonsillectomy 

adenotonsillectom 

y 

Success rate (% with no AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenoidectomy:31% (19/61)
 

Placebo: 22% (17/79)
 

Mean difference
 

(95% CI): 9.6% (-5.0%, 24.2%)
 

Success rate (% with<=1 AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenoidectomy:48% (29/61)
 

Placebo: 51% (40/79)
 

Mean difference
 

(95% CI): -3.1% (-19.8%, 13.6%)
 

Success rate (% with no AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenoidectomy: 31% (19/61)
 

Adenotonsillectomy: 37% (26/71)
 

Mean difference
 

(95% CI): -5.5% (-21.7%, 10.7%)
 

Success rate (% with<=1 AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenoidectomy: 48% (29/61)
 

Adenotonsillectomy: 59% (42/71)
 

Mean difference
 

(95% CI): -11.7% (-28.7%, 5.4%)
 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

116
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

10	 Adenotonsillectom Paradise, 3-15yrs Adenotonsillectomy 

y vs. placebo 199926 1 hosp in US Placebo 

11	 Ceftibuten 5d vs. Roos, 0.5-8yrs Ceftibuten 5d (9mg/kg/d) 131 Ceftibuten 10d 2000 6 centers in Ceftibuten 10d 

Sweden (9mg/kg/d) 

Success rate (% with no AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenotonsillectomy: 37% (26/71)
 

Placebo: 22% (17/79)
 

Mean difference
 

(95% CI): 15.1% (0.6%, 29.6%)
 

Success rate (% with<=1 AOM episode) in 

1 year in patients with no tonsil-related 

indications:
 

Adenotonsillectomy : 59% (42/71)
 

Placebo: 51% (40/79)
 

Mean difference
 

(95% CI): 8.6% (-7.4%, 24.6%)
 

Success rate (no recurrence after 

treatment) up to day 14 from start of
 

treatment:
 

Ceftibuten 5d: 79% (70/89)
 

Ceftibuten 10d: 96% (85/89)
 

Mean difference
 

(95% CI): -17% (-27%, -7%)
 

Success rate (no recurrence after 

treatment) up to day 40 from start of
 

treatment:
 

Ceftibuten 5d: 65% (58/89)
 

Ceftibuten 10d: 70% (62/89)
 

Mean difference
 

(95% CI): -5.0% (-18.8%, 8.8%)
 

Not enough 

evidence to 

conclude 

Ceftibuten 10d 

had a higher 

short-term 

success rate 

than 

Ceftibuten 5d 

but there is not 

enough 

evidence to 

conclude for 

success rate 

on day 40. 

117
 
Comp Comparison Author, Patient Intervention Findings Conclusion 

# Year Population 

12 Probiotics vs. 

placebo 

Hatakka, 

200791 

10mo-6yrs 

Helsinki, 

One probiotic capsule 

(Lactobacillus 

Success rate (% with no AOM) during 6­

month intervention 

Not enough 

evidence to 

Finland rhamnosus GG and Probiotic: 28% (38/135) conclude 

LC705, Bifidobacterium Placebo: 35% (47/134) 

breve 99 and Mean difference 

propionibacterium (95% CI): -7% (-18%, 4%) 

freudenreichii JS) qd for 

6mos Success rate (%<3 AOM) during 6-month 

Placebo, qd for 6mos intervention 

Probiotic: 82% (111/135) 

Placebo: 83% (111/134) 

Mean difference 

(95% CI): -1% (-10%, 8%) 

13 Adenoidectomy Hammare 1-2yrs Adenoidectomy + Mean±SD (n) number of otitis media Not enough 

and 

tympanostomy vs. 

n-Malmi, 

2005132 

Helsinki, 

Finland 

tympanostomy 

Tympanostomy only 

episodes during 1-year follow-up 

Adeno+Tympan: 1.9 ± 1.9 (74) 

evidence to 

conclude 

Tympanostomy Tympan only: 1.6 ± 1.6 (72) 

only Difference 

of mean (95% CI): 0.30 (-0.28, 0.88) 

14 Propolis and zinc 

vs. Elimination of 

environmental risk 

Marchisio, 

2010133 

1-5yrs 

Italy 30% hydroglyceric 

extract of propolis; 1.2% 

zinc sulfate 

Outcome: 1 episode of AOM during 3­

month study period 

Propolis+Zinc Controls Diff (95% CI) 

Propolis and 

zinc had a 

lower 

factors 0.3 ml/kg/d 

= QD for 3 months 

Plus Elimination of 

environmental risk 

factors 

51% (31/61) 71% (43/61) -20% (-37, -3) 

Outcome: mean number of episodes of 

AOM per child/month during 3-month study 

period 

Propolis/Zn Controls Diff(95% CI) p 

proportion of 

children with 

AOM and 

mean number 

of AOM 

episodes than 

0.23 0.26 0.34 0.29 0.11(0.01, 0.21) 0.3 the control 

during the 

study period. 

118
 
Findings on Treatment of Acute Otitis Media in Children With 

Recurrent Otitis Media 

The systematic review by Abes (2003) is relevant only for children with tympanostomy 

tubes, presumably for ROM or persistent OME or some other chronic middle-ear condition not 

specified by the investigators.134 Abes (2003) compared ofloxacin 0.3% otic solution to other 

otic antibiotic drops and oral antibiotics in treating acute or chronic suppurative otitis media in a 

systematic review that complied with nine of 11 quality criteria but was not focused solely on 

children.134 They identified two studies of children 1-12 years old with tympanostomy tubes and 

135, 136 AOM. Goldblatt (1998) reported a clinical success rate (Peto odds ratio) of 1.44 (95% CI: 

0.86, 2.42) between ofloxacin otic solution received by 140 children and other medical 

treatments received by 146 children.137 Dohar (1999) reported a clinical success rate (Peto odds 

ratio) of 2.76 (95% CI: 1.72, 4.42) between ofloxacin otic solution received by 143 children and 

other medical treatments received by 218 children.136 Based on these two studies with different 

findings, we cannot draw any conclusion regarding the superiority of any of the treatments or 

their equivalence in these children with tympanostomy tubes who presumably had ROM or 

persistent otitis media with effusion or some other chronic middle-ear condition, not specified by 

Abes. Another review, by Wall (2009), complied with only two of 11 quality criteria, so the 

results are not reported here.138(Table 22). 

119
 
Table 22. Review Articles Examining Comparative Effectiveness of Treatment Strategies in Recurrent Acute Otitis Media or Persistent or Relapsing 

Acute Otitis Mediaa 

Author (year) Review Databases (included Study Target Outcomes Number of Author’s 

(quality) b focus dates) design population trials and highlight 

participants conclusion 

Bonati, ab MEDLINE (1966 through RCT Patients with AOM rate 8 studies chemoprophyl 

1992139 prophylaxis 1991); hand search ROM5 420 children axis effective 

(y,y,n,n,n, in reducing in reducing 

y,y,y,y,n,n) ROM AOM episodes 

during winter 

and spring 

Williams. Use of MEDLINE (1966 through RCT Patients with Number of episodes 9 studies antibiotics 

1993140 antibiotics in April 1993); Current ROM or OME of AOM per patient­ 958 participants have beneficial 

(y,y,y,y,n, preventing Contents (1990 through month while under but limited 

y,y,n,y,n,n) ROM and in 1992); textbooks, treatment effect on ROM 

treating monographs 

OME 

Abes, 2003134 ofloxacin otic Medline through PubMed RCT and Adults and/or Cure rate; resolution 2 studies No conclusion 

(y,y,y,y,y,y, solution (1966 to 2000); CD version non- children with of otalgia; resolution (children with offered by 

y,n,y,y,n) of the Cochrane Library; randomize acute or chronic of otorrhea; bacterial tympanostomy authors on 

Centerwatch Clinical Trial d clinical suppurative otitis eradication; adverse tubes and these two 

Listing Service; Trial Banks; trial media events AOM) studies 

Research and Researcher 

Registry; Manual searches 

Straetemans, PPV & PCV CENTRAL (TCL, Issue2, RCT 0-12y AOM total number; 8 trials on PPV pneumococcal 

2004141 to prevent 2003); MEDLINE (Jan proportion of children 4 trials on PCV vaccine does 

(y,y,y,y,y, AOM 1966-Jun 2003; EMBASE with AOM; bacterial not benefit 

y,y,y,y,y,n) (Jan 1990-June 2003); hand culture results children with 

search ROM <1y old 

Leach. long-term ab CENTRAL (TCL, Issue 1, RCT 0-18y at AOM/CSOM during 13 studies long-term ab 

2008142 vs. placebo 2006); MEDLINE (Jan increased risk for intervention; number 1358 children reduce AOM 

(y,y,y,y,y, or no 1966-March week 3 2006); future AOM in of episodes of probability 

y,y,y,y,y,n) treatment to OLD MEDLINE (1950­ otitis prone and AOM/CSOM during while on 

prevent 1965); EMBASE (1990-Dec high risk children3 intervention per child- treatment; ab 

AOM 2005); hand search year reduce number 

of AOM 

episodes per 

year from 3 to 

~1.5 

120
 
Author (year) 

(quality) b 

Review 

focus 

Databases (included 

dates) 

Study 

design 

Target 

population 

Outcomes Number of 

trials and 

Author’s 

highlight 

McDonald. 

2008143 

tympanosto 

my tube vs. 

CENTRAL (TCL, Issue 1, 

2008); MEDLINE (1950­

RCT 0-16y with ROM4 AOM frequency 

following treatment; 

participants 

2 studies 

148 children 

conclusion 

ventilation tube 

plays 

(y,y,y,n,y, non-surgical March 2008); EMBASE proportion of children significant role 

y,y,y,y,n,n) treatment to (1974-March 2008); with ROM following to maintain a 

reduce ROM CINAHL; mRCT; NRR; treatment disease-free 

LILACS; KoreaMed; state in the 

IndMed; PakMediNet; first six months 

Zetoc; ISI Proceedings; after tube 

Cambridge Scientific insertion. 

Abstracts; hand search (last 

search date Mar 2008) 

Wall. 2009138 ciprodex otic MEDLINE; hand search Not AOM in children Not specified a priori 3 trials total topical 

(n,n,n,n,n,y, suspension specified a with fluoroquinolon 

y,n,n/a,n/a,n) vs. priori tympanostomy Identified studies es safe and 

ciprofloxacin, tubes & acute included clinical efficacious in 

ofloxacin, or RCTs otitis externa outcome “per treatment of 

amox-clav identified (Identified studies protocol” and ear infections 

included children bacteriologic cure 

6m-12y) a

Abbreviations: ab=antibiotic; AOM=acute otitis media; CENTRAL=Cochrane Central Register of Controlled Trials; CINAHL=Cumulative Index to Nursing & Allied Health 

Literature; CSOM=chronic suppurative otitis media; HlthSTAR=HealthSTAR; IPA=International Pharmaceutical Abstracts; MEE=middle ear effusion; mRCT=metaRegister; 

NRR=National Research Register; Rx=treatment; PCV=pneumococcal conjugated vaccines; PPV=pneumococcal polysaccharide vaccines; TCL=The Cochrane Library 

b

AMSTAR quality criteria (Shea, Grimshaw, Wells, et al., 2007)144 

1. Was an  ̳a priori‘ design provided? 

2. Was there duplicate study selection and data extraction? 

3. Was a comprehensive literature search performed? 

4. Was the status of publication (i.e. grey literature) used as an inclusion criteria? 

5. Was a list of studies (included and excluded) provided? 

6. Were the characteristics of the included studies provided? 

7. Was the scientific quality of the included studies assessed and documented? 

8. Was the scientific quality of the included studies used appropriately in formulating conclusions? 

9. Were the methods used to combine the findings of studies appropriate? 

10. Was the likelihood of publication bias assessed? 

11. Was the conflict of interested stated? c Otitis prone children with 3 AOM in 6 months or 4 AOM in 1 year; high-risk children with history of AOM with perforation; children in high-risk populations with CSOM 

prevalence 

d ROM defined

4% 

 as 4 AOM in 1 year e Included patients wit3 AOM in six months or 

h 3 or more documented episodes of RAOM/diagnosed on the basis of tympanic membrane exam, and who had received continued antimicrobial 

121
 
The overall quality of evidence for these comparisons is considered low, meaning that further 

high quality research is very likely to have an important impact on our confidence in the estimate 

of effect and is likely to change the estimate. 

Studies identified by the AOM review update on treatment of AOM in children with 

recurrent and/or persistent AOM. Five individual studies compared antibiotic treatments for 

AOM in children with ROM or persistent AOM. None of the studies demonstrated significant 

121-125 advantage for any particular treatment.

Amoxicillin-clavulanate vs. gatifloxacin. Two RCTs addressed this comparison among 367 

and 241 children with recurrent AOM and/or AOM with treatment failure (AOMTF), where 

AOMTF was defined as infection within 14 days of the last antibiotic dose or failure to improve 

121, 122 after 48 hours. The children ranged in age from 6 months to 7 years. Saez-Llorens (2005) 

examined the success rate on day 3-10 while Sher (2005) examined the success rate on day 10. 

Saez-Llorens (2005) found a mean difference of –6% (95% CI: -13%, 1.%) and Sher (2005) 

found a mean difference of –6% (95% CI: -16%, 4%), both favoring gatifloxacin but without 

statistical significance. The advantage of either treatment over the other or their equivalence 

cannot be established based on the current evidence. 

Amoxicillin-clavulanate vs. levofloxacin. One RCT addressed this comparison in children 

with recurrent and/or persistent AOM, where persistence was defined as signs or symptoms of 

AOM after 48 hours of treatment or after three days of treatment.123 It compared the treatment 

success rates among children 6 months to 5 years of age in 6 different countries on day 2-5 of 

treatment (Jadad quality score 3 of 5). The success rate difference between amoxicillinclavulanate and levofloxacin was -3% (95% CI: -6%, -0.2%). We cannot determine the 

advantage of either treatment or their equivalence based on the current evidence. In order to 

show equivalence, the 95% confidence interval must lie within the zone of MCID. 

Amoxicillin-clavulanate vs. azithromycin. One RCT addressed this comparison in children 

with recurrent and/or persistent AOM.124 The study, which included 294 children 6 months to 6 

years of age (Jadad quality score 3 of 5), reported a treatment success rate difference of -2% 

(95% CI : -10%, 6%) between amoxicillin-clavulanate and azithromycin. We cannot draw any 

conclusion regarding the superiority of either treatment or their equivalence from the existing 

evidence. 

Cefaclor vs. cefuroxime. One RCT addressed this comparison.125 The study, which included 

148 children 3 months to 12 years of age who had failed initial AOM treatment (Jadad quality 

score 2 of 5), reported a treatment success rate difference between cefaclor and cefuroxime at 

day 10 of 0.7% (95% CI : -7%, 9%) at day 10 and -1.2% (95% CI : -12%, 10%) at day 20-26. 

We cannot draw any conclusion regarding the superiority of either treatment or their equivalence 

from the existing evidence in these children, who had failed initial AOM treatment, presumably 

with persistent or relapsing AOM, although not specified by the authors. 

The overall quality of evidence for these comparisons is considered low, meaning that further 

research is very likely to have an important impact on our confidence in the estimate of effect 

and is likely to change the estimate. 

Children with tympanostomy tubes. Three additional individual studies were identified 

that studied the effect of otic antibiotic drops in treatment of AOM in children who had 

tympanostomy tubes. As was the case for the studies included in the Abes (2003) review, these 

studies are unclear on the indication for tympanostomy tubes, whether for ROM or persistent 

122
 
otitis media with effusion or some other chronic middle-ear condition, so it is difficult to assess 

80, 126, 127 the generalizability of the findings.

Amoxicillin-clavulanate vs. ciprofloxacin-dexamethasone. One RCT addressed this 

comparison.80 The study, which included 80 children 6 months to 12 years of age with 

tympanostomy tubes and AOM (Jadad quality score 2 of 5), reported a treatment success rate 

difference between amoxicillin-clavulanate and ciprofloxacin 0.3%-dexamethasone 0.1% otic 

drops at day 18-21 of -26% (95% CI: -46%, -6%). Ciprofloxacin-dexamethasone otic drops had a 

higher success rate than amoxicillin-clavulanate in these children with tympanostomy tubes for 

indications not specified by the investigators. 

Ciprofloxacin vs. ciprofloxacin-dexamethasone. One RCT addressed this comparison.126 The 

study, which included 167 children 6 months to 12 years of age with tympanostomy tubes and 

AOM (Jadad quality score 2 of 5), reported a treatment success rate difference between 

ciprofloxacin 0.3% otic drops and ciprofloxacin 0.3%-dexamethasone 0.1% otic drops at day 8 

of -3% (95% CI: -11%, 5%) and at day 14 of -5% (95% CI: -11%, 0.5%). We cannot draw any 

conclusion regarding the superiority of either treatment or their equivalence from the existing 

evidence in these children with tympanostomy tubes for indications not specified by the 

investigators. 

Ciprofloxacin-dexamethasone vs. ofloxacin. One RCT addressed this comparison.127 The 

study, which included 423 children 6 months to 12 years of age with tympanostomy tubes and 

AOM (Jadad quality score 2 of 5), reported a treatment success rate difference between 

ciprofloxacin 0.3%-dexamethasone 0.1% otic drops and ofloxacin 0.3% otic drops of 14% (95% 

CI: 8%, 21%), at day 3, of 6% (95% CI: 1%, 11%) at day 11,of 5% (95% CI: -0.2%, 11%) at day 

18, and difference in clinical cure rate at day 18-21 of 12% (95% CI: 4%, 19%). The study also 

reported a difference in otorrhea absence of 14% (95% CI: 5.4%, 22%) at day 3, 21% (95% CI: 

13%, 30%) at day 11, and 14% (95% CI: 6%, 22%) at day 18. Ciprofloxacin-dexamethasone otic 

drops had a higher success rate than ofloxacin otic drops for clinical success at day 3, for clinical 

cure at days 18-21, and for otorrhea absence at days 3, 11, and 18 in these children with 

tympanostomy tubes for indications not specified by the investigators. 

Findings on Prevention of Acute Otitis Media in Children with 

Recurrent Otitis Media 

Previous systematic reviews. We identified five previous systematic reviews of prevention 

139-143 of AOM in children with ROM. (See Appendix I for complete descriptions of these 

139, 140, 142 systematic reviews.) Three addressed antibiotic prophylaxis of children with ROM. One 

addressed the role of tympanostomy tubes for children with ROM.143 Table 22 summarizes the 

references found in these five systematic reviews and the controls, interventions, and outcomes 

utilized in each of the relevant studies from these systematic reviews. As comparison, Table 22 

also includes the seven articles identified for this report on prevention of AOM in children with 

ROM. Of the articles identified for this report, only Teele (2000) was included in one of the 

previous systematic reviews (Leach, 2006), although the study by Koivunen (2004) was listed as 

129, 130, 142 pending assessment in that same review. Note that these systematic reviews utilized the 

95% confidence limits to judge significance of findings and did not use the concept of the zone 

of MCID. 

123
 
Antibiotic prophylaxis. Because the 2006 review by Leach included all studies utilized by the 

earlier reviews by Bonati (1992) and Williams (1993), we will report only the main findings 

139, 140, 142 from Leach (2006).

Leach (2006) conducted a literature search encompassing 1950–2006 and identified 16 

129, 145-159 studies that addressed the effectiveness of antibiotic prophylaxis to prevent AOM in 

children 0-18 years old at increased risk of future episodes of AOM as defined as otitis prone 

with three or more episodes of AOM in six months or four or more episodes of AOM in one 

year, high-risk children with a history of AOM with perforation, and children in high-risk 

populations with chronic suppurative otitis media prevalence ≥4%. The Leach (2006) systematic 

review scored affirmatively on 10 of 11 AMSTAR quality criteria but did not specifically 

address the conflicts of interest of each study included in the review.142 The following are the 

primary outcomes of this review for all high-risk populations: 

Pooling data from 13 studies, 12 on children with ROM of varying definition (of which seven 

met the current review‘s criteria and one was on children from a high-risk population), the risk 

ratio for any AOM during the intervention was 0.6 (95% CI: 0.5, 0.8; random-effects model, 

I

2

=52%, p=0.02), i.e. an absolute risk reduction of 20%, equivalent to needing to treat five 

children (95% CI: 4, 6) with long-term antibiotics to prevent one child from getting an episode of 

129, 145, 146, 148, 150, 152-159 AOM while on treatment. Pooling data from 12 studies, the incidence rate 

ratio for episodes of AOM during the intervention was 0.5 (95% CI: 0.4, 0.6; random effects2 145, 147, 148, 150, 151, 153-157, 159 model, I =65%), but the studies were statistically hetereogeneous. For 

both primary outcomes, none of the studies reported on AOM with perforation or chronic 

suppurative otitis media. 

Perhaps more relevant to the current review, the Leach review (2006) did sub-group analysis 

of otitis prone vs. non-otitis-prone children for the primary outcomes. Pooling data from seven 

studies, the risk ratio for any AOM during the intervention for otitis prone children was 0.7 (95% 

2 150, 151, 153-156, 159, 160 CI: 0.6, 0.8; fixed-effect model, I =33%).

Pooling data from eight studies, the incidence rate ratio for episodes of AOM during the 

intervention for otitis prone children was 0.5 (95% CI: 0.4, 0.7; random-effects model, I2=73%), 

147, 150, 151, 153-156, 159 but the studies were statistically heterogeneous. Leach (2006) concluded that 

antibiotics will prevent 1.5 episodes of AOM for every 12 months of treatment per otitis-prone 

child (95% CI: 1.2, 2.1) who would otherwise average three episodes of AOM annually. The 

results were not affected by sensitivity analyses. 

Tympanostomy tubes. McDonald and colleagues (2008) conducted a literature search 

encompassing 1950–2008 and identified two studies that addressed the effectiveness of 

tympanostomy tube placement to prevent AOM in children 0-16 years old with ROM as defined 

161, 162 as three or more AOM episodes in six months or four or more AOM episodes in one year.

The McDonald (2008) systematic review scored affirmatively on eight of 11 AMSTAR quality 

criteria but did not address publication status, publication bias assessment, and conflicts of 

interest of each study included in the review.143 Pooling data from two studies, the odds ratio for 

more than one episode of AOM for six months following tympanostomy tube placement was 0.2 

161, 162 (95% CI: 0.1, 0.4). McDonald (2008) concluded that ventilation tube placement played a 

significant role in maintaining a disease-free state in the first six months after tube insertion in 

children with ROM in these two studies.143 

Studies identified by the AOM review update on prevention of AOM in children with 

ROM. Seven studies identified by our searches address the prevention of AOM in children with 

124
 
26, 91, 128-132 ROM. These studies include five not identified by or pertinent to previous systematic 

reviews, one excluded by a previous systematic review, and one included in a previous review 

for which we provide greater detail.129 

Antibiotic or non-surgical treatment. Seven individual studies compared antibiotic or nonsurgical treatments to prevent AOM in children with ROM. None of the studies demonstrated a 

long-term advantage for any particular antibiotic or non-surgical treatment. 

Amoxicillin vs. azithromycin. One RCT addressed the comparison of amoxicillin and 

azithromycin (three months treatment duration) among 69 children ranging in age from 9 months 

to 10 years (Jadad quality score 2 of 5).128 The treatment outcome of interest was 50% reduction 

in AOM episodes. The study reported a rate difference of 9% in this outcome between 

amoxicillin and azithromycin at six to 27 months (95% CI: -8%, 26%). No conclusion can be 

derived from the existing evidence regarding the superiority of one or the other agent or their 

equivalence. The overall quality of evidence for this comparison is considered low, meaning that 

further high quality research is very likely to have an important impact on our confidence in the 

estimate of effect and is likely to change the estimate. 

Amoxicillin vs. sulfisoxazole. One RCT (Teele, 2000) addressed the comparison of 

amoxicillin and sulfisoxazole among 76 children ranging in age from birth to 1 year (Jadad 

quality score 3).129 The study reported a success rate difference between amoxicillin and 

sulfisoxazole of 12% (95% CI: -4%, 29%) in six-month follow-up and a success rate difference 

of 4% (95% CI: -18%, 25%) in 12-month follow-up. No conclusion of antibiotic advantage or 

equivalence can be derived from the existing evidence. The overall quality of evidence for this 

comparison is considered low, meaning that further high quality research is very likely to have 

an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Amoxicillin vs. placebo. The Teele (2000) study also compared amoxicillin vs. placebo 

among 81 children.129 The study reported a success rate difference between amoxicillin and 

placebo of 19% (95% CI: 2%, 37%) in six-month follow-up and a success rate difference of 2% 

(95% CI: -19%, 22%) in 12-month follow-up. No conclusion can be derived from the existing 

evidence regarding the efficacy of amoxicillin with a MCID of 5%. The overall quality of 

evidence for this comparison is considered low, meaning that further high quality research is 

very likely to have an important impact on our confidence in the estimate of effect and is likely 

to change the estimate. 

Sulfisoxazole/sulfafurazole vs. placebo. Two RCTs addressed this comparison among 77 

129, 130 children, 0 to 12 months of age, and 93 children, 10 months to 2 years of age, respectively.

The Teele 2000 article defined success as one or fewer AOM episodes at six-month or one-year 

follow-up, whereas Koivunen (2004) defined success as one or fewer AOM episodes in two 

months, two or fewer AOM episodes in six months, or less than two months of MEE at six129, 130 month or two-year follow-up (Jadad quality score 3 of 5). The Teele 2000 study reported a 

success rate difference between sulfisoxazole and placebo of 7% (95% CI: -13%, 27%) in sixmonth follow-up and a success rate difference of -2% (95% CI: -23%, 20%) in 12-month follow129, 130 up. reported a success rate difference between sulfafurazole and placebo of 18% (95% CI: ­

2%, 39%) at six-month follow-up and a success rate difference of 12% (95% CI of -7%, 31%) at 

two-year follow-up.130 No conclusion can be derived from the existing evidence regarding the 

efficacy of sulfisoxazole/sulfafurazole for either outcome. The overall quality of evidence for 

this comparison is considered low, meaning that further high quality research is very likely to 

125
 
have an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Ceftibuten 5-day vs. ceftibuten 10-day. One trial compared five days with 10 days of 

ceftibuten.131 The study included 178 children, ages 6 months to 8 years, and defined treatment 

success as no recurrence. Treatment success was measured at two different time points: at day 14 

and at day 40. At day 14, the difference in treatment success between the five-day and 10-day 

treatment options was -17% (95% CI: -27%, -7%); the 95% CI for the day-14 success rate is 

outside the zone of MCID of 5%, favoring the longer treatment option. At day 40, the 

difference in treatment success between the five-day and 10-day treatment options was -5% 

(95% CI: -19%, 9%), again favoring the longer treatment. The long-term effectiveness of the 

ceftibuten 10-day treatment option cannot be established at this point. The overall quality of 

evidence for this comparison is considered low, meaning that further research is very likely to 

have an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Probiotics vs. placebo. One RCT assessed the effects of treatment with probiotics compared 

with placebo in a group of 269 children ages 10 months to 6 years.91 The Jadad quality score for 

this trial was 5. The treatment consisted of one capsule daily for six months; the capsule 

contained Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve 99, and 

propionibacterium freudenreichii JS. Treatment success was defined by the number of AOM 

episodes during the 6-month intervention period (proportion of children experiencing no 

episodes of AOM, proportion experiencing fewer than three AOM episodes). The difference in 

treatment success between probiotics and placebo was -7% (95% CI: -18%, 4%) for no AOM 

episodes and -1% (95% CI: -10%, 8%) for fewer than three AOM episodes during the six-month 

follow-up period. No conclusion of treatment advantage or equivalence can be derived from the 

existing evidence for either outcome. The overall quality of evidence for this comparison is 

considered low, meaning that further research is very likely to have an important impact on our 

confidence in the estimate of effect and is likely to change the estimate. 

Propolis and zinc vs. elimination of environmental risk factors. Propolis is ―a natural 

product collected by bees from the exudates of plants‖ (Marchisio, 2010).133 One RCT assessed 

the effects of treatment with propolis and zinc plus elimination of environmental risk factors 

compared with elimination of environmental risk factors alone. The Jadad quality score for this 

trial was 2. The treatment consisted of 0.3 ml/kg/d of 30% hydroglyceric extract of propolis and 

1.2% zinc sulfate once daily for three months. The proportion of children with AOM and febrile 

respiratory tract infections and of children treated with antibiotics for those conditions during the 

study period was measured as was the mean number of episodes of AOM and respiratory tract 

infections and antibiotic courses. Also, mean duration of bilateral OME and parental satisfaction 

were measured. The difference in the proportion of children with one or more episodes of AOM 

was 26.2% (95% CI: 9.6%, 42.8%) less in the treatment group as was the mean number of 

antibiotic courses for AOM, -0.34 (95% CI: -0.59, -0.09). The overall quality of evidence for 

this comparison is considered low, meaning that further research is very likely to have an 

important impact on our confidence in the estimate of effect and is likely to change the estimate. 

Surgical vs. surgical or non-surgical treatment. Six comparisons of surgical vs. surgical or 

non-surgical treatments to prevent AOM in children with ROM were identified. None of the 

comparisons demonstrated a significant advantage for any particular surgical or non-surgical 

treatment. 

126
 
Sulfafurazole vs. adenoidectomy. Koivunen (2004) also reported a comparison between 

sulfafurazole and adenoidectomy.130 The study defined treatment success as one or fewer 

episodes of AOM in two months or two or fewer episodes of AOM in six months or less than 

two months of MEE at six-month or two-year follow-ups. A total of 105 children were examined 

at six months. The reported difference in success rate between sulfafurazole and adenoidectomy 

was 5% (95% CI: -14%, 24%) at the six-month follow-up and a difference of 7% (95% CI: ­

12%, 25%) at the two-year follow-up, both favoring the drug. Thus, no conclusion of advantage 

or equivalence can be derived for either treatment from the existing evidence for either outcome. 

The overall quality of evidence for this comparison is considered low, meaning that further high 

quality research is very likely to have an important impact on our confidence in the estimate of 

effect and is likely to change the estimate. 

26, 130 Adenoidectomy vs. placebo. Two RCTs addressed this comparison. Paradise (1999) 

defined treatment success as no AOM episode in one year, or one or fewer AOM episodes in one 

year in patients with no tonsil-related indications.26 This study compared 140 children ranging in 

age from 3 to 15 years and had a Jadad quality score of 2.26 Koivunen (2004) defined treatment 

success as one or fewer episodes of AOM in two months, or two or fewer episodes of AOM in 

six months, or less than two months of MEE at the six-month or two-year follow-ups.130 Paradise 

(1999) reported a difference in treatment success rates of 10% (95% CI: -5%, 24%) when 

success was defined as no AOM episodes during the year (favoring the procedure) and a 

difference of -3% (95% CI: -20%, 14%) when success was defined as one or fewer AOM 

episodes during the year.26 Koivunen (2004) reported a difference of 13% (95% CI: -6%, 32%) 

at 6-month follow-up and a success rate difference of 5% (95% CI: -11%, 22%) at two-year 

follow-up, both favoring the procedure.130 Thus, no conclusion of surgical advantage or 

equivalence can be derived from the existing evidence for any outcome. The overall quality of 

evidence for this comparison is considered low, meaning that further high quality research is 

very likely to have an important impact on our confidence in the estimate of effect and is likely 

to change the estimate. 

Adenoidectomy vs. adenotonsillectomy. Paradise (1999) also compared adenoidectomy with 

adenotonsillectomy in a total of 132 children.26 The study defined treatment success as no AOM 

episode in one year or as one or fewer AOM episodes in one year in patients with no tonsilrelated indications. The reported difference in treatment success was -6% (95% CI: -22%, 11%) 

when success was defined as no AOM episodes during the year and -12% (95% CI: -29%, 5%) 

when success was defined as one or fewer AOM episodes during the year, both favoring 

adenotonsillectomy. Thus, no conclusion of advantage or equivalence for the surgical procedures 

can be derived from the existing evidence for either outcome. The overall quality of evidence for 

this comparison is considered low, meaning that further high quality research is very likely to 

have an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Adenotonsillectomy vs. placebo. Paradise (1999) also compared adenotonsillectomy with 

placebo in a total of 150 children.26 The study defined treatment success as no AOM episode in 

one year or as one or fewer AOM episodes in one year in patients with no tonsil-related 

indications. The difference in success rates was 15% (95% CI: 0.6%, 30%) when success was 

defined as no AOM episodes during the year and 9% (95% CI: -7%, 25%) when success was 

defined as one or fewer AOM episodes during the year, both favoring the procedure. Thus, no 

conclusion of advantage or equivalence can be derived for either intervention from the existing 

127
 
evidence for either outcome with a MCID of 5%. The overall quality of evidence for this 

comparison is considered low, meaning that further high quality research is very likely to have 

an important impact on our confidence in the estimate of effect and is likely to change the 

estimate. 

Adenoidectomy plus tympanostomy vs. tympanostomy alone. One RCT compared the efficacy 

of adenoidectomy plus tympanostomy with that of tympanostomy alone for prevention of AOM 

in children with ROM.132 The study, which enrolled a total of 198 children ranging in age from 

one to two years, defined treatment success as the mean number of otitis media episodes during 

one year of follow-up (Jadad quality score was 2 of 5). No conclusion of advantage or 

equivalence of the surgical procedure can be derived from the existing evidence for either 

outcome. The overall quality of evidence for this comparison is considered low, meaning that 

further high quality research is very likely to have an important impact on our confidence in the 

estimate of effect and is likely to change the estimate. 

Summary 

To answer the question, we assessed the efficacy of both treatment and prevention of AOM 

in children with ROM, persistent AOM, or AOM treatment failure. 

Regarding the treatment of AOM in children with ROM, persistent AOM, or AOM treatment 

failure, the available evidence identified for this study provided the following conclusions: 

The evidence did not allow us to reach strong conclusions regarding the comparisons 

of amoxicillin-clavulanate vs. gatifloxacin, amoxicillin-clavulanate vs. levofloxacin, 

and amoxicillin-clavulanate vs. azithromycin. 

For children with tympanostomy tubes and AOM, ciprofloxacin 0.3%-dexamethasone 

0.1% otic drops appeared to have higher success rate than amoxicillin-clavulanate at 

days 18-21 in one study.80 

In another study of children with tympanostomy tubes, ciprofloxacin-dexamethasone 

had a higher success rate than ofloxacin 0.3% otic drops at day three but not at days 

11, 18, or 18-21 (end of treatment assessment), and produced a higher rate of otorrhea 

absence at days 3, 11, and 18.127 However, in both studies it is not entirely clear why 

the children had tympanostomy tubes, whether for ROM, persistent otitis media with 

effusion, or some other chronic middle-ear condition; so, the generalizability of these 

findings is limited. 

Regarding the prevention of AOM in children with ROM, the available evidence from prior 

systematic reviews provided the following conclusions: 

Long-term antibiotics, defined as weeks or longer, decreased episodes of AOM from 

3 to 1.5 for every 12 months of treatment per otitis-prone child during active 

142 treatment. 

Tympanostomy tube placement played a significant role in maintaining a disease-free 

state in the first six months after tube insertion in children with ROM.143 This 

conclusion is qualified by the observation that only two studies contributed data to 

this pooled analysis. It may also be tempered by the issue of AOM diagnostic 

accuracy in the presence of tympanostomy tubes possibly confounding these results, 

i.e. the pressure equalization and drainage afforded by the tubes and their physical 

128
 
presence decreasing the intensity or visibility of signs and symptoms used to diagnose 

AOM, leading to false negatives. 

A statement cannot be made regarding the role of pneumococcal vaccine in reducing 

AOM in children with ROM based on the available systematic review.141 Although 

pooled analyses favored a modest benefit for the vaccine, methodologic problems 

with the original studies included in the analysis preclude a strong conclusion. 

No definitive conclusions could be drawn regarding the 13 comparisons identified by this 

study for prevention of AOM in children with ROM that looked at amoxicillin vs. azithromycin, 

amoxicillin vs. sulfisoxazole, amoxicillin vs. placebo, sulfisoxazole vs. placebo, ceftibuten fiveday vs. 10-day, probiotics vs. placebo, sulfafurazole vs. adenoidectomy, adenoidectomy vs. 

placebo, adenoidectomy vs. adenotonsillectomy, adenotonsillectomy vs. placebo, ceftibuten fiveday vs. 10-day, probiotics vs. placebo and adenoidectomy plus tympanostomy vs. 

tympanostomy. 

Key Question V.
 

Do Treatment Outcomes in Key Questions III and IV Differ by
 

Characteristics of the Condition (AOM), Patient,
 

Environment, and/or Health Care Delivery System?
 

Of the 48 RCTs newly identified in our review that addressed the effectiveness of treatment 

options in uncomplicated acute otitis media (Key Question 3), 15 trials reported analyses for 

subgroups stratified by age, presence of MEE, laterality, identity of daytime caretaker (use of 

daycare), hearing deficit and severity, otorrhea, examiner, and pneumococcal vaccine. Of the 10 

trials identified in our review that addressed the effectiveness of treatment options in recurrent 

otitis media (Key Question 4), three reported analysis by age subgroups. One reported stratified 

analysis by laterality and severity of otitis media. A listing of the articles reporting subgroup 

analysis and the drug comparisons studied is provided in Table 23. In addition, we report 

relevant findings from previous systematic reviews as cited in the responses to Key Questions III 

and IV. 

Table 23. Listing of Articles Reported Subgroup Analysis on Effectiveness of Treatment Options 

(A) KQ3 – Uncomplicated Otitis Media 

Factor # Comp Comparisons Author, Year 

Age 14 Amoxicillin vs. Azithromycin Arguedas, 200566 

Amoxicillin vs. Azithromycin Morris, 201067 

Amoxicillin vs. Erythromycin Le Saux, 200589 

Amoxicillin vs. Wait-and-see McCormick, 20053 

Amoxicillin (Amox)-clavulanate (clav) Cifaldi, 200474 

5d vs. Amox-clav 10d 

Amox-clav vs. Cefdinir (qd10d) Block, 200072 

Amox-clav vs. Cefdinir (bid10d) Block, 200072 

Amox-clav vs. Cefdinir (bid5d) Block, 200475 

Amox-clav vs. Cefprozil Hedrick, 200176 

Amox-clav vs. Cefuroxime Pessey, 199979 

Azithromycin vs. Cefdinir Block, 200583 

129
 
Factor # Comp Comparisons Author, Year 

Cefpodoxime 5d vs. Cefpodoxime Cohen, 2000100 

10d 

Laterality 2 

Caretaker 2 

Cefprozil vs. Cefdinir 

Amoxicillin vs. Erythromycin 

Amox-clav vs. Cefprozil 

Cefpodoxime 5d vs. Cefpodoxime 

Block, 200085 

Scholz, 19984 

Hedrick, 200176 

Cohen, 2000100 

10d 

Hearing deficit and 1 

Amox-clav 5d vs. Amox-clav 10d 

Amox-clav vs. Cefprozil 

Cohen, 199898 

Hedrick, 200176 

severity 

Otorrhea 1 

Examiner 1 

Pneumococcal 1 

Amoxicillin vs. Erythromycin 

Aqueous lidocaine drop vs. placebo 

Amox-clav vs. Cefdinir 

Scholz, 19984 

Bolt, 200890 

Block, 200475 

vaccine 

(B) KQ4 – Recurrent Otitis Media 

Factor # Comp Comparisons Author, Year 

Age 3 Amox-clav vs. Levofloxacin Noel, 2008123 

Amox-clav vs. Gatifloxacin Sher, 2005122 

Amox-clav vs. Azithromycin Arrieta, 2003124 

Laterality 1 Amox-clav vs. Gatifloxacin Sher, 2005122 

Severity 1 Amox-clav vs. Gatifloxacin Sher, 2005122 

Age Factor in Uncomplicated Acute Otitis Media 

We identified 14 trials for the review update that analyzed the effectiveness of treatment 

options by age group. The study by Cifaldi (2004) examined effectiveness from the parent‘s 

perspective only, whereas the other 13 articles reported other clinical outcomes. The latter 13 

studies assessed 14 treatment comparisons by age group. Table 24 provides a summary of the 

findings on clinical success rate by age groups. 

130
 
Table 24. Summary of Findings from 13 Articles (14 Comparisons) Assessing Clinical Success Rate of Interventions in Uncomplicated Acute Otitis 

Media Stratified by Age 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

1	 Amoxicillin vs. 

Azithromycin 

2	 Amoxicillin vs. 

Azithromycin 

Arguedas, 6-30 months 

66 2005 Multi-centers in 

US, Finland, 

Chile, 

Costa Rica 

Morris, 6 months-6 

201067 years 

Amoxicillin 90 

mg/kg/day / bid for 

10 days 

vs. 

Azithromycin 30 

mg/kg/day = qd for 1 

day 

Amoxicillin 50 

mg/kg/day / bid for 7 

Outcome: Success rate (cure or improvement) at 

day 12-14: -0.2% (-10, 9) 

Amox Azithromy 

cin 

Diff (95% CI) 

All pts 84.1% 

(127/151) 

3.9% 

(130/155) 

0.2% (-8, 8) 

<=2yrs 81.8% 

(99/121) 

82.0% 

(109/133) 

-0.2% (-10, 9) 

>2yrs 93.3% 

(28/30) 

95.4% 

(21/22) 

-2.1% (-15, 11) 

Diff (95% 

CI) 

-12% 

(-26, 3.1) 

-13% 

(-30, 3.2) 

Outcome: Clinical success between day 6 and day 

11 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

Aboriginal days Amox Azithromy Diff (95% CI) conclude 

16 centers Vs. cin 

Australia Azithromycin 30 All pts 46% 50% -4% (-15, 7) 

Rural and mg/kg as a single (72/155) (83/165) 

remote dose <=2yrs 46% 51% -5% (-18, 7) 

communities (57/125) (64/125) 

>2yrs 50% 47% 3% (-21, 26) 

(15/30) (19/40) 

Diff (95% -4% 4% 

CI) (-24, 15) (-14, 21) 

131
 
3 

4 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

Amoxicillin vs. Scholz, 6 months-11 Amoxicillin 50 Outcome: Clinical success on day 9-11 Not enough 

Erythromycin 19984 years mg/kg/day / bid for evidence to 

19 centers in 10 days Amox
 Erythromycin
 Diff (95% CI)
 

By drugs
 96% 94% 2% (-3, 7)
 

(133/139)
 (132/141)
 

conclude
 

Germany vs.
 

Pediatric Erythromycin 40
 

practice mg/kg/day / bid for 

10 days (combines both antibiotic groups) 

<=2yrs >2years Diff (95% CI) 

By Age 90% 95% -6% (-13, 2) 

(35/39) (230/241) 

Amoxicillin vs. Le Saux, 6 months-5 Amoxicillin 60 Outcome: Cumulative clinical resolution rates at 14 Not enough 

Erythromycin 200589	 years mg/kg/day / tid for days evidence to 

Canada 10 days conclude 

Emergency vs. 

Amox
 Placebo
 Diff (95% CI)
 

All ages
 93% 

(232/250)
 

84% 

(202/240)
 

-9% (-14, -3)
 

6-23 mo
 85% 

(76/89)
 

79% 

(73/92)
 

-6% (-17,5.2)
 

2-5 yrs
 97% 

(156/161)
 

87% 

(129/148)
 

-10% (-16,
 

-3.8)
 

Diff
 

(95% CI)
 

-12%
 

(-19, -5.3)
 

-8%
 

(-18, 1.6)
 

between
 

room, placebo
 treatment 

Pediatric effectivenes 

practice s within age 

group. Age 

<2 years 

had lower 

success 

rate than 

>=2 years 

132
 
5 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

Amoxicillin vs. McCormic 6 months- Amoxicillin 90 Outcome: Success rate at Day 0-12 Amox had 

Wait-and-see k, 20053 12years mg/kg/day / bid for higher 

U.S. 10 days success 

Hospital clinic/ vs. rate for all 

outpatient, Wait and see age; cannot 

University/ conclude by 

academic age group. 

Amox Wait-andsee Diff (95% CI) 

Total 95% 

(102/107) 

80% 

(86/107) 

15% (6, 24) 

<2 yrs 94% 

(60/64) 

78% 

(42/54) 

16% (4, 28) 

≥2 yrs 98% 

(42/43) 

83% 

(44/53) 

5% (-4, 13) 

Diff (95% 

CI) 

-4% 

(-12, 3.9) 

-5% 

(-20, 10) 

133
 
6 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

Amox-clav vs. Dunne, 6 months- Amoxicillin- Outcome: Clinical success (cure+improvement) at Clinical 

Azithromycin 200370	 12years clavulanate 45 day 10 success at 

Multi-centers in mg/kg/day / bid for day 24-28 

U.S. 10 days 

Amoxclav Azithro Diff (95% CI) 

All ages 88% 

(159/181) 

83% 

(153/183) 

5%(-2, 12) 

≤2 yrs 85% 

(44/52) 

76% 

(45/59) 

9% (-6, 24) 

>2 yrs 73% 

(94/129) 

86% 

(108/126) 

-13%(-23, -3) 

Diff (95% 

CI) 

12% 

(-2, 26) 

-10% 

(-22, 2) 

for 

vs. Azithromyci 

Azithromycin 10 n higher 

mg/kg/day = qd for 3 among 

days those >2yrs 

than 

Others are 

inconclusive 

Outcome: Clinical success (cure+improvement) at 

day 24-28 

2yrs. 

Amox-clav Azithro Diff (95% CI) 

All ages 69% 

(124/180) 

74% 

(134/182) 

-5%(-14, 4.3) 

≤2 yrs 58% 

(30/52 

60% 

(35/58) 

-2%(-20, 16) 

>2 yrs 73% 

(94/128) 

80% 

(99/124) 

-7% (-18, 3.5) 

Diff (95% 

CI) 

-15% 

(-30, 0) 

-20% 

(-34, -6) 

134
 
Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

7	 Amox-clav vs. Block, 6 monthsCefdinir (QD 200072 12years 

10days) Multi-centers in 

U.S. 

8	 Amox-clav vs. Block, 6 monthsCefdinir (BID 200072 12years 

10days) Multi-centers in 

U.S. 

Amoxicillinclavulanate 40/10 

mg/kg/day / tid for 

10 days 

vs. 

Cefdinir 14 

mg/kg/day = qd for 

10 days 

Amoxicillinclavulanate 40/10 

mg/kg/day / tid for 

10 days 

vs. 

Cefdinir 7 mg/kg/day 

= bid for 10 days 

Outcome: Clinical success (cure or improvement) 

2-4 days after treatment: Amox-clav vs. Cefdinir QD 

A-C CDR-QD Diff (95% CI) 

Total 86% 

(86/100) 

83% 

(85/102) 

0.7% (-7, 13) 

<2 yrs 79% 

(31/39) 

80% 

(45/56) 

-1% (-17, 15) 

≥2 yrs 90% 

(55/61) 

87% 

(40/46) 

3% (-9, 15) 

2-5 yrs 85% 

(35/41) 

84% 

(31/37) 

1.6% (-14, 18) 

6-12 yrs 100% 

(20/20) 

100% (9/9) 0.0% 

Diff (95% 

CI) 

-11% 

(-25, 2.8) 

-7% 

(-22, 8) 

Outcome: Clinical success (cure or improvement) 

2-4 days after treatment: Amox-clav vs. Cefdinir 

BID 

A-C CDR-BID Diff (95% CI) 

Total 86% 

(86/100) 

80% 

(81/101) 

6% (-4, 16) 

<2 yrs 79% 

(31/39) 

62% 

(30/48) 

17% (-2, 36) 

≥2 yrs 90% 

(55/61) 

96% 

(51/53) 

-6% (-15, 3.4) 

2-5 yrs 85% 

(35/41) 

95% 

(35/37) 

-9% (-23, 4) 

6-12 yrs 100% 

(20/20) 

100% 

(16/16) 

0.0% 

Diff 

(95% 

CI) 

-11% 

(-25, 2.8) 

-34% 

(-50, -19) 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

relative 

effectivenes 

s between 

treatments 

within each 

age group. 

Age <2 

years had 

lower 

success 

rate with 

CDR-BID 

135
 
Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

9	 Amox-clav vs. Block, 

Cefdinir (BID 5- 200475 

day) 

10	 Amox-clav vs. Hedrick, 

Cefprozil 200176 

6 months6years 

Multi-centers in 

U.S. 

6 months7years 

Multi-centers in 

U.S. 

Amoxicillinclavulanate 45/6.4 

mg/kg/day / bid for 

10 days 

vs. 

Cefdinir 14 

mg/kg/day / bid for 5 

days 

Amoxicillinclavulanate 90/6.4 

mg/kg/day / bid for 

10 days 

vs. 

Cefprozil 30 

mg/kg/day / bid for 

10 days 

Outcome: Success at end-of-treatment visit (study 

days 7-9 for Cefdinir; study days 12-14 for Amoxclav) 

A-C Cefdinir Diff (95% CI) 

Total 85% 

(164/19 

2) 

88% 

(170/194 

) 

-2% (-9, 4.6) 

<2 yrs 78% 

(64/82) 

88% 

(79/90) 

-10% (-21, 

2.4) 

2-6 yrs 91% 

(100/11 

0) 

88% 

(91/104) 

3% (-4.9, 12) 

Diff (95% 

CI) 

-13% 

(-23, -3) 

0% 

(-9, 9) 

Outcome: Clinical success (cure or improved) at 

day 4-7 after treatment 

A-C Cefprozil Diff (95% CI) 

Total 89% 

(116/130) 

87% 

(110/127) 

2% (-6, 10) 

<2 yrs 86% 

(55/64) 

80% 

(47/59) 

6% (-7, 19) 

2-7 yrs 92% 

(61/66) 

93% 

(63/68) 

-1% (-10, 8) 

Diff (95% 

CI) 

-6% 

(-17, 4.7) 

-13% 

(-25, -1.3) 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

136
 
Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

11 Amox-clav vs. Pessey, 6 monthsCefuroxime 199979 3years 

Multi-centers in 

France 

Amoxicillinclavulanate 40 

mg/kg/day / tid for 

10 days (A-C10d) 

vs. 

Amoxicillinclavulanate 80 

mg/kg/day / tid for 8 

days (A-C8d) 

vs. 

Cefuroxime 30 

mg/kg/day / bid for 5 

days (CAE) 

Outcome: Satisfactory clinical response posttreatment – A-C10d vs. CE 

A-C10d CAE Diff (95% CI) 

Total 88% 

(181/20 

5) 

86% 

(175/203 

) 

2% (-4.5, 8.5) 

<1.5 yrs 89% 

(116/13 

1) 

83% 

(111/134 

) 

6% (-2.4, 14) 

1.5-3 yrs 88% 

(65/74) 

93% 

(64/69) 

-5% (-15, 4.7) 

Diff (95% 

CI) 

1% 

(-8, 10) 

-10% 

(-20, 0) 

Outcome: Satisfactory clinical response posttreatment – A-C8d vs. CE 

Not enough 

evidence to 

conclude 

A-C8d CAE Diff (95% CI) 

Total 88% 

(145/165) 

86% 

(175/203) 

2% (-4.9, 9) 

<1.5 yrs 84% 

(83/99) 

83% 

(111/134) 

1% (-9, 11) 

1.5-3 yrs 94% 

(62/66) 

93% 

(64/69) 

1% (-7, 9) 

Diff (95% 

CI) 

-10% 

(-20, 0) 

-10% 

(-20, 0) 

137
 
Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

12 Azithromycin vs. Block, 6 monthsCefdinir 200583 6years 

Multi-centers in 

U.S. 

13	 Cefpodoxime 5d Cohen, 4-30 months 

vs. Cefpodoxime 2000100 Multi-centers in 

10d France 

Azithromycin 10 

mg/kg/day = qd for 1 

day, 

--- 5 mg/kg/day = qd 

for 4 days 

vs. 

Cefdinir 7 mg 

Cefpodoxime 8 

mg/kg/day / bid for 

10 days 

vs. 

Cefpodoxime 8 

mg/kg/day / bid for 5 

days 

Outcome: Clinical success (cure or improve) on day 

7-9 at end-of-therapy 

Azithro Cefdinir Diff (95% CI) 

Total 85% 

(149/176) 

87% 

(151/174) 

-2% (-9, 5.3) 

0-2 yrs 82% 

(54/66) 

81% 

(48/59) 

1% (-13, 15) 

>2 yrs 86% 

(95/110) 

90% 

(103/115) 

-4% (-12, 4.5) 

Diff (95% 

CI) 

-4% 

(-15, 7) 

-9% 

(-20, 1.6) 

Outcome: Clinical success (cure or improve) on day 

12-14 per protocol population 

CPD 5d CPD 10d Diff (95% CI) 

Total 84.1% 92.4% -8% (-14, -2.1) 

(175/208) (194/210) 

Data by age group not reported. 

Multivariable analysis showed that younger age 

(Odds ratio 1.074, p=0.0096), treatment duration 

(Odds ratio, not reported), day-care attendance 

(Odds ratio 0.390, p=0.0098), and history of otitis 

media with effusion (Odds ratio 0.346, p=0.0091) 

“were independently predictive of poor treatment”

outcome. 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

138
 
Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

14	 Cefdinir 

Vs. 

Cefprozil 

Block, 6months200085 12years 

Multi-centers in 

U.S. 

Cefprozil 30 

mg/kg/day / bid for 

10 days 

vs. 

Cefdinir 14 

mg/kg/day / bid for 5 

days 

Outcome: clinical cure on day 9-11 (4-6 days post 

therapy for cefdinir and +/-1 day post therapy for 

Cefprozil) 

Cefdinir Cefprozil Diff (95% CI) 

Total 80.0% 

(152/190) 

82.5% 

(151/183) 

-2.5%(-10,5.4) 

<2yrs 71% 

(49/69) 

71% 

(41/58) 

0.3%(-16, 16) 

≥2 yrs 84% 

(102/121) 

88% 

(110/125) 

-4% (-12, 4.9) 

Diff (95% 

CI) 

-13% 

(-25, 1.4) 

-17% 

(-29, -5.5) 

2-5yrs 85.1% 

(57/67) 

87.1% 

(61/70) 

-2% (-14, 10) 

6-12yrs 83.3% 

(45/54) 

89.1% 

(49/55) 

-6% (-19, 7) 

Not enough 

evidence to 

conclude 

the 

effectivenes 

s between 

treatments 

within age 

group. Age 

<2 years 

had lower 

success 

rate than 

age >=2 

years when 

treated 

with 

Cefprozil. 

139
 
Using the articles identified in the 2001 report and articles newly identified in this review 

that assessed the effectiveness of treatment options in uncomplicated AOM by age groups, we 

identified two treatment comparisons with more than two trials: Ampicillin/Amoxicillin vs. 

placebo and Amoxicillin-clavulanate (7-10 days) vs. Azithromycin (<5 days). The findings of 

the meta-analysis are presented in Tables 25, 26, 27, 28, and 29, respectively. The shrinkage 

plots are presented in Figures 11, 12, 13, and 14, respectively. 

140
 
Table 25. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate for Age 2 Years 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Differenc Rate Difference 

outcome Size Rate (%) Rate (%) e In % 

Sample In % 

Size 

Howie, 

1972106 2yrs Success at day 2-7 

36 116 47.2 20.7 26.5 8.6, 44.4 

Kaleida, 

1991108 2yrs No effusion at day 2 

226 209 47.8 32.1 15.7 6.7, 24.8 

Damoiseaux, 

200088 2yrs Clinical success at day 11 

112 120 35.7 30.0 5.7 -6.4, 17.8 

Le Saux, 

200589 2yrs Clinical resolution at day 

89 92 85.4 79.3 6.0 -5.0, 17.1 

14 

Random effects estimates 463 537 54.2 40.5 12.2 4.2, 20.2 

Test of heterogeneity Chi-square test value 5.40 

Test of heterogeneity Chi-square test p-value 0.14 

Test of heterogeneity I-squared 44.5% 

Number Needed to Treat (NNT) 8 (5, 24) 

Test of publication bias, Egger’s asymmetry test p-value 0.66 

141
 
Table 26. Ampicillin/Amoxicillin vs. Placebo; Outcome Indicator: Treatment Success Rate for Age >2 Years 

Amoxicillin/ Placebo Amoxicillin Placebo Rate 95% CI of 

Author, Year Age Definition of Ampicillin Sample Success Success Differenc Rate Difference 

outcome Size Rate (%) Rate (%) e In % 

Sample In % 

Size 

Burke, 3-<10yrs Success at day 114 118 98.2 85.6 12.7 5.9, 19.4 

1991107 7 

Kaleida, >2-12yrs No effusion at 226 209 47.8 32.1 15.7 6.7, 24.8 

1991108 day 14 

Le Saux, >2-5yrs Clinical 161 148 96.9 87.2 9.7 3.7, 15.7 

200589 resolution at day 

14 

Random effects estimates 501 475 81.3 68.3 11.9 7.9, 16.0 

Test of heterogeneity Chi-square test value 1.54 

Test of heterogeneity Chi-square test p-value 0.46 

Test of heterogeneity I-squared 0% 

Number Needed to Treat (NNT) 8 (6, 13) 

Test of publication bias, Egger’s asymmetry test p-value 0.19 

142
 
Table 27. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (<5 Days); Outcome Indicator: Treatment Success Rate for Age 2 Years 

Amox-clav Azithromyci Amox-clav Azithromyci Rate 95% CI of 

Author, Year Age Definition of n Success n Difference Rate Difference 

outcome Sample Size Sample Rate (%) Success In % In % 

Size Rate (%) 

Schaad, 

1993117 2yrs Success at day 7­20 

14 14 85.7 85.7 0.0 -25.9, 25.9 

Principi, 

1995118 2yrs Success at day 10-14 

49 61 61.2 75.4 -14.2 -31.6, 3.2 

Dunne, 

200370 2yrs Success at day 10 

52 59 84.6 76.3 8.3 -6.3, 23.0 

Random effects estimates 115 134 74.8 76.94 -1.6 -16.6, 13.4 

Test of heterogeneity Chi-square test value 3.88 

Test of heterogeneity Chi-square test p-value 0.14 

Test of heterogeneity I-squared 48.4% 

Test of publication bias, Egger’s asymmetry test p-value 0.81 

143
 
Table 28. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (<5 Days); Outcome Indicator: Treatment Success Rate for Age >2 Years 

Amox-clav Azithromyci Amox-clav Azithromyci Rate 95% CI of 

Author, Year Age Definition of n Success n Difference Rate Difference 

outcome Sample Size Sample Rate (%) Success In % In % 

Size Rate (%) 

Daniel, >2-8yrs Success at day 54 103 100.0 94.2 5.8 0.5, 11.1 

1993116 10-12 

Schaad, >2-10yrs Success at day 175 178 98.3 94.4 3.9 0.0, 7.8 

1993117 7-20 

Principi, >2-12yrs Success at day 149 154 77.2 89.0 -11.8 -20.2, -3.4 

1995118 10-14 

Dunne, >2-12yrs Success at day 129 126 89.1 85.7 3.4 -4.7, 11.5 

200370 10 

Random effects estimates 507 561 89.9 90.9 0.8 -6.6, 8.3 

Test of heterogeneity Chi-square test value 18.2 

Test of heterogeneity Chi-square test p-value <0.001 

Test of heterogeneity I-squared 83.5% 

Test of publication bias, Egger’s asymmetry test p-value 0.38 

144
 
Table 29. Comparison of Treatment Success Rate Between Age ≤2 And Age >2 Years by Treatment Option Based on Pooled Data 

Treatment Studies Success Rate in % Rate Difference in % 

(95% CI) 

Ampicillin/Amoxicillin 4 studies for age <=2 years (Howie, 1972106; 

108 88 Kaleida, 1991 ; Damoiseaux, 2000 ; Le Saux, 

200589) 

3 studies for age >2 years (Burke, 1991107 ; 

108 89 Kaleida, 1991 ; Le Saux, 2005 ) 

Placebo 4 studies for age <=2 years (Howie, 1972106; 

108 88 Kaleida, 1991 ; Damoiseaux, 2000 ; Le Saux, 

200589) 

3 studies for age >2 years (Burke, 1991107 ; 

108 89 Kaleida, 1991 ; Le Saux, 2005 ) 

Amoxicillin-clavulanate 3 studies for age <=2 years (Schaad, 1993117 ; 

118 70 (7-10 days) Principi, 1995 ; Dunne, 2003 ) 

4 studies for age >2 years (Daniel, 1993116; 

117 118 Schaad, 1993 ; Principi, 1995 ; Dunne, 

200370) 

Azithromycin (<5 days) 3 studies for age <=2 years (Schaad, 1993117 ; 

118 70 Principi, 1995 ; Dunne, 2003 ) 

4 studies for age >2 years (Schaad, 1993117 ; 

118 70 Principi, 1995 ; Dunne, 2003 ) 

Age <=2 52.% (241/463) -23% (-29, -17) 

Age > 2 75% (376/501) 

Age <=2 37% (200/537) -25% (-32, -19) 

Age > 2 63% (297/475) 

Age <=2 75% ( 86/115) -15% (-22, -8) 

Age > 2 90% (456/507) 

Age <=2 77% (103/134) -14% (-20, -8) 

Age > 2 91% (510/561) 

145
 
Figure 11. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for AGE ≤2 Years 

Risk difference (%) 

Study (95% CI) 

Howie 1972
 27 (9, 44) 

Kaleida 1991
 16 (7, 25) 

Damoiseaux 2000
 6 (-6, 18) 

Le Saux 2005
 6 (-5, 17) 

Overall 12 (4, 20) 

-40 -20 0 20 40
 

Risk difference (%)
 

Favors Placebo Favors Amoxicillin/Ampicillin
 

146
 
Figure 12. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for AGE>2 Years 

-40 -20 0 20 40 

Study 

Risk difference (%) 

(95% CI) 

Burke 1991 13 (6, 19) 

Kaleida 1991 16 (7, 25) 

Le Saux 2005 10 (4, 16) 

Overall 12 (8, 16) 

Risk difference (%)
 

Favors Placebo Favors Amoxicillin/Ampicillin
 

147
 
Figure 13. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Azithromycin (<5 days) for Treatment 

Success for AGE ≤2 Years 

-40 -20 0 20 40 

Study 

Risk difference (%) 

(95% CI) 

Schaad 1993 0 (-26, 26) 

Principi 1995 -14 (-32, 3) 

Dunne 2003 8 (-6, 23) 

Overall -2 (-17, 13) 

Risk difference (%)
 

Favors Azithromycin Favors Amox-Clav
 

148
 
Figure 14. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (<5 days) for Treatment 

Success for AGE >2 Years 

Study 

Risk difference (%) 

(95% CI) 

Daniel 1993 6 (1, 11) 

Schaad 1993 4 (0, 8) 

Principi 1995 -12 (-20, -3) 

Dunne 2003 3 (-5, 12) 

Overall 1 (-7, 8) 

-40 -20 0 20 40
 

Risk difference (%) 

Favors Azithromycin Favors Amoxicillin-Clavulanate 

Difference in treatment effect between age groups. In general, the results of individual 

trials and of meta-analyses show that children over the age of 2 have better outcomes from 

AOM, regardless of whether they are treated with antibiotics or not, compared to children 2 

years of age or younger. No differences were seen in our meta-analyses in the rate difference for 

treatment success between children younger or older than 2 years when comparing 

ampicillin/amoxicillin to placebo or when comparing amoxicillin-clavulanate to azithromycin 

(Figures 11-14). Similar conclusions were found in an individual patient meta-analysis 

conducted by Rovers (2006). 

Meta-analyses. Data from two trials, one comparing ampicillin or amoxicillin vs. placebo 

and the other comparing amoxicillin-clavulanate vs. azithromycin, demonstrated that children 

over 2 years old had better clinical success rates in both treatment arms for uncomplicated AOM 

than children 2 years old and under. First, comparing the clinical success between children 2 

88, 89, 106, 108 years old and under treated with ampicillin or amoxicillin in four trials with children 

89, 107, 108 over 2 years of age in three trials treated with ampicillin or amoxicillin, a rate difference 

of -23% (95% CI: -29%, -17%; NNT=4 (95% CI: 3, 6)) favoring treatment of children over 2 

years old was demonstrated (Table 29). A similar result was demonstrated utilizing the same 

trials to compare children 2 years of age and under with those over 2 years of age treated with 

placebo, resulting in a rate difference of -25% (95% CI: -32, -19%; NNT=4 (95% CI: 3, 5) 

149
 
favoring children over 2 years old. Thus, children over 2 years of age had better clinical success 

rates in both ampicillin and placebo groups for treatment of uncomplicated AOM. 

Comparing the clinical success between children 2 years old and under treated with 

70, 117, 118 70, 116-118 amoxicillin-clavulanate in three trials with those over 2 years old in four trials, a 

rate difference of -15% (95% CI: -22%, -8%); NNT=7 (95% CI: 5, 13), favoring treatment of 

children over 2 years old was demonstrated (Table 29). A similar result was demonstrated using 

the same trial to compare children 2 years old or less treated with azithromycin with those over 2 

years old, resulting in a rate difference of -14% (95% CI: -20, -8; NNT=7, 95% CI: 5, 13), 

favoring treatment of children over 2 years old. 

Thus, children over 2 years old also had better clinical success rates in both 

ampicillin/amoxicillin, amoxicillin-clavulanate and azithromycin groups for treatment of 

uncomplicated AOM. Children over 2 years were also more likely to get better on their own than 

children 2 and under. 

Individual studies. Four additional individual RCTs demonstrated a higher clinical success 

rate for children older than two years of age than for children less than two years of age using an 

a priori established MCID of +/- 5%. 

The 2005 study by LeSaux demonstrated success rate differences between 6-23-month-old 

children and 2-5-year-old children of –12% (95% CI: -19, -5.3; NNT=8, 95% CI: 5, 19) for 

amoxicillin treatment and of –8% (95% CI: -18, 1.6; NNT= 13, 95% CI: 5, 63) for placebo.89 

A 2000 study by Block demonstrated a success rate difference for twice-daily cefdinir 

between children under 2 years old and those 2 years old and older of –34% (95% CI: -50, -19; 

NNT=3, 95% CI: 2, 5).85 

Another 2000 study by Block also demonstrated a success rate difference for twice daily 

cefprozil between children under 2 years old and those 2 years old and older of –17% (95% CI: ­

29, -5.5; NNT=6, 95% CI: 3, 18).85 

The 2000 study by Cohen that compared the effectiveness of 5- and 10-day cefpodoxime 

treatments did not report the clinical success rate by age but performed a multivariate analysis 

and reported that younger age (Odds ratio [OR] 1.074, p=0.0096), treatment duration (OR not 

reported), day-care attendance (OR 0.390, p=0.0098), and history of OME (OR 0.346, p=0.0091) 

―were independently predictive of poor treatment‖ outcome.100 

Previous systematic reviews. Using individual patient data from six of ten eligible studies 

identified, a systematic review56 provided information on the effect of antibiotic treatment of 

uncomplicated AOM between age groups. Though Rovers (2006) reported that the effect of 

antibiotics was not modified by age alone, their data indicate that children 2 years of age or older 

had less pain or fever at 3-7 days than those younger than 2 years old when not treated with 

antibiotics (RD=-17%, 95% CI: -24, -10; NNT=6, 95% CI: 4, 10) and also when treated with 

antibiotics (RD=-13%, 95% CI: -19,-7; NNT=8, 95% CI: 5, 14). As noted below, age and 

laterality together modify the effect of treatment. 

Difference in treatment effect within age groups. A difference in treatment effect within 

age groups was demonstrated in one meta-analysis conducted for this review and in a previous 

meta-analysis that used individual patient data (Rovers, 2006). Another meta-analysis conducted 

for this review and a previous meta-analysis that looked only at children 2 years old or under 

(Damoiseaux, 1998) showed no difference between treatment groups. 

Meta-analyses. Comparing ampicillin or amoxicillin vs. placebo by age group showed a rate 

difference of 12% (95% CI: 4%, 20%; NNT=8; 95% CI: 5, 25), favoring ampicillin/amoxicillin 

150
 
88, 89, 106, 108 in children 2 years old and under. and a rate difference of 12% (95% CI: 8%, 16%; 

89, 107, 108 NNT=8, 95% CI: 6, 13), favoring ampicillin/amoxicillin in children over 2 years old. The 

meta-analyses showed no heterogeneity within each group of articles and no evidence of 

publication bias. (Table 25, Table 26, Figure 11 and Figure 12) It should be noted that the Howie 

(1972), Burke (1991), and Kaleida (1991) studies had 95% confidence intervals outside of the 

106-108 MCID favoring ampicillin/amoxicillin. Thus, the only definitive conclusion possible from 

these data is that for children over 2 years old, ampicillin/amoxicillin appears to have an 

advantage over placebo (NNT=8, 95% CI: 6, 13). 

Comparing amoxicillin-clavulanate vs. azithromycin by age group showed a rate difference 

of –2% (95% CI: -17%, 13%) in children 2 years old and under and a rate difference of 0.8% 

70, 117, 118 (95% CI: -7%, 8%) in children over 2 years old in meta-analyses that showed possible 

heterogeneity within the group of articles reporting data for children over 2 years of age but no 

evidence of publication bias. (Table 27, Table 28, Figure 13, and Figure 14) It should be noted 

that the study by Principi (1995) had 95% confidence intervals clearly favoring azithromycin for 

children over 2 years, unlike the other studies.118 Thus, no conclusion regarding the advantage of 

either treatment over the other or their equivalence for either age group can be made. 

Previous systematic reviews. Two systematic reviews (Damoiseaux, 1998; Rovers, 2006) 

provide information on the role of age within treatment groups for uncomplicated AOM in 

average risk children. Damoiseaux (1998) studied children under two years old and found no 

effect of antibiotics on clinical improvement within seven days (OR 1.31, 95% CI: 0.83-2.08). 

Rovers found a positive effect of antibiotics on pain, fever, or both at 3-7 days for both age 

groups, and the rate difference for children 2 years old or under was –15% (95% CI: -23, -7; 

NNT=7, 95% CI: 4, 14), whereas that for children over 2 years old was –11% (95% CI: -16, -6; 

NNT=9, 95% CI: 6, 17). 

Laterality Factor in Uncomplicated Acute Otitis Media 

We identified two individual articles and one systematic review that analyzed the 

effectiveness of treatment options by laterality. Table 30 provides a summary of the findings. 

151
 
Table 30. Summary of Findings from Two Articles and One Previous Systematic Review Reporting Effectiveness of Interventions in Uncomplicated 

Otitis Media Stratified by Laterality 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

1	 Amoxicillin vs. 

Erythromycin 

2	 Amox-clav vs. 

Cefprozil 

3	 Antibiotic vs. 

placebo 

Scholz, 

4 1998

Hedrick 

76 , 2001

Rovers, 

56 2006

6 months-11 

years 

19 centers in 

Germany 

Pediatric 

practice 

6 months7years 

Multi-centers in 

U.S. 

0-12years 

Systematic 

review of 

individual 

patient data 

from six studies 

Amoxicillin 50 

mg/kg/day / bid for 

10 days 

vs. 

Erythromycin 40 

mg/kg/day / bid for 

10 days 

Amoxicillinclavulanate 90/6.4 

mg/kg/day / bid for 

10 days 

vs. 

Cefprozil 30 

mg/kg/day / bid for 

10 days 

Antibiotics vs. No 

antibiotic 

Outcome: Clinical success on day 9-11 by laterality 

(combines both antibiotic groups) 

Bilateral Unilateral Diff(95% CI) 

87.3% (69/79) 97.5% -10%(-16, -4) 

(196/201) 

Outcome: Clinical success (cure or improved) at day 

4-7 after treatment by Laterality 

A-C Cefprozil Diff (95% CI) 

Total 89% 

(116/130) 

87% 

(110/127) 

2% (-6, 10) 

Unilateral 93% 

(66/71) 

89% 

(73/82) 

4% (-5.2, 13) 

Bilateral 85% 

(50/59) 

82% 

(37/45) 

3% (-11, 17) 

Diff (95% 

CI) 

8% 

(-3, 19) 

7% 

(-5.4, 19) 

Outcome: Pain, fever, or both at 3-7 days by 

Laterality 

Unilateral Bilateral Diff (95% CI) 

Antibiotic 24% 

(104/432) 

27%(64/2 

37) 

-3%(-10, 4) 

Placebo 30%(132/ 

440) 

47%(104/ 

219) 

-17%(-25, -10) 

Diff (95% 

CI) 

-6%(-12, 

0) 

-20%(-28, 

-11) 

<2 years 

old 

Antibiotic 35%(45/1 

29) 

30%(42/1 

39) 

5%(-6, 16) 

Placebo 40%(53/1 

32) 

55%(74/1 

34) 

-15%(-27, -3) 

Not enough 

evidence to 

conclude 

Not enough 

evidence to 

conclude 

In the no 

antibiotic 

group, a 

smaller 

proportion of 

children with 

unilateral 

disease had 

pain or fever 

at 3-7 days 

then children 

with bilateral 

disease; but, 

not enough 

evidence to 

conclude 

152
 
Diff 

(95%CI) 

-5%(-17, 

7) 

-25%(-36, 

-14) 

when 

stratified by 

≥ 2 years 

old 

age. 

Antibiotic 19%(59/3 

04) 

23%(20/8 

7) 

-4%(-14, 5) 

Placebo 26%(79/3 

07) 

35%(30/8 

6) 

-9%(-20, 2) 

Diff (95% 

CI) 

-7%(-14, 

0) 

-12%(-25, 

1) 

153 
Difference in treatment effect between laterality groups. In general, the results of 

individual trials and meta-analyses show that children with bilateral disease responded as well to 

treatment as those with unilateral disease. If left untreated, children with unilateral disease did 

better than those with bilateral disease. 

Individual studies. Scholz 1998 compared amoxicillin with erythromycin in 280 children 

ranging in age from 6 months to 11 years at days 9 to 11 after treatment initiation (Jadad quality 

score was 5 out 5).127 This study demonstrated a success rate difference between unilateral and 

bilateral AOM for children on either amoxicillin or erythromycin of -10% (95% CI: -16, ­

4[NNT=10, 95% CI: 6, 25]). 

Hedrick 2001 compared amoxicillin-clavulanate with cefprozil in 257 children ranging in age 

from 6 months to 7 years at days 4 to 7 after treatment initiation (Jadad quality score was 2 of 

5).128 This study demonstrated a lack of success rate differences between unilateral and bilateral 

AOM for amoxicillin-clavulanate of 8% (95% CI: -3%, 19%) and for cefprozil of 7% (95% CI: ­

5.4%, 19%). 

Previous systematic reviews. A meta-analysis by Rovers (2006) of individual patient data 

from six studies reported data showing a greater proportion of children without pain or fever at 

3-7 days in children with unilateral compared to bilateral disease when not treated with 

antibiotics (RD=-18, 95% CI: -25,-10; NNT=6, 95% CI: 4, 10).53 The effect of laterality was not 

seen in the group treated with antibiotics (RD=-3%, 95% CI: -10, 4). 

Treatment effect within laterality groups. The comparison of treatment effect in an 

individual study and a previous systematic review identified for the present review generally 

showed better clinical outcomes for children receiving antibiotics than for those receiving no 

treatment among children with bilateral AOM but not for those with unilateral disease; this 

difference was also seen in children less-than two years old. 

Individual studies. The Hedrick 2001 study also demonstrated a lack of success rate 

differences between amoxicillin-clavulanate cefprozil treatment among patients with unilateral 

AOM (RD=4%, 95% CI: -5.2, 13) and those with bilateral AOM (RD= 3%, 95% CI: -11, 17). 

Previous Systematic Reviews. Rovers‘ (2006) meta-analysis of individual patient data from 

six studies reported a benefit for antibiotics compared to placebo for resolving pain and/or fever 

at 3 to 7 days in children with bilateral disease (RD=-20%, 95% CI: -28%, -11%; NNT=5, 95% 

CI: 4, 9) but not for children with unilateral disease (RD=-6%, 95% CI: -12, 0). When stratified 

by age, this effect was seen in children under 2 years of age with bilateral AOM, as treatment 

with antibiotics resulted in a significant resolution of pain or fever at 3-7 days compared to 

placebo (RD=-25%, 95% CI: -36%, -14%; NNT=4, 95% CI: 3, 7) but not for children under 2 

years old with unilateral disease (RD=-5%, 95% CI: -17, 7). 

Childcare Setting Factor in Uncomplicated Otitis Media 

We identified two studies by Cohen that analyzed the effectiveness of treatment options by 

child care setting (home vs. caretaker vs. sitter vs. external day care). Table 31 provides a 

98, 100 summary of the findings. The 1998 study by Cohen compared the clinical success of 5-and 

10-day regimens of amoxicillin-clavulanate by child care setting among 518 children 4 to 30 

months of age (Jadad quality score was 5). The 2000 study by Cohen compared the clinical 

success of 5- and 10-day cefpodoxime regimens by child care setting among 649 children 4 to 30 

154
 
months of age (Jadad quality score was 3). The following success rate differences were found 

between home and outside care sites (either sitter or day-care): 

Amoxicillin-clavulanate 5-day regimen, 14% (95% CI: 1.1%, 28%) 

Amoxicillin-clavulanate 10-day regimen, 3% (95% CI: -7%, 13%) 

Cefpodoxime 5-day regimen, 7% (95% CI: -3.4%, 17%) 

Cefpodoxime 10-day regimen, –0.3% (95% CI: -7.5%, 7%). 

155
 
1 

2 

Table 31. Summary of Findings from 2 Articles Reporting Effectiveness of Interventions in Uncomplicated Otitis Media Stratified by Childcare Setting 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

Amox-clav 5d Cohen, 4-30 months Amoxicillin- Outcome: Clinical success (cure or improve) per Not enough 

vs. Amox-clav 199898 Multi-centers clavulanate 80/10 protocol population by setting of child care evidence to 

10d in France mg/kg/day / tid for conclude 

10 days 

vs. 

Amoxicillinclavulanate 80/10 

for 5 days 

Amoxclav 5d Amoxclav 10d Diff (95% CI) 

Home 85.1% 

(57/67) 

89.6% 

(69/77) 

-4.5%(-15, 6) 

Caretaker 70.8% 

(68/96) 

86.8.% 

(79/91) 

-16% (-28, ­

4.2) 

Sitter 73.6%(39 

/53) 

88.6% 

(39/44) 

-15%(-31, 0.9) 

Day-care 67.3% 

(29/43) 

85.1% 

(40/47) 

-18%(-35, 0.3) 

Diff (H-C) 

(95% CI) 

14% 

(1.1, 28) 

3% 

(-7, 13) 

Cefpodoxime Cohen, 4-30 months Cefpodoxime 8 Outcome: clinical success (cure or improve) per protocol Not enough 

5d vs. 2000100 Multi-centers mg/kg/day / bid for population by day-care modality evidence to 

Cefpodoxime in France 10 days conclude 

10d	 vs.
 

Cefpodoxime 8
 

mg/kg/day / bid for 

5 days
 

CPD 5d CPD 10d Diff (95% CI) 

Home 88.1% 

(74/84) 

92.2% 

(95/103) 

-4.1% (-13, 

4.4) 

Caretaker 81.4% 

(101/124) 

92.5% 

(99/107) 

-11% (-20, ­

2.3) 

Sitter 86.8% 

(66/76) 

100%(47/ 

47) 

-13% (-23, ­

3.2) 

Day-care 72.9% 

(35/48) 

86.7% 

(52/60) 

-14% (-29, 1.2) 

Diff (H-C) 

(95% CI) 

7% 

(-3.4, 17) 

-0.3% 

(-7.5, 7) 

156
 
Thus, no conclusion can be drawn regarding differences in clinical success of a treatment 

option with the type of caretaker and setting based on these two studies. 

Other Factors Studied in Uncomplicated Otitis Media 

We identified only four other factors whose influence on treatment effectiveness was 

assessed---severity factor, presence of otorrhea at initial visit, examiner (parent vs. physician), 

and pneumococcal vaccine status---and only one article assessed the effect of each of these 

factors. Table 32 provides a summary of the findings. With one exception (presence or absence 

of otorrhea at initial visit), no differences were seen. 

157
 
1 

1 

Table 32. Summary of Findings from Articles Each Reporting Effectiveness of Interventions in Uncomplicated Otitis Media Stratified by a Risk Factor 

(A) Hearing deficit and severity 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

Amox-clav vs. Hedrick, 6 months-7 Amoxicillin- Outcome: Clinical success (cure or improved) at day 4 Not enough -7 

Cefprozil 200176 years clavulanate evidence to after treatment by Severity Multi-centers in 90/6.4 mg/kg/day conclude 

U.S.	 / bid for 10 days 

vs. 

Cefprozil 30 

mg/kg/day / bid 

for 10 days 

A-C Cefprozil Diff (95% CI) 

Moderate 92% 

(83/90) 

85% 

(64/75) 

7% (-2.7, 17) 

Severe 82% 

(32/39) 

88% 

(45/51) 

-6% (-21, 9) 

Diff (95% 

CI) 

10% 

(-2, 22) 

-3% 

(-15, 9) 

(B) Otorrhea 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

Amoxicillin vs. Scholz, 6 months-11 Amoxicillin 50 Outcome: Clinical success on day 9 Not enough -11 by otorrhea at Erythromycin	 19984 years mg/kg/day / bid entry 19 centers in for 10 days 

Germany vs. 

Pediatric Erythromycin 40 

practice mg/kg/day / bid 

for 10 days 

Otorrhea at entry 

94.7% (36/38) 

evidence to 

conclude No Otorrhea Diff (95% CI) 

at entry 

94.6% 0.1%(-8, 8) 

(229/242) 

158
 
1 

(C) Examiner 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

1 Aqueous Bolt, 3-17 years 2% aqueous	 Significantly 90 Outcome: Reduction by 50% in pain score on day 30
 lidocaine drop 2008 Tertiary lidocaine 3 drops
 Lidocaine Placebo Diff (95% CI) 

By parent 90% 

(28/31) 

63% 

(20/32) 

27%(6, 48) 

By doctor 84% 

(26/31) 

66% 

(21/32) 

18% (-3.4,39) 

Diff (95% 

CI) 

6% 

(-11, 23) 

-3% 

(-26, 20) 

more reduction 

vs. placebo children’s hourly for 1 day in pain by 

hospital vs. parent if treated 

emergency Placebo with lidocaine. 

department in Not enough 

Australia evidence to 

conclude for 

doctor’s

assessment 

(D) Pneumococcal vaccine 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

Amox-clav vs. Block, 6 months- Amoxicillin-clavulanate Not enough 75 Outcome: Success at end-of-treatment visit (study Cefdinir 2004 6years 45/6.4 mg/kg/day / bid evidence to days 7-9 for Cefdinir; study days 12-14 for Amox­ Multi-centers in for 10 days conclude clav) by PCV7 U.S.	 vs. 

Cefdinir 14 mg/kg/day / 

bid for 5 days 

Amoxclav Cefdinir Diff (95% CI) 

Had PCV7 82% 

(102/124) 

92% 

(115/125) 

-10%(-18, -2) 

No PCV7 91% 

(62/68) 

80% 

(55/69) 

11% (-0.8, 23) 

Diff (95% 

CI) 

-9% 

(-20, 1.5) 

12% 

(2.4, 22) 

159
 
Moderate vs. severe disease. The 2001 study by Hedrick compared the clinical success of 

amoxicillin-clavulanate with that of cefprozil stratified by illness severity among 255 children 

ranging in age from 6 months to 7 years (Jadad quality score 2).76 This study demonstrated 

success rate differences between moderate and severe disease for amoxicillin-clavulanate of 10% 

(95% CI: -2%, 22%) and for cefprozil of -3% (95% CI: -15%, 9%). 

Presence or absence of otorrhea. Scholz (1998) compared the clinical success of 

amoxicillin vs. erythromycin, stratified by the presence or absence of otorrhea at initial visit, 

among 280 children, ranging in age from 6 months to 11 years (Jadad quality score 5).4 This 

study demonstrated a success rate difference between those with and without otorrhea at study 

entry and treated with either amoxicillin or erythromycin of 0.1% (95% CI: -8, 8). Data from a 

systematic review by Rovers (2006) using individual patient data from six studies suggested that 

in children not treated with antibiotics, those with otorrhea were more likely to have pain, fever, 

or both at 3-7 days than those without otorrhea, a rate difference of 18% (95% CI: 4%, 32%), but 

this was not the case for children on antibiotics, where no difference was demonstrated (RD=­

4%, 95% CI: -18%, 10%). The Rovers (2006) systematic review also found that the benefit from 

antibiotics vs. no antibiotics for resolution of pain, fever, or both at 3-7 days was greater for 

children with otorrhea (RD=-36%, 95% CI: -53%, -19%; NNT=3, 95% CI: 2, 5) than for 

children without otorrhea (RD=-14%, 95% CI: -23%, -5%; NNT=8, 95% CI: 4, 20). 

Physician vs. parent assessment. Bolt (2008) compared the reduction in pain score using 

aqueous lidocaine drop vs. placebo, stratified by assessor— parent vs. doctor—among 162 

children ranging in age from 3 to 17 years (Jadad quality score 4).90 This study demonstrated 

50% pain score reduction differences between those examined by a parent vs. a doctor when 

using lidocaine of 6% (95% CI: -11%, 23%) and for placebo of -3% (95% CI: -26, 20). Although 

the type of examiner had no significant effect within treatment groups, lidocaine was 

significantly better than placebo in the children with a parent examiner (difference of 27% [95% 

CI: 6%, 48%]). 

Vaccine treatment. Block (2004) compared the clinical success of amoxicillin-clavulanate 

with cefdinir (5 days) stratified by whether the patient had received PCV7 vaccine or not, among 

386 children ranging in age from 6 months to 6 years (Jadad quality score 2).75 The study 

demonstrated success rate differences between those who received PCV7 and those who did not 

receive PCV7 of –9% (95% CI: -20%, 1.5%) for amoxicillin-clavulanate and of 12% (95% CI: 

2.4%, 22%) for cefdinir. 

Effectiveness of Treatments in Recurrent Otitis Media, Stratified by 

Age, Laterality, and Severity 

We identified three studies that analyzed the effectiveness of treatment options by age groups 

122-124 in recurrent otitis media. The 2005 study by Sher also provided subgroup analysis by 

laterality and severity.122 Table 33 provides a summary of the findings. 

160
 
Table 33. Summary of Findings from Three Articles Reporting Effectiveness of Interventions in Recurrent Otitis Media Stratified by Age, Laterality, and 

Severity. 

(A) Age 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

1	 Amox-clav vs. 

Azithromycin 

2	 Amox-clav vs. 

Gatifloxacin 

Arrieta, 0.5-6 years Amox-clav 

2003124 13 US and 5 (95mg/kg, bid, 

Latin American 10d) 

centers Azithromycin 

(20mg/kg, qd, 3d) 

Sher, 0.5-7 years Amox-clav 

2005122 26 sites in US (90mg/6.4mg/kg/ 

1 site in Costa d in 2 doses), 10d 

Rica Gatifloxacin 

(10mg/kg, qd) 

10d 

Outcome: Success rate on day 12-16 

Amoxclav Azithromy 

cin 

Diff (95% CI) 

<=2yrs 79% 

(73/92) 

85% 

(82/96) 

-6% (-17, 5) 

>2yrs 92% 

(49/53) 

87% 

(46/53) 

5% (-7, 17) 

Diff (95% 

CI) 

-13% 

(-26, ­

0.5) 

-2% 

(-14, 10) 

Outcome: Success rate on day 10 (test of day 

visit) by age group 

Not enough evidence 

to conclude 

Not enough evidence 

to conclude 

Amoxclav Gatifloxac 

in 

Diff (95% CI) 

<2yrs 78% 

(45/58) 

79% 

(49/62) 

-1% (-16, 14) 

>=2yrs 80% 

(47/59) 

90% 

(56/62) 

-11% (-23,2.7) 

Diff (95% 

CI) 

-2% 

(-17, 13) 

-11% 

(-24, 1.7) 

161
 
3 

Comp # Comparison Article Patient Intervention Findings Conclusion 

Population 

Amox-clav vs. Noel, 0.5-<5 years Amox-clav Outcome: Clinical success (cure and improved) at Not enough evidence 

Levofloxacin 2008123 66 centers in 6 (45mg/kg bid, 10-17 days to conclude difference in 

effectiveness between countries, incl US 10d) treatments within each Levofloxacin age group. Age <=2yrs (10mg/kg bid, had lower success rate 10d) for both treatments. 

Levofloxa 

cin 

Amoxclav Diff (95% CI) 

0.5-2yr 79% 

(318/404) 

76% 

(315/417) 

-3.2 (-8.9, 2.6) 

>2-<5yr 90% 

(267/296) 

87% 

(263/302) 

-3.1 (-8.2, 2.0) 

Diff (95% 

CI) 

-11% 

(-16, ­

5.5) 

-11% 

(-17, -5.1) 

(B) Laterality 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

1 Amox-clav vs. Sher, 0.5-7 years Amox-clav Outcome: Success rate on day 10 (test of day visit) Not enough 

Gatifloxacin 2005122 26 sites in US (90mg/6.4mg/kg/d in 2 by laterality evidence to 

1 site in Costa doses), 10d conclude 

Rica Gatifloxacin (10mg/kg, 

qd) 10d 

Amoxclav Gatifloxac 

in 

Diff (95% CI) 

Unilateral 82% 

(40/49) 

84% 

(48/57) 

-3% (-17, 12) 

Bilateral 76% 

(52/68) 

85% 

(57/67) 

-9% (-22, 4.7) 

Diff (95% 

CI) 

6% 

(-9, 21) 

-1% 

(-14, 12) 

162
 
(C) Severity 

Comp Comparison Article Patient Intervention Findings Conclusion 

# Population 

1 Amox-clav vs. Sher, 0.5-7 years Amox-clav Outcome: Success rate on day 10 (test of day visit) Not enough 

Gatifloxacin 2005122 26 sites in US (90mg/6.4mg/kg/d in 2 by severity evidence to 

1 site in Costa doses), 10d conclude 

Rica Gatifloxacin (10mg/kg, 

qd) 10d 

Amox-clav Gatifloxacin Diff (95% CI) 

Mild/Mo 

d 

85% (45/53) 84% (47/56) 1% (-13, 15) 

Severe 73% (47/64) 85% (58/68) -12 (-26, 2) 

Diff 

(95% CI) 

12% 

(-3, 27) 

-1% 

(-14, 12) 

163
 
The three studies compared the effectiveness of amoxicillin-clavulanate vs. three different 

124 122 123 treatments: azithromycin, gatifloxacin, and levofloxacin by age groups. It can be 

observed from the 95% confidence intervals that no definitive conclusions could be made for the 

first two comparisons. For levofloxacin, Noel (2008) demonstrated a success rate difference by 

day 17 between 0.5-2-year-old children and 2-5 year old children treated with levofloxacin of – 

11% (95% CI: -16, -5.5); the confidence limit outside of the MCID (NNT=9, 95% CI: 6, 18), 

implies a lower success rate for younger children.123 A similar age association was seen for 

amoxicillin-clavulanate in this study, with a success rate difference between the two age groups 

of –11% (95% CI: -17, -5; NNT=9, 95% CI: 6, 20). It should be noted that the differences in 

clinical success rate between levofloxacin and amoxicillin-clavulanate within each age group 

was not significant. 

Sher (2005) included stratified analysis by laterality and by severity. Based on the 95% 

confidence intervals for the success rates, no definitive conclusions can be made, and more data 

or studies are needed.122 

Summary 

For uncomplicated AOM, the available evidence indicates that treatment effect may be 

modified by age, laterality, and otorrhea. In a meta-analysis conducted for this report, children 

over 2 years old did better than children two years old and under in the ampicillin/amoxicillin 

group (NNT=4, 95% CI: 3, 6) and in the placebo group (NNT=4, 95% CI: 3, 5). A systematic 

review by Rovers (2006) reported data that also show that children 2 years and older had less 

pain or fever at 3-7 days than younger children, whether treated or not treated with antibiotics. 

Comparing children over 2 years to those two and under, another meta-analysis in this review 

showed the older age group with better clinical success than the younger age group whether 

treated with amoxicillin-clavulanate (NNT=7, 95% CI: 5, 13) or with azithromycin (NNT=7, 

95% CI: 5, 13). In addition three individual studies showed greater success rates in children 

older than two years of age in treatment of uncomplicated AOM with amoxicillin, cefdinir, and 

85, 89, 163 cefprozil and also in the placebo group of one study.

In addition, for children over 2 years old, ampicillin/amoxicillin appeared to have an 

advantage over placebo (NNT=8, 95% CI: 6, 13). For children 2 years old and under, the 95% 

confidence interval also favored ampicillin/amoxicillin but crossed the +/-5% MCID, so a 

definitive conclusion could not be made. Meta-analyses by age sub-group for a comparison of 

amoxicillin-clavulanate vs. azithromycin were without definitive conclusion. 

The systematic review by Rovers (2006) also found that the effect of antibiotics (compared to 

placebo or no treatment) was greater in children with bilateral AOM (NNT=5, 95% CI: 4, 9) than 

in those with unilateral AOM, in which there was no difference. Also, the increase in effect of 

antibiotics (compared to placebo or no treatment) in bilateral AOM was of greater magnitude in 

children 2 years and younger (NNT=4, 95% CI: 3, 7) than in children over 2 years old, in whom 

there was again no difference. We also identified two individual studies (Scholz, 1998; Hedrick, 

2001) that assessed laterality, with results that did not allow for definitive conclusions and were 

not included in the Rovers (2006) systematic review. 

164
 
Rovers (2006) also found that antibiotic effect was greater in children with AOM who had 

otorrhea (NNT=3, 95% CI: 2, 5) compared to those without otorrhea (NNT=8, 95% CI: 4, 20), 

and we identified one individual study (Scholz, 1998) that did not show such an effect. 

Definitive conclusions could not be made regarding subgroup analyses by childcare setting, 

severity, examiner, or pneumococcal vaccine status. 

For ROM, the available evidence in one study by Noel (2008) demonstrated an association of 

treatment success with age, favoring children older than two years of age treated with either 

levofloxacin (NNT=9, 95% CI: 6, 18) or amoxicillin-clavulanate (NNT=9, 95% CI: 6, 20).123 

However, the available evidence did not allow definitive conclusions when assessing available 

treatment options by laterality and severity, when taking into consideration both the 95% 

confidence limit and a +/-5 % zone of MCID. 

The overall quality of evidence for these comparisons is considered low, meaning that further 

high quality research is very likely to have an important impact on our confidence in the estimate 

of effect and is likely to change the estimate. 

Key Question VI. 

What Adverse Effects Have Been Observed for the 

Treatments Whose Outcomes Are Addressed in Key
 

Questions 3 and 4?
 

Description of the Studies 

We examined the incidence of adverse events in the RCTs identified for this report that 

compared the effectiveness of one or more treatment options. We also searched the FDA 

MedWatch Database for adverse events associated with use of medications for the treatment of 

AOM; however, none could be identified. 

Adverse Effects Observed In Treatment of Uncomplicated Acute Otitis 

Media 

Of the 44 RCTs newly identified for this report that compared the effectiveness of treatment 

options in uncomplicated AOM, there are 63 treatment comparisons. Of the 63 treatment 

comparisons, 42 included comparisons of the percent of cases that had experienced an adverse 

event between pairs of treatment options. The incidence rate for each treatment group and the 

rate difference between two treatment options can be found in the Evidence Tables. The findings 

for newly identified RCTs are summarized in Table 34. The combined findings for the 2001 

report and the present report are summarized in Table 34a. 

165
 
Table 34. Findings of Adverse Events by Treatment Option Comparisons for Uncomplicated Otitis Media 

Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

reported 

1 Amox vs. Zielnik-Jurkiewicz, 200565 No 

Amox+Fenspiride 

3 Amox vs. Zhang, 200368 No 

Ceftriaxone 

4 Amox vs. Scholz, 19984 Yes Tx related, possibly tx 

Erythromycin related 

5 Amox-clav vs. Casellas, 200569 Yes Severe diarrhea (0.7% Any mention, diarrhea day 

Amox-sulbactam in both treatment arm) 12-14, diarrhea day3, 

minor 

6 Amox-clav vs. Dagan, 20007 Yes Any mention, diarrhea, tx 

Azithromycin related, vomiting 

7 Amox-clav vs. Dunne, 200370 Yes Vomiting (1% vs. 2%) Any mention, diarrhea, 

Azithromycin rash 

8 Amox-clav vs. Guven, 200652 Yes Any mention, abd pain, 

Azithromycin diarrhea 

9 Amox-clav vs. Biner, 200771 Yes Diarrhea, vomiting 

Azithromycin 

10 Amox-clav vs. Subba Rao, 19985 Yes Fever (0% vs. 1.7%) Diarrhea, headache, 

Cefaclor vomiting 

11 Amox-clav vs. Block, 200072 Yes Any mention higher in Rash 

Cefdinir Amox-clav (42% vs. 

14% in CefQD and 

23% in CefBID) 

Diarrhea higher in 

Amox-clav (35% vs. 

10% in CefQD and 

13% in CefBID) 

12 Amox-clav vs. Adler, 200073 Yes Any mention, diarrhea, tx 

Cefdinir related 

13 Amox-clav vs. Cifaldi, 200474 No 

Cefdinir 

14 Amox-clav vs. Block, 200475 Yes Diaper rash, diarrhea, 

Cefdinir vomiting 

15 Amox-clav vs. Hedrick, 200176 Yes Any mention, diarrhea, 

166
 
Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

reported 

Cefprozil rash, vomiting 

16 Amox-clav vs. Cohen, 199977 Yes Any mention higher in 

Ceftriaxone Amox-clav (31% vs. 

14%) 

Diarrhea higher in 

Amox-clav (27% vs. 

14%) 

17 Amox-clav vs. Wang, 200478 Yes Any mention, diarrhea, GI, 

Ceftriaxone skin and appendages, rash 

18 Amox-clav vs. Biner, 200771 Yes Diarrhea, vomiting 

Ceftriaxone 

19 Amox-clav vs. Pessey, 199979 Yes Any mention, diarrhea 

Cefuroxime 

20 Azithromycin vs. Dagan, 200081 No 

Cefaclor 

21 Azithromycin vs. Oguz, 200382 Yes Diarrhea, vomiting 

Cefaclor 

22 Azithromycin vs. Block, 200583 Yes Abnormal stool, diarrhea 

Cefdinir 

23 Azithromycin vs. Biner, 200771 Yes Diarrhea, vomiting 

Ceftriaxone 

24 Cefaclor vs. Carvalho, 199884 Yes Any mention, vomiting 

Cefprozil 

25 Cefdinir vs. Block, 200085 Yes Rash (3.2% vs. 3.8%) Diarrhea 

Cefprozil 

26 Cefaclor vs. Tsai, 199886 Yes Any mention, abd 

Cefpodoxime discomfort, diarrhea, 

intolerable abd discomfort, 

intolerable urticaria, 

pruritis, skin rash, sweating 

27 Cefaclor vs. Turik, 1998125 Yes Asthma, respiratory Any mention, diarrhea, 

Cefuroxime disorder, vomiting (0% diarrhea during tx, 

vs. 1%) increased cough, rhinitis 

28 Amox vs. Wait- McCormick, 20053 Yes Serious events (0% in 

and-see both arms) 

167
 
Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

reported 

29 PcV vs. Wait-and- Neumark, 200787 No 

see 

30 Amox vs. Placebo Damoiseaux, 200088 Yes Diarrhea day 4, diarrhea 

day 10 

31 Amox vs. Placebo Le Saux, 200589 Yes Diarrhea, rash 

32 Lidocaine drop vs. Bolt, 200890 Yes Ear discharge, dizziness 

Placebo 

33 Probiotic vs. Hatakka, 200791 No 

Placebo 

34 Homeopathic vs. Jacobs, 200192 Yes Any mention (0% in 

Placebo both arms) 

35 Amox vs. Little, 20012 No 

Prescription to 

Hold 

36 Amox vs. Little, 200693 No 

Prescription to 

Hold 

37 Antibiotic vs. Spiro, 200694 Yes Diarrhea at 4-6 day Diarrhea at 11-14 day 

Prescription to follow-up higher in follow-up, otalgia, vomiting 

Hold Antibiotic group 

(21% vs. 7%) 

38 Prescription to Chao, 200895 No 

Hold vs. Wait-andsee 

39 Amox high vs. low Garrison, 200496 Yes GI distress, skin rash 

dose 

40 Amox-clav high vs. Pessey, 199979 Yes Any mention, diarrhea 

low dose 

41 Amox-clav high vs. Bottenfield, 199897 Yes Diaper rash (4% vs. Any mention, need tx, 

low dose 5%) cough, fever, severe 

diarrhea, URI, vomiting 

Severe rash (1% vs. 

0%) 

Severe erythema 

multiform (0% vs. 0.4%) 

168
 
Comp# Comparison Author, Year Adverse 

effects 

reported 

Significant 

Differences 

Equivalence 

Severe GI (0% vs. 

0.4%) 

Inconclusive 

42 Amox-clav bid vs. 

tid 

Damrikarnlert, 20006 Yes 

Severe moniliasis (0.4% 

vs. 0%) 

Abd pain, enteritis, 

fever, rash (0.5% vs. 

0%) 

Tx related, diarrhea 

Constipation, ear 

disorder, enlarged 

abdomen, enterocolitis, 

erythematous rash, 

nervousness, 

somnolence, stomatitis 

(ulcerative): (0% vs. 

0.5%) 

Dermatitis (0.5% vs. 

1.9%) 

Nervousness (1% vs. 

0%) 

Otitis media (0.5% vs. 

1%) 

Uticaria (0% vs. 1.5%) 

43 Cefdinir high vs. 

low dose 

44 Amox vs. 

Azithromycin 

45 Cefdinir high vs. 

low dose 

Adler, 200073 

Arguedas, 2005 66 

Block, 200072 

Yes 

Yes 

Yes 

Vomiting (2% vs. 0.5%) 

Rash (2.6% vs. 2.5%) 

Any mention, diarrhea, tx 

related 

Abd pain, diarrhea, 

vomiting, tx related 

Any mention, diarrhea, and 

rash 

169
 
Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

reported 

46 Amox-clav 5-day Cohen, 199898 Yes Any mention, drug-related, 

vs. 10-day diarrhea, skin rash 

47 Cefaclor 5-day vs. Catania, 200499 Yes Abd pain (1.5% vs. New AOM episode 

10-day 2.4%) 

Skin rash (2.5% vs. 

2.9%) 

Diarrhea (2.0% vs. 

2.4%) 

Vomiting (0.5% vs. 

0.5%) 

48 Cefpodoxime 5­ Cohen, 2000100 Yes Any mention 

day vs. 10-day 

49 Ceftriaxone vs. Chonmaitree, 2003101 No 

Ceftriaxone+Predn 

isolone 

50 Ceftriaxone vs. Chonmaitree, 2003101 No 

Ceftriaxone+Antihi 

stamine 

51 Ceftriaxone vs. Chonmaitree, 2003101 No 

Ceftriaxone+Predn 

isolone+Antihistam 

ine 

52 Ceftriaxone+Predn Chonmaitree, 2003101 No 

isolone vs. 

Ceftriaxone+Antihi 

stamine 

53 Ceftriaxone+Predn Chonmaitree, 2003101 No 

isolone vs. 

Ceftriaxone+Predi 

nisolone+Antihista 

mine 

170
 
Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

54 Ceftriaxone+Antihi Chonmaitree, 2003101 

reported 

No 

stamine vs. 

Ceftriaxone+Predi 

nisolone+Antihista 

mine 

55 Ciprofloxacindexamethasone Roland, 2003126 Yes Burning (1% vs. 2%) Precipitate 

drops vs. Cipro otic 

drops 

Excessive crying (1% 

vs. 1%) 

Pain (1% vs. 2%) 

Pruritus (1% vs. 1%) 

Taste perversion (0% 

56 Ciprofloxacindexamethasone 

drops vs. 

Ofloxacin drops 

Roland, 2004127 Yes 

vs. 1%) 

Cough, crying, 

diarrhea, ear debris, 

edema eardrum, 

headache, hyperemia 

eardrum: (0% vs. 

0.3%) 

Discomfort ear (3.4% 

vs. 1%) 

Dizziness, erythema, 

tinnitus, 

tympanostomy tube 

blockage: (0.3% vs. 

0%) 

Super-Infection ear, 

irritation ear, pruritus 

ear, irritability, pruritus 

ear: (0% vs. 0.7%) 

171
 
Comp# Comparison Author, Year Adverse Significant Equivalence Inconclusive 

effects Differences 

reported 

57	 Otikon drops vs. 

Topical 

Anesthetic 

58	 Anesthetic vs. 

Anesthetic+Amox 

59	 Anesthetic vs. 

NHED 

60	 Anesthetic vs. 

NHED+Amox 

61	 Anesthetic+Amox 

vs. NHED 

62	 Anesthetic+Amox 

vs. NHED+Amox 

63	 NHED vs. 

NHED+Amox 

Sarrell, 2001102 Yes 

Sarrell, 2003103 Yes 

Sarrell, 2003103 Yes 

Sarrell, 2003103 Yes 

Sarrell, 2003103 Yes 

Sarrell, 2003103 Yes 

Sarrell, 2003103 Yes 

Monilia oral (0.3% vs. 

0.3%) 

Pain ear (2.4% vs. 

3%) 

Precipitate ear (2.4% 

vs. 3%) 

Serious tx related (0% 

in both arms) 

Taste perversion 

(0.3% vs. 1%) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

Any mention (0% in 

both arms) 

172
 
Table 34a. Comparison of Rates of Adverse Events Between Drugs (Significant Differences Only) 

2001 Report 2009 Update 

Comparison Number AE rate Number Total AE rate Conclusion 

of trials Difference (95% of new number difference 

CI) trials of trials (95% CI) 

Overall AE 

Amoxicillin-clavulanate (7-10d) vs. 

Azithromycin (5d) 

Amoxicillin-clavulanate vs. cefdinir 

(qd) 

Amoxicillin-clavulanate vs. cefdinir 

(bid) 

Amoxicillin clavulanate vs. 

ceftriaxone 

Gastrointestinal AEs 

Amoxicillin-clavulanate (7-10d) vs. 

Azithromycin (5d) 

Diarrhea 

Ampicillin or amoxicillin vs. cefixime 

Amoxicillin clavulanate vs. cefdinir 

Amoxicillin clavulanate vs. 

ceftriaxone 

Uncomplicated AOM 

3 19%( 9%, 29%) 0 3 

0 N/A 1 1 

0 N/A 1 1 

0 N/A 1 1 

3 18% (8%, 28%) 0 0 

5 -8% (-13, -4) 0 0 

0 1 1 

0 1 1 

N/A 

28% (17%, 39%) 

19% (8%, 31%) 

16% (9%, 24%) 

N/A 

N/A 

25% (15%, 35%)
 

in Cef QD and 

22% (11%, 32%)
 

in Cef BID
 

13% (6%, 20%)
 

Amoxicillin-clavulanate 

associated with greater 

overall AE rate 

Amoxicillin-clavulanate 

associated with greater 

overall AE rate 

Amoxicillin-clavulanate 

associated with greater 

overall AE rate 

Amoxicillin-clavulanate 

associated with greater 

overall AE rate 

Amoxicillin-clavulanate 

associated with greater rate 

of GI AE 

Cefixime associated with 

greater rate of diarrhea 

Amoxicillin clavulanate 

associated with greater rate 

of diarrhea 

Amoxicillin clavulanate 

associated with greater rate 

of diarrhea 

173
 
2001 Report 2009 Update 

Comparison Number AE rate Number Total AE rate Conclusion 

of trials Difference (95% of new number difference 

CI) trials of trials (95% CI) 

Recurrent Otitis Media 

Diarrhea 

Amoxicillin-clavulanate vs. 0 N/A Greater for amoxicillinciprofloxacin-dexamethasone ear clavulanate in 1 study, but 

drops equivalent in 41; no 

conclusion possible in 23 

comparisons 

Table notes: AE adverse event; bid twice a day; CI confidence interval; d day; NNT number needed to treat; qd once a day 

174
 
Using the 95% confidence intervals for the rate differences and the zone of MCID of 5% as 

reference, we grouped the findings into ―significant differences,‖ ―equivalence,‖ or 

―inconclusive.‖ The findings in many studies are inconclusive. However some findings show 

significant differences or equivalence. 

Diarrhea was found to be significantly higher in children treated with amoxicillin-clavulanate 

85 77 when compared to cefdinir and ceftriaxone. The adverse event rates ranged from 27% to 35% 

with amoxicillin-clavulanate and from 10% to 14% in the other treatment options. Diarrhea was 

also significantly higher in children treated with antibiotics (primarily amoxicillin) than in 

children given a prescription to hold on days 4-6 (23% vs. 8%; 95% CI: 6, 24) in one study.94 

When any mention of an adverse event was considered, the rate for amoxicillin-clavulanate 

was found to be significantly higher than for cefdinir given once a day (42% vs. 14%),85 higher 

85 77 than cefdinir given twice a day (42% vs. 23%), and higher than ceftriaxone (31% vs. 14%).

Findings of equivalence were identified in the following comparisons: 

Severe diarrhea in amoxicillin-clavulanate vs. amoxicillin-sulbactam (0.7% for 

both)69 

Vomiting in amoxicillin-clavulanate vs. azithromycin (1% vs. 2%)70 

Fever in amoxicillin-clavulanate vs. cefaclor (0% vs. 2%)5 

Rash in cefdinir vs. cefprozil (3% vs. 4%)85 

Serious events in amoxicillin vs. wait-and-see (0% for both)3 

Any mention of an adverse event in children receiving a homeopathic remedy vs. 

placebo (5% in both arms)92 

Diaper rash (4% vs. 5%), severe rash (1% vs. 0%), severe erythema multiform (0% 

vs. 0.4%), severe gastroenteritis (0% vs. 0.4%), and severe moniliasis (0.4% vs. 0%) 

in amoxicillin-clavulanate high dose vs. low dose97 

Abdominal pain, enteritis, fever, rash (0.5% vs. 0%), constipation, ear disorder, 

enlarged abdomen, enterocolitis, erythematous rash, nervousness, somnolence, 

ulcerative stomatitis (0% vs. 0.5%), dermatitis (0.5% vs. 2%), nervousness (1% vs. 

0%), otitis media (0.5% vs. 1%), urticaria (0% vs. 1.5%), vomiting (2% vs. 0.5%) in 

amoxicillin-clavulanate twice daily vs. three times daily comparison6 

Rash (2.6% vs. 2.5%) in amoxicillin vs. azithromycin comparison66
 

Abdominal pain (1.5% vs. 2.4%), skin rash (2.5% v. 2.9%), diarrhea (2% vs. 2.4%), 

vomiting (0.5% vs. 0.5%) in cefaclor 5-day vs. 10-day comparison99 

Any mention of an adverse event (0% in all arms) in comparisons between otikon 

drops, topical anesthetic, anesthetic plus amoxicillin, naturopathic treatment ear drops 

(NHED), and NHED plus amoxicillin102 

Adverse Effects in Studies of Treatment of Acute Otitis Media in 

Children with Recurrent Otitis Media or Persistent Acute Otitis Media 

Of the 58 RCTs identified in our review update that addressed the effectiveness of treatment 

options, 14 studied children with ROM, persistent AOM, or AOM treatment failure. Among the 

14 studies are 21 treatment comparisons. Eight comparisons studied the treatment of AOM in 

children with presumed or explicitly defined recurrent and/or persistent AOM, and/or AOM with 

175
 
treatment failure. Table 35 provides the findings on the comparison of the adverse event rates 

between treatment options for the eight comparisons. 

176
 
Table 35. Comparison of Adverse Event Rates Between Treatment Options from Eight Comparisons on Effectiveness of Treatment of Acute Otitis 

Media in Recurrent Otitis Media 

Comp Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

# Year Population 

1	 Amox-clav Saez- 0.5-7 years 

vs. Llorens, ROM and/or 

gatifloxacin 2005121 AOM 

treatment 

failurea 

20 sites nonUS 

2	 Amox-clav Sher, 0.5-7 years 

vs. 2005122 ROM and/or 

gatifloxacin AOM 

treatment 

failurea 

26 sites in 

US 

1 site in 

Costa Rica 

Amox-clav 

(45mg/6.4mg/kg/ 

d in 2 divided 

doses, 10d) 

Gatifloxacin 

(10mg/kg, qday, 

10d) 

* one was generalized seizure 

Amox-clav 

(90mg/6.4mg/kg/ 

d in 2 doses, 10d) 

Gatifloxacin 

(10mg/kg, qd, 

10d) 

Amox-clav Gatifloxacin Diff(95%CI) 

Any 59% (81/136) 55% 

(153/277) 

4% (-6, 14) 

Arthralgia 2% (2/136) 2% (6/277) 0% (-2.9, 2.9) 

Drug-related 15% (20/136) 18% (49/277) -3% (-11, 4.7) 

Vomiting 5% (7/136) 8% (23/277) -3% -8, 2.2) 

Diarrhea 7% (10/136) 3% (8/277) 4% (-0.2, 8) 

Abd pain 2% (2/136) 4% (11/277) -2% (-5.7, 1.7) 

Diaper rash 2% (3/136) 1% (2/277) 1%(-1.4, 3 .4) 

Serious* 2% (2/136) 0% (0/277) 2%(0.3, 3.7) 

Amox-clav Gatifloxacin Diff(95%CI) 

Any 27% (46/173) 24% (42/176) 3%(-6, 12) 

Abd pain or 

diarrhea 

(severe in 

intensity) 

0.6% (1/173) 0% (0/176) 0.6(-0.4,1.7) 

Anorexia 0% (0/173) 0.6% (1/176) -0.6%(­

1.8,0.6) 

Arthralgia 

event 

unrelated to 

treatment 

1.2% (2/173) 0.5% (1/176) 0.6%(-1.4,2.6) 

Deaths or 

Serious drug 

related events 

0% (0/173) 0% (1/173) 0% (0, 0) 

Diaper rash 6.4% (11/173) 5.1% (9/176) 1.3%(-3.6,6) 

Diarrhea 18% (31/173) 10% (17/176) 8% (1, 15) 

Vomiting 6% (10/173) 7% (12/176) -1%(-6, 4) 

Arthralgia, diaper 

rash, serious 

events equivalent 

Drug-related, 

vomiting, 

diarrhea, abd 

pain inconclusive 

Abd pain, severe 

diarrhea, 

anorexia, 

arthralgia 

unrelated to 

treatment, deaths 

or serious drugrelated 

equivalent. 

Diaper rash, 

diarrhea, 

vomiting 

inconclusive 

177
 
Comp Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

# Year Population 

3 Amox-clav 

vs. 

Noel, 

2008123 

0.5-<5 years 

ROM and/or 

Amox-clav 

(45mg/kg bid, 1 or more up 

Levofloxacin 

54% 

Amox-clav 

58% 

Diff(95%CI) 

-4%(-8,1.3) 

Arthralgia, 

arthralgia 

levofloxacin persistent 

AOMb 

10d) 

Levofloxacin 

to visit 4 

Arthralgia 

(448/827) 

1.5% (12/827) 

(475/823) 

0.7%(6/823) 0.8%(-0.2,1.8) 

disorder, arthritis 

disorder, 

66 centers in (10mg/kg bid, Arthralgia 1.2% (10/827) 0.6% (5/823) 0.6%(-0.3,1.5) arthropathy, 

6 countries, 10d) disorder fever, gait 

incl US Arthritis 0.2% (2/827) 0% (0/823) 0.2%(-0.1,0.5) disorder, muscle 

disorder weakness, otitis 

Arthropathy 0% (0/827) 0.2% (2/823) -0.2%(­ media not related 

0.5,0.1) to treatment 

Dermatitis 

Diarrhea 

Fever 

Gait 

abnormality 

disorder 

13% 

(108/827) 

13% 

(108/827) 

7% (60/827) 

0.1% (1/827) 

16% 

(129/823) 

20% 

(161/823) 

8% (64/823) 

0% (0/823) 

-3%(-6, 0.8) 

-7%(-10, -3) 

-1%(-3, 2) 

0.1%(-0.1,0.3) 

failure, pathologic 

fracture, 

musculoskeletal 

disorder, 

musculoskeletal 

adverse events, 

rhinitis, synovitis: 

equivalent 

Muscle 

weakness 

Otitis media 

not related to 

0% (0/827) 

5% (45/827) 

0.1% (1/823) 

4% (34/823) 

-0.1%(­

0.3,0.1) 

1% (-0.8, 3.4) 

Dermatitis, 

diarrhea, URI, 

vomiting: 

inconclusive treatment 

failure 

Pathologic 0% (0/827) 0.5% (4/823) -0.5%(-1, 0) 

fracture 

Musculoskelet 1.5% (12/827) 0.6% (5/823) 1%(-0.1, 1.9) 

al disorder 

(DSMC) 

Musculoskelet 2.8% (23/827) 2.3% (19/823) 0.5%(-1, 2) 

al adverse 

events 

Rhinitis 5% (43/827) 5% (39/823) 0.5%(-1.6,2.6) 

Synovitis 0.1% (1/827) 0% (0/823) 0.1%(-0.1,0.3) 

URI 6% (53/827) 9% (78/823) 3%(-5.7,-0.5) 

Vomiting 10% (81/827) 7% (61/823) 2%(-0.3, 5.1) 

178
 
Comp Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

# Year Population 

4	 Amox-clav 

vs. 

azithromycin 

5	 Amox-clav 

vs. 

ciprofloxacin 

0.3%­

dexamethaso 

ne 0.1% 

(cipro-dex) 

otic drops 

Arrieta, 

124 2003

Dohar, 

80 2006

0.5-6 years 

ROM and/or 

persistent b AOM

13 US and 5 

Latin 

American 

centers 

0.5-12 years 

with 

tympanostom 

y tubes 

6 site in US 

Amox-clav
 

(95mg/kg, bid, 

10d)
 

Azithromycin 

(20mg/kg, qd, 3d)
 

Amox-clav
 

(90mg/kg/d, bid, 

10d)
 

Cipro-dex (4 

drops, bid, 7d)
 

Amox-clav Azithromycin Diff(95%CI) 

Any 42.2% 

(62/147) 

32.0% 

(49/153) 

10%(-0.7, 21) 

Abd pain 2.0% (3/147) 3.9% (6/153) -2%(-5.7, 2) 

Anorexia 2.7% (4/147) 3.3% (6/153 -0.6%(-4, 3) 

Dermatitis 2.0% (3/147) 0.7% (1/153) 1.3%(-1.3, 4) 

Diarrhea 29.9% 

(44/147) 

19.6% 

(30/153) 

10%(0.5, 20) 

Rash 4.8% (7/147) 3.3% (5/153) 1.5%(-3, 6) 

Vomiting 8.2% (12/147) 5.2% (8/153) 3%(-2.6, 9) 

Amox-clav Cipro-Dex Diff(95%CI) 

Any 29% (12/41) 13% (5/39) 16%(-1.4,34) 

Dermatitis 7% (3/41) 0% (0/39) 7%(-1,16) 

Device block 

or taste 

perversion 

0% (0/41) 3% (1/39) -3%(-8,2.3) 

Diarrhea 20% (8/41) 0% (0/39) 20%(6.4,33) 

Ear pain 0% (0/41) 5% (2/39) -5%(-2,1.7) 

Gastroenteriti 

s 

5% (2/41) 0% (0/39) 5%(-2,12) 

Infection skin 

or nausea or 

oral moniliasis 

2.4% (1/41) 0% (0/39) 2.4%(-2.4,7) 

Vomiting 2.4% (1/41) 2.6% (1/39) -0.2%(-7, 7) 

Anorexia, 

dermatitis: 

equivalent 

Abd pain, 

diarrhea, rash, 

vomiting: 

inconclusive 

Diarrhea: higher 

in amox-clav 

Any, dermatitis, 

device block or 

taste perversion, 

ear pain, 

gastroenteritis, 

infection skin or 

nausea or oral 

moniliasis, 

vomiting: 

inconclusive 

179
 
Comp Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

# Year Population 

6	 Cefaclor vs. Turik, 

125 cefuroxime 1998

7	 Ciprofloxacin Roland, 

0.3% (cipro) 2003126 

otic drops vs. 

Cipro 0.3%­

dex 0.1% otic 

drops 

3 months-12 

years 

AOM 

treatment 

failure 

13 sites 

0.5-12 years 

with 

tympanostom 

y tubes 

18 sites in 

US 

Cefaclor 

(40mg/kg/d, bid, 

10d) 

Cefuroxime 

(40mg/kg/d, bid, 

10d) 

Cipro (3 drops, 

bid, 7d) 

Cipro-dex (3 

drops, bid, 7d) 

Cefaclor Cefuroxime 

axetil 

Diff(95%CI) 

Any 31% (32/104) 31% (32/104) -5%(-18, 8) 

Asthma or 

Bronchospas 

m unrelated to 

study drug or 

respiratory 

disorder or 

vomiting 

0% (0/104) 1% (1/101) -1%(-2.9, 0.9) 

Diarrhea 2% (2/104) 1% (11/101) -9%(-16,-2.3) 

Diarrhea 

during 

treatment 

0% (0/104) 8% (8/101) -8%(-13,-2.5) 

Increased 

cough 

7% (7/104) 0% (0/101) 7% (1.7,12) 

Rhinitis 9% (9/104) 10% (10/101) -1%(-9, 7) 

Cipro alone Cipro-dex Diff(95%CI) 

Excessive 

crying 

1% (1/98) 1% (1/103) 0% (-2.8, 2.8) 

Burning 1% (1/98) 2% (2/103) -1%(-4.2,2.4) 

Pain 1% (1/98) 2% (2/103) -1%(-4.2,2.4) 

Precipitate 3% (3/98) 0% (0/103) 3%(-0.3,6.5) 

Pruritus 1% (1/98) 1% (1/103) 0%(-2.8,2.8) 

Taste 

perversion 

0% (0/98) 1% (1/103) -1%(-3, 1) 

Asthma or 

bronchospasm 

unrelated to 

study drug or 

respiratory 

disorder or 

vomiting: 

equivalent 

Any, diarrhea, 

diarrhea during 

treatment, 

increased cough, 

rhinitis: 

inconclusive 

Excessive crying, 

burning, pain, 

pruritis, taste 

perversion: 

equivalent 

Precipitate: 

inconclusive 

180
 
8 

Comp Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

# Year Population 

Cipro 0.3%- Roland, 0.5-12 years Cipro-dex (4 

dex 0.1% otic 2004127 with drops, bid, 7d) 

drops vs. tympanostom Ofloxacin (5 

ofloxacin y tubes drops, bid, 10d) 

0.3% otic 39 sites in 

drops US 

Cipro-dex Ofloxacin Diff(95%CI) 

Cough or 

crying or 

diarrhea or 

ear debris or 

edema 

eardrum or 

headache or 

hyperemia 

eardrum 

0% (0/297) 0.3% (1/302) -0.3%(­

0.9,0.3): 

Discomfort 

ear 

3.4% (10/297) 1% (3/302) 2.4%(0.1,4.7) 

Dizziness or 

erythema or 

tinnitus or 

tympanostom 

y tube 

blockage 

0.3% (1/297) 0%(0/302) 0.3%(-0.3,0.9) 

Infection 

super ear or 

irritation ear or 

pruritus ear 

0% (0/297) 0.7% (2/302) -0.7%(­

1.6,0.2) 

Irritability 0.7% (2/297) 0% (0/302) 0.7%(-0.2,1.6) 

Monilia oral 0.3% (1/297) 0.3% (1/302) 0%(-0.9,0.9) 

Pain ear 2.4% (7/297) 3.0% (9/302) -0.6%(-3.2,2) 

Precipitate ear 0.7% (2/297) 1.0% (3/302) -0.3%(­

1.8,1.2) 

Serious Tx 

related 

0% (0/297) 0% (0/302) 0% (0, 0) 

Taste 

perversion 

0.3% (1/297) 1% (3/302) -0.7%(-2,0.6) 

Cough or crying 

or diarrhea or ear 

debris or edema 

eardrum or 

headache or 

hyperemia 

eardrum; 

discomfort ear; 

dizziness or 

erythema or 

tinnitus or 

tympanostomy 

tube blockage; 

super-infection 

ear or irritation 

ear or pruritus 

ear; irritability; 

monilia oral; pain 

ear; precipitate 

ear; serious 

treatment related; 

taste perversion: 

equivalent 

a AOM Treatment Failure: infection within 14 days of last antibiotic dose or failure to improve after 48 hours 

b Persistent AOM: signs or symptoms of AOM after 48 hours of treatment 

181 
In the comparison between amoxicillin-clavulanate and gatifloxacin, equivalence was found 

with respect to the rate of arthralgia, diaper rash, and serious events (ranged from 0% to 2%).121 

The rates for other adverse events were inconclusive: abdominal pain 2% vs. 4%, diarrhea 7% 

vs. 3%, vomiting 5% vs. 8% and drug-related events 15% vs. 18%. 

In the comparison between high-dose amoxicillin-clavulanate and gatifloxacin, equivalence 

was found with respect to the rate of abdominal pain, severe diarrhea, anorexia, arthralgia 

unrelated to treatment, deaths, or serious drug-related events (ranging from 0% to 1.2%).122 The 

rates for the following adverse events were inconclusive: diaper rash 6% vs. 5%, diarrhea 18% 

vs. 10%, and vomiting 6% vs. 7%. 

In the comparison between amoxicillin-clavulanate and levofloxacin, equivalence was found 

in a majority of adverse events including arthralgia, arthralgia disorder, arthritis disorder, 

arthropathy, fever, gait disorder, muscle weakness, otitis media not related to treatment failure, 

pathologic fracture, musculoskeletal disorder, musculoskeletal adverse events, rhinitis, and 

synovitis.123 Their rates ranged from 0% to 8%. The rates for the following adverse events were 

inconclusive: dermatitis 13% vs. 16%, diarrhea 13% vs. 20%, upper respiratory infection 6% vs. 

9%, and vomiting 10% vs. 7%. 

In the comparison between amoxicillin-clavulanate and azithromycin, equivalence was found 

in anorexia (2.7% vs. 3.3%) and dermatitis (2% vs. 1%).124 The rates for the following adverse 

events are inconclusive: abdominal pain 2% vs. 4%, diarrhea 30% vs. 20%, rash 5% vs. 3%, and 

vomiting 8% vs. 5%. 

In the comparison between amoxicillin-clavulanate and ciprofloxacin-dexamethasone ear 

drops, diarrhea was found to be significantly higher in amoxicillin-clavulanate-treated children, 

with a rate difference of 20% (95% CI: 6%, 33%) and NNT=5.80 

In the comparison between cefaclor and cefuroxime, equivalence was found with respect to 

the rate of asthma or bronchospasm unrelated to study drug, respiratory disorder, and vomiting 

(0% vs. 1%). The rates for the following adverse events were inconclusive: any adverse event 

31% vs. 36%, diarrhea 2% vs. 1%, diarrhea during treatment 0% vs. 8%, increased cough 7% vs. 

0%, and rhinitis 10% vs. –1%.125 

In the comparison between ciprofloxacin-dexamethasone and ciprofloxacin ear drops, 

equivalence was found with respect to the rate of excessive crying (both 1%), burning (1% vs. 

2%), pain (1% vs. 2%), pruritis (3% vs. 0%), and taste perversion (0% vs. 1%). The rate for the 

ear precipitate was inconclusive (3% vs. 0%).126 

In the comparison between ciprofloxacin-dexamethasone and ofloxacin ear drops, 

equivalence was found with respect to the rate of cough or crying or diarrhea or ear debris or 

eardrum edema or headache or eardrum hyperemia (0% vs. 0.3%), ear discomfort (3% vs. 1%), 

dizziness or erythema or tinnitus or tympanostomy tube blockage (0.3% vs. 0%), ear superinfection or ear irritation or ear pruritus (0% vs. 0.7%), irritability (0.7% vs. 0%), oral monilia 

(both 0.3%), ear pain (2% vs. 3%), ear precipitate (0.7% vs. 1%), serious treatment related events 

(both 0%), and taste perversion (0.3% vs. 1%).127 

182
 
Adverse Events Associated with Prevention of Acute Otitis Media in 

Children with Recurrent Otitis Media 

Of the 58 RCTs identified in our review update that addressed the effectiveness of treatment 

options, 14 studied children with ROM. Among the 14 studies are 21 treatment comparisons. 

Thirteen comparisons studied the prevention of AOM in children with ROM. Of the 13 

comparisons, four did not report or did not study adverse events. Table 36 provides the findings 

on the comparison of the adverse event rates between treatment options for the remaining 

comparisons. 

183
 
Table 36. Findings of Adverse Events from Eight Articles on Effectiveness of Prevention of Acute Otitis Media in Recurrent Otitis Media 

Comp # Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

Year Population 

1	 Amox vs. 

azithromycin 

2	 Amox vs. 

sulfisoxazole 

3	 Amox vs. placebo 

4	 Sulfisoxazole vs. 

placebo 

5	 Sulfafurazole vs. 

placebo 

6	 Sulfafurazole vs. 

De Diego, 128 2001

Teele, 

129 2000

Teele, 

129 2000

Teele, 

129 2000

Koivunen, 

130 2004

Koivunen, 

9-120 

months 

1 institution 

in Spain 

0-1 year 

2 sites in US 

0-1 year 

2 sites in US 

0-1 year 

2 sites in US 

10mos-2yrs 

1 hosp in 

Finland 

10mos-2yrs 

Amoxicillin 

(20mg/kg/d, 3mos) 

Azithromycin 

(10mg/kg/wk, 

3mos) 

Amoxicillin 

(20mg/kg/d) 

Sulfisoxazole 

(50mg/kg/d) 

Amoxicillin 

(20mg/kg/d) 

Placebo 

Sulfisoxazole 

(50mg/kg/d) 

Placebo 

Sulfafurazole 

(50mg/kg, qd, 

6mos) 

Placebo 

Sulfafurazole 

Amoxicillin Azithromycin Diff(95% CI) 

GI 2.5% (1/40) 0% (0/31) 2.5%(-3. 8) 

No adverse events studied.
 

No adverse events studied.
 

No adverse events studied.
 

Sulfafurazol 

e 

Placebo Diff (95% 

CI) 

Any 8% (5/60) 3% (2/60) 5% (-3.4, 

13) 

Diarrhea 3% (2/60) 2% (1/60) 2% 

(-4.8,7.2) 

Skin rash 3% (2/60) 0% (0/60) 3% 

(-1.3,7.9) 

Unknown 2% (1/60) 2% (1/60) 0% 

(-4.6, 4.6) 

GI: Inconclusive 

Unknown 

adverse events 

equivalent. 

Any mention, 

diarrhea, and 

skin rash 

inconclusive. 

Unknown 

adenoidectomy 2004130 1 hosp in (50mg/kg,qd, AE Sulfafuraz Adenoidec Diff(95% adverse events 

Finland 6mos) ole tomy CI) equivalent. 

Adenoidectomy Any 8.3% 0% (0/60) 8%(1.2,15 Any mention, 

(5/60) ) diarrhea, and 

Diarrhea 3% (2/60) 0% (0/60) 3%(-1.3, 

8) 

skin rash 

inconclusive. 

Skin rash 3% (2/60) 0% (0/60) 3%(-1.3, 

184
 
Comp # Comparison Author, 

Year 

Patient 

Population 

Intervention Findings of Adverse Events Conclusion 

Unknown 2% (1/60) 0% (0/60) 

8) 

2%(­

1.6,5.0) 

7 Adenoidectomy 

vs. placebo 

Koivunen, 

2004130 

10mos-2yrs 

1 hosp in 

Finland 

Adenoidectomy 

Placebo 

8 Adenoidectomy 

vs. placebo 

Paradise, 

199926 

3-15yrs 

1 hosp in 

US 

Adenoidectomy 

Placebo 

9 Adenoidectomy 

vs. 

adenotonsillecto 

my 

Paradise, 

199926 

3-15yrs 

1 hosp in 

US 

Adenoidectomy 

Adenotonsillectom 

y 

Adenoide 

ctomy 

Placebo Diff (95% 

CI) 

Any 0% (0/60) 3% (2/60) -3% (-8, 

1.3) 

Diarrhea 0% (0/60) 2% (1/60) -2% 

(-5.0,1.6) 

Skin rash 0% (0/60) 0% (0/60) 0% (0, 0) 

Unknown 0% (0/60) 2% (1/60) -2% 

(-5.0,1.6) 

Adenoide Placebo Diff(95% 

ctomy CI) 

Erythemat 7.2% 3.9% 3%(-2.3, 

ous (6/83) (7/181) 9) 

rashes 

during 

treatment 

AE Adenoidect Adenotonsil Diff(95% 

omy lectomy CI) 

Erythemato 7.2% (6/83) 2.2% 5% (0,10) 

us rashes (4/178) 

during 

treatment 

Hemorrhag 0% (0/83) 2.2% -2% 

e after (4/178) (-5.4,1) 

hospital 

Diarrhea, skin 

rash and 

unknown are 

equivalent. 

Any mention 

inconclusive 

Inconclusive 

Equivalence in 

incipient 

malignant 

hyperthermia, 

postoperative 

pneumonia, 

postoperative 

persistent 

velopharyngea 

l insufficiency, 

185
 
Comp # Comparison Author, Patient Intervention Findings of Adverse Events Conclusion 

Year Population 

discharge and serious 

Incipient 1.2% (1/83) 0.6% 0.6% sickness 

malignant (1/178) (-1.7,1) during 

hyperthermi antimicrobial 

a treatment. 

Periop & 4.8% (4/83) 14.6% -10% 

postop (26/178) (-18,-1.5) 

complicatio Inconclusive in 

ns erythematous 

Postop 1.2% (1/83) 0% (0/178) 1.2% rashes during 

pneumonia (-0.4,2.8) treatment, 

Postop 0% (0/83) 0.6% hemorrhage -0.6% 

velopharyn (1/178) (-2.3,1.1) after hospital 

geal discharge, 

insufficienc perioperative 

y – and 

persistent postoperative 

(9mo) complications, 

Postop 2.4% (2/83) 5.1% postoperative -2.7% 

velopharyn (9/178) (-8,2.6) transient 

geal (under 44 

insufficienc days) 

y-transient velopharyngea 

(<=43 d) l insufficiency, 

Retained in retained in 0% (0/83) 6% -6% (-11,­

hospital 1 > (11/178) 0.8) hospital one 

day and/or additional day. 

readmitted 

to hospital 

due to 

fever, poor 

fluid intake 

orally, 

vomiting, 

and/or 

dehydration 

Serious 0% (0/83) 0.6% -0.6% 

sickness (1/178) (-2.3,1.1) 

186
 
Comp # Comparison Author, 

Year 

Patient 

Population 

Intervention Findings of Adverse Events Conclusion 

during 

antimicrobi 

al treatment 

10 Adenotonsillecto 

my vs. placebo 

Paradise, 

199926 

3-15yrs 

1 hosp in 

US 

Adenotonsillectom 

y 

Placebo 

11 Ceftibuten 5d vs. 

Ceftibuten 10d 

Roos, 

2000131 

0.5-8yrs 

6 centers in 

Sweden 

Ceftibuten 5d 

(9mg/kg/d) 

Ceftibuten 10d 

(9mg/kg/d) 

12 Probiotics vs. 

placebo 

Hatakka, 

200791 

10mo-6yrs 

Helsinki, 

Finland 

One probiotic 

capsule 

(Lactobacillus 

rhamnosus GG 

and LC705, 

Bifidobacterium 

breve 99 and 

propionibacterium 

freudenreichii JS) 

qd for 6mos 

Placebo, qd for 

6mos 

Adenotonsil Placebo Diff (95% 

lectomy CI) 

Erythemato 2.2% 3.9% -1.7% 

us rashes (4/178) (7/181) (-5.3,1.9) 

during 

treatment 

Inconclusive 

Inconclusive 

Ceftibuten Ceftibuten Diff (95% 

5d 10d CI) 

GI 6.7% (6/90) 16.7% -10% (-19,­

disturbance (15/900) 0.6) 

No adverse events studied. 

Equivalent 

187
 
Comp # Comparison Author, Patient Intervention Fin

Adeno+Ty Tympan Diff (95% 

mpan only CI) 

Neck 0% 1% -1%(-3, 1) 

abscess (0/109) (1/108) 

or type 1 

diabetes 

dings of Adverse Events Conclusion 

Year Population 

13	 Adenoidectomy 

and 

tympanostomy 

vs. 

Tympanostomy 

only 

14	 Propolis and 

zinc vs. 

Elimination of 

environmental 

risk factors 

Hammar 

en-Malmi, 

132 2005

Marchisio, 

133 2010

1-2yrs 

Helsinki, 

Finland 

1-5yrs 

Italy 

Adenoidectomy + 

tympanostomy 

Tympanostomy 

only 

30% hydroglyceric 

extract of propolis; 

1.2% zinc sulfate 

0.3 ml/kg/d 

= QD for 3 months 

Plus Elimination of 

environmental risk 

factors 

Propolis+Zi Controls Diff (95% 

nc CI) 

Vomiting 1.6% (1/61) 1.6% (1/61) 0% (-5, 5) 

Rash 1.6% (1/61) 0.0% (0/61) 1.6% (-2, 5) 

Equivalence in 

vomiting and 

rash. 

188
 
In the comparison between amoxicillin and azithromycin, the difference in gastrointestinal 

adverse event rate was inconclusive (2.5% vs. 0%).128 

In the comparisons between sulfafurazole and placebo and between sulfafurazole and 

adenoidectomy, equivalence was found in ―unknown‖ adverse events (2% in sulfafurazole and 

placebo, 0% in adenoidectomy).130 The rates for the following adverse events are inconclusive: 

diarrhea (ranged from 0% to 3%), skin rash (ranged from 0% to 3%), and any mention (ranged 

from 0% in adenoidectomy to 8% in sulfafurazole). 

In the comparison between adenoidectomy and placebo, equivalence was found in diarrhea, 

skin rash, and unknown events (range from 0% to 2%).130 Difference in any mention of adverse 

event rate was inconclusive. 

In the comparison between adenoidectomy and adenotonsillectomy, equivalence in adverse 

event rates was found in incipient malignant hyperthermia (1.2% vs. 0.6%), postoperative 

pneumonia (1.2% vs. 0%), postoperative persistent (9 months) velopharyngeal insufficiency (0% 

vs. 0.6%), and serious sickness during antimicrobial treatment (0% vs. 0.6%).26 The rate 

differences for the following adverse events are inconclusive: erythematous rashes during 

treatment (7% vs. 2%), hemorrhage after hospital discharge (0% vs. 2%), perioperative and 

postoperative complications (5% vs. 15%), postoperative transient (under 44 days) 

velopharyngeal insufficiency (2% vs. 5%), and retention in hospital one additional day due to 

fever, poor fluid intake orally, vomiting, and/or dehydration (0% vs. 6%). 

In the comparisons between adenoidectomy and placebo and between adenotonsillectomy 

and placebo, the difference in erythematous rashes during treatment rates between treatment 

options was inconclusive, ranging from 2% in adenotonsillectomy to 7% in adenoidectomy.26 

In the comparison between ceftibuten 5-day and ceftibuten 10-day, the difference in 

gastrointestinal disturbance rates between the two treatment options (7% vs. 17%) was 

inconclusive. 

In the comparison between propolis and zinc vs. the control, the rates of vomiting and rash 

were found to be equivalent (1.6% vs. 1.6% and 1.6% vs. 0%). 

The Leach (2006) systematic review found that one additional child experienced diarrhea or 

an allergic reaction for every 100 children treated, which was not statistically significant (relative 

risk 2.0, 95% CI: 0.3, 15; random-effects model, I2

=53%) based on eleven studies (Casselbrant, 

1992; Gaskins, 1982; Gonzalez, 1986; Gray 1981; Liston 1983; Perrin 1974; Principi, 1989; 

Schuller, 1983; Sigh, 1993; Teele, 2000; Varsano, 1985), they reiterated a concern in their 

discussion that antibiotics are not without risk. 

Leach (2006) also studied the issue of antibiotic resistant organisms in two studies and found 

a statistically insignificant relative risk of 1.4 (95% CI: 0.8, 2.3; fixed-effect model, I2

=0%) 

though there appeared to be an increased carriage of resistant pneumococcus or haemophilus 

(Casselbrant, 1992; Mandel 1996). This review concluded that the choice of whether or not to 

treat children with ROM with antibiotics to prevent AOM would have to balance the benefits and 

these risks. 

Summary 

Although in general we could not reach definitive conclusions regarding clinically important 

differences in adverse event rates between most pairs of antibiotics, we noted significant 

189
 
differences in adverse event rates for a few antibiotic comparisons and equivalence in adverse 

event rates for several comparisons. For treatment of uncomplicated AOM, five adverse event 

rate comparisons showed a significant difference between two treatment options. Amoxicillinclavulanate was associated with diarrhea more often than was cefdinir (with a NNT of four)85 

and ceftriaxone (with a NNT of seven).77 The adverse event rates ranged from 27% to 35% with 

amoxicillin-clavulanate and from 10% to 14% for the other treatment options. For mention of 

any adverse event, amoxicillin-clavulanate had a higher rate than cefdinir once or twice daily85 

77 85 and ceftriaxone. However, in the Block (2000) study, amoxicillin dose was 40mg/kg/day; 

whereas in the Cohen (1999) study,58 amoxicillin dose was 80mg/kg/day. Equivalence was 

demonstrated in 29 comparisons, leaving 99 comparisons inconclusive. 

These findings complement the findings from the original review13 that showed that children 

treated with amoxicillin-clavulanate for seven to ten days had a 19% increased rate of overall 

adverse effects and an 18% increased rate of gastrointestinal adverse effects compared to 

children treated with five days of azithromycin for uncomplicated AOM. (Though not specified 

in the studies, the clavulanate/amoxicillin ratio was likely 31.25 mg per 125 mg of amoxicillin, 

i.e. the original formulation.) Six children would need to be treated with azithromycin rather than 

amoxicillin-clavulanate to avoid a gastrointestinal adverse event. The original review also found 

that children treated with cefixime had an 8% greater rate of diarrhea than children treated with 

ampicillin or amoxicillin for uncomplicated AOM, so 12 children would need to be treated with 

ampicillin or amoxicillin rather than cefixime to avoid a case of diarrhea. 

For treatment of AOM in children with presumed or explicitly defined recurrent and/or 

persistent otitis media, and/or AOM with treatment failure, we found one significant difference 

in adverse event rate comparisons. Amoxicillin-clavulanate (90 mg/kg/day and 6.4 mg/kg/day) 

was associated with diarrhea more often than ciprofloxacin-dexamethasone ear drops with a 

NNT of five.80 (In the Dohar (2006) study amoxicillin 90mg/kg/day was prescribed with 

clavulanate 6.4mg/kg/day.) However, in 41 comparisons, the adverse event rates were 

equivalent. In 23 comparisons, a definitive conclusion was not possible. 

For prevention of AOM in children with ROM, we did not find any significant differences in 

any of the adverse event rate comparisons. In 11 comparisons, the adverse event rates were 

equivalent, and in 18 comparisons, a definitive conclusion was not possible. 

Although for all three groups, the evidence was generally insufficient to allow definitive 

conclusions, the available evidence did indicate an increased rate of gastrointestinal effects and 

diarrhea specifically with amoxicillin-clavulanate and cefixime in comparison with cefdinir, 

ceftriaxone, or ciprofloxacin-dexamethasone ear drops and with ampicillin or amoxicillin, 

respectively. In addition, amoxicillin-clavulanate appeared to have a higher overall adverse 

effect rate than cefdinir, ceftriaxone, or azithromycin. 

190
 
Chapter 4. Discussion 

Limitations 

Publication Bias 

Our literature search procedures were extensive and included canvassing experts from 

academia, the clinical arena, and the FDA MedWatch database for studies. However, it is 

possible that other unpublished trial results exist for the treatments included in our report. 

Publication bias may occur, resulting in an overestimation of the efficacy of these treatments. In 

a few instances, we detected statistical evidence of possible publication bias (these instances are 

noted in the text). 

Study Quality 

An important limitation common to systematic reviews is the quality of the original studies. 

Recent attempts to assess which elements of study design and execution are related to bias have 

shown that in many cases, such efforts are not reproducible. Therefore, the current approach is to 

avoid using quality criteria to reject studies, which could affect meta-analysis results. However, 

for the assessment of quality of trials, we did use the Jadad scale, which is the only set of quality 

criteria for trials for which there is empirical evidence of an association with bias. Where 

feasible, we performed sensitivity analyses that used only the ―high quality‖ studies (those 

scoring 3 or more on Jadad‘s scale). In some cases, this sensitivity analysis yielded a pooled 

result that was lower than the result of the primary analysis, a result seen in other clinical 

settings. Therefore, it is possible that some individual trials and some primary pooled analyses 

overestimate the true effectiveness of treatments. To assess the quality of diagnostic studies, we 

used QUADAS criteria. As there is a lack of empirical evidence regarding other study 

characteristics and their relationship to bias, we did not attempt to use other criteria. 

Further limitations are provided below with respect to each of the key questions. 

Conclusions 

Key Question I. Diagnosis of AOM 

Limited evidence exists on clinicians‘ accuracy and precision in identifying the three clinical 

criteria necessary for a diagnosis of AOM. There is some evidence to suggest that clinicians 

accurately identify MEE by reliance on otoscopic findings of decreased mobility or abnormal 

position. However, there is little evidence to help us fully understand how accurate and precise 

clinicians are at identifying all three criteria in one patient to make a diagnosis of AOM. 

We reviewed studies that examined the association of individual physical exam findings 

with a diagnosis of AOM, which did not fully address this key question. Further studies are 

needed that examine clinician‘s identification of all three clinical criteria of AOM in a patient, 

compared to identification of all three criteria by an independent examiner to serve as the 

criterion standard. These types of studies should clearly identify the level of expertise of the 

191
 
studied clinicians to help evaluate the level of generalizability of results to clinicians in practice. 

Perhaps the most important way to improve diagnosis is to increase clinicians’ ability to 

recognize and rely on key otoscopic findings. 

Key Question II. The impact of the Pneumococcal Heptavalent 

Immunization (PCV7) on AOM Microbial Epidemiology 

Since the introduction of PCV7, there have been significant shifts in AOM microbiology. 

Our review indicates that overall, SP is becoming less prevalent, yet still important, while HF is 

increasing in its importance as an infectious agent of AOM. The pattern of penicillinsusceptibility among SP isolates is unclear; some studies have indicated that the proportion of 

penicillin–non susceptibility among vaccine serotype SP isolates has increased, while others 

have indicated that the proportion of SP that are non-susceptible has decreased. Future studies 

may need to consider susceptibility separately for vaccine and non-vaccine SP serotypes. 

One of the major limitations of our review for this particular key question is that 

tympanocentesis, which is required for the isolation of a microbiologic agent, is not routinely 

performed in children with uncomplicated AOM. Most of the studies that compared the 

microbiology of AOM before and after the introduction and use of PCV7 examined middle-ear 

fluid samples for children with complicated, recurrent, or persistent OM. Another limitation is 

that we do not have adequate data to understand the possible impact of PCV7 on non-bacterial 

agents (i.e., viruses). Although the importance of non-bacterial agents has been studied for 

AOM, we were unable to find studies examining the impact of PCV7 on the importance of nonbacterial causes of AOM. 

Key Question III. Treatment of Uncomplicated AOM 

Immediate antibiotic therapy is more effective than placebo for treating uncomplicated 

AOM. However, between eight and nine children would need to be treated with immediate 

antibiotics in order to observe this difference in clinical success. Clinicians will have to 

determine if this number needed to treat justifies the immediate prescription of antibiotics in 

children with uncomplicated AOM and average risk. The evidence for immediate antibiotic 

therapy vs. a delayed prescription or a wait-and-see approach is mixed, with two studies showing 

an advantage for immediate antibiotics and two studies showing inconclusive results. 

Amoxicillin-clavulanate is superior to azithromycin in terms of clinical success by day 14 

when the pathogen is HF. This finding has clinical significance, given the microbiologic shift 

following the introduction of PCV7 that seems to indicate that HF is becoming more prevalent 

than SP as a cause of AOM. 

Our review of data to address this key question (as well as questions pertaining to prevention 

and treatment of ROM) had several limitations. First, as described above in our list of the general 

limitations, definitions for clinical success were usually not equivalent between studies 

comparing the same treatments. For example, studies used different clinical criteria to define 

success, and success was often measured at different time points. Second, the inclusion criteria 

for participants also varied widely among studies. Some studies used only one of the three 

criteria for AOM diagnosis, while others considered two or all three. It is possible that some 

studies with less stringent inclusion criteria may have included participants who did not have 

192
 
AOM, but rather had OME or no middle ear infective process at all. Third, the timing of study 

completion could affect results. As evidenced by the analysis of changes in epidemiology, the 

microbiology of AOM is changing, in part, based on the introduction of PCV7. It is unclear how 

differences in AOM microbiology over time might affect our findings from pooled analyses. 

Because we considered a minimum clinically important difference (MCID) of 5%, we sometimes 

considered results as clinically insignificant that were statistically significant. Since the 

minimum clinically significant difference for AOM is not empirically known, readers who 

assume an MCID different than 5% would reach modestly different conclusions. Any decision to 

suggest antibiotic treatment or choice of antibiotic involves a trade-off between the expectation 

of benefit compared with the risks. 

Key Question IV. Prevention or Treatment of Acute Otitis Media in 

Children with Recurrent Otitis Media 

We are unable to draw any definitive conclusions regarding the comparative effectiveness of 

different antibiotic treatments for treatment of AOM in children with ROM. Leach (2006) found 

on systematic review that long-term antibiotics, defined as treatment for six weeks or longer, 

prevented 1.5 episodes of AOM for every 12 months of treatment per otitis-prone child during 

active treatment (95% CI: 1.2, 2.1) who would otherwise average three episodes of AOM 

annually without treatment. Since this reduced risk of AOM was present only during therapy, the 

drawbacks of long-term antibiotics (including adverse effects such as diarrhea and allergic 

reactions, and emergence of bacterial resistance to antibiotics) must be weighed against the 

occurrence of another episode of AOM in the patient. In addition, all of the studies on which this 

finding is based were conducted prior to the widespread introduction of the heptavalent 

pneumococcal vaccine, which may influence bacterial etiology and resistance as noted in the 

findings for Key Question II in this review. It was decided that a review of the effectiveness of 

vaccines in preventing AOM was beyond the scope of this report. Thus, it may be difficult to 

generalize the Leach (2006) findings to the current population of children with ROM. 

Further, we can also conclude that tympanostomy tubes can help decrease the likelihood of a 

repeat infection in a child with a history of ROM within the first six months after tube insertion. 

This conclusion may be tempered by the issue of AOM diagnostic accuracy in the presence of 

tympanostomy tubes possibly confounding these results, i.e. the pressure equalization and 

drainage afforded by the tubes and their physical presence decreasing the intensity or visibility of 

signs and symptoms used to diagnose AOM leading to false negatives. Again, whether or not the 

benefit of avoiding a repeat episode of AOM over six months outweighs the costs of a 

tympanostomy tube placement will depend on the clinician‘s assessment of the child with AOM, 

and discussions of advantages and disadvantages with the family. 

The limitations in our ability to address this question mirror those for Key Question III. The 

lack of uniformity of definitions for ROM and clinical success and differences in measurement 

times made synthesis of the available evidence difficult. Similar to Key Question III, one 

treatment comparison that demonstrated statistically significant results did not demonstrate 

clinically significant results in terms of the zone of MCID. We again acknowledge that others 

may practice from a zone of MCID different from the +/-5% standard utilized in this study. 

193
 
Key Question V 

Whereas the 2001 evidence review identified only sufficient evidence to allow the 

assessment of age on treatment effectiveness, the current review identified information to assess 

the effect of laterality and otorrhea, as well. Few to no conclusions can be made on the effect of 

other influencing factors such as characteristics of the patient, AOM episode, environment, and 

the health care system on the comparative effectiveness of treatment. 

Meta-analysis conducted for this review indicates that children over the age of 2 years had 

better outcomes with various treatment options including placebo or no treatment than children 

under age 2. Data from a systematic review by Rovers (2006) utilizing individual patient data 

showed a similar effect of age on antibiotic treatment of uncomplicated AOM. In addition, 

Rovers (2006) found that laterality, especially in children 2 years and younger, and otorrhea had 

impacts on antibiotic effectiveness. These findings suggest that clinicians may need to monitor 

response to treatment and outcomes more closely when treating very young children with AOM, 

particularly those with bilateral AOM and those with otorrhea. The primary limitation related to 

this question was that the available evidence was limited and primarily focused on the 

association of age with AOM treatment, though other influencing factors are commonly cited as 

being important, such as AOM characteristics, including severity and characteristics of the 

patient, environment, and the healthcare delivery system. In addition, if the operating 

characteristics of AOM diagnostic criteria differ by age, then it is possible that treatment 

outcomes stratified by age may be confounded by a differential rate of inclusion of children who 

do not actually have AOM. 

Key Question VI 

The available evidence indicated an increased rate of gastrointestinal adverse effects and 

diarrhea specifically with amoxicillin-clavulanate and cefixime in comparison with cefdinir, 

ceftriaxone, or ciprofloxacin-dexamethasone ear drops and with ampicillin or amoxicillin, 

respectively. In addition amoxicillin-clavulanate appeared to have a higher overall adverse effect 

rate than cefdinir, ceftriaxone, or azithromycin. 

The limitations in our assessment for this question are similar to those cited above. The lack 

of uniformity of definitions for AOM and ROM and adverse effects and the differences in 

measurement times made synthesis of the available evidence difficult. As with key questions III 

and IV, treatment comparisons that demonstrated statistically significant results did not always 

demonstrate clinically significant results in terms of the zone of MCID. We again acknowledge 

that others may practice from a zone of MCID that is different from the +/-5% standard used in 

this study. 

Future Research Suggestions 

Based on the findings of this review, we provide the following suggestions for future 

research directions. 

194
 
Key Question I: Diagnostic Criteria for AOM 

Additional studies are needed to more fully understand the precision of the current diagnostic 

criteria for AOM: acute onset of signs and symptoms, MEE, and middle ear inflammation. For 

example, evidence is insufficient to guide clinicians on the most effective and efficient ways to 

assess each of these elements in the clinical setting. Also needed are more studies that use a 

reference standard that can take into account all three criteria of an AOM diagnosis. Thus, a 

reference standard that takes into account only MEE does not provide sufficient evidence on 

overall diagnostic accuracy for AOM. 

Key Question II: Effects of the PCV7 Vaccine 

The five studies included in this report that address Key Question II provide information 

about the changing microbiologic patterns of otitis media since the introduction of PCV7, 

specifically, that HF has become more prevalent as a causative agent of AOM, although SP 

remains an important pathogen. The introduction of the vaccine has also resulted in a greater 

proportion of non-vaccine serotypes and a smaller proportion of vaccine serotypes as causative 

agents in AOM. However, none of the studies addressed the implications of this observed 

evolution in microbiology subsequent to introduction of the vaccine. For example, will this shift 

in microbiology translate to a shift in the type and incidence of suppurative and other 

complications? Further research is needed to explore the impact of PCV7 on the clinical 

progression and outcomes of uncomplicated AOM, and of AOM in otitis-prone children with 

recurrent AOM. 

More inquiry is needed into microbiologic shifts in AOM, especially as it relates to resistance 

patterns of the non-PCV7 serotypes of SP that seem to be increasing since the introduction of 

PCV7. Such research will require continued surveillance of both shifts in the causative 

organisms of AOM and in the antibiotic resistance/susceptibility of these organisms. 

A recent study of a single pediatric practice, not meeting our inclusion criteria, found 

evidence suggesting that an increase in the proportion of AOM with non-vaccine SP serotypes 

may be leading to another shift in AOM microbiology.8 These new data support the need for 

ongoing surveillance of AOM isolates. 

Continued surveillance will also help us understand the impact of new pneumococcal 

vaccines, such as the newly-licensed PCV 13, that include more serotypes than PCV7 currently 

does. It will be important to have information to help conduct cost-benefit analysis of vaccines 

that cover more than the current seven serotypes. 

A growing body of research is assessing the efficacy of the vaccine in preventing AOM. 

Although a review of this literature was beyond the scope of this report, such a review may be 

warranted in the near future. 

Key Questions III-VI: Treatment Efficacy and Adverse Effects 

Research issues identified in the original AOM review13 are still applicable to the review 

update as it relates to treatment of uncomplicated AOM as well as to treatment of ROM, which 

was not previously addressed. Though we report several definitive conclusions, the usefulness of 

195
 
these conclusions to the practitioner is suspect because of concerns regarding the internal validity 

of some of the source studies and the generalizability of the findings because of a lack of 

standard definitions for AOM and ROM as well as for treatment outcomes across studies; the 

variability of study quality; and the relative paucity of evidence related to influencing factors 

such as AOM severity, and other important factors. In addition, the impact of PCV7 as noted in 

this review‘s findings for KQ2, and of changing patterns of AOM bacterial etiology and 

resistance in general, must be considered in designing future studies. 

Standard definitions of AOM and ROM that lead to standard diagnostic criteria and that are 

acceptable to both researchers and practitioners have not been developed since the initial review 

and are still needed. In the studies newly identified for this review update, only two of the 43 

articles on treatment of uncomplicated AOM and one of the fifteen articles on treatment of 

children with ROM, persistent AOM, or AOM treatment failure included all three AOM 

diagnostic criteria recommended by the AAP AOM guidelines. This finding represents a slight 

improvement compared to the original review (Table 37).13 The continued diversity of 

definitions for AOM as well as for ROM and, therefore, the diversity of diagnostic criteria that 

control entry of participants into these treatment trials make it difficult to synthesize and 

generalize findings, as it is unclear if the same condition is being assessed across studies. Greater 

knowledge regarding the operating characteristics of criteria used to diagnose children of 

different ages will also help to assess results of studies comparing treatment options (e.g., are we 

more likely to be treating real AOM in an infant or an older child diagnosed with AOM?) In 

addition, knowledge of the effect of tympanostomy tube presence on these diagnostic operating 

characteristics will help to better assess the true impact of tympanostomy tubes on prevention of 

AOM in children with ROM. 

Table 37. Number of Randomized Controlled Trials in the Original Review by Marcy (2001)13 and the Review 

Update by Number of AOM Diagnostic Criteria Used and by Number of Jadad Study Quality Criteria Met 

Topic AOM diagnostic criteria Jadad study quality criteria 

Number Number of studies Number Number of studies (Percent) 

(Percent) 

Original Review Update Original Review Update 

Review Review 

Treatment of 0 38 (35%) 8 (19%) 0 1 (1%) 0 (0%) 

uncomplicated 1 34 (43%) 4 (9%) 1 8 (11%) 5 (12%) 

AOM 2 18 (23%) 29 (67%) 2 26 (35%) 14 (32%) 

3 0 (0%) 2 (5%) 3 21 (28%) 15 (35%) 

4 12 (16%) 3 (7%) 

5 6 (8%) 6 (14%) 

Treatment of 0 n/a 6 (40%) 0 n/a 0 (0%) 

recurrent otitis 1 0 (0%) 1 1 (7%) 

media, 2 8 (53%) 2 6 (40%) 

persistent acute 3 1 (7%) 3 6 (40%) 

otitis media, or 4 0 (0%) 

AOM treatment 5 2 (13%) 

failure 

Total 0 38 (35%) 14 (24%) 0 1 (1%) 0 (0%) 

1 34 (43%) 4 (7%) 1 8 (11%) 6 (10%) 

2 18 (23%) 37 (64%) 2 26 (35%) 20 (34%) 

3 0 (0%) 3 (5%) 3 21 (28%) 21 (36%) 

4 12 (16%) 3 (5%) 

5 6 (8%) 8 (14%) 

196
 
Standard definitions related to the quality of AOM management in terms of specific 

structures, processes, and outcomes are still needed. For example, Table 8 documents the 

diversity of high-level outcomes chosen for measurement in the 63 treatment option comparisons 

for uncomplicated AOM. Though 62 comparisons measured clinical success, only three 

measured invasive infections 14, bacteriologic cure; 24, disease recurrence; 48, adverse effects; 

four, quality of life; seven, patient satisfaction; six, cost; and 16, other outcomes. Information in 

the evidence table demonstrates the varying definitions of clinical success among the 62 

comparisons. Differences in terminology and in particular outcome choice and definitions 

between studies make it difficult to synthesize the results across studies and to generalize 

findings. This issue should be addressed in future studies. 

Higher quality studies as well as improved reporting of study characteristics related to quality 

are still needed to come to definitive conclusions for AOM and ROM treatment options. Of the 

58 RCTs newly identified for this review update, reported compliance with the 5 Jadad study 

quality criteria was not universal: one criterion in six studies; two criteria in 20 studies; three 

criteria in 21 studies; four criteria in three studies; five criteria in eight studies. Thus, study 

quality is not improved compared to the original review.13(Table 37) Although we recognize that 

the issue may be the documentation of study characteristics rather than the actual study quality, 

sensitivity analysis by quality in this review significantly affected the results of the comparisons 

of ampicillin/amoxicillin in treatment of uncomplicated AOM, changing the results from 

significant to not significant when pooling studies. This finding suggests that the quality of the 

studies as currently documented may indeed reflect the true quality of these studies and may 

have an effect on the study results. 

Since the previous review, further evidence confirms that age is an important factor 

influencing treatment outcome in uncomplicated AOM and ROM with particular treatment 

options, and new evidence suggests a role for laterality and otorrhea. In addition, the role of 

laterality on antibiotic effect was associated with age and highlights the need to have studies of 

sufficient power to allow study of interactions as is suggested by the studies of Leibovitz (2007) 

and McCormick (2007), which describe the clinical and microbiologic characteristics of patients 

with bilateral vs. unilateral AOM. Both studies found that bilateral disease is more often 

associated with bacteria in the MEE, in particular HF; younger age; and greater severity disease. 

However, additional high quality research is needed to establish definitive conclusions regarding 

the influence of other factors, including characteristics of the AOM episode (such as disease 

severity), the patient, the environment (such as the daytime caretaker and use of daycare), and 

the healthcare delivery systems (such as the examiner) on treatment success. Future research 

must be designed so the selection of study participants balances the need for generalizability of 

findings with the need to study the applicability of findings to patients with specific 

characteristics. Practitioners take these unique characteristics into account when treating 

individual patients. Thus, future research will lead to greater improvements if it also addresses 

individual patient characteristics. 

Finally, we recommend that the concept of an a priori established zone of MCID be included 

in assessing the impact of treatment options in addition to statistical significance. As noted 

throughout the report results, many instances of statistically significant results with clinically 

insignificant impacts were identified during the review update. Clinical practice should be 

guided by evidence that exceeds a MCID for the practitioner. However, we acknowledge that the 

minimal clinically important difference must be established by the clinician based on the 

particular decision in question. 

197
 
198
 
References
 

1.	 Laine MK, Tahtinen PA, Ruuskanen O, 

Huovinen P, Ruohola A. Symptoms or symptombased scores cannot predict acute otitis media at 

otitis-prone age. Pediatrics. 2010 

May;125(5):e1154-61. 

2.	 Little P, Gould C, Williamson I, Moore M, 

Warner G, Dunleavey J. Pragmatic randomised 

controlled trial of two prescribing strategies for 

childhood acute otitis media. BMJ. 2001 Feb 

10;322(7282):336-42. 

3.	 McCormick DP, Chonmaitree T, Pittman C, 

Saeed K, Friedman NR, Uchida T, et al. 

Nonsevere acute otitis media: a clinical trial 

comparing outcomes of watchful waiting versus 

immediate antibiotic treatment. Pediatrics. 2005 

Jun;115(6):1455-65. 

4.	 Scholz H, Noack R. Multicenter, randomized, 

double-blind comparison of erythromycin 

estolate versus amoxicillin for the treatment of 

acute otitis media in children. AOM Study 

Group. Eur J Clin Microbiol Infect Dis. 1998 

Jul;17(7):470-8. 

5.	 Subba Rao SD, Macias MP, Dillman CA, Ramos 

BD, Kierszenbaum JS, Soliman AE. A 

randomized, observer-blind trial of 

amoxycillin/clavulanate versus cefaclor in the 

treatment of children with acute otitis media. 

Augmentin 415 Study Group. J Chemother. 1998 

Dec;10(6):460-8. 

6.	 Damrikarnlert L, Jauregui AC, Kzadri M. 

Efficacy and safety of amoxycillin/clavulanate 

(Augmentin) twice daily versus three times daily 

in the treatment of acute otitis media in children. 

The Augmentin 454 Study Group. J Chemother. 

2000 Feb;12(1):79-87. 

7.	 Dagan R, Johnson CE, McLinn S, Abughali N, 

Feris J, Leibovitz E, et al. Bacteriologic and 

clinical efficacy of amoxicillin/clavulanate vs. 

azithromycin in acute otitis media. Pediatr Infect 

Dis J. 2000 Feb;19(2):95-104. 

8.	 Casey JR, Adlowitz DG, Pichichero ME. New 

patterns in the otopathogens causing acute otitis 

media six to eight years after introduction of 

pneumococcal conjugate vaccine. Pediatr Infect 

Dis J. 2010 Apr;29(4):304-9. 

9.	 Daly KA, Brown JE, Lindgren BR, Meland MH, 

Le CT, Giebink GS. Epidemiology of otitis 

media onset by six months of age. Pediatrics. 

1999 Jun;103(6 Pt 1):1158-66. 

10.	 McCaig LF, Besser RE, Hughes JM. Trends in 

antimicrobial prescribing rates for children and 

adolescents. JAMA. 2002 Jun 19;287(23):3096-

102. 

11.	 Teele DW, Klein JO, Rosner B. Epidemiology of 

otitis media during the first seven years of life in 

children in greater Boston: a prospective, 

cohortstudy. J Infect Dis. 1989 Jul;160(1):83-94. 

12.	 Bharmal M, Kamble S. Incremental cost of otitis 

media among children in the United States. 

Qunitles, Inc, Falls Church, CA, USA; University 

of North Carolina at Charlotte, NC, USA. 

2009:PIH20. 

13.	 Marcy M, Takata G, Chan LS, Shekelle P, Mason 

W, Wachsman L, et al. Management of Acute 

Otitis Media. Evidence Report/Technology 

Assessment No. 15 Rockville, MD: Agency for 

Healthcare Research and Quality; 2001. Report 

No.: AHRQ Publication No. 01-E010 Contract 

No.: Document Number|. 

14.	 Rosenfeld RM. Diagnostic certainty for acute 

otitis media. Int J Pediatr Otorhinolaryngol. 2002 

Jun 17;64(2):89-95. 

15.	 Rothman R, Owens T, Simel DL. Does this child 

have acute otitis media? JAMA. 2003 Sep 

24;290(12):1633-40. 

16.	 Diagnosis and management of acute otitis media. 

Pediatrics. 2004 May;113(5):1451-65. 

17.	 Paradise JL. Otitis media in infants and children. 

Pediatrics. 1980 May;65(5):917-43. 

18.	 Segal N, Leibovitz E, Dagan R, Leiberman A. 

Acute otitis media-diagnosis and treatment in the 

era of antibiotic resistant organisms: updated 

clinical practice guidelines. Int J Pediatr 

Otorhinolaryngol. 2005 Oct;69(10):1311-9. 

19.	 Froom J, Culpepper L, Grob P, Bartelds A, 

Bowers P, Bridges-Webb C, et al. Diagnosis and 

antibiotic treatment of acute otitis media: report 

from International Primary Care Network. BMJ. 

1990 Mar 3;300(6724):582-6. 

20.	 Coco AS, Horst MA, Gambler AS. Trends in 

broad-spectrum antibiotic prescribing for children 

with acute otitis media in the United States, 

1998-2004. BMC Pediatr. 2009;9:41. 

21.	 Dowell SF, Butler JC, Giebink GS, Jacobs MR, 

Jernigan D, Musher DM, et al. Acute otitis 

media: management and surveillance in an era of 

pneumococcal resistance--a report from the 

Drug-resistant Streptococcus pneumoniae 

Therapeutic Working Group. Pediatr Infect Dis J. 

1999 Jan;18(1):1-9. 

22.	 Arrieta A, Singh J. Management of recurrent and 

persistent acute otitis media: new options with 

familiar antibiotics. Pediatr Infect Dis J. 2004 

Feb;23(2 Suppl):S115-24. 

23.	 Pichichero ME. Recurrent and persistent otitis 

media. Pediatr Infect Dis J. 2000 Sep;19(9):911-

6. 

24.	 Jacobs MR. Antibiotic-resistant Streptococcus 

pneumoniae in acute otitis media: overview and 

update. Pediatr Infect Dis J. 1998 

Oct;17(10):947-52. 

25.	 Preventing pneumococcal disease among infants 

and young children. Recommendations of the 

Advisory Committee on Immunization Practices 

(ACIP). MMWR Recomm Rep. 2000 Oct 

6;49(RR-9):1-35. 

199
 
26.	 Paradise JL, Bluestone CD, Colborn DK, Bernard 

BS, Smith CG, Rockette HE, et al. 

Adenoidectomy and adenotonsillectomy for 

recurrent acute otitis media: parallel randomized 

clinical trials in children not previously treated 

with tympanostomy tubes. Jama. 1999 Sep 

8;282(10):945-53. 

27.	 Hendley JO. Clinical practice. Otitis media. N 

Engl J Med. 2002 Oct 10;347(15):1169-74. 

28.	 Pichichero ME, Arguedas A, Dagan R, Sher L, 

Saez-Llorens X, Hamed K, et al. Safety and 

efficacy of gatifloxacin therapy for children with 

recurrent acute otitis media (AOM) and/or AOM 

treatment failure. Clin Infect Dis. 2005 Aug 

15;41(4):470-8. 

29.	 Jadad AR, Moore RA, Carroll D, Jenkinson C, 

Reynolds DJ, Gavaghan DJ, et al. Assessing the 

quality of reports of randomized clinical trials: is 

blinding necessary? Control Clin Trials. 1996 

Feb;17(1):1-12. 

30.	 Sackett DL, Tugwell P, Guyatt GH. Clinical 

epidemiology: a basic science for clinical 

medicine. 1991. 

31.	 Trout KS. How to read clinical journals: IV. To 

determine etiology or causation. Can Med Assoc 

J. 1981;124:985-90. 

32.	 Tugwell P. How to read clinical journals: III. To 

determine etiology or causation. Can Med Assoc 

J. 1981;124:869-72. 

33.	 Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, 

Kleijnen J. The development of QUADAS: a tool 

for the quality assessment of studies of diagnostic 

accuracy included in systematic reviews. BMC 

Med Res Methodol. 2003 Nov 10;3:25. 

34.	 DerSimonian R, Laird N. Meta-analysis in 

clinical trials. Control Clin Trials. 1986 

Sep;7(3):177-88. 

35.	 Laird NM, Mosteller F. Some statistical methods 

for combining experimental results. Int J Technol 

Assess Health Care. 1990;6(1):5-30. 

36.	 Higgins JP, Thompson SG, Deeks JJ, Altman 

DG. Measuring inconsistency in meta-analyses. 

BMJ. 2003 Sep 6;327(7414):557-60. 

37.	 StataCorp. Stata Statistical Software: Release 10. 

College Station, TX; 2007. 

38.	 Cohen J. Statistical Power Analysis for the 

Behavioral Sciences. Academic Press, Inc; 1977. 

p. 179-213. 

39.	 Saeed K, Coglianese CL, McCormick DP, 

Chonmaitree T. Otoscopic and tympanometric 

findings in acute otitis media yielding dry tap at 

tympanocentesis. Pediatr Infect Dis J. 2004 

Nov;23(11):1030-4. 

40.	 Legros JM, Hitoto H, Garnier F, Dagorne C, 

Parot-Schinkel E, Fanello S. Clinical qualitative 

evaluation of the diagnosis of acute otitis media 

in general practice. Int J Pediatr 

Otorhinolaryngol. 2008 Jan;72(1):23-30. 

41.	 Niemela M, Uhari M, Jounio-Ervasti K, 

Luotonen J, Alho OP, Vierimaa E. Lack of 

specific symptomatology in children with acute 

otitis media. Pediatr Infect Dis J. 1994 

Sep;13(9):765-8. 

42.	 Heikkinen T, Ruuskanen O. Signs and symptoms 

predicting acute otitis media. Arch Pediatr 

Adolesc Med. 1995 Jan;149(1):26-9. 

43.	 Ingvarsson L. Acute otalgia in children - findings 

and diagnosis. Acta Paediatr Scand. 1982 

Sep;71(5):705-10. 

44.	 Kontiokari T, Koivunen P, Niemela M, Pokka T, 

Uhari M. Symptoms of acute otitis media. Pediatr 

Infect Dis J. 1998 Aug;17(8):676-9. 

45.	 Legros JM, Hitoto H, Garnier F, Dagorne C, 

Dubin J, Fanello S. [Reliability of the diagnosis 

of acute otitis media by general practitioners]. 

Arch Pediatr. 2007 May;14(5):427-33. 

46.	 Block SL, Hedrick J, Harrison CJ, Tyler R, Smith 

A, Findlay R, et al. Community-wide vaccination 

with the heptavalent pneumococcal conjugate 

significantly alters the microbiology of acute 

otitis media. Pediatr Infect Dis J. 2004 

Sep;23(9):829-33. 

47.	 Casey JR, Pichichero ME. Changes in frequency 

and pathogens causing acute otitis media in 1995-

2003. Pediatr Infect Dis J. 2004 Sep;23(9):824-8. 

48.	 McEllistrem MC, Adams JM, Patel K, 

Mendelsohn AB, Kaplan SL, Bradley JS, et al. 

Acute otitis media due to penicillinnonsusceptible Streptococcus pneumoniae before 

and after the introduction of the pneumococcal 

conjugate vaccine. Clin Infect Dis. 2005 Jun 

15;40(12):1738-44. 

49.	 Brook I, Gober AE. Bacteriology of 

spontaneously draining acute otitis media in 

children before and after the introduction of 

pneumococcal vaccination. Pediatr Infect Dis J. 

2009 Jul;28(7):640-2. 

50.	 Veenhoven R, Bogaert D, Uiterwaal C, Brouwer 

C, Kiezebrink H, Bruin JI, et al. Effect of 

conjugate pneumococcal vaccine followed by 

polysaccharide pneumococcal vaccine on 

recurrent acute otitis media: a randomised study. 

Lancet. 2003 Jun 28;361(9376):2189-95. 

51.	 Eskola J, Kilpi T, Palmu A, Jokinen J, 

Haapakoski J, Herva E, et al. Efficacy of a 

pneumococcal conjugate vaccine against acute 

otitis media. N Engl J Med. 2001 Feb 

8;344(6):403-9. 

52.	 Guven M, Bulut Y, Sezer T, Aladag I, Eyibilen 

A, Etikan I. Bacterial etiology of acute otitis 

media and clinical efficacy of amoxicillinclavulanate versus azithromycin. Int J Pediatr 

Otorhinolaryngol. 2006 May;70(5):915-23. 

53.	 Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe 

SE, Wincott JL, Sitar DS, Klassen TP, et al. Short 

course antibiotics for acute otitis media. 

Cochrane Database Syst Rev. 

2000(2):CD001095. 

200
 
54.	 Glasziou PP, Del Mar CB, Sanders SL, Hayem 

M. Antibiotics for acute otitis media in children. 

Cochrane Database Syst Rev. 

2004(1):CD000219. 

55.	 Foxlee R, Johansson A, Wejfalk J, Dawkins J, 

Dooley L, Del Mar C. Topical analgesia for acute 

otitis media. Cochrane Database Syst Rev. 

2006;3:CD005657. 

56.	 Rovers MM, Glasziou P, Appelman CL, Burke P, 

McCormick DP, Damoiseaux RA, et al. 

Antibiotics for acute otitis media: a meta-analysis 

with individual patient data. Lancet. 2006 Oct 

21;368(9545):1429-35. 

57.	 Spurling GK, Del Mar CB, Dooley L, Foxlee R. 

Delayed antibiotics for respiratory infections. 

Cochrane Database Syst Rev. 

2007(3):CD004417. 

58.	 Coleman C, Moore M. Decongestants and 

antihistamines for acute otitis media in children. 

Cochrane Database Syst Rev. 

2008(3):CD001727. 

59.	 Thanaviratananich S, Laopaiboon M, Vatanasapt 

P. Once or twice daily versus three times daily 

amoxicillin with or without clavulanate for the 

treatment of acute otitis media. Cochrane 

Database Syst Rev. 2008(4):CD004975. 

60.	 Del Mar C, Glasziou P, Hayem M. Are 

antibiotics indicated as initial treatment for 

children with acute otitis media? A metaanalysis. BMJ. 1997 May 24;314(7093):1526-9 

61.	 Rosenfeld RM, Vertrees JE, Carr J, Cipolle RJ, 

`Uden DL, Giebink GS, et al. Clinical efficacy of 

antimicrobial drugs for acute otitis media: 

metaanalysis of 5400 children from thirty-three 

randomized trials. J Pediatr. 1994 

Mar;124(3):355-67. 

62.	 Damoiseaux RA, van Balen FA, Hoes AW, de 

Melker RA. Antibiotic treatment of acute otitis 

media in children under two years of age: 

evidence based? Br J Gen Pract. 1998 

Dec;48(437):1861-4. 

63.	 Rosenfeld RM, Kay D. Natural history of 

untreated otitis media. Laryngoscope. 2003 

Oct;113(10):1645-57. 

64.	 Rosenfeld RM. What to expect from medical 

theraphy: In: Bluestone CD, eds. Evidence-baed 

otitis media. Decker Inc. 1999:179-205. 

65.	 Zielnik-Jurkiewicz B, Jurkiewicz D. [Usefulness 

of fenspiride in the treatment of acute otitis media 

in children]. Pol Merkur Lekarski. 2005 

Jun;18(108):624-8. 

66.	 Arguedas A, Emparanza P, Schwartz RH, Soley 

C, Guevara S, de Caprariis PJ, et al. A 

randomized, multicenter, double blind, double 

dummy trial of single dose azithromycin versus 

high dose amoxicillin for treatment of 

uncomplicated acute otitis media. Pediatr Infect 

Dis J. 2005 Feb;24(2):153-61. 

67.	 Morris PS, Gadil G, McCallum GB, Wilson CA, 

Smith-Vaughan HC, Torzillo P, et al. Single-dose 

azithromycin versus seven days of amoxycillin in 

the treatment of acute otitis media in Aboriginal 

children (AATAAC): a double blind, randomised 

controlled trial. Med J Aust. 2010 Jan 

4;192(1):24-9. 

68.	 Zhang YM, Dong P, Lu P. [Efficacy and safety of 

one dose ceftriaxone vs. ten-day oral amoxicillin 

for treatment of acute otitis media in children]. 

Zhonghua Er Ke Za Zhi. 2003 Feb;41(2):135-8. 

69.	 Casellas JMJ, Israele V, Marin M, Ishida MT, 

Heguilen R, Soutric J, et al. Amoxicillinsulbactam versus amoxicillin-clavulanic acid for 

the treatment of non-recurrent-acute otitis media 

in Argentinean children. Int J Pediatr 

Otorhinolaryngol. 2005 Sep;69(9):1225-33. 

70.	 Dunne MW, Latiolais T, Lewis B, Pistorius B, 

Bottenfield G, Moore WH, et al. Randomized, 

double-blind study of the clinical efficacy of 3 

days of azithromycin compared with coamoxiclav for the treatment of acute otitis media. 

J Antimicrob Chemother. 2003 Sep;52(3):469-72. 

71.	 Biner B, Celtik C, Oner N, Kucukugurluoglu Y, 

Guzel A, Yildirim C, et al. The comparison of 

single-dose ceftriaxone, five-day azithromycin, 

and ten-day amoxicillin/clavulanate for the 

treatment of children with acute otitis media. 

Turk J Pediatr. 2007 Oct-Dec;49(4):390-6. 

72.	 Block SL, McCarty JM, Hedrick JA, Nemeth 

MA, Keyserling CH, Tack KJ. Comparative 

safety and efficacy of cefdinir vs 

amoxicillin/clavulanate for treatment of 

suppurative acute otitis media in children. Pediatr 

Infect Dis J. 2000 Dec;19(12 Suppl):S159-65. 

73.	 Adler M, McDonald PJ, Trostmann U, 

Keyserling C, Tack K. Cefdinir vs. 

amoxicillin/clavulanic acid in the treatment of 

suppurative acute otitis media in children. Pediatr 

Infect Dis J. 2000 Dec;19(12 Suppl):S166-70. 

74.	 Cifaldi MA, Paris MM, Devcich KJ, Bukofzer S. 

Parent-reported outcomes for treatment of acute 

otitis media with cefdinir or 

amoxicillin/clavulanate oral suspensions. Paediatr 

Drugs. 2004;6(6):387-93. 

75.	 Block SL, Busman TA, Paris MM, Bukofzer S. 

Comparison of five-day cefdinir treatment with 

ten-day low dose amoxicillin/clavulanate 

treatment for acute otitis media. Pediatr Infect 

Dis J. 2004 Sep;23(9):834-8. 

76.	 Hedrick JA, Sher LD, Schwartz RH, Pierce P. 

Cefprozil versus high-dose 

amoxicillin/clavulanate in children with acute 

otitis media. Clin Ther. 2001 Feb;23(2):193-204. 

201
 
77.	 Cohen R, Navel M, Grunberg J, Boucherat M, 

Geslin P, Derriennic M, et al. One dose 

ceftriaxone vs. ten days of 

amoxicillin/clavulanate therapy for acute otitis 

media: clinical efficacy and change in 

nasopharyngeal flora. Pediatr Infect Dis J. 1999 

May;18(5):403-9. 

78.	 Wang CY, Lu CY, Hsieh YC, Lee CY, Huang 

LM. Intramuscular ceftriaxone in comparison 

with oral amoxicillin-clavulanate for the 

treatment of acute otitis media in infants and 

children. J Microbiol Immunol Infect. 2004 

Feb;37(1):57-62. 

79.	 Pessey JJ, Gehanno P, Thoroddsen E, Dagan R, 

Leibovitz E, Machac J, et al. Short course therapy 

with cefuroxime axetil for acute otitis media: 

results of a randomized multicenter comparison 

with amoxicillin/clavulanate. Pediatr Infect Dis J. 

1999 Oct;18(10):854-9. 

80.	 Dohar J, Giles W, Roland P, Bikhazi N, Carroll 

S, Moe R, et al. Topical 

ciprofloxacin/dexamethasone superior to oral 

amoxicillin/clavulanic acid in acute otitis media 

with otorrhea through tympanostomy tubes. 

Pediatrics. 2006 Sep;118(3):e561-9. 

81.	 Dagan R, Leibovitz E, Fliss DM, Leiberman A, 

Jacobs MR, Craig W, et al. Bacteriologic 

efficacies of oral azithromycin and oral cefaclor 

in treatment of acute otitis media in infants and 

young children. Antimicrob Agents Chemother. 

2000 Jan;44(1):43-50. 

82.	 Oguz F, Unuvar E, Suoglu Y, Erdamar B, Dundar 

G, Katircioglu S, et al. Etiology of acute otitis 

media in childhood and evaluation of two 

different protocols of antibiotic therapy: 10 days 

cefaclor vs. 3 days azitromycin. Int J Pediatr 

Otorhinolaryngol. 2003 Jan;67(1):43-51. 

83.	 Block SL, Cifaldi M, Gu Y, Paris MM. A 

comparison of 5 days of therapy with cefdinir or 

azithromycin in children with acute otitis media: 

a multicenter, prospective, single-blind study. 

Clin Ther. 2005 Jun;27(6):786-94. 

84.	 Carvalho ES, Campos SO, Pignatari SN, Weckx 

LL. [Efficacy and safety of cefprozil versus 

cefaclor in the treatment of acute otitis media in 

pediatric patients]. J Pediatr (Rio J). 1998 NovDec;74(6):461-6. 

85.	 Block SL, Kratzer J, Nemeth MA, Tack KJ. Fiveday cefdinir course vs. ten-day cefprozil course 

for treatment of acute otitis media. Pediatr Infect 

Dis J. 2000 Dec;19(12 Suppl):S147-52. 

86.	 Tsai HY, Huang LM, Chiu HH, Hsueh PR, Lee 

PI, Lu CY, et al. Comparison of once daily 

cefpodoxime proxetil suspension and thrice daily 

cefaclor suspension in the treatment of acute 

otitis media in children. J Microbiol Immunol 

Infect. 1998 Sep;31(3):165-70. 

87.	 Neumark T, Molstad S, Rosen C, Persson LG, 

Torngren A, Brudin L, et al. Evaluation of 

phenoxymethylpenicillin treatment of acute otitis 

media in children aged 2-16. Scand J Prim Health 

Care. 2007 Sep;25(3):166-71. 

88.	 Damoiseaux RA, van Balen FA, Hoes AW, 

Verheij TJ, de Melker RA. Primary care based 

randomised, double blind trial of amoxicillin 

versus placebo for acute otitis media in children 

aged under 2 years. BMJ. 2000 Feb 

5;320(7231):350-4. 

89.	 Le Saux N, Gaboury I, Baird M, Klassen TP, 

MacCormick J, Blanchard C, et al. A 

randomized, double-blind, placebo-controlled 

noninferiority trial of amoxicillin for clinically 

diagnosed acute otitis media in children 6 months 

to 5 years of age. CMAJ. 2005 Feb 1;172(3):335-

41. 

90.	 Bolt P, Barnett P, Babl FE, Sharwood LN. 

Topical lignocaine for pain relief in acute otitis 

media: results of a double-blind placebocontrolled randomised trial. Arch Dis Child. 2008 

Jan;93(1):40-4. 

91.	 Hatakka K, Blomgren K, Pohjavuori S, 

Kaijalainen T, Poussa T, Leinonen M, et al. 

Treatment of acute otitis media with probiotics in 

otitis-prone children-a double-blind, placebocontrolled randomised study. Clin Nutr. 2007 

Jun;26(3):314-21. 

92.	 Jacobs J, Springer DA, Crothers D. Homeopathic 

treatment of acute otitis media in children: a 

preliminary randomized placebo-controlled trial. 

Pediatr Infect Dis J. 2001 Feb;20(2):177-83. 

93.	 Little P, Moore M, Warner G, Dunleavy J, 

Williamson I. Longer term outcomes from a 

randomised trial of prescribing strategies in otitis 

media. Br J Gen Pract. 2006 Mar;56(524):176-

82. 

94.	 Spiro DM, Tay KY, Arnold DH, Dziura JD, 

Baker MD, Shapiro ED. Wait-and-see 

prescription for the treatment of acute otitis 

media: a randomized controlled trial. JAMA. 

2006 Sep 13;296(10):1235-41. 

95.	 Chao JH, Kunkov S, Reyes LB, Lichten S, Crain 

EF. Comparison of two approaches to 

observation therapy for acute otitis media in the 

emergency department. Pediatrics. 2008 

May;121(5):e1352-6. 

96.	 Garrison GD, Sorum PC, Hioe W, Miller MM. 

High-dose versus standard-dose amoxicillin for 

acute otitis media. Ann Pharmacother. 2004 

Jan;38(1):15-9. 

97.	 Bottenfield GW, Burch DJ, Hedrick JA, Schaten 

R, Rowinski CA, Davies JT. Safety and 

tolerability of a new formulation (90 mg/kg/day 

divided every 12 h) of amoxicillin/clavulanate 

(Augmentin) in the empiric treatment of pediatric 

acute otitis media caused by drug-resistant 

Streptococcus pneumoniae. Pediatr Infect Dis J. 

1998 Oct;17(10):963-8. 

202
 
98. Cohen R, Levy C, Boucherat M, Langue J, de La 

Rocque F. A multicenter, randomized, doubleblind trial of 5 versus 10 days of antibiotic 

110. Varsano I, Frydman M, Amir J, Alpert G. Single 

intramuscular dose of ceftriaxone as compared to 

7-day amoxicillin therapy for acute otitis media 

99. 

therapy for acute otitis media in young children. J 

Pediatr. 1998 Nov;133(5):634-9. 

Catania S, Gallo A. [Clinical efficacy and 

tolerability of short course therapy with cefaclor 

compared with long-term therapy for treatment of 

acute otitis media in children]. Infez Med. 2004 

111. 

112. 

in children. A double-blind clinical trial. 

Chemotherapy. 1988;34 Suppl 1:39-46. 

Green SM, Rothrock SG. Single-dose 

intramuscular ceftriaxone for acute otitis media in 

children. Pediatrics. 1993 Jan;91(1):23-30. 

Kara CO, Ozuer MZ, Kilic I, Yalcin AN, Ergin 

100. 

Dec;12(4):259-65. 

Cohen R, Levy C, Boucherat M, Langue J, Autret 

E, Gehanno P, et al. Five vs. ten days of 

antibiotic therapy for acute otitis media in young 

children. Pediatr Infect Dis J. 2000 

May;19(5):458-63. 

113. 

H. Comparison of amoxicillin with second and 

third generation cephalosporins in the treatment 

of acute otitis media. Infez Med. 1998;6(2):93-5. 

Bauchner H, Adams W, Barnett E, Klein J. 

Therapy for acute otitis media. Preference of 

parents for oral or parenteral antibiotic. Arch 

101. Chonmaitree T, Saeed K, Uchida T, Heikkinen T, 

Baldwin CD, Freeman Jr. DH, et al. A 114. 

Pediatr Adolesc Med. 1996 Apr;150(4):396-9. 

Varsano I, Volovitz B, Horev Z, Robinson J, 

randomized, placebo-controlled trial of the effect 

of antihistamine or corticosteroid treatment in 

acute otitis media. J Pediatr. 2003 

Laks Y, Rosenbaum I, et al. Intramuscular 

ceftriaxone compared with oral amoxicillinclavulanate for treatment of acute otitis media in 

102. 

103. 

Sep;143(3):377-85. 

Sarrell EM, Mandelberg A, Cohen HA. Efficacy 

of naturopathic extracts in the management of ear 

pain associated with acute otitis media. Arch 

Pediatr Adolesc Med. 2001 Jul;155(7):796-9. 

Sarrell EM, Cohen HA, Kahan E. Naturopathic 

115. 

children. Eur J Pediatr. 1997 Nov;156(11):858-

63. 

Pestalozza G, Cioce C, Facchini M. 

Azithromycin in upper respiratory tract 

infections: a clinical trial in children with otitis 

media. Scand J Infect Dis Suppl. 1992;83:22-5. 

treatment for ear pain in children. Pediatrics. 116. Daniel RR. Comparison of azithromycin and co104. 

2003 May;111(5 Pt 1):e574-9. 

Halsted C, Lepow ML, Balassanian N, Emmerich 

J, Wolinsky E. Otitis media: microbiology and 

evaluation of therapy. Ann N Y Acad Sci. 1967 

Sep 27;145(2):372-8. 

117. 

amoxiclav in the treatment of otitis media in 

children. J Antimicrob Chemother. 1993 Jun;31 

Suppl E:65-71. 

Schaad UB. Multicentre evaluation of 

azithromycin in comparison with co-amoxiclav 

105. Laxdal OE, Merida J, Jones RH. Treatment of for the treatment of acute otitis media in children. 

acute otitis media: a controlled study of 142 

children. Can Med Assoc J. 1970 Feb 

J Antimicrob Chemother. 1993 Jun;31 Suppl 

E:81-8. 

106. 

14;102(3):263-8. 

Howie VM, Ploussard JH. Efficacy of fixed 

combination antibiotics versus separate 

118. Principi N. Multicentre comparative study of the 

efficacy and safety of azithromycin compared 

with amoxicillin/clavulanic acid in the treatment 

components in otitis media. Effectiveness of 

erythromycin estrolate, triple sulfonamide, 

ampicillin, erythromycin estolate- triple 

sulfonamide, and placebo in 280 patients with 

acute otitis media under two and one-half years 

119. 

of paediatric patients with otitis media. Eur J Clin 

Microbiol Infect Dis. 1995 Aug;14(8):669-76. 

Arguedas A, Loaiza C, Herrera M, Mohs E. 

Comparative trial of 3-day azithromycin versus 

10-day amoxycillin/clavulanate potassium in the 

107. 

of age. Clin Pediatr (Phila). 1972 Apr;11(4):205-

14. 

Burke P, Bain J, Robinson D, Dunleavey J. Acute 

red ear in children: controlled trial of nonantibiotic treatment in general practice. BMJ. 

1991 Sep 7;303(6802):558-62. 

120. 

treatment of children with acute otitis media with 

effusion. Int J Antimicrob Agents. 1996 

Apr;6(4):233-8. 

Rodriguez AF. An open study to compare 

azithromycin with cefaclor in the treatment of 

children with acute otitis media. J Antimicrob 

108. 

109. 

Kaleida PH, Casselbrant ML, Rockette HE, 

Paradise JL, Bluestone CD, Blatter MM, et al. 

Amoxicillin or myringotomy or both for acute 

otitis media: results of a randomized clinical trial. 

Pediatrics. 1991 Apr;87(4):466-74. 

Glasziou PP, Hayem M, Del Mar CB. Antibiotics 

121. 

Chemother. 1996 Jun;37 Suppl C:63-9. 

Saez-Llorens X, Rodriguez A, Arguedas A, 

Hamed KA, Yang J, Pierce P, et al. Randomized, 

investigator-blinded, multicenter study of 

gatifloxacin versus amoxicillin/clavulanate 

treatment of recurrent and nonresponsive otitis 

for acute otitis media in children. Cochrane media in children. Pediatr Infect Dis J. 2005 

Database Syst Rev. 2000(2):CD000219. Apr;24(4):293-300. 

203
 
122. Sher L, Arguedas A, Husseman M, Pichichero M, 

Hamed KA, Biswas D, et al. Randomized, 

investigator-blinded, multicenter, comparative 

131. Roos K, Larsson P. Efficacy of ceftibuten in 5 

versus 10 days treatment of recurrent acute otitis 

media in children. Int J Pediatr Otorhinolaryngol. 

study of gatifloxacin versus 

amoxicillin/clavulanate in recurrent otitis media 

and acute otitis media treatment failure in 

children. Pediatr Infect Dis J. 2005 

132. 

2000 Sep 29;55(2):109-15. 

Hammaren-Malmi S, Saxen H, Tarkkanen J, 

Mattila PS. Adenoidectomy does not significantly 

reduce the incidence of otitis media in 

123. 

Apr;24(4):301-8. 

Noel GJ, Blumer JL, Pichichero ME, Hedrick JA, 

conjunction with the insertion of tympanostomy 

tubes in children who are younger than 4 years: a 

Schwartz RH, Balis DA, et al. A randomized 

comparative study of levofloxacin versus 

amoxicillin/clavulanate for treatment of infants 

and young children with recurrent or persistent 

acute otitis media. Pediatr Infect Dis J. 2008 

Jun;27(6):483-9. 

133. 

randomized trial. Pediatrics. 2005 Jul;116(1):185-

9. 

Marchisio PE, S. Bianchini, S. Desantis, C. 

Galeone, C. Nazzari, E. Pignataro, L. Principi, N. 

Effectiveness of a propolis and zinc solution in 

preventing acute otitis media in children with a 

124. Arrieta A, Arguedas A, Fernandez P, Block SL, 

Emperanza P, Vargas SL, et al. High-dose 

azithromycin versus high-dose amoxicillinclavulanate for treatment of children with 

recurrent or persistent acute otitis media. 

134. 

history of recurrent acute otitis media. Int J 

Immunopathol Pharmacol. 2010 AprJun;23(2):567-75. 

Abes G, Espallardo N, Tong M, Subramaniam 

KN, Hermani B, Lasiminigrum L, et al. A 

125. 

Antimicrob Agents Chemother. 2003 

Oct;47(10):3179-86. 

Turik MA, Johns D, Jr. Comparison of cefaclor 

and cefuroxime axetil in the treatment of acute 

otitis media with effusion in children who failed 135. 

systematic review of the effectiveness of 

ofloxaxin otic solution for the treatment of 

suppurative otitis media. ORL J Otorhinolaryngol 

Relat Spec. 2003 Mar-Apr;65(2):106-16. 

Goldblatt EL, Dohar J, Nozza RJ, Nielsen RW, 

amoxicillin therapy. J Chemother. 1998 Goldberg T, Sidman JD, et al. Topical ofloxacin 

Aug;10(4):306-12. versus systemic amoxicillin/clavulanate in 

126. Roland PS, Anon JB, Moe RD, Conroy PJ, Wall 

GM, Dupre SJ, et al. Topical 

ciprofloxacin/dexamethasone is superior to 

ciprofloxacin alone in pediatric patients with 

acute otitis media and otorrhea through 

136. 

purulent otorrhea in children with tympanostomy 

tubes. Int J Pediatr Otorhinolaryngol. 1998 Nov 

15;46(1-2):91-101. 

Dohar JE, Garner ET, Nielsen RW, Biel MA, 

Seidlin M. Topical ofloxacin treatment of 

127. 

tympanostomy tubes. Laryngoscope. 2003 

Dec;113(12):2116-22. 

Roland PS, Kreisler LS, Reese B, Anon JB, 

Lanier B, Conroy PJ, et al. Topical 

ciprofloxacin/dexamethasone otic suspension is 

superior to ofloxacin otic solution in the 

137. 

otorrhea in children with tympanostomy tubes. 

Arch Otolaryngol Head Neck Surg. 1999 

May;125(5):537-45. 

Goldblatt EL. Efficacy of ofloxacin and other otic 

preparations for acute otitis media in patients 

with tympanostomy tubes. Pediatr Infect Dis J. 

128. 

treatment of children with acute otitis media with 

otorrhea through tympanostomy tubes. Pediatrics. 

2004 Jan;113(1 Pt 1):e40-6. 

De Diego JI, Prim MP, Alfonso C, Sastre N, 

Rabanal I, Gavilan J. Comparison of amoxicillin 

138. 

2001 Jan;20(1):116-9; discussion 20-2. 

Wall GM, Stroman DW, Roland PS, Dohar J. 

Ciprofloxacin 0.3%/dexamethasone 0.1% sterile 

otic suspension for the topical treatment of ear 

infections: a review of the literature. Pediatr 

129. 

and azithromycin in the prevention of recurrent 

acute otitis media. Int J Pediatr Otorhinolaryngol. 

2001 Apr 6;58(1):47-51. 

Teele DW, Klein JO, Word BM, Rosner BA, 

Starobin S, Earle R, Jr. , et al. Antimicrobial 

prophylaxis for infants at risk for recurrent acute 

139. 

Infect Dis J. 2009 Feb;28(2):141-4. 

Bonati M, Marchetti F, Pistotti V, Agostin M, 

Bisogno G, Bussi R, et al. Metaanalysis of 

antimicrobial prophylaxis for recurrent acute 

otitis-media. Clinical Trials and Meta-Analysis. 

1992;28(1):39-50. 

otitis media. Vaccine. 2000 Dec 8;19 Suppl 

1:S140-3. 

140. Williams RL, Chalmers TC, Stange KC, 

Chalmers FT, Bowlin SJ. Use of antibiotics in 

130. Koivunen P, Uhari M, Luotonen J, Kristo A, 

Raski R, Pokka T, et al. Adenoidectomy versus 

chemoprophylaxis and placebo for recurrent 

acute otitis media in children aged under 2 years: 

preventing recurrent acute otitis media and in 

treating otitis media with effusion. A metaanalytic attempt to resolve the brouhaha. JAMA. 

1993 Sep 15;270(11):1344-51. 

randomised controlled trial. BMJ. 2004 Feb 141. Straetemans M, Sanders EA, Veenhoven RH, 

28;328(7438):487. Schilder AG, Damoiseaux RA, Zielhuis GA. 

Pneumococcal vaccines for preventing otitis 

media. Cochrane Database Syst Rev. 

2004(1):CD001480. 

204
 
142. Leach AJ, Morris PS, Mathews JD. Compared to 

placebo, long-term antibiotics resolve otitis 

media with effusion (OME) and prevent acute 

154. Gonzalez C, Arnold JE, Woody EA, Erhardt JB, 

Pratt SR, Getts A, et al. Prevention of recurrent 

acute otitis media: chemoprophylaxis versus 

143. 

otitis media with perforation (AOMwiP) in a 

high-risk population: a randomized controlled 

trial. BMC Pediatr. 2008;8:23. 

McDonald S, Langton Hewer CD, Nunez DA. 

Grommets (ventilation tubes) for recurrent acute 

otitis media in children. Cochrane Database Syst 

155. 

tympanostomy tubes. Laryngoscope. 1986 

Dec;96(12):1330-4. 

Principi N, Marchisio P, Massironi E, Grasso 

RM, Filiberti G. Prophylaxis of recurrent acute 

otitis media and middle-ear effusion. Comparison 

of amoxicillin with sulfamethoxazole and 

144. 

Rev. 2008(4):CD004741. 

Shea BJ, Grimshaw JM, Wells GA, Boers M, 

Andersson N, Hamel C, et al. Development of 

AMSTAR: a measurement tool to assess the 

methodological quality of systematic reviews. 

BMC Med Res Methodol. 2007;7:10. 

156. 

trimethoprim. Am J Dis Child. 1989 

Dec;143(12):1414-8. 

Casselbrant ML, Kaleida PH, Rockette HE, 

Paradise JL, Bluestone CD, Kurs-Lasky M, et al. 

Efficacy of antimicrobial prophylaxis and of 

tympanostomy tube insertion for prevention of 

145. 

146. 

Maynard JE, Fleshman JK, Tschopp CF. Otitis 

media in Alaskan Eskimo children. Prospective 

evaluation of chemoprophylaxis. JAMA. 1972 

Jan 31;219(5):597-9. 

Perrin JM, Charney E, MacWhinney JB, Jr., 

157. 

recurrent acute otitis media: results of a 

randomized clinical trial. Pediatr Infect Dis J. 

1992 Apr;11(4):278-86. 

Sih T, Moura R, Caldas S, Schwartz B. 

Prophylaxis for recurrent acute otitis media: a 

147. 

McInerny TK, Miller RL, Nazarian LF. 

Sulfisoxazole as chemoprophylaxis for recurrent 

otitis media. A double-blind crossover study in 

pediatric practice. N Engl J Med. 1974 Sep 

26;291(13):664-7. 

Gray B. Controlled trial of sulfamethoxazole158. 

Brazilian study. Int J Pediatr Otorhinolaryngol. 

1993 Jan;25(1-3):19-24. 

Mandel EM, Casselbrant ML, Rockette HE, 

Bluestone CD, Kurs-Lasky M. Efficacy of 

antimicrobial prophylaxis for recurrent middle 

ear effusion. Pediatr Infect Dis J. 1996 

trimethoprim for the prevention of recurrent otitis Dec;15(12):1074-82. 

148. 

media in young children. Current Cheomotherapy 

and Immunotherapy: Proceedings of the 12th 

International Congress of Chemotherapy. 1981. 

Gaskins JD, Holt RJ, Kyong CU, Weart CW, 

Ward J. Chemoprophylaxis of recurrent otitis 

159. Roark R, Berman S. Continuous twice daily or 

once daily amoxicillin prophylaxis compared 

with placebo for children with recurrent acute 

otitis media. Pediatr Infect Dis J. 1997 

Apr;16(4):376-81. 

149. 

media using trimethoprim/sulfamethoxazole. 

Drug Intell Clin Pharm. 1982 May;16(5):387-90. 

Schwartz RH, Puglise J, Rodriguez WJ. 

Sulphamethoxazole prophylaxis in the otitisprone child. Arch Dis Child. 1982 

Aug;57(8):590-3. 

160. Gray B, editor. Controlled trial of 

sulfamethoxazole-trimethoprim for the 

prevention of recurrent acute otitis media in 

young children. . Proceedings of the 12th 

International Congrress of Chemotherapy 1981; 

Florence, Italy. 

150. 

151. 

Liston TE, Foshee WS, Pierson WD. 

Sulfisoxazole chemoprophylaxis for frequent 

otitis media. Pediatrics. 1983 Apr;71(4):524-30. 

Schuller DE. Prophylaxis of otitis media in 

asthmatic children. Pediatr Infect Dis. 1983 Jul161. 

162. 

Gebhart DE. Tympanostomy tubes in the otitis 

media prone child. Laryngoscope. 1981 

Jun;91(6):849-66. 

El Sayed Y. Treatment of recurrent acute otitis 

media chemoprophylaxis versus ventilation 

152. 

Aug;2(4):280-3. 

Persico M, Podoshin L, Fradis M, Grushka M, 

Golan D, Foltin V, et al. Recurrent acute otitis 163. 

tubes. . Australian Journal of Otolaryngology. 

1996;2(4):352-5. 

Block SL, Hedrick JA, Kratzer J, Nemeth MA, 

media--prophylactic penicillin treatment: a 

prospective study. Part I. Int J Pediatr 

Otorhinolaryngol. 1985 Oct;10(1):37-46. 

Tack KJ. Five-day twice daily cefdinir therapy 

for acute otitis media: microbiologic and clinical 

efficacy. Pediatr Infect Dis J. 2000 Dec;19(12 

153. Varsano I, Volovitz B, Mimouni F. Sulfisoxazole 

prophylaxis of middle ear effusion and recurrent 

acute otitis media. Am J Dis Child. 1985 

Jun;139(6):632-5. 

164. 

Suppl):S153-8. 

Bezakova N, Damoiseaux RA, Hoes AW, 

Schilder AG, Rovers MM. Recurrence up to 3.5 

years after antibiotic treatment of acute otitis 

media in very young Dutch children: survey of 

trial participants. BMJ. 2009;338:b2525. 

205
 

List of Acronyms/Abbreviations 

AOM: acute otitis media 

AMX: amoxicillin 

CI: confidence interval 

ENT: ear, nose, and throat specialist 

GP: general practitioner 

HF: Haemophilus influenzae 

LR: likelihood ratio 

MEE: middle ear effusion 

MEF: middle ear fluid 

NNT: number-to-treat 

OME: Otitis media with effusion 

OR: Odds ratio 

PcV: phenoxymethylpencillin 

PPV: polysaccharide pneumococcal vaccine 

RCT: randomized controlled trial 

RD: Rate difference 

ROM: Recurrent otitis media 

SP: streptococcus pneumoniae 

TF: tympanic fluid 

TM: tympanic membrane 

Tx: treatment 

207
 
Appendix A. Scope, Definitions and Search Strategies 

Table A.1 Scope of the Report and Definitions 

Disease Entity Uncomplicated AOM, including recurrent and persistent AOM1 

Patient Population Age 4 weeks to 18 years 

Exclude: patients with immunodeficiencies and craniofacial deficiencies 

including cleft palate 

Settings All types of providers and practice settings 

Interventions2 “Wait and see” approach/placebo 

Antibiotic treatment (all classes, schedule, dosage, length, and mode) 

Delayed antibiotic 

Analgesics/other non-antibiotic medical therapies/surgery (including PE tubes) 

Influencing factors Age 

Race/ethnicity 

Laterality 

Otorrhea or perforation 

AOM severity 

Signs and physical symptoms (ear pulling, otorrhea, irritability, fever, tympanic 

membrane (TM) inflammation, retracted TM, middle ear effusion [MEE]) 

Comorbidities (e.g., asthma) 

Day care attendance 

Environmental factors 

Practitioner 

Setting 

Parent/caretaker 

Examiner 

Recurrent OM/otitis prone 

Persistent/relapse OM (continued on next page) 

Diagnostic mode (otoscopy; tympanocentesis; pneumatic otoscopy/ 

tympanometry; acoustic reflectometry 

1 Definition of AOM: A diagnosis of AOM requires 1) a history of acute onset of signs and symptoms, 2) the presence of middle 

ear effusion (MEE), and 3) signs and symptoms of middle-ear inflammation. 

Elements of the definition of AOM are all of the following: 

1. Recent, usually abrupt, onset of signs and symptoms of middle-ear inflammation and MEE 

2. The presence of MEE that is indicated by any of the following: 

a. Bulging of the tympanic membrane 

b. Limited or absent mobility of the tympanic membrane 

c. Air-fluid level behind the tympanic membrane 

d. Otorrhea 

3. Signs or symptoms of middle-ear inflammation as indicated by either 

a. Distinct erythema of the tympanic membrane or 

b. Distinct otalgia (discomfort clearly referable to the ear[s] that results in interference with or precludes normal 

activity or sleep) 

Definition of Recurrent AOM (RAOM): A diagnosis of RAOM requires three or more episodes of acute otitis media within 6 

months or four episodes within 12 months, including at least 1 episode during the preceding 6 months. 

Definition of Persistent Otitis Media: Persistent otitis media is manifested by persistence during antimicrobial therapy of 

symptoms and signs of middle ear infection (treatment failure) and/or relapse of acute otitis media within 1 month of completion 

of antibiotic therapy. When two episodes of otitis media occur within 1 month, it may be difficult to distinguish recurrence of 

acute otitis media (i.e. a new episode) from persistent otitis media (i.e. relapse). 

2 Antibiotics and other treatment modalities are considered individually for questions 3-6 on treatment outcomes; 

A-1
 
Pn 

ea

Appendix A. Scope, Definitions and Search Strategies
 

Outcome measures Treatment failure 

Duration of symptoms or illness 

Presence of MEE by otoscopic findings (Bulging, cloudy, erythematous TM; air 

fluid level behind TM; Loss of landmarks; otorrhea) 

Presence of MEE by Pneumatic otoscopy/tympanometry (Limited or absent 

mobility of TM) 

Presence of MEE by acoustic reflectometry (presence of MEF) 

Presence of MEE by tympanocentesis 

Signs and symptoms of middle ear inflammation (MEI) by symptoms (otalgia, 

r fullness) 

Signs or symptoms of MEI by otoscopy (distinct TM erythema) 

Other symptoms (decreased hearing, fever) 

Invasive infections 

Bacteriological cure/failure 

Disease recurrence 

Adverse effects of treatment (e.g., diarrhea, vomiting, bacterial resistance) and 

method of assessment 

Quality of life or functional outcome 

Parental satisfaction 

Cost of outcomes, e.g., Days school/daycare missed 

Bacteriologic outcomes by nasopharyngeal 

cultures 

Otologic complications- i.e., cholestetoma 

PE tube placement 

Health care utilization 

Microbial epidemiology and antibiotic resistance3 

Time Period 1998-20094 

Literature Sources Medline 

Web of Science 

Cochrane Database of Systematic Reviews 

Proceedings of International Society of Otolaryngology 

References 

Languages No restriction 

Study Design Randomized controlled trials, blinded and unblinded 

Non-randomized controlled trials, blinded and unblinded 

Prospective and retrospective observational studies5 

Case-control studies6 

3 These outcomes are considered only for question 2 on PNC7 vaccine. 

4 Search for articles on recurrent and persistent AOM spanned 1966-2009 

5 Where RCTs unavailable to answer a particular question 

A-2 
Appendix A. Scope, Definitions and Search Strategies
 

ACUTE OTITIS MEDIA – SEARCH METHODOLOGIES
 

UPDATES FROM JULY 2008-AUGUST 2010
 

JULY 2008 – JANUARY 2009 UPDATES (Searches run 1/13-1/15/09) 

DATABASE SEARCHED & TIME PERIOD COVERED: 

PubMed – 7/1/2008-1/13/2009 

SEARCH STRATEGY: 

otitis media 

NUMBER OF ITEMS RETRIEVED: 288 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Cochrane – 7/1/2008-1/13/2009 

SEARCH STRATEGY: 

otitis media.mp. 

NUMBER OF ITEMS RETRIEVED: 

Systematic Reviews - 14 

DARE – 45 

CCTR - 11 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Web of Science – 2008-2009 

SEARCH STRATEGY: 

Topic=otitis media 

NOT 

Topic=(dog OR cat OR mice OR rats OR chinchilla* OR pig) 

NUMBER OF ITEMS RETRIEVED: 725 

================================================================== 

JANUARY – AUGUST 2009 UPDATES (Search run 8/24/09) 

DATABASE SEARCHED & TIME PERIOD COVERED: 

PubMed – 2009 

SEARCH STRATEGY: 

otitis media 

NUMBER OF ITEMS RETRIEVED: 412 

A-3
 
Appendix A. Scope, Definitions and Search Strategies
 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Cochrane - 2009 

SEARCH STRATEGY: 

otitis media.mp. 

NUMBER OF ITEMS RETRIEVED: 

Systematic Reviews -87 

DARE – 51 

CCTR – 4 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Web of Science Databases - SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH. 

– 2009 

SEARCH STRATEGY: 

Topic=(otitis media) NOT Topic=(dog OR cat OR mice OR rats OR chinchilla* OR pig OR mouse) 

NUMBER OF ITEMS RETRIEVED: 441 

================================================================== 

AUGUST 2009 – MAY 2010 UPDATES (Searches run 5/5/10) 

DATABASE SEARCHED & TIME PERIOD COVERED: 

PubMed – 8/2009– 5/5/2010 

SEARCH STRATEGY: 

otitis media 

NOT 

animal NOT (human OR humans) 

NOT 

dog OR cat OR mice OR mouse OR rat OR rats OR chinchilla* OR pig 

NUMBER OF ITEMS RETRIEVED: 426 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Web of Science Databases - SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH.– 2009– 5/5/2010 

SEARCH STRATEGY: 

Topic=(otitis media)
 

NOT
 

Topic=(dog OR cat OR mice OR MOUSE OR RAT OR rats OR chinchilla* OR pig)
 

NUMBER OF ITEMS RETRIEVED: 879 

A-4
 
Appendix A. Scope, Definitions and Search Strategies
 

================================================================== 

MAY-AUGUST 2010 UPDATES (Searches run 8/3/10): 

DATABASE SEARCHED & TIME PERIOD COVERED: 

PubMed – 4/1/2010– 8/3/2010 

SEARCH STRATEGY: 

otitis media 

NUMBER OF ITEMS RETRIEVED: 200 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Cochrane – 4/1/2010– 8/3/2010 

SEARCH STRATEGY: 

otitis media.mp. 

NUMBER OF ITEMS RETRIEVED: 

Reviews - 33 

DARE - 4 

================================================================== 

DATABASE SEARCHED & TIME PERIOD COVERED: 

Web of Science – 2010 

SEARCH STRATEGY: 

TS=(otitis media)
 

NOT
 

TS=(dog OR cat OR mice OR MOUSE OR RAT OR rats OR chinchilla* OR pig)
 

NUMBER OF ITEMS RETRIEVED: 374 

A-5
 
Appendix A. Scope, Definitions and Search Strategies 

Figure A.1. Literature Flow Diagram 

A-6
 
Appendix B. Sample Data Abstraction Forms
 

Screening Form........................................................................................................................... B-2
 

Key Question 1 Data Abstraction Form...................................................................................... B-4
 

Key Question 2 Second Level Screener...................................................................................... B-3
 

Key Questions 3-6 Data Abstraction Form................................................................................. B-9
 

B-1
 
Appendix B. Sample Data Abstraction Forms
 

Evidence-based Practice Center 

Acute Otitis Media – Update 

Form #1: Screening Form 

Article ID: __________ 

Last Name of First Author:________ 

Reviewer:___ _____ 

Year Published:___ _____ 

1. Type of article 

Editorial, letter, opinion, commentary...........................................................................1 (STOP)
 

Clinical practice............................................................................................................2 (STOP)
 

Overview......................................................................................................................3 (STOP)
 

Practice guidelines.......................................................................................................4 (STOP)
 

Consensus statements ................................................................................................5 (STOP)
 

Unknown......................................................................................................................6
 

2. Non-human subjects ................................................................................................ (STOP)
 

3. Study condition is NOT acute otitis media................................................................ (STOP)
 

4. Age of study population >=18 years......................................................................... (STOP)
 

5. Study population on patients with immunodeficiencies or Craniofacial
 

deficiencies including cleft palate................................................................................. (STOP)
 

6. Key questions addressed: 

KQ1: Diagnosis of AOM..............................................................................................

KQ2: Antimicrobial resistance and PNC7 ...................................................................

KQ3-7: Effectiveness of treatment options..................................................................

Unknown.....................................................................................................................

None of the above.......................................................................................................(STOP)
 

7. Country 

United States ..............................................................................................................

Canada .......................................................................................................................

Europe - specify ____/____/____/____/____ .............................................................

Asia - specify ____/____/____/____/____ .................................................................

South or Central America or Mexico - specify ____/____/____/____/____ ...............

Other - specify ____/____/____/____/____ ...............................................................

Not specified ..............................................................................................................

8. Study design 

Randomized controlled trial..........................................................................................1
 

Nonrandomized controlled trial ....................................................................................2
 

Comparative cohort study ...........................................................................................3
 

Single cohort study (Before-After, Time series) ...........................................................4
 

Case control study .......................................................................................................5
 

Cross-sectional study...................................................................................................6
 

Case Series/Report......................................................................................................7
 

Review/meta-analysis ..................................................................................................8
 

Other design ................................................................................................................9
 

Unknown.................................................................................................................... 10
 

B-2
 
Appendix B. Sample Data Abstraction Forms
 

B-3
 
Appendix B. Sample Data Abstraction Forms
 

B-4
 
Appendix B. Sample Data Abstraction Forms
 

B-5
 
Appendix B. Sample Data Abstraction Forms
 

B-6
 
Appendix B. Sample Data Abstraction Forms
 

B-7
 
Appendix B. Sample Data Abstraction Forms
 

B-8
 
Appendix B. Sample Data Abstraction Forms
 

B-9
 
Appendix B. Sample Data Abstraction Forms
 

B-10
 
Appendix B. Sample Data Abstraction Forms
 

B-11
 
Appendix B. Sample Data Abstraction Forms
 

B-12
 
Appendix B. Sample Data Abstraction Forms
 

B-13
 
Appendix B. Sample Data Abstraction Forms
 

B-14
 
Appendix B. Sample Data Abstraction Forms
 

B-15
 
Appendix B. Sample Data Abstraction Forms
 

B-16
 
Appendix B. Sample Data Abstraction Forms
 

B-17
 
Appendix B. Sample Data Abstraction Forms
 

B-18
 
Appendix B. Sample Data Abstraction Forms
 

B-19
 
Appendix B. Sample Data Abstraction Forms
 

B-20
 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Adler 

200073 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

13.3 mg/kg/day 

Place: 

Multicenter: 

38 centers 

Entering: 

N=752 

N=251 AmoxicillinTreatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success rate (cure or improvement) at day 11-16 

A-C Cef QD Diff (95%CI) 

90% (177/197) 91% (177/195) -1% (-7, 4.8) 

(0-5):2 = tid for 10 days clavulanate OME]; 

[1,0,1,0,0] Inclusion: N=248 Cefdinir 14 mg QD Signs or symptoms of A-C Cef BID Diff (95%CI) 

vs. 6 mo-12 yr, N=253 Cefdinir 7 mg BID MEI; 90% (177/197) 89% (180/203) 1% (-5, 7) 

Presence of middle ear effusion (MEE), Other symptoms: fever; 

Definition: Cefdinir Pneumatic otoscopy/tympanometry Completing: Other symptoms: Cef QD Cef BID Diff (95%CI) 

Presence 14 mg/kg/day (limited or absent mobility of TM), N=665 decreased hearing; 91% (177/195) 89% (180/203) 2% (-4, 8) 

of MEE = qd for 10 days Otoscopy (distinct TM erythema), N=210 Amoxicillin- Disease recurrence; 

AOM < 1 week clavulanate Adverse effects of Outcome: Adverse events 

vs. N=226 Cefdinir 14 mg QD treatment A-C Cef QD Diff (95%CI) 

Exclusion: N=229 Cefdinir 7 mg BID Any 26.3% (66/251) 16.5% (41/248) 10%(2.6, 17) 

Cefdinir Penicillin/beta-lactams, Diarrhea 12.7% (32/251) 10.9% (27/248) 2% (-3.9, 7.5) 

7 mg/kg/day Antibiotic within 7 days, Analyzed: Tx related 20.3% (51/251) 14.1% (35/248) 6% (-0.2, 13) 

= bid for 10 days Concomitant/Concurrent infection N=595 

needing N=197 Amoxicillin- A-C Cef BID Diff (95%CI) 

antibiotic treatment, clavulanate Any 26.3% (66/251) 23.3% (59/253) 3%(-4.5, 10) 

Topical antibiotic drops prior to study, N=195 Cefdinir 14 mg QD Diarrhea 12.7% (32/251) 15.8% (40/253) -3%(-9, 3) 

Chronic suppurative OM, N=203 Cefdinir 7 mg BID Tx related 20.3% (51/251) 17.8% (45/253) 2%(-4.4, 9) 

OME (serous OM, nonsuppurative OM, 

mucoid OM Cef QD Cef BID Diff (95%CI) 

secretory OM, glue ear), Any 16.5% (41/248) 23.3% (59/253) -7% (-14, 0.2) 

TM perforation/Otorrhea, Diarrhea 10.9% (27/248) 15.8% (40/253) 5% (-11, 1.1) 

Complication of OM, Tx related 14.1% (35/248) 17.8% (45/153) -4% (-11, 3.6) 

PE tubes/history of PE tubes, 

Cranio-facial, 

GI disorders/Liver, 

Renal Disorders 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Arguedas 

200566 

Jadad 

quality 

score 1 

Amoxicillin 

90 mg/kg/day 

/ bid for 10 days 

Study Time: 

9/2002-7/2003 

Influencing 

factors: 

Middle ear effusion, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success rate (cure or improvement) at day 12-14 

Amoxicillin Azithromycin Diff (95%CI) 

All pts 84% (127/151) 84% (130/155) 0.2%(-8, 8) 

(0-5):3 Place: Age, OME]; <=2yrs 82% (99/121) 82% (109/133) -0.2% (-10, 9) 

[1,1,1,0,0] vs. United States, Baseline pathogen Signs or symptoms of 

Finland, MEI; Outcome: Success rate (cure) at day 25-28 visit 

Azithromycin Chile, Disease recurrence; All pts 78% (117/151) 77% (117/152) -0.5% (-10, 9) 

Definition: 30 mg/kg/day Costa Rica Entering: Adverse effects of <=2yrs 75% (91/121) 75% (98/130) -0.2%(-11,11) 

Presence = qd for 1 day Multicenter: N=312 treatment 

of MEE, 19 centers N=154 Amoxicillin Outcome: Adverse events 

S&S of N=158 Azithromycin Abd pain: 1.9% (3/154) 3.8% (6/158) -2%(-5.6, 1.8) 

MEI Inclusion: Diarrhea: 17.5% (27/154) 8.2% (13/158) 9%(2, 17) 

6-30 mo, Completing: Rash: 2.6% (4/154) 2.5% (4/158) 0.1%(-3.4,3.6) 

Presence of middle ear effusion (MEE), N=306 Vomiting 8.4% (13/154) 8.2% (13/158) 0.2%(-6, 6) 

Bulging tympanic membrane [TM], N=151 Amoxicillin Tx related 28.6% (44/154) 19.6% (31/158) 9%(-0.5, 18) 

Cloudy TM, N=155 Azithromycin 

Otorrhea, 

Pneumatic otoscopy/tympanometry Analyzed: 

(limited or absent mobility of TM), N=312 

S&S of middle ear inflammation N=154 Amoxicillin 

(MEI), N=158 Azithromycin 

Otalgia, 

Otoscopy (distinct TM erythema), 

Fever 

Exclusion: 

Penicillin/beta-lactams, 

Macrolides, 

Antibiotic within 30 days, 

Chronic suppurative OM, 

TM perforation/Otorrhea >24 hours, 

PE tubes/history of PE tubes, 

Major Systemic disease/ condition, 

medical problem, 

Resistant bacteria 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Arrieta 

2003124 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/45 

Study Time: 

3/2001-3/2002 

Influencing 

factors: 

Age 

Treatment failure; 

Bacteriologic cure/failure; 

Adverse effects of 

Outcome: Success rate on day 12-16 

Amox-clav Azithromycin 

Total 84% (122/145) 86% (128/149) 

Diff (95%CI) 

-2% (-10, 6) 

(0-5):3 Place: treatment; <=2yrs 79% (73/92) 85% (82/96) -6% (-17, 5) 

[1,1,1,0,0] vs. United States Other antibiotic: No new >2yrs 92% (49/53) 87% (46/53) 5% (-7, 17) 

Multicenter: Completing: abx Rx/no change in abx 

Azithromycin 18 centers N=296 Rx Outcome: Adverse events 

Definition: N=145 Amoxicillin- Any 42.2% (62/147) 32.0% (49/153) 10%(-0.7, 21) 

Presence Inclusion: clavulanate Abd pain 2.0% (3/147) 3.9% (6/153) -2%(-5.7, 2) 

of MEE, 6 mo-6 yr, N=151 Azithromycin Anorexia 2.7% (4/147) 3.3% (6/153) -0.6%(-4, 3) 

S&S of <25 kg, Dermatitis 2.0% (3/147) 0.7% (1/153) 1.3%(-1.3, 4) 

MEI Presence of middle ear effusion (MEE), Analyzed: Diarrhea 29.9% (44/147) 19.6% (30/153) 10%(0.5, 20) 

Bulging tympanic membrane [TM], N=296 Rash 4.8% (7/147) 3.3% (5/153) 1.5%(-3, 6) 

Cloudy TM, N=145 Amoxicillin- Vomiting 8.2% (12/147) 5.2% (8/153) 3%(-2.6, 9) 

Erythematous TM, clavulanate 

Otorrhea, N=151 Azithromycin 

Pneumatic otoscopy/tympanometry 

(limited or absent mobility of TM), 

S&S of middle ear inflammation 

(MEI), 

Otalgia, 

Ear fullness, 

Recurrent AOM, 

Persistent AOM 

Exclusion: 

Penicillin/beta-lactams, 

Macrolides, 

Antibiotic within 30 days, 

TM perforation/Otorrhea, 

Complication of OM, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem, 

Heme/Onc Disorders, 

Investigational drug within 1 month, 

Hospitalization/need for admission 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Bezakova 

2009164 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

2/1996-5/1998 

Entering: 

N=240 

N=123 Placebo 

Disease recurrence; 

Healthcare utilization 

Outcome: Clinical outcome between 6 months and 3 years 

Amoxicillin Placebo Diff (95% CI) 

No recurrent AOM 

(0-5):4 Place: 37% (28/75) 57% (49/86) -20% (-5, -35) 

[1,1,0,1,1] Amoxicillin Netherlands Completing: 

40 mg/kg/day Multicenter: N=168 No referral 

/ tid for 10 days 53 centers N=90 Placebo 31% (24/78) 30% (62/89) 0% (-14, 14) 

Definition: Office setting/ 

Acute private practice, Analyzed: No surgery 

onset General/ N=168 79% (16/78) 70% (27/90) 9%(-23, 4) 

of S&S, family practice N=90 Placebo 

S&S of 

MEI Inclusion: 

6-24 mo, 

Acute onset S&S (parent/guardian 

report), 

Presence of middle ear effusion (MEE), 

Bulging tympanic membrane [TM], 

Erythematous TM, 

Otorrhea, 

S&S of middle ear inflammation 

(MEI), 

Otalgia, 

Fever, 

Irritability, 

Other constitutional symptoms NOS 

Exclusion: 

Penicillin/beta-lactams, 

Antibiotic within 4 weeks, 

Cranio-facial, 

Immunosuppressed 

/compromised/deficient 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Biner 

200771 

Jadad 

quality 

score 1 

Ceftriaxone 

50 mg/kg/day 

= qd for 1 day 

Study Time: 

2/2001-4/2003 

Analyzed: 

N=104 

N=34 Ceftriaxone 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Cumulative clinical resolution rate at day 3 after treatment 

initiation 

(0-5):1 Place: N=31 Azithromycin OME]; Amox-clav Ceftriaxon Diff (95%CI) 

[1,0,0,0,0] vs. Hospital, N=39 Amoxicillin- Signs or symptoms of 87.2% (34/39) 85.3% (29/34) 2%(-14, 18) 

ENT clavulanate MEI; 

Azithromycin Other symptoms: fever; Amox-clav Azithro Diff (95%CI) 

Definition: 10 mg/kg/day Inclusion: Disease recurrence; 87.2% (34/39) 87.1% (27/31) 0.1%(-16, 16) 

Acute = qd for 1 day, 6 mo-10 yr, Adverse effects of 

onset Azithromycin Acute onset S&S (parent/guardian treatment Outcome: Persistent middle ear fluid on day 30 

of S&S, 5 mg/kg/day report), Amox-clav Ceftriaxon Diff (95%CI) 

Presence = qd for 4 days Presence of middle ear effusion (MEE), 14.7% (5/34) 17.2% (5/29) -2.5%(-21, 16) 

of MEE, Bulging tympanic membrane [TM], 

S&S of vs. Cloudy TM, Amox-clav Azithro Diff (95%CI) 

MEI Erythematous TM, 14.7% (5/34) 22.2% (6/27) -7.5%(-27, 12) 

Amoxicillin- S&S of middle ear inflammation 

clavulanate (MEI), Outcome: Adverse events 

90 mg/kg/day Otalgia, Amox-clav Ceftriaxon Diff (95%CI) 

/ bid for 10 days Fever >38 C Diarrhea 7.7% (3/39) 5.9% (2/34) 2%(-10, 13) 

Vomiting 2.6% (1/39) 2.9% (1/34) -0.3%(-8, 7) 

Exclusion: 

Penicillin/beta-lactams, Amox-clav Azithro Diff (95%CI) 

Macrolides, Diarrhea 7.7% (3/39) 6.5% (2/31) 1%(-11, 13) 

Antibiotic within 2 weeks, Vomiting 2.6% (1/39) 3.2% (1/31) -0.6%(-8, 7) 

AOM within 1 months, 

Recurrent AOM (>3 episodes in 12 

months), 

TM perforation/Otorrhea, 

PE tubes/history of PE tubes, 

Cranio-facial, 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem, 

On other medication/treatment 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Block 

200085 

Jadad 

quality 

score 1 

Cefprozil 

30 mg/kg/day 

/ bid for 10 days 

Study Time: 

10/1996-2/1997 

Influencing 

factors: 

Age 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: clinical cure on day 9-11 (4-6 days post therapy for cefdinir 

and +/-1 day post therapy for Cefprozil) 

Cefdinir Cefprozil Diff (95%CI) 

(0-5):2 Place: OME]; Total 80.0% (152/190) 82.5% (151/183) -2.5%(-10,5.4) 

[1,0,1,0,0] vs. United States Signs or symptoms of <2yrs 71.0% (49/69) 70.7% (41/58) 0.3%(-16, 16) 

Multicenter: Entering: MEI; 2-5yrs 85.1% (57/67) 87.1% (61/70) -2% (-14, 10) 

Cefdinir 13 centers N=435 Adverse effects of 6-12yrs 83.3% (45/54) 89.1% (49/55) -6% (-19, 7) 

Definition: 14 mg/kg/day N=216 Cefprozil 10 days treatment 

Not / bid for 5 days Inclusion: N=219 Cefdinir 5 days Outcome: clinical cure on test-of-cure visit on 17-21 day post therapy 

specified 6 mo-12 yr, (days 17-21 for cefdinir and days22-26 for Cefprozil) 

Presence of middle ear effusion (MEE), Completing: Cefdinir Cefprozil Diff (95%CI) 

Pneumatic otoscopy/tympanometry N=373 Total 65.3% (124/190) 64.5% (118/183) 0.8% (-9, 10) 

(limited or absent mobility of TM), N=183 Cefprozil 10 days <2yrs 49.3% (34/69) 48.3% (28/58) 1% (-16, 18) 

Otoscopy (distinct TM erythema), N=190 Cefdinir 5 days 2-5yrs 73.1% (49/67) 64.3% (45/70) 9% (-7, 24) 

AOM 6-12yrs 75.9% (41/54) 81.8% (45/55) -6%(-21, 9) 

Analyzed: 

Exclusion: N=373 Outcome: Adverse events 

Penicillin/beta-lactams, N=183 Cefprozil 10 days Cefdinir Cefprozil Diff (95%CI) 

Antibiotic within 7 days, N=190 Cefdinir 5 days Diarrhea 7.9% (15/190) 4.4% (8/183) 3.5%(-1.4,8) 

Topical antibiotic drops prior to study, Rash 3.2% (6/190) 3.8% (7/183) -0.6%(-4.3,3.1) 

Chronic suppurative OM, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea, 

Complication of OM, 

PE tubes/history of PE tubes, 

Cranio-facial, 

GI disorders/Liver, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem, 

On other medication/treatment 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Block 

200072 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

40/10 mg/kg/day 

Enrollment 

Time: 

4/1992-8/1993 

Influencing 

factors: 

Age 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success (cure or improvement) 2-4 days after 

treatment: Amox-clav vs. Cefdinir QD 

A-C CDR-QD Diff (95%CI) 

(0-5):2 / tid for 10 days OME]; Total 86% (86/100) 83.3% (85/102) 0.7%(-7, 13) 

[1,0,1,0,0] Place: Signs or symptoms of <2yrs 79% (31/39) 80% (45/56) -0.9%(-17,15) 

vs. United States Entering: MEI; 2-5yrs 85% (35/41) 84% (31/37) 1.6%(-14, 18) 

Multicenter: N=384 Adverse effects of 6-12yrs 100% (20/20) 100% (9/9) 0.0% 

Definition: Cefdinir 13 centers N=128 Amoxicillin­ treatment; 

Presence 14 mg/kg/day clavulanate Other antibiotic: No new Outcome: Clinical success (cure or improvement) 2-4 days after 

of MEE, = qd for 10 days Inclusion: N=128 Cefdinir 14 mg QD abx Rx/no change in abx treatment: Amox-clav vs. Cefdinir BID 

S&S of 6 mo-12 yr, N=128 Cefdinir 7 mg BID Rx A-C CDR-BID Diff (95%CI) 

MEI vs. Presence of middle ear effusion (MEE), Total 86% (86/100) 80% (81/101) 5.9% (-4, 16) 

Bulging tympanic membrane [TM], Completing: <2yrs 79% (31/39) 62% (30/48) 17% (-2, 36) 

Cefdinir Loss of landmarks, N=303 2-5yrs 85% (35/41) 95% (35/37) -9%(-23, 4) 

7 mg/kg/day Pneumatic otoscopy/tympanometry N=100 Amoxicillin­ 6-12yrs 100% (20/20) 100% (16/16) 0.0% 

= bid for 10 days (limited or absent mobility of TM), clavulanate 

S&S of middle ear inflammation N=102 Cefdinir 14 mg QD Outcome: Clinical success (cure or improvement) 2-4 days after 

(MEI), N=101 Cefdinir 7 mg BID treatment: Amox-clav vs. Cefdinir BID 

Otalgia, CDR-QD CDR-BID Diff (95%CI) 

Otoscopy (distinct TM erythema), Analyzed: Total 83% (85/102) 80% (81/101) 3% (-7, 14) 

Decreased hearing, N=303 <2yrs 80% (45/56) 62% (30/48) 18%(0.6,35) 

Onset of AOM symptoms within 7 days N=100 Amoxicillin­ 2-5yrs 84% (31/37) 95% (35/37) -11%(-25, 3) 

before entry, clavulanate 6-12yrs 100% (9/9) 100% (16/16) 0.0% 

Irritability, N=102 Cefdinir 14 mg QD 

Other constitutional symptoms NOS N=101 Cefdinir 7 mg BID Outcome: Adverse events 

A-C CDR-QD Diff (95%CI) 

Exclusion: Any 42% (54/128) 14% (18/128) 28%(17, 39) 

Antibiotic within 7 days, Diarrhea 35% (45/128) 10% (13/128) 25%(15, 35) 

TM perforation/Otorrhea, Rash 8% (10/128) 5% (6/128) 3%(-2.8, 9) 

PE tubes/history of PE tubes, 

Resistant bacteria 

A-C CDR-BID Diff (95%CI) 

Any 42% (54/128) 23% (29/128) 20%(8, 31) 

Diarrhea 35% (45/128) 13% (17/128) 22%(11, 32) 

Rash 8% (10/128) 6% (8/128) 2%(-4.8, 7.8) 

CDR-QD CDR-BID Diff (95%CI) 

Any 14% (18/128) 23% (29/128) -9%(-18,0.9) 

Diarrhea 10% (13/128) 13% (17/128) -3%(-11,4.8) 

Rash 5% (6/128) 6% (8/128) -2%(-7, 4) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Block 

200475 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/6.4 mg/kg/day 

Enrollment 

Time: 

2/2003-4/2003 

Influencing 

factors: 

Age, 

Treatment failure; 

By otoscopic findings:; 

Bulging tympanic 

Outcome: Success at end-of-treatment visit (study days 7-9 for Cefdinir; 

study days 12-14 for Amox-clav) by age group 

Amox-clav Cefdinir Diff (95%CI) 

(0-5):2 / bid for 10 days Pneumococcal Vaccine membrane [TM]; Total 85% (164/192) 88% (170/194) -2% (-9, 4.6) 

[1,0,1,0,0] Place: Loss of landmarks; <2yrs 78% (64/82) 88% (79/90) -10%(-21, 1.4) 

vs. United States Air fluid level behind TM; 2-6yrs 91% (100/110) 88% (91/104) 3% (-4.9, 12) 

Multicenter: Entering: Presence of MEF by 

Definition: Cefdinir 28 centers N=425 acoustic reflectometry; Outcome: Success at end-of-treatment visit (study days 7-9 for Cefdinir; 

Presence 14 mg/kg/day N=214 Augmentin Signs or symptoms of study days 12-14 for Amox-clav) by PCV7 

of MEE, / bid for 5 days Inclusion: [Amoxicillin- MEI; Amox-clav Cefdinir Diff (95%CI) 

S&S of 6 mo-6 yr, clavulanate] By symptoms Total 85% (164/192) 88% (170/194) -2% (-9, 4.6) 

MEI Presence of middle ear effusion (MEE), N=211 Cefdinir (otalgia, ear fullness); HadPCV7 82% (102/124) 92% (115/125) -10%(-18, -2) 

Bulging tympanic membrane [TM], By otoscopy NoPCV7 91% (62/68) 80% (55/69) 11% (-0.8, 23) 

Cloudy TM, Completing: (distinct TM erythema); 

Air fluid level behind TM, N=425 Other symptoms: fever; Outcome: Adverse events 

Otorrhea, N=214 Augmentin Other symptoms: Amox-clav Cefdinir Diff (95%CI) 

Pneumatic otoscopy/tympanometry [Amoxicillin­ decreased hearing; Dia.rash 10% (21/214) 8% (17/211) 2%(-4, 7) 

(limited or absent mobility of TM), clavulanate] Adverse effects of Diarrhea 10% (21/214) 7% (15/211) 3%(-3, 8) 

Presence of MEF by acoustic N=211 Cefdinir treatment Vomiting 5% (11/214) 1% (2/211) 4%(1, 7.5) 

reflectometry, 

Otalgia, Analyzed: 

Decreased hearing N=425 

N=214 Augmentin 

Exclusion: [AmoxicillinAntibiotic within 2 weeks, clavulanate] 

Concomitant/Concurrent infection N=211 Cefdinir 

needing 

antibiotic treatment, 

Long acting antibiotic within 4 weeks, 

Otitis externa, 

Chronic suppurative OM, 

No symptoms of AOM, 

PE tubes/history of PE tubes 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Block 

200583 

Jadad 

quality 

score 1 

Azithromycin 

10 mg/kg/day 

= qd for 1 day, 

Enrollment 

Time: 

11/2003-1/2004 

Influencing 

factors: 

Age 

Treatment failure; 

By otoscopic findings:; 

Bulging tympanic 

Outcome: Clinical success (cure or improve) on day 7-9 at end-of-therapy 

Azith Cefdinir Diff (95%CI) 

Total 85% (149/176) 87% (151/174) -2% (-9, 5.3) 

(0-5):3 --- 5 mg/kg/day membrane [TM]; 0-2yrs 82% (54/66) 81% (48/59) 1% (-13, 15) 

[1,0,1,1,1] = qd for 4 days Place: Cloudy TM; >2yrs 86% (95/110) 90% (103/115) -4% (-12, 4.5) 

United States Entering: Loss of landmarks; 

vs. Multicenter: N=357 Erythematous TM; Outcome: Adverse events 

Definition: 27 centers N=181 Azithromycin Air fluid level behind TM; Azith Cefdinir Diff (95%CI) 

Presence Cefdinir N=176 Cefdinir Otorrhea; Abn Stool 4% (7/176) 7% (12/174) -3%(-8,2) 

of MEE, 7 mg/kg/day Inclusion: By Pneumatic Diarrhea 3% (5/176) 6% (10/174) -3%(-6,0.6) 

S&S of = bid for 5 days 6 mo-6 yr, Completing: otoscopy/tympanometry; 

MEI Bulging tympanic membrane [TM], N=350 Presence of MEF by 

Loss of landmarks, N=176 Azithromycin acoustic reflectometry; 

Erythematous TM, N=174 Cefdinir By symptoms 

Otorrhea, (otalgia, ear fullness); 

Pneumatic otoscopy/tympanometry Analyzed: By otoscopy 

(limited or absent mobility of TM), N=350 (distinct TM erythema); 

Presence of MEF by acoustic N=176 Azithromycin Other symptoms: fever; 

reflectometry, N=174 Cefdinir Other symptoms: 

Otalgia, decreased hearing; 

Decreased hearing, Adverse effects of 

Ear fullness, treatment; 

AOM < 1 week Parent satisfaction; 

Cost outcomes; 

Exclusion: Healthcare utilization 

Antibiotic within 2 weeks, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

Long acting antibiotic within 4 weeks, 

Otitis externa, 

Chronic suppurative OM, 

TM perforation/Otorrhea >24 hours, 

PE tubes/history of PE tubes 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Bolt 

200890 

Jadad 

quality 

score 1 

Placebo 

vs. 

Enrollment 

Time: 

10/2003-7/2004 

Influencing 

factors: 

Examiner 

By symptoms 

(otalgia, ear fullness); 

Adverse effects of 

Outcome: Reduction by 50% in pain score on day 30 

Lidocaine Placebo 

By parent 90% (28/31) 63% (20/32) 

Diff (95%CI) 

27%(6, 48) 

(0-5):4 treatment By doctor 84% (26/31) 66% (21/32) 18% (-3.4,39) 

[1,1,1,0,1] 2% aqueous Place: 

lidocaine Emergency room Entering: Outcome: Reduction by 25% in pain score on day 30 

3 drops hourly for N=63 Lidocaine Placebo Diff (95%CI) 

Definition: 1 day Inclusion: N=32 Placebo By parent 95% (28/31) 78% (25/32) 21%(1, 41) 

Presence 3-17 yr, N=31 Lidocaine By doctor 90% (28/31) 78% (25/32) 12%(-6, 30) 

of MEE, 34-35 lbs, 

S&S of Bulging tympanic membrane [TM], Completing: Outcome: Adverse events 

MEI Cloudy TM, N=60 Lidocaine Placebo Diff (95%CI) 

Erythematous TM, N=31 Placebo Ear Discharge 

Otalgia within last 3 days N=29 Lidocaine 6% (2/31) 9% (3/32) -3%(-16,10) 

Dizziness 10% (3/31) 0% (0/32) 10%(-0.8,20) 

Exclusion: Analyzed: 

Any antibiotic, N=60 

TM perforation/Otorrhea, N=31 Placebo 

PE tubes/history of PE tubes, N=29 Lidocaine 

GI disorders/Liver, 

Renal Disorders, 

Neurological disease/impairment, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Bottenfield 

199897 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/6.4 mg/kg/day 

Enrollment 

Time: 

12/1996-2/1997 

Entering: 

N=453 

N=230 AmoxicillinTreatment failure; 

Disease recurrence; 

Adverse effects of 

Outcome: Clinical success at the end of therapy 

A-C 90 A-C 45 Diff (95% CI) 

84.1%(149/177) 78.8% (149/189) 5% (-3, 13) 

(0-5):3 / bid for 10 days clavulanate 45 mg treatment 

[1,1,1,0,0] Place: N=223 Amoxicillin- Outcome: Global clinical success including recurrence on days 22-28 

vs. United States clavulanate 90 mg A-C 90 A-C 45 Diff (95%CI) 

Multicenter: 68.9% (122/177) 67.9% (128/189) 1% (-8, 10) 

Definition: Amoxicillin­ 19 centers Completing: 

Presence clavulanate N=404 Outcome: Adverse events 

of MEE, 90/6.4 mg/kg/day Inclusion: N=207 Amoxicillin- A-C 90 A-C 45 Diff (95%CI) 

S&S of / bid for 10 days 3 mo-12 yr, clavulanate 45 mg Any 45% (101/223) 43% (98/230) 3%(-6,12) 

MEI <40 kg, N=197 Amoxicillin- Need Tx 24% (54/223) 26% (61/230) -2%(-10,5.7) 

Presence of middle ear effusion (MEE), clavulanate 90 mg Cough 11% (24/223) 6% (14/230) 5%(-0.4,10) 

Bulging tympanic membrane [TM], Fever 5% (11/223) 4% (8/230) 1%(-2.3,5.1) 

Cloudy TM, Analyzed: Dia Rash 4% (9/223) 5% (11/230) -1%(-4.6,3) 

Erythematous TM, N=404 Sev diarr 10% (22/223) 8% (19/230) 2%(-3.7, 7) 

Otorrhea, N=207 Amoxicillin- Sev Rash 1% (3/223) 0% (0/230) 1%(-0.2,2.8) 

Pneumatic otoscopy/tympanometry clavulanate 45 mg Sev erythema multiform 

(limited or absent mobility of TM), N=197 Amoxicillin­ 0% (0/223) 0.4% (1/230) -0.4(-1.2,0.4) 

S&S of middle ear inflammation clavulanate 90 mg Sev GI 0% (0/223) 0.4% (1/230) -0.4(-1.2,0.4) 

(MEI), Sev moniliasis 

Otalgia, 0.4% (1/223) 0% (0/230) 0.4(-0.4,1.2) 

Otoscopy (distinct TM erythema) URI 3% (6/223) 8% (19/230) -6%(-10,-1.4) 

Vomiting 6% (13/223) 7% (16/230) -1%(-5.7,3.3) 

Exclusion: 

Penicillin/beta-lactams, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

PE tubes/history of PE tubes, 

Cranio-facial, 

GI disorders/Liver, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem, 

Metabolic/Inborn Errors of metabolism, 

Bowel function-altering meds within 48 

hours, 

On other medication/treatment 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Author 

Year 

Quality 

& AOM 

definition Intervention 

Time, Place, Inclusion, Exclusion 

Criteria 

Influencing 

Factors and 

Sample Size Outcomes Findings 

Carvalho Jadad Cefprozil Inclusion: Entering: Treatment failure; Outcome: Clinical success at the end of therapy (3rd visit) 

199884 quality 

score 1 

(0-5):1 

[1,0,0,0,0] 

Definition: 

Other 

30 mg/kg/day 

/ bid for 10 days 

vs. 

Cefaclor 

40 mg/kg/day 

/ tid for 10 days 

Otalgia, 

Fever, 

Irritability, 

Otoscopy characteristics 

Exclusion: 

Antibiotic within 7 days, 

Long acting antibiotic within 2 weeks, 

Cranio-facial, 

GI disorders/Liver, 

Renal Disorders 

N=40 

N=21 Cefprozil 

N=19 Cefaclor 

Presence of MEE 

[also persistent effusion, 

OME]; 

By otoscopic findings:; 

Bulging tympanic 

membrane [TM]; 

Signs or symptoms of 

MEI; 

By symptoms 

(otalgia, ear fullness); 

Other symptoms: fever; 

Adverse effects of 

treatment 

Cefaclor Cefprozil 

Cured *(18/19) 95.2% (20/21) 

Partial cure 0 0 

Failure 0 4.8% (1/21) 

*Incomplete data 1 0 

Outcome: Adverse events 

Cefaclor Cefprozil Diff995CI) 

Any 11% (2/19) 0% (0/21) 11% (-3, 24) 

Vomiting 0% (0/19 10% (2/21) -10% (-23, 4) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Casellas 

200569 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

80 mg/kg/day 

Study Time: 

10/2001-10/2003 

Entering: 

N=289 

N=149 AmoxicillinTreatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Clinical success at days 12-14 

A-C A-S 

98% (115/117) 98% (115/117) 

Diff (95%CI) 

0% (-3.3, 3.3) 

(0-5):2 = bid for 10 days Place: clavulanate Disease recurrence; 

[1,0,1,0,0] Argentina N=140 Amoxicillin Adverse effects of Outcome: Clinical success at days 28-42 

vs. Multicenter: Sulbactam treatment; A-C A-S Diff (95%CI) 

4 centers Bacteriologic outcomes 95% (98/103) 94% (97/103) 1% (-5.2, 7) 

Definition: Amoxicillin Completing: by nasopharyngeal cultures 

Presence Sulbactam Inclusion: N=234 Outcome: Adverse events 

of MEE, 80 mg/kg/day 6-48 mo, N=117 Amoxicillin- A-C A-S Diff (95%CI) 

S&S of = bid for 10 days >6 kg, clavulanate Any 27% (40/149) 36% (50/140) -9%(-20, 1.8) 

MEI Presence of middle ear effusion (MEE), N=117 Amoxicillin Diarrhea, day 12-14 

Bulging tympanic membrane [TM], Sulbactam 3% (4/149) 6% (8/140 -3%(-8, 2) 

Erythematous TM, Diarrhea, day 3 

S&S of middle ear inflammation Analyzed: 5% (7/149) 16% (23/140) -12%(-19, -4.7) 

(MEI), N=234 Minor 26% (39/149) 36% (50/140) -10%(-20, 1.2) 

Otalgia, N=117 Amoxicillin- Severe diarrhea 

Otoscopy (distinct TM erythema), clavulanate 0.7% (1/149) 0.7% (1/140) 0% (-1.9, 1.9) 

Fever, N=117 Amoxicillin 

New/first episode of AOM Sulbactam 

Exclusion: 

Penicillin/beta-lactams, 

Antibiotic within 2 weeks, 

Recurrent AOM, 

TM perforation/Otorrhea, 

Complication of OM, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Catania 

200499 

Jadad 

quality 

score 1 

Cefaclor 

50 mg/kg/day 

= bid for 5 days 

Study Time: 

11/2001-3/2002 

Entering: 

N=410 

N=204 Cefaclor 50 mg/5 days 

Treatment failure; 

By otoscopic findings:; 

Bulging tympanic 

Outcome: Cured at end of therapy 

Cef 5D Cef10D 

95.5% (195/204) 94.8% (195/206) 

Diff (95%CI) 

1%(-3.5, 4.9) 

(0-5):3 Place: N=206 Cefaclor 40 mg/10 membrane [TM]; 

[1,0,1,1,0] vs. Pediatric practice days Otorrhea; Outcome: Adverse events 

Multicenter: Signs or symptoms of Cef5D Cef10D Diff (95%CI) 

Cefaclor 22 centers Completing: MEI; Any 6% (12/204) 8% (17/206) -2%(-7, 3.2) 

Definition: 40 mg/kg/day N=400 By symptoms Abd pain 1.5% (3/204) 2.4% (5/206) -1%(-3.6, 1.8) 

Other = bid for 10 days Inclusion: N=204 Cefaclor 50 mg/5 days (otalgia, ear fullness); Cut rash 2.5% (5/204) 2.9% (6/206) -0.4%(-2.5,2.7) 

2-6 yr, N=196 Cefaclor 40 mg/10 Other symptoms: fever; Diarrhea 2.0% (4/204) 2.4% (5/206) -0.4%(-3.2,2.4) 

Erythematous TM, days Disease recurrence; New OMA episode 

Otalgia, Adverse effects of 9% (19/204) 8% (17/206) 1%(-4.5, 6.5) 

Fever >38 C, Analyzed: treatment Vomiting 0.5% (1/204) 0.5% (1/206) 0% (-1.4, 1.4) 

Onset of AOM symptoms within 2 days N=400 

before entry N=204 Cefaclor 50 mg/5 days 

N=196 Cefaclor 40 mg/10 

Exclusion: days 

Allergic to other medication NOS, 

Antibiotic within 72 hours, 

GI disorders/Liver, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient, 

Heme/Onc Disorders 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Chao 

200895 

Jadad 

quality 

score 1 

Wait and see 

vs. 

Study Time: 

12/2005-11/2006 

Entering: 

N=232 

N=117 Wait and see 

Parent satisfaction; 

Duration of AOM; 

Other antibiotic: No new 

No clinical success rate studied. 

Adverse events not reported 

(0-5):3 Place: N=115 Prescription abx Rx/no change in abx 

[1,0,1,1,0] Prescription to Emergency room to Hold Rx 

Hold 

Inclusion: Completing: 

Definition: 2-12 yr, N=206 

Not AOM N=100 Wait and see 

specified N=106 Prescription 

Exclusion: to Hold 

Any antibiotic during present illness, 

Concomitant/Concurrent infection Analyzed: 

needing N=206 

antibiotic treatment, N=100 Wait and see 

AOM within 30 days, N=106 Prescription 

Cranio-facial, to Hold 

Immunosuppressed 

/compromised/deficient, 

No telephone, 

Prolonged ear pain 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Chonmaitree 

2003101 

Jadad 

quality 

score 1 

Ceftriaxone 

50 mg/kg/day 

= qd for 1 day 

Enrollment 

Time: 

7/1995-6/2000 

Completing: 

N=179 

N=46 Placebo 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success on days 5-14 

Corticosteroid Placebo 

84.4% (38/45) 78.3% (36/46) 

Diff (95%CI) 

6%(-10, 22) 

(0-5):2 N=45 Prednisolone OME]; 

[1,1,0,0,0] vs. Place: N=44 Antihistamine Signs or symptoms of Antihistamine Placebo Diff (95%CI) 

United States N=44 Prednisolone & MEI; 75.0% (33/44) 78.3% (36/46) -3%(-21, 14) 

Ceftriaxone Hospital clinic/ antihistamine Disease recurrence; 

Definition: 50 mg/kg/day outpatient PE tube placement; Both drug Placebo Diff (95%CI) 

Presence = qd for 1 day, Analyzed: Healthcare utilization 88.6% (39/44) 78.3% (36/46) 10%(-5.1, 26) 

of MEE, Prednisolone Inclusion: N=179 

S&S of 2 mg/kg/day 3 mo-6 yr, N=46 Placebo Corticosteroid Antihistamine Diff (95%CI) 

MEI / tid for 5 days Presence of middle ear effusion (MEE), N=45 Prednisolone 84.4% (38/45) 75.0% (33/44) 9% (-7, 26) 

Bulging tympanic membrane [TM], N=44 Antihistamine 

vs. Cloudy TM, N=44 Prednisolone & Corticosteroid Both drugs Diff (95%CI) 

Pneumatic otoscopy/tympanometry antihistamine 84.4% (38/45) 88.6% (39/44) -4%(-18, 10) 

Ceftriaxone (limited or absent mobility of TM), 

50 mg/kg/day S&S of middle ear inflammation Antihistamine Both drugs Diff (95%CI) 

= qd for 1 day, (MEI), 75.0% (33/44) 88.6% (39/44) -14%(-30,2.5) 

Antihistamine Otalgia, 

0.35 mg/kg/day Otoscopy (distinct TM erythema), Adverse events not reported 

/ tid for 5 days Fever, 

Recurrent AOM 

vs. 

Exclusion: 

Ceftriaxone Penicillin/beta-lactams, 

50 mg/kg/day Antibiotic within 7 days, 

= qd for 1 day, PE tubes/history of PE tubes, 

Antihistamine Cranio-facial, 

0.35 mg/kg/day Major Systemic disease/ condition, 

/ tid for 5 days, medical problem, 

Prednisolone On other medication/treatment, 

2 mg/k Exposure to varicella w/in 3 weeks 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Cifaldi Jadad Amoxicillin- Place: Influencing Parent satisfaction; This study does not report clinical success. It reports parent-reported 

200474 quality 

score 1 

clavulanate 

45/6.4 mg/kg/day 

Multicenter factors: 

Age 

Cost outcomes; 

Compliance; 

outcomes. 

(0-5):1 / bid for 10 days Inclusion: Tolerability 

[1,0,0,0,0] 6 mo-6 yr, 

vs. AOM 

Definition: Cefdinir Exclusion: 

Not 14 mg/kg/day NR 

specified / bid for 5 days 

Cohen 

199898 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

80/10 mg/kg/day 

Enrollment 

Time: 

2/1995-5/1996 

Influencing 

factors: 

Parent/caretaker 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success (cure or improve) per protocol population By 

outcome days 

(0-5):5 / tid for 10 days OME]; Amox-clav 5d Amox-clav 10d Diff (95%CI) 

[1,1,1,1,1] Place: Signs or symptoms of 12-14 d 76.7% (125/163) 88.1% (148/168) -11%(-20,-3.2) 

vs. France Entering: MEI; 28-42 d 40.4% (57/141) 46% (64/139) -5.6%(-17, 6) 

Multicenter N=385 Other symptoms: fever; 

Definition: Amoxicillin­ N=191 Amoxicillin- Disease recurrence; Outcome: Clinical success 9cure or improve) per protocol population by 

Presence clavulanate Inclusion: clavulanate 10 day Adverse effects of setting of child care 

of MEE, 80/10 for 5 days 4-30 mo, N=194 Amoxicillin­ treatment; 

S&S of Presence of middle ear effusion (MEE), clavulanate 5 day Bacteriologic outcomes Amox-clav 5d Amox-clav 10d Diff (95%CI) 

MEI Bulging tympanic membrane [TM], by nasopharyngeal Home 85.1% (57/67) 89.6% (69/77) -4.5%(-15, 6) 

Erythematous TM, Completing: cultures; Caretaker 70.8% (68/96) 86.8% (79/91) -16% (-28,- 4) 

S&S of middle ear inflammation N=331 Otologic complications, Sitter 73.6% (39/53) 88.6% (39/44) -15%(-31, 0.9) 

(MEI), N=168 Amoxicillin­ i.e., cholestetoma; Day-care 67.3% (29/43) 85.1% (40/47) -18%(-35, 0.3) 

Otalgia, clavulanate 10 day Other antibiotic: No new 

Fever N=163 Amoxicillin­ abx Rx/no change in abx Outcome: Adverse events 

clavulanate 5 day Rx Amox-clav 5d Amox-clav 10d Diff (95%CI) 

Exclusion: Any 45% (88/194) 43% (80/188) 2.8%(-7, 13) 

Penicillin/beta-lactams, Analyzed: Drug-related 

Antibiotic within 7 days, N=378 31% (60/194) 29% (55/188) 2%(-8,, 11) 

TM perforation/Otorrhea, N=186 Amoxicillin- Diarrhea 23% (44/194) 26% (49/188) -3%(-12, 5.2) 

PE tubes/history of PE tubes, clavulanate 10 day Skin rash 4% (8/194) 7% (13/188) -3%(-7, 1.8) 

Major Systemic disease/ condition, N=192 Amoxicillinmedical problem clavulanate 5 day 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Cohen 

199977 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

80/10 mg/kg/day 

Enrollment 

Time: 

2/1995-5/1996 

Entering: 

N=513 

N=258 AmoxicillinTreatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Success rate at days 12-14: 

Amox-clav Ceftriaxon Diff (95%CI) 

Per Protocol 

(0-5):3 / tid for 10 days clavulanate Other symptoms: fever; 82.5% (188/228) 79.2% (186/235) 3% (-3.9, 10) 

[1,0,1,1,0] Place: N=255 Ceftriaxone Adverse effects of Intent-to-treat 

vs. France treatment; 77.1% (199/258) 74.5% (190/255) 3% (-4.8, 10) 

Multicenter Completing: Bacteriologic outcomes 

Definition: Ceftriaxone N=463 by nasopharyngeal Outcome: Success rate at days 28-42: 

Presence 50 mg/kg/day Inclusion: N=228 Amoxicillin­ cultures; Amox-clav Ceftriaxon Diff (95%CI) 

of MEE, = qd for 1 day 4-30 mo, clavulanate Otologic complications, Per Protocol 

S&S of Presence of middle ear effusion (MEE), N=235 Ceftriaxone i.e., cholestetoma; 55.1% (103/187) 59.0% (108/183) -4% (-14, 6.2) 

MEI Bulging tympanic membrane [TM], PE tube placement Intent-to-treat 

Erythematous TM, Analyzed: 55.8% (111/199) 58.9% (112/190) -3% (-13, 6.7) 

Otalgia, N=513 

Otoscopy (distinct TM erythema), N=258 Amoxicillin- Outcome: Otitis media with effusion at days 28-42: 

Fever clavulanate Amox-clav Ceftriaxon Diff (95%CI) 

N=255 Ceftriaxone Per Protocol 

Exclusion: 20.3% (38/187) 16.9% (31/183) 3% (-4.5, 11) 

Penicillin/beta-lactams, Intent-to-treat 

Antibiotic within 7 days, 20.6% (41/199) 16.3% (31/190) 4% (-3.4, 12) 

TM perforation/Otorrhea, 

PE tubes/history of PE tubes, Outcome: Other infections at days 28-42: 

Major Systemic disease/ condition, Amox-clav Ceftriaxon Diff (95%CI) 

medical problem Per Protocol 

9.1% (17/187) 11.5% (21/183) -2% (-9, 3.8) 

Intent-to-treat 

8.0% (16/199) 10.5% (20/190) -2.5% (-8, 3) 

Outcome: Adverse events 

Amox-clav Ceftriaxon Diff (95%CI) 

Any 31% (79/258) 14% (36/255) 16%(9, 24) 

Diarrhea 27% (70/258) 14% (36/255) 13%(6, 20) 

The article also publishes data on the carriage of Streptococcus 

pneumoniae, Haemophilus influenzae and Moraxella catarrhalis before 

treatment and at Days 12 to 14. 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Cohen 

2000100 

Jadad 

quality 

score 1 

Cefpodoxime 

8 mg/kg/day 

/ bid for 10 days 

Enrollment 

Time: 

10/1996-4/1997 

Influencing 

factors: 

Age, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success (cure or improve) on day 12-14 per protocol 

population 

(0-5):5 Parent/caretaker OME]; CPD 5d CPD 10d Diff (95%CI) 

[1,1,1,1,1] vs. Place: Signs or symptoms of Total 84.1% (175/208) 92.4% (194/210) -8% (-14, -2.1) 

France MEI; Data by age group not reported. 

Cefpodoxime Multicenter Entering: Other symptoms: fever; Multivariable analysis showed the response to treatment was significantly 

Definition: 8 mg/kg/day N=450 Disease recurrence; influenced by the treatment duration, the day-care modality, age, and a 

Presence / bid for 5 days Inclusion: N=223 Cefpodoxime 10 day Adverse effects of history of otitis media with effusion. 

of MEE, 4-30 mo, N=227 Cefpodoxime 5 day treatment 

S&S of Presence of middle ear effusion (MEE), Outcome: Clinical success (cure or improve) on day 28-42 per protocol 

MEI Bulging tympanic membrane [TM], Completing: population 

Erythematous TM, N=418 

Otalgia, N=210 Cefpodoxime 10 day CPD 5d CPD 10d Diff (95%CI) 

Otoscopy (distinct TM erythema), N=208 Cefpodoxime 5 day Total 85.4% (134/157) 83.7% (144/172) -2% (-6, 9) 

Fever 

Analyzed: Outcome: Relapse or recurrence 

Exclusion: N=448 CPD 5d CPD 10d Diff (95%CI) 

Penicillin/beta-lactams, N=222 Cefpodoxime 10 day Total 14.6% (23/157) 16.3% (28/172) -2% (-9, 6.1) 

Antibiotic within 7 days, N=226 Cefpodoxime 5 day 

TM perforation/Otorrhea, Outcome: clinical success (cure or improve) per protocol population by 

PE tubes/history of PE tubes, day-care modality 

Major Systemic disease/ condition, 

medical problem CDP 5d CDP 10d Diff (95%CI) 

Home 88.1% (74/84) 92.2% (95/103) -4.1%(-13, 4) 

Caretaker 81.4% (101/124) 92.5% (99/107) -11%(-20, -2) 

Sitter 86.8% (66/76) 100%(47/47) -13%(-23, -3) 

Day-care 72.9% (35/48) 86.7% (52/60) -14%(-29, 1) 

Outcome: Adverse events 

CDP 5d CDP 10d Diff (95%CI) 

Any 12% (26/224) 16% (36/222) 3% (-11, 1.8) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Dagan 

20007 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/6.4 mg/kg/day 

Enrollment 

Time: 

12/1997-8/1998 

Influencing 

factors: 

Pathogen 

Treatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Clinical success at days 12-14 

Pathogen Amox-clav Azithromycin 

All type 86% (60/70) 70% (51/73) 

Diff (95%CI) 

16%(2, 30) 

(0-5):2 / bid for 10 days Bacteriologic cure/failure; HF 91% (30/33) 65% (22/34) 26% (6, 46) 

[1,0,1,0,0] Place: Adverse effects of SP 86% (18/21) 80% (16/20) 6% (-17, 29) 

vs. United States, Entering: treatment Others 75% (12/16) 68% (13/19) 7% (-23, 37) 

Israel, N=238 

Definition: Azithromycin Dominican Republic N=118 Amoxicillin- Outcome: Clinical success at days 22-28 

Presence 10 mg/kg/day Multicenter: clavulanate Pathogen Amox-clav Azithromycin Diff (95%CI) 

of MEE, = qd for 1 day, 12 centers N=120 Azithromycin All type 71% (46/65) 66% (44/67) 5%(-11,21) 

S&S of --- 5 mg/kg/day HF 81% (25/31) 58% (18/31) 23%(0.1, 46) 

MEI = qd for 4 days Inclusion: Completing: SP 62% (13/21) 72% (13/18) -10%(-40,20) 

6-48 mo, N=169 Others 62% (8/13) 72% (13/18) -10%(-43,23) 

<41 kg, N=84 AmoxicillinPresence of middle ear effusion (MEE), clavulanate Outcome: Bacteriologic success at days 4-6 

Bulging tympanic membrane [TM], N=85 Azithromycin Pathogen Amox-clav Azithromycin Diff (95%CI) 

Cloudy TM, All type 83% (64/65) 49% (35/71) 34%(18, 50) 

Loss of landmarks, Analyzed: HF 87% (26/30) 39% (13/33) 48%(24, 72) 

Otorrhea, N=136 SP 90% (18/20) 68% (13/19) 22%(-3.4, 47) 

Pneumatic otoscopy/tympanometry N=65 Amoxicillin- Others 67% (10/15) 47% (9/19) 20%(-14, 54) 

(limited or absent mobility of TM), clavulanate 

S&S of middle ear inflammation N=71 Azithromycin Outcome: Adverse events 

(MEI), Amox-clav Azithromycin Diff (95%CI) 

Otalgia within last 24 hours, Any 27% (32/118) 22% (26/120) 3% (-11, 1.8) 

Otoscopy (distinct TM erythema), Related to treatment 

Ear fullness 10% (12/118) 2% (2/120) 8% (2.5, 14) 

Diarrhea 8% (9/118) 4% (5/120) 3% (-2.6, 9) 

Exclusion: Vomiting 8% (10/118) 0% (0/120) 8% (3.4, 14) 

Allergic to other medication NOS, 

Penicillin/beta-lactams, 

Macrolides, 

Antibiotic within 72 hours, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient, 

Other Infectious diseases (meningitis), 

On other medication/treatment 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Dagan 

200081 

Jadad 

quality 

score 1 

Cefaclor 

40 mg/kg/day 

/ tid for 10 days 

Place: 

Israel 

Emergency room 

Influencing 

factors: 

Pathogen 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success 

Cefaclor Azithromycin Diff (95%CI) 

Day 10 85% (50/59) 82% (51/62) 3%(-10, 16) 

(0-5):2 OME]; 

[1,0,1,0,0] vs. Inclusion: Signs or symptoms of Outcome: Bacteriologic success in initially culture-positive cases 

3-36 mo, Entering: MEI; Cefaclor Azithromycin Diff (95%CI) 

Azithromycin Presence of middle ear effusion (MEE), N=138 Bacteriologic cure/failure; SP 63% (17/27) 71% (12/17) -8%(-37, 21) 

Definition: 10 mg/kg/day Bulging tympanic membrane [TM], N=68 Cefaclor Adverse effects of HF 48% (12/25) 47% (14/30) 1%(-26, 28) 

Presence = qd for 3 days Erythematous TM, N=70 Azithromycin treatment Others 100% (4/4) 100% (4/4) 0% (0, 0) 

of MEE, S&S of middle ear inflammation 

S&S of (MEI), Completing: Outcome: Bacteriologic success in initially culture-negative cases 

MEI Otalgia, N=122 Cefaclor Azithromycin Diff (95%CI) 

Otoscopy (distinct TM erythema), N=59 Cefaclor SP 81% (26/32) 98% (45/46) -17%(-30, -4) 

Fever, N=63 Azithromycin HF 88% (30/34) 85% (28/33) 3%(-13, 19) 

Onset of AOM symptoms within 7 days Others 95% (52/55) 98% (58/59) -3%(-10, 4) 

before entry, Analyzed: 

Tympanocentesis preformed Fluid N=122 Adverse events not reported by drug arm. 

obtained, N=59 Cefaclor 

Irritability, N=63 Azithromycin 

Other constitutional symptoms NOS 

Exclusion: 

Antibiotic within 72 hours, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

Chronic suppurative OM, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

Lack of effusion on tympanocentesis, 

TM perforation/Otorrhea, 

Endocrine disorders (diabetes), 

Immunosuppressed 

/compromised/deficient 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Damoiseaux 

200088 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

2/1996-5/1998 

Entering: 

N=240 

N=123 Placebo 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical outcome at day 4 

Amoxicillin Placebo 

No persistent symptoms 

Diff (95% CI) 

(0-5):5 Place: N=117 Amoxicillin OME]; 41% (48/117) 28% (34/123) 13% (1, 25) 

[1,1,1,1,1] Amoxicillin Netherlands Signs or symptoms of Improvement in eardrum 

40 mg/kg/day Multicenter: Completing: MEI; 23% (26/114) 17% (21/120) 6% (-4, 16) 

/ tid for 10 days 53 centers N=235 Other symptoms: fever; 

Definition: Office setting/ N=120 Placebo Adverse effects of Outcome: Clinical success at day 11 

Acute private practice, N=115 Amoxicillin treatment Amoxicillin Placebo Diff (95% CI) 

onset General/ 36% (40/112) 30% (36120) 6% (-6, 18) 

of S&S, family practice Analyzed: 

S&S of N=235 Outcome: Middle ear effusion present at 6 weeks 

MEI Inclusion: N=120 Placebo Amoxicillin Placebo Diff (95% CI) 

6-24 mo, N=115 Amoxicillin 64% (69/107) 67% (70/105) 3% (-10, 16) 

Acute onset S&S (parent/guardian 

report), Outcome: Adverse effects - Diarrhea 

Presence of middle ear effusion (MEE), Amoxicillin Placebo Diff (95% CI) 

Bulging tympanic membrane [TM], Day 4 17% (20/117) 10% (12/123) -7% (-16, 2) 

Erythematous TM, Day 10 12% (14/117) 8% (10/123) -4% (-12, 4) 

Otorrhea, 

S&S of middle ear inflammation Outcome: Duration of symptoms in days 

(MEI), Amoxicillin Placebo 

Otalgia, Median Median p-value 

Fever, Fever 2 3 0.004 

Irritability, Pain/crying 8 9 0.43 

Other constitutional symptoms NOS 

Exclusion: 

Penicillin/beta-lactams, 

Antibiotic within 4 weeks, 

Cranio-facial, 

Immunosuppressed 

/compromised/deficient 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Damrikarnlert 

20006 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

40/10 mg/kg/day 

Study Time: 

8/1996-3/1998 

Entering: 

N=415 

N=206 AmoxicillinTreatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Clinical success at the end of therapy on day 7-12 

A-C BID A-C TID Diff (95%CI) 

94.0% (187/199) 94.1% (175/186) 0.1%(-4.8,4.6) 

(0-5):3 / tid for 7-10 days Place: clavulanate 40/10 TID By symptoms 

[1,0,1,1,0] Multicenter: N=209 Amoxicillin­ (otalgia, ear fullness); Outcome: Clinical success at follow-up on day 38-42 

vs. 18 centers clavulanate 45/6.4 BID By otoscopy A-C BID A-C TID Diff (95%CI) 

(distinct TM erythema); 93.3% (168/180) 87.9% (153/174) 5.4%(-0.7, 12) 

Definition: Amoxicillin- Inclusion: Completing: Bacteriologic cure/failure; 

Presence clavulanate 2 mo-12 yr, N=324 Adverse effects of Outcome: Bacteriological success at end of therapy on day 7-12 

of MEE, 45/6.4 mg/kg/day Presence of middle ear effusion (MEE), N=151 Amoxicillin­ treatment; A-C BID A-C TID Diff (95%CI) 

S&S of / bid for 7-10 days Bulging tympanic membrane [TM], clavulanate 40/10 TID Other antibiotic: No new 77.8% (7/9) 84.6% (11/13) -7%(-40, 26) 

MEI Loss of landmarks, N=173 Amoxicillin­ abx Rx/no change in abx 

Erythematous TM, clavulanate 45/6.4 BID Rx Outcome: Adverse events 

Otorrhea, A-C BID A-C TID Diff (95%CI) 

Pneumatic otoscopy/tympanometry Analyzed: At least 1 treatment related 

(limited or absent mobility of TM), N=386 12% (25/209) 18% (37/206) -6%(-13, 0.9) 

S&S of middle ear inflammation N=187 Amoxicillin- Abdominal pain or enteritis or fever or rash 

(MEI), clavulanate 40/10 TID 0.5% (1/209) 0% (0/206) 0.5%(-0.5,1.5) 

Otalgia, N=199 Amoxicillin- Constipation or ear disorder or enlarged abdomen or enterocolitis or 

Otoscopy (distinct TM erythema), clavulanate 45/6.4 BID erythematous rash or somnolence or stomatitis (ulcerative) 

Decreased hearing, 0% (0/209) 0.5% (1/206) -0.5%(-1.5,0.5) 

Ear fullness Dermatitis 

0.5% (1/209) 1.9% (4/206) -1.4%(-3.5,0.7) 

Exclusion: Diarrhea 7% (15/209) 11% (22/206) -3.5%(-9, 2.8) 

Penicillin/beta-lactams, Nervous 1% (2/209) 0% (0/206) -0.5%(-0.4,2.4) 

Antibiotic within 10 days, Otitis media 

Concomitant/Concurrent infection 0.5% (1/209) 1% (2/206) -0.5%(-2.2,1.2) 

needing Urticaria 0% (0/209) 1.5% (3/206) -1.5%(-3.2,0.2) 

antibiotic treatment, Vomiting 2% (4/209) 0.5% (1/206) 1.4%(-0.7,3.5) 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Investigational drug within 30 days 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

De Diego 

2001128 

Jadad 

quality 

score 1 

Amoxicillin 

20 mg/kg/day 

= qd for 12 weeks 

Study Time: 

1/1998-5/1999 

Entering: 

N=71 

N=40 Amoxicillin 

Disease recurrence; 

Adverse effects of 

treatment 

Outcome: Effective rate (#AOM episodes dropped to <50% after 

prophylaxis) in 6-27 months 

Amoxicillin Azithromycin Diff (95%CI) 

(0-5):2 Inclusion: N=31 Azithromycin 89% (34/38) 81% (25/31) 9% (-8, 26) 

[1,0,1,0,0] vs. Recurrent AOM 

Completing: Outcome: Adverse events 

Azithromycin N=69 Amoxicillin Azithromycin Diff (95%CI) 

Definition: 10 mg/kg/day N=38 Amoxicillin GI 2.5% (1/40) 0% (0/31) 2.5%(-3. 8) 

Not = q week for 12 N=31 Azithromycin 

specified weeks 

Analyzed: 

N=69 

N=38 Amoxicillin 

N=31 Azithromycin 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Dohar 

200680 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

90 mg/kg/day 

Enrollment 

Time: 

5/2003-5/2004 

Entering: 

N=80 

N=41 AmoxicillinTreatment failure; 

By otoscopic findings:; 

Otorrhea; 

Outcome: Clinical cure or absence of otorrhea at test-of-cure visit on day 

18-21 

Amox-clav Ciprodex Diff (95%CI) 

(0-5):2 / bid for 10 days clavulanate Bacteriologic cure/failure; 58.5% (24/41) 84.6% (33/39) -26%(-46, -6) 

[1,0,0,1,0] Inclusion: N=39 Ciprodex Adverse effects of 

vs. 6 mo-12 yr, treatment Outcome: Adverse events 

Otorrhea, Analyzed: Amox-clav Ciprodex Diff (95%CI) 

Definition: Ciprodex drops AOM < 3 weeks, N=80 Any 29% (12/41) 13% (5/39) 16%(-1.4,34) 

Not 4 drops Patent tympanostomy tubes N=41 Amoxicillin- Dermatitis 7% (3/41) 0% (0/39) 7%(-1,16) 

specified = bid for 7 days clavulanate Device block or taste perversion 

Exclusion: N=39 Ciprodex 0% (0/41) 3% (1/39) -3%(-8,2.3) 

Any antibiotic, Diarrhea 20% (8/41) 0% (0/39) 20%(6.4,33) 

Antibiotic within 3 days, Ear pain 0% (0/41) 5% (2/39) -5%(-12,1.7) 

Any complications requiring Gastroenteritis 

antibiotics, 5% (2/41) 0% (0/39) 5%(-2,12) 

Concomitant/Concurrent infection Infection skin or nausea or oral moniliasis 

needing 2.4% (1/41) 0% (0/39) 2.4%(-2.4,7) 

antibiotic treatment, Vomiting 2.4% (1/41) 2.6% (1/39) -0.2%(-7, 7) 

Topical antibiotic drops prior to study, 

Otitis externa, 

TM perforation/Otorrhea >3 weeks, 

Complication of OM, 

History of otic/ME surgery (excluding 

tubes), 

Cranio-facial, 

Endocrine disorders (diabetes), 

GI disorders/Liver, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient, 

On other medication/treatment, 

Menarche 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Dunne 

200370 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45 mg/kg/day 

Study Time: 

1/2000-3/2000 

Influencing 

factors: 

Age 

Treatment failure; 

Presence of MEF by 

otoscopic findings; 

Outcome: Clinical success (cure+improvement) at day 10 

Amox-clav Azithro Diff (95%CI) 

All ages 88% (159/181 83% (153/183) 5%(-2, 12) 

(0-5):5 / bid for 10 days Place: Bulging tympanic <=2 yrs 85% (44/52) 76% (45/59) 9% (-6, 24) 

[1,1,1,1,1] Multicenter: membrane [TM]; >2 yrs 73% (94/129) 86% (108/126) -13%(-23, -3) 

vs. 28 centers Entering: Loss of landmarks; 

N=373 Impaired TM mobility; Outcome: Clinical success (cure+improvement) at day 24-28 

Definition: Azithromycin Inclusion: N=185 Amoxicillin- Presence of MEF by Amox-clav Azithro Diff (95%CI) 

Presence 10 mg/kg/day 6 mo-12 yr, clavulanate acoustic reflectometry; All ages 69% (124/180) 74% (134/182) -5%(-14, 4.3) 

of MEE, = qd for 3 days Presence of middle ear effusion (MEE), N=188 Azithromycin Adverse effects of <=2 yrs 58% (30/52) 60% (35/58) -2%(-20, 16) 

S&S of Bulging tympanic membrane [TM], treatment >2 yrs 73% (94/128) 80% (99/124) -7% (-18, 3.5) 

MEI Loss of landmarks, Completing: 

Erythematous TM, N=362 Outcome: Signs of tympanic membrane disease at day 10 

Otorrhea, N=180 Amoxicillin­ Amox-clav Azithro Diff (95%CI) 

Pneumatic otoscopy/tympanometry clavulanate Bulging 13% (23/178) 22% (40/183) -9%(-17, -1.1) 

(limited or absent mobility of TM), N=182 Azithromycin Loss of landmarks 

Presence of MEF by acoustic 20% (36/178) 31% (56/183) -11%(-20, -2) 

reflectometry, Analyzed: Impaired mobility 

S&S of middle ear inflammation N=362 28% (46/162) 39% (67/170) -11%(-21,-0.8) 

(MEI), N=180 AmoxicillinOtalgia, clavulanate Outcome: Signs of tympanic membrane disease at day 24-28 

Otoscopy (distinct TM erythema), N=182 Azithromycin Amox-clav Azithro Diff (95%CI) 

Decreased hearing, Bulging 16% (29/176) 10% (17/177) 6% (-1, 13) 

Ear fullness, Loss of landmarks 

Fever 22% (38/176) 11% (20/178) 11% (3.3, 19) 

Impaired mobility 

Exclusion: 26% (42/160) 18% (29/164) 8%(-1, 17) 

Penicillin/beta-lactams, 

Macrolides, Outcome: Abnormal acoustic reflectometry 

Any antibiotic, Amox-clav Azithro Diff (95%CI) 

Antibiotic within 30 days, Day 10 63% (109/174) 61% (108/176) 2%(-8, 12) 

Other antibiotic Tx, Day 24-28 59% (100/170) 45% (77/170) 14%(3.4, 25) 

AOM of more than 4 weeks duration, 

Metabolic/Inborn Errors of metabolism Outcome: Adverse events 

Amox-clav Azithro Diff (95%CI) 

Any 20% (37/185) 11% (21/188) 9% (1.4, 16) 

Diarrhea 15% (27/185) 6% (11/188) 9% (2.6, 15) 

Rash 4% (8/185) 0% (0/188) 4% (1.4, 7) 

Vomiting 1% (2/185) 2% (4/188) -1%(-3.5,1.5) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Garrison 

200496 

Jadad 

quality 

score 1 

Amoxicillin 

40-45 mg/kg/day 

for 5-10 days 

Study Time: 

12/1999-12/2002 

Entering: 

N=162 

N=80 Amoxicillin 40-45 

Treatment failure; 

Disease recurrence; 

Adverse effects of 

Outcome: Clinical success at 3-4 day visit 

Amox-low dose Amox-high dose 

95% (68/76) 88% (66/75) 

Diff (95%CI) 

7%(-2, 16) 

(0-5):2 Place: N=82 Amoxicillin 80-90 treatment; 

[1,1,0,0,0] vs. United States Other antibiotic: No new Outcome: Adverse events 

Office setting/ Completing: abx Rx/no change in abx Amox-low dose Amox-high dose Diff (95%CI) 

Amoxicillin private practice, N=151 Rx Skin rash 15% (11/75) 12% (9/77) 3%(-8, 14) 

Definition: 80-90 mg/kg/day Pediatric practice N=76 Amoxicillin 40-45 GI distress 30% (22/74) 33% (25/76) -3%(-18, 12) 

Not for 5-10 days N=75 Amoxicillin 80-90 

specified Inclusion: 

>3 mo, Analyzed: 

<18 kg, N=151 

AOM, N=76 Amoxicillin 40-45 

AOM requiring antibiotic, N=75 Amoxicillin 80-90 

Age of child Upper age limit not 

specified, 

Weight of child Lower weight limit not 

specified 

Exclusion: 

Penicillin/beta-lactams, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

Other antibiotic Tx, 

Unable/unlikely to return to follow-up 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Guven 

200652 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/6.4 mg/kg/day 

Study Time: 

6/2002-4/2004 

Influencing 

factors: 

Pathogen 

Treatment failure; 

Disease recurrence; 

Adverse effects of 

Outcome: Clinical cure (complete resolution of signs and symptoms 

Amox-clav Azithromycin Diff (95%CI) 

Day2-4 37% (32/86) 36% (32/90) 1%(-13, 15) 

(0-5):2 / bid for 10 days Place: treatment Day11-13 81% (68/84) 78% (70/90) 3%(-9, 15) 

[1,0,1,0,0] Turkey Day26-28 88% (74/80) 78% (70/78) 10%(-2, 22) 

vs. Hospital clinic/ Entering: 

outpatient N=180 Outcome: Clinical cure (complete resolution of signs and symptoms 

Definition: Azithromycin N=86 Amoxicillin- Culture Amox-clav Azithromycin Diff (95%CI) 

Presence 10 mg/kg/day Inclusion: clavulanate Negative 80% (24/30) 100% (38/38) -20%(-34,-6) 

of MEE, = qd for 3 days 6 mo-12 yr, N=94 Azithromycin SP 100% (10/10) 67% (20/30) 33% (2, 64) 

S&S of Presence of middle ear effusion (MEE), Others 88% (28/32) 71% (10/14) 17% (-7, 41) 

MEI Bulging tympanic membrane [TM], Completing: 

Loss of landmarks, N=174 Outcome: Reinfection rate 

Erythematous TM, N=84 Amoxicillin­ Amox-clav Azithromycin Diff (95%CI) 

Otorrhea, clavulanate Day26-28 5% (4/84) 13% (12/90) -8%(-17, 0.6) 

Pneumatic otoscopy/tympanometry N=90 Azithromycin 

(limited or absent mobility of TM), Outcome: Persistence of MEE 

S&S of middle ear inflammation Analyzed: Amox-clav Azithromycin Diff (95%CI) 

(MEI), N=174 Day11-13 19% (16/84) 22% (20/90) -3%(-15, 9) 

Otalgia, N=84 Amoxicillin­ Day26-28 8% (6/80) 10% (8/78) -2%(-11, 7) 

Fever clavulanate 

N=90 Azithromycin Outcome: Side effects 

Exclusion: Amox-clav Azithromycin Diff (95%CI) 

Penicillin/beta-lactams, Any 5% (4/84) 4% (4/90) 1%(-5.2, 7) 

Macrolides, Abd pain 5% (4/84) 0% (0/90) 5%(0.3, 9) 

Antibiotic within 2 weeks, Diarrhea 0% (0/84) 4% (4/90) 4%(-9, 0) 

Chronic suppurative OM, 

TM perforation/Otorrhea 24 hours, 

GI disorders/Liver, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Hammaren- Jadad Tympanostomy Study Time: Influencing Disease recurrence; Outcome: Number of otitis media episodes during 1-year follow-up 

Malmi 

2005132 

quality 

score 1 

tubes 3/2001-12/2002 factors: 

Recurrent otitis media/ 

Adverse effects of 

treatment 

Mean±SD (n) Mean±SD (n) 

Adeno+Tympan: Tympan only: Diff (95%CI) 

(0-5):2 vs. Place: otitis prone 1.9 ± 1.9 (74) 1.6 ± 1.6 (72) 0.3(-0.9, 0.9) 

[1,0,1,0,0] Hospital 

Adenoidectomy, Outcome: Adverse events 

Tympanostomy Inclusion: Entering: Adeno+Tympan: Tympan only: Diff (95%CI) 

Definition: tubes 1-4 yr, N=217 Neck abscess or type 1 diabetes 

Acute Recurrent AOM, N=108 Tubes 0% (0/109) 1% (1/108) -1%(-3, 1) 

onset OME N=109 Tubes & Adenoid 

of S&S, 

S&S of Exclusion: Completing: 

MEI PE tubes/history of PE tubes, N=207 

Respiratory Illness, N=103 Tubes 

Cranio-facial, N=104 Tubes & Adenoid 

Endocrine disorders (diabetes), 

Adenoidectomy and/or tonsillectomy Analyzed: 

N=198 

N=96 Tubes 

N=102 Tubes & Adenoid 

Hatakka 

200791 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

9/2001-4/2002 

Entering: 

N=309 

N=154 Placebo 

Disease recurrence; 

Duration of AOM 

Outcome: Success rate (% <4 URI) during 6-month intervention 

Probiotic Placebo Diff (95%CI) 

28% (38/135) 18% (24/134) 10% (0.2, 20) 

(0-5):5 Place: N=155 Probiotic bacteria 

[1,1,1,1,1] Probiotic bacteria Finland Outcome: Success rate (%<6URI) during 6-month intervention 

1 capsule Completing: Probiotic Placebo Diff (95%CI) 

= qd for 24 weeks Inclusion: N=269 80% (108/135) 70% (94/134) 10% (-0.5, 20) 

Definition: 10 mo-6 yr, N=134 Placebo 

Presence Recurrent AOM N=135 Probiotic bacteria Adverse events not reported 

of MEE, 

S&S of Exclusion: Analyzed: 

MEI OME (serous OM, nonsuppurative OM, N=269 

mucoid OM N=134 Placebo 

secretory OM, glue ear), N=135 Probiotic bacteria 

History of otic/ME surgery (excluding 

tubes), 

PE tubes/history of PE tubes, 

Cranio-facial, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Hedrick 

200176 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

90/6.4 mg/kg/day 

Place: 

United States, 

Costa Rica 

Influencing 

factors: 

Hearing deficit and severity, 

Treatment failure; 

Adverse effects of 

treatment 

Outcome: Clinical success (cure or improved) at day 4-7 after treatment 

by Age 

A-C Cefprozil Diff (95%CI) 

(0-5):2 / bid for 10 days Multicenter Laterality, Total 89% (116/130) 87% (110/127) 2% (-6, 10) 

[1,0,1,0,0] Age <2 yrs 86% (55/64) 80% (47/59) 6% (-7, 19) 

vs. Inclusion: 2-7yrs 92% (61/66) 93% (63/68) -1% (-10, 8) 

6 mo-7 yr, 

Definition: Cefprozil Bulging tympanic membrane [TM], Completing: Outcome: Clinical success (cure or improved) at day 4-7 after treatment 

Presence 30 mg/kg/day Cloudy TM, N=303 by Laterality 

of MEE, / bid for 10 days Loss of landmarks, N=153 Amoxicillin- A-C Cefprozil Diff (95%CI) 

S&S of Air fluid level behind TM, clavulanate Total 89% (116/130) 87% (110/127) 2% (-6, 10) 

MEI Otorrhea, N=150 Cefprozil Unilateral 93% (66/71) 89% (73/82) 4% (-5.2, 13) 

Pneumatic otoscopy/tympanometry Bilateral 85% (50/59) 82% (37/45) 3% (-11, 17) 

(limited or absent mobility of TM), Analyzed: 

Otalgia, N=292 Outcome: Clinical success (cure or improved) at day 4-7 after treatment 

Decreased hearing, N=146 Amoxicillin­ by Severity 

Ear fullness clavulanate A-C Cefprozil Diff (95%CI) 

N=146 Cefprozil Total 89% (116/130) 87% (110/127) 2% (-6, 10) 

Exclusion: Moderate 92% (83/90) 85% (64/75) 7% (-2.7, 17) 

Penicillin/beta-lactams, Severe 82% (32/39) 88% (45/51) -6% (-21, 9) 

Antibiotic within 7 days, 

Concomitant/Concurrent infection Outcome: Adverse events 

needing A-C Cefprozil Diff (95%CI) 

antibiotic treatment, Any 32% (49/153) 19% (28/150 13%(3.5, 23) 

Recurrent AOM (>2 episodes in 6 Diarrhea 19% (29/153) 9% (14/150) 10%(1.8,18) 

months), Rash 11% (16/153) 6% (9/150) 5%(-1.7,11) 

Otitis externa, Vomiting 6% (9/153) 2% (3/150) 4%(-0.5, 8) 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 48 hours, 

Complication of OM, 

PE tubes/history of PE tubes, 

Respiratory Illness, 

Cranio-facial, 

GI disorders/Liver, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem, 

Metabolic/Inborn Errors of metabolism, 

Investigational drug within 1 month 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Jacobs 

200192 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

1/1996-1/1997 

Influencing 

factors: 

Middle ear effusion 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success at different time points 

Homeopathic Placebo 

5-day 81% (29/36) 69% (27/39) 

Diff (95%CI) 

11%(-8, 31) 

(0-5):4 Place: OME]; 2-wk 69% (25/36) 51% (20/39) 18%(-4, 40) 

[1,1,1,0,1] Homeopathic NOS United States Adverse effects of 6-wk 58% (21/36) 38% (15/39) 20%(-3, 42) 

3 pellets Office setting/ Entering: treatment 

= tid for 5 days private practice, N=75 Outcome: Absence of MEE 

Definition: Pediatric practice N=39 Placebo Homeopathic Placebo Diff (95%CI) 

Presence N=36 Homeopathic 2-wk 28% (10/36) 23% (9/39) 5%(-15, 24) 

of MEE, Inclusion: 6-wk 44% (16/36) 59% (23/39) -14%(-37, 8) 

S&S of 18 mo-6 yr, Completing: 

MEI Presence of middle ear effusion (MEE), N=72 Outcome: Adverse events 

Pneumatic otoscopy/tympanometry N=38 Placebo Homeopathic Placebo Diff (95%CI) 

(limited or absent mobility of TM), N=34 Homeopathic Any 0% (0/36) 0% (0/39) 0% (0, 0) 

Otalgia, 

Fever Analyzed: 

N=75 

Exclusion: N=39 Placebo 

Antibiotic within 1 week, N=36 Homeopathic 

TM perforation/Otorrhea, 

History of otic/ME surgery (excluding 

tubes), 

PE tubes/history of PE tubes, 

Cranio-facial, 

Major Systemic disease/ condition, 

medical problem, 

On other medication/treatment, 

Adenoidectomy and/or tonsillectomy, 

Prolonged ear pain 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Koivunen 

2004130 

Jadad 

quality 

score 1 

Sulfa alone 

50 mg/kg/day 

= qd for 24 weeks 

Study Time: 

4/1994-4/1997 

Entering: 

N=180 

N=60 Placebo 

Disease recurrence; 

Adverse effects of 

treatment; 

Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

<2 months of MEE) at 6 months 

Sulfafurazole Placebo Diff (95%CI) 

(0-5):3 Place: N=60 Sulfa alone Healthcare utilization 63% (29/46) 45% (21/47) 18% (-2, 39) 

[1,0,1,1,0] vs. Finland N=60 Adenoidectomy 

Hospital clinic/ Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

Placebo outpatient Completing: <2 months of MEE) at 2 years 

Definition: N=174 Sulfafurazole Placebo Diff (95%CI) 

Not vs. Inclusion: N=59 Placebo 34% (14/41) 22% (10/45) 12% (-7, 31) 

specified 10-24 mo, N=56 Sulfa alone 

Adenoidectomy Recurrent AOM N=59 Adenoidectomy Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

<2 months of MEE) at 6 months 

Exclusion: Analyzed: Sulfafurazole Adenoidectomy Diff (95%CI) 

Any antibiotic during present illness, N=180 63% (29/46) 58% (34/59) 5% (-14, 24) 

History of otic/ME surgery (excluding N=60 Placebo 

tubes), N=60 Sulfa alone Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

PE tubes/history of PE tubes, N=60 Adenoidectomy <2 months of MEE) at 2 years 

Cranio-facial, Sulfafurazole Adenoidectomy Diff (95%CI) 

Immunosuppressed 34% (14/41) 28% (16/58) 6% (-12, 25) 

/compromised/deficient 

Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

<2 months of MEE) at 6 months 

Adenoidectomy Placebo Diff (95%CI) 

58% (34/59) 45% (21/47) 13% (-6, 32) 

Outcome: Success rate (<=1 in 2 months or <=2 in 6 months of AOM or 

<2 months of MEE) at 2 years 

Adenoidectomy Placebo Diff (95%CI) 

28% (16/58) 22% (10/45) 5% (-12, 22) 

Outcome: Adverse events 

Sulfafurazole Placebo Diff (95%CI) 

Any 8% (5/60) 3% (2/60) 5%(-3.4, 13) 

Diarrhea 3% (2/60) 2% (1/60) 2%(-4.8,7.2) 

Skin rash 3% (2/60) 0% (0/60) 3%(-1.3,7.9) 

Unknown 2% (1/60) 2% (1/60) 0%(-4.6, 4.6) 

Sulfafurazole Adenoidectomy Diff (95%CI) 

Any 8.3% (5/60) 0% (0/60) 8%(1.2,15) 

Diarrhea 3% (2/60) 0% (0/60) 3%(-1.3, 8) 

Skin rash 3% (2/60) 0% (0/60) 3%(-1.3, 8) 

Unknown 2% (1/60) 0% (0/60) 2%(-1.6,5.0) 

Adenoidectomy Placebo Diff (95%CI) 

Any 0% (0/60) 3% (2/60) -3%(-8, 1.3) 

Diarrhea 0% (0/60) 2% (1/60) -2%(-5.0,1.6) 

Skin rash 0% (0/60) 0% (0/60) 0%(0, 0) 

Unknown 0% (0/60) 2% (1/60) -2%(-5.0,1.6) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Le Saux 

200589 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

12/1999-3/2002 

Influencing 

factors: 

Middle ear effusion, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Cumulative clinical resolution rates at 14 days-ALL 

Amox Placebo Diff (95%CI) 

All ages 92.8% (232250) 84.2% (202/240) -9% (-14,-3) 

(0-5):5 Place: Age OME]; 6-23 mo 85.4% (76/89) 79.3% (73/92) -6% (-17, 5.2) 

[1,1,1,1,1] Amoxicillin Canada Other symptoms: fever; 2-5 yrs 96.9% (156/161) 87.2% (129/148) -10% (-16,-4) 

60 mg/kg/day Multicenter: Invasive infections, 

/ tid for 10 days 3 centers Entering: e.g., mastoiditis, Outcome: Cumulative clinical resolution rates at 14 days-Among 

Definition: Emergency room, N=512 bacteremia; Children with MEE 

Acute Pediatric practice N=254 Placebo Adverse effects of Amox Placebo Diff (95%CI) 

onset N=258 Amoxicillin treatment; All ages 93.2% (150/161) 83.0% (112/135) -10% (-18,-3) 

of S&S, Inclusion: Duration of AOM 6-23 mo 87.1% (54/62) 83.3% (45/54) -4% (-17, 9) 

Presence 6 mo-5 yr, Completing: 2-5 yrs 99.0% (96/99) 82.7% (67/81) -14% (-24,-6) 

of MEE, Acute onset S&S (parent/guardian N=490 

S&S of report), N=240 Placebo Outcome: Presence of middle ear fluid 

MEI Presence of middle ear effusion (MEE), N=250 Amoxicillin Amox Placebo Diff (95%CI) 

Bulging tympanic membrane [TM], At 1-mo 29.2% (68/233) 34.7% (77/222) -5%(-14, 3.1) 

Cloudy TM, Analyzed: At 3-mo 25.4% (58/228) 22.4% (47/210) 3%(-5, 11) 

Erythematous TM, N=490 

Pneumatic otoscopy/tympanometry N=240 Placebo Outcome: Occurrence of adverse events - 6 to 23 months 

(limited or absent mobility of TM), N=250 Amoxicillin Amox Placebo Diff (95%CI) 

Otalgia, Diarrhea 22.5% (20/89) 18.5% (17/92) 4%(-8, 16) 

Fever, Rash 14.6% (13/89) 9.8% (9/92) 5%(-4.7, 14) 

Onset of AOM symptoms within 4 days 

before entry Outcome: Occurrence of adverse events - 2-5 years 

Amox Placebo Dif(95%CI) 

Exclusion: Diarrhea 4.1% (6/146) 6.8% (10/148) -3%(-8, 2.5) 

Allergic to other medication NOS, Rash 2.7% (4/146) 7.4% (11/148) -5%(-10, 0.3) 

Penicillin/beta-lactams, 

Antibiotic within 2 weeks, The article also published results for Days 1, 2, and 3 for: fever, pain, 

Recurrent AOM (>4 episodes in 12 irritability, vomiting, No. of analgesic doses, No. of codeine doses, and 

months), able to do usual activities. 

TM perforation/Otorrhea, 

Complication of OM, 

History of otic/ME surgery (excluding 

tubes), 

PE tubes/history of PE tubes, 

Respiratory Illness, 

Cranio-facial, 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Little 

20012 

Jadad 

quality 

score 1 

Amoxicillin tid for 

7 days 

Place: 

United Kingdom 

Multicenter 

Entering: 

N=315 

N=151 Amoxicillin 

Signs or symptoms of 

MEI; 

Adverse effects of 

Outcome: Success rate at day 3 after first visit 

Antibiotic RxHold 

86% (116/135) 70% (105/150) 

Diff (95%CI) 

16%(6.3, 26) 

(0-5):3 vs. Office setting/ N=164 Prescription to hold treatment; 

[1,1,0,1,0] private practice, Quality of life or Outcome: Duration of symptoms (days), mean (range) 

Prescription to General/ Completing: functional outcome; Antibiotic RxHold Diff (95% CI) p-value 

Hold family practice N=285 Parent satisfaction; Earache 2.6(0-10) 3.6 (0-11) -1.1 (-0.5, -1.5) <0.01 

Definition: N=135 Amoxicillin Cost outcomes Discharge 0.6 (0-7) 1.2 (0-14) -0.7 (-0.2, -1.1) <0.01 

Presence Inclusion: N=150 Prescription to hold Night dist 1.6 (0-8) 2.4 (0-11) -0.7 (-0.3, -1.1) <0.01 

of MEE, 6 mo-10 yr, Crying 1.5 (0-7) 2.2 (0-11) -0.7 (-0.3, -1.1) <0.01 

S&S of Presence of middle ear effusion (MEE), Analyzed: Pain score 2.3 (1-5) 2.4 (1-6) -0.2 (-0.4, 0.1) 0.24 

MEI Bulging tympanic membrane [TM], N=285 

Cloudy TM, N=135 Amoxicillin Outcome: Side effects 

Erythematous TM, N=150 Prescription to hold Antibiotic RxHold Diff (95%CI) 

Air fluid level behind TM, Rash 5% (6/133) 5% (8/149) -1%(-6, 4.2) 

S&S of middle ear inflammation Diarrhea 19% (25/133) 9% (14/149) 9%(1, 18) 

(MEI), 

Otalgia, Outcome: Healthcare utilization, mean (range) 

Otoscopy (distinct TM erythema) Antibiotic RxHold Diff (95% CI) p-value 

School days missed 

Exclusion: 2.0 (0-8) 2.2 (0-13) -0.2 (-0.8, 0.4) 0.56 

Antibiotic within 2 weeks, Daily No. of spoons of paracetamol consumed 

Strong indication of antibiotics 1.7 (0-6) 2.3 (0-8) -0.5 (-0.8, -0.3) <0.01 

(bulging eardrum, 

perforation, pus, tubes), Outcome: Parents' belief and satisfaction 

Chronic suppurative OM, Antibiotic RxHold Diff (95% CI) 

OME (serous OM, nonsuppurative OM, Belief that antibiotics are very effective 

mucoid OM 76% (100/131) 46% (64/140) 31%(19, 42) 

secretory OM, glue ear), Very satisfied with treatment approach 

Complication of OM, 94% (123/131) 77% (115/150) 17%(9, 26) 

Major Systemic disease/ condition, Very likely to consult doctor in future 

medical problem 83% (109/132) 63% (92/147) 20%(9, 31) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Little 

200693 

Jadad 

quality 

score 1 

Amoxicillin 

vs. 

Place: 

United Kingdom 

Influencing 

factors: 

Symptoms and signs, 

By symptoms 

(otalgia, ear fullness); 

Quality of life or 

Outcome: Earache 

Amox RxHold OR (95% CI) 

At 3 mos 0.89 (0.48, 1.65) 

(0-5):3 Inclusion: Prior episodes of otitis media, functional outcome At 1 yr 1.03 (0.60, 1.78) 

[1,0,1,1,0] Prescription to 6 mo-10 yr, Child care setting 

Hold S&S of middle ear inflammation Outcome: Poor scores on the function scale 

(MEI), Amox RxHold OR (95% CI) 

Definition: Otalgia, Entering: At 3 mos 1.37 (0.72, 2.60) 

S&S of Otoscopy (distinct TM erythema) N=315 At 1 yr 1.16 (0.61, 2.23) 

MEI N=151 Amoxicillin 

Exclusion: N=164 Prescription 

Antibiotic within 2 weeks, to Hold Data by influencing factor could not be abstracted by treatment groups. 

Strong indication of antibiotics 

(bulging eardrum, Completing: 

perforation, pus, tubes), N=219 

AOM within 2 weeks, N=99 Amoxicillin 

Chronic suppurative OM, N=120 Prescription 

OME (serous OM, nonsuppurative OM, to Hold 

mucoid OM 

secretory OM, glue ear), Analyzed: 

Complication of OM, N=219 

Major Systemic disease/ condition, N=99 Amoxicillin 

medical problem N=120 Prescription 

to Hold 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Marchisio Jadad Elimination of Study Time: Entering: Treatment failure; Outcome: 1 episode during 3-month study period 

2010133 quality environmental risk 12/2004-3/2005 N=122 By Pneumatic Propolis+Zinc Controls Diff (95%CI) 

score 1 factors N=61 Envt otoscopy/tympanometry; AOM 50.8% (31/61) 70.5% (43/61 -19.7% (-36.7, -2.7) 

(0-5):2 Place: By otoscopy RTI* 73.8% (45/61) 77.0% (47/61) -3.3% (-18.5, 12.1) 

[1,0,0,1,0] vs. Italy Analyzed: (distinct TM erythema); *febrile respiratory tract infection (RTI) 

University/ N=122 Disease recurrence; 

30% hydroglyceric academic N=61 Envt Adverse effects of Outcome: 1 antibiotic course during 3-month study period 

Definition: extract of propolis; treatment; Propolis+Zinc Controls Diff (95%CI) 

Presence 1.2% zinc sulfate Inclusion: Quality of life or AOM 49.2% (30/61) 75.4% (46/61) -26.2% (-42.8, -9.6) 

of MEE, 0.3 ml/kg/d 1-5 yr, functional outcome; RTI* 75..4% (46/61) 81.9% (50/61) -6.5% (-21.0, 8.0) 

S&S of = QD for 3 months Otoscopy (distinct TM erythema), Parent satisfaction; *febrile respiratory tract infection (RTI) 

MEI 

ROM ­ 3 

AOM in 

preceding 6 

months or 

4 episodes 

in preceding 

12 months 

with most 

recent in 

previous 2-8 

Plus Elimination of 

environmental risk 

factors 

Recurrent AOM, 

Free of AOM currently, 

OME, 

>= 2 episodes documented with 

symptoms, otoscopy, tympanometry 

Exclusion: 

Antibiotic within 2 weeks, 

Persistent TM perforation/Otorrhea, 

Tympanostomy tubes, 

Cleft palate, 

Immunosuppressed 

Bacteriologic outcomes 

by nasopharyngeal 

cultures; 

Episodes of AOM 

(prevention study); 

Compliance; 

Any respiratory, relaspe 

defined as reappearance of 

any s or s <= 4 days after 

treatment ended; 

recurrence: 5-14 days 

Outcome: Parent satisfaction 

Degree satisfaction Propolis+Zinc Controls Diff (95%CI) 

Unsatisfied 0.0% (0/61) 27.4% (17/61) -27.9% (-38, -16) 

Satisfied 65.6% (40/61) 62.3% (38/61) -3.3% (-13, 20) 

Very satisfied 34.4% (21/61) 9.8% (6/61) 24.6% (10, 39) 

Outcome: adverse events 

Adverse event Propolis+Zinc Controls Diff (95%CI) 

Vomiting 1.6% (1/61) 1.6% (1/61) 0% (-5, 5) 

Rash 1.6% (1/61) 0.0% (0/61) 1.6% (-2, 5) 

weeks /compromised/deficient, Outcome: mean number of episodes per child/month during 3-month 

Received blood products recently, study period 

Severe atopy, Propolis+Zinc Controls Diff (95%CI) p-value 

Obstructive adenoids, AOM 0.23 ( 0.26) 0.34 ( 0.29) 0.11 (0.01, 0.21) 0.3 

Sleep apnea RTI* 1.20 ( 0.94) 1.36 ( 1.26) 0.43 (-0.23, 0.55) 0.43 

*febrile respiratory tract infection (RTI) 

Outcome: mean number of antibiotic course for AOM during 3-month 

study period 

Propolis+Zinc Controls Diff (95%CI) p-value 

AOM 0.64 ( 0.69) 0.98 ( 0.73) 0.34 (0.09, 0.59) 0.005 

RTI* 1.29 ( 1.15) 1.31 ( 0.96) 0.92 (-0.36, 0.40) 0.92 

*febrile respiratory tract infection (RTI) 

Outcome: mean duration in months of bilateral OME per child 

Propolis+Zinc Controls Diff (95%CI) p-value 

8.62 ( 3.73) 9.50 ( 4.06) 0.88 (-0.50, 2.26) 0.24 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

McCormick 

20053 

Jadad 

quality 

score 1 

Amoxicillin 

90 mg/kg/day 

/ bid for 10 days 

Enrollment 

Time: 

5/2000-3/2003 

Influencing 

factors: 

Age 

Treatment failure; 

Invasive infections, 

e.g., mastoiditis, 

Outcome: Success rate at Day 12 

Age Amoxicillin Wait-and-see Diff (95%CI) 

0.5-12yrs 95.3% (102/107) 80.4% (86/107) 15%(6, 24) 

(0-5):3 bacteremia; <2yrs 93.8% (60/64) 77.8% (42/54) 16% (4, 28) 

[1,0,1,1,0] vs. Place: Disease recurrence; >=2yrs 97.7% (42/43) 83.0% (44/53) 15% (2, 27) 

Hospital clinic/ Entering: Adverse effects of 

Wait and see outpatient, N=223 treatment; Outcome: Cure rate before Day 30 

Definition: University/ N=112 Amoxicillin Quality of life or Age Amoxicillin Wait-and-see Diff((95%CI) 

Presence academic N=111 Wait and see functional outcome; 0.5-12yrs 77.1% (84/109) 66.0% (66/100) 11%(-1, 23) 

of MEE, Parent satisfaction; <2yrs 76.9% (50/65) 56% (28/50) 21%(4, 38) 

S&S of Inclusion: Completing: Cost outcomes; >=2yrs 77.3% (34/44) 76% (38/50) 1.3%(-16, 18) 

MEI 6 mo-12 yr, N=218 Bacteriologic outcomes 

Presence of middle ear effusion (MEE), N=110 Amoxicillin by nasopharyngeal cultures Outcome: Parent/Child Quality of Life 

S&S of middle ear inflammation N=108 Wait and see Measure Amoxicillin Wait-and-see Diff (95%CI) 

(MEI), AOM-related extra office visit 

Non-severe AOM at onset Analyzed: 13% (14/111) 20% (22/108) -7%(-17, 3) 

N=218 AOM-related emergency department visit 

Exclusion: N=110 Amoxicillin 1% (1/111) 4% (4/108) -3%(-7, 1) 

Penicillin/beta-lactams, N=108 Wait and see AOM-related extra phone calls 

Concomitant/Concurrent infection 23% (26/111) 24% (26/108) -1%(-12, 10) 

needing Parent missed work or school 

antibiotic treatment, 14% (14/111) 9% (10/108) 5%(-3.5, 14) 

TM perforation/Otorrhea, Doses of pain medicine [Mean±SD (n)] p-value 

PE tubes/history of PE tubes, 3.4± 4.0 (105) 7.7±7.5 <0.01 

Cranio-facial, 

Immunosuppressed Outcome: Adverse events 

/compromised/deficient, Amoxicillin Wait-and-see Diff (95%CI) 

Major Systemic disease/ condition, ABX-related adverse events 

medical problem 12% (13/111) 5% (5/108) 7%(-0.4, 14) 

Serious adverse events related to AIM 

0% (0/111) 0% (0/108) 0% (0, 0) 

[The article also reported ABX-Resistance patterns of S. Pneumoniae 

strains isolated from the nasopharynx of subjects at enrollment and day 

12.] 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Morris 

201067 

Jadad 

quality 

score 1 

(0-5):3 

[1,1,1,0,0] 

Definition: 

AOM 

without 

perforation 

any 

tympanic 

membrane 

bulging and 

type B 

tympanogra 

m; 

Azithromycin 30 

mg/kg as a single 

dose plus 

Amoxicillin 

Placebo 

vs. 

Amoxicillin 

50 mg/kg/day 

/ BID for 7 days, 

plus Azithromycin 

Placebo 

= QD for 1 day 

Study Time: 

3/2003-7/2005 

Place: 

Australia 

Multicenter: 

16 centers 

Hospital clinic/ 

outpatient, 

Setting rural and remote communities 

Inclusion: 

Aboriginal children, 

6 mos-6 y, 

New/first episode of AOM, 

Willingness of parents to bring child 

for follow-up visit 

Influencing 

factors: 

Carriers/non carriers of Sp or 

NCHI - resistant or sensitive 

to antibiotic 

Entering: 

N=320 

Completing: 

N=306 

Analyzed: 

N=306 

Treatment failure; 

Bulging tympanic 

membrane [TM]; 

Otorrhea; 

By symptoms 

(otalgia, ear fullness); 

Disease recurrence; 

Bacteriologic outcomes 

by nasopharyngeal 

cultures; 

Failure of a TM perforation 

to heal 

Outcome: Clinical success 

between day 6 and day 11 

Azithromycin Amoxicillin Diff (95%CI) 

Intention to treat 50% (83/165) 46% (72/155) 4% (-7, 15) 

Per protocol 53% (74/140) 47% (63/135) 6% (-6, 18) 

Age Azithromycin Amoxicillin Diff (95%CI) 

<2 years old 51% (64/125) 46% (57/125) 6% (-7, 18) 

2 years old 47% (19/40) 50% (15/30) -3% (-26, 21) 

Diff (95%CI) 4% (-14, 21) -4% (-24, 15) 

Baseline 

Diagnosis* Azithromycin Amoxicillin Diff (95%CI) 

AOMwoP 60% (81/134) 54% (68/125) 6% (-6, 18) 

AOMwiP 8% (2/24) 17 % (4/23) -9% (-28, 10) 

*AOMwoP=without perforation; AOMwiP=with perforation 

AOM with Exclusion: Nasal perforation ­ Antibiotic within 7 days, Pathogen* Azithromycin Amoxicillin Diff (95%CI) middle ear Prior assignment to another arm of (+) SP 50% (21/42) 43% (40/92) 7% (-12, 24) discharge study, (-) SP 54% (62/115) 57 % (30/53) -3% (-19, 13) observed Allergy to penicillin or azithromycin, (+) NCHi 46% (40/86) 44% (55/124) 2% (-12, 16) and Other major illness requiring IV or IM (-) NCHi 61% (43/71) 71% (15/21) -11% (-33, 12) perforation antibiotics, * S pneumoniae (SP) or non-capsular Haemophilus influenzae (NCHi) recently Perforation covering >2% of the 

healed or tympanic membrane Outcome: Improvement by end of therapy present for < Azithromycin Amoxicillin Diff (95%CI) 6 weeks or Intention to treat 55% (87/158) 51% (76/148) 4% (-7, 15) covering < Per protocol 56% (78/140) 50% (67/135) -6% (-6, 18) 2% of the 

pars tensa Outcome: Other clinical outcomes 

Azithromycin Amoxicillin Diff (95%CI) 

No new pain 99% (155/156) 98% (144/147) 1% (-1, 4) 

Runny nose 35% (55/158) 46% (67/146) -11% (-22, 0.1) 

Skin sores 4% (7/158) 3% (4/146) 2% (-3, 6) 

Nasal carriage of S. pneumonia, non-capsular H. influenzae, resistant S. 

pneumoniae, beta-lactamase-posituve non-capsular H. influenzae: See 

article. 

Ear discharge cultures positive for S. pneumoniae or non-capsular H. 

influenzae: See article. 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Neumark 

200787 

Jadad 

quality 

score 1 

Wait and see 

vs. 

Place: 

Sweden 

Multicenter: 

Completing: 

N=179 

N=92 Wait & See 

Treatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Success (recovery) 

PcV Wait-and-see 

Day2-7 100% (76/76) 95% (83/87) 

Diff (95% CI) 

5% (0, 10) 

(0-5):3 32 centers N=87 By symptoms Day14 82% (71/87) 85% (70/82) -4%(-15, 7) 

[1,0,1,1,0] Phenoxymethyl- Public health center/ Phenoxymethylpenicillin (otalgia, ear fullness); 3Months 85% (73/86) 84% (63/75) 1%(-10, 12) 

penicillin clinic/CHC Other symptoms: fever; 

25 mg/kg/day Analyzed: Cost outcomes; Outcome: Long-term outcome at 3 months 

Definition: = bid for 5 days Inclusion: N=179 Otologic complications, PcV Wait-and-see Diff (95% CI) 

Presence 2-16 yr, N=92 Wait & See i.e., cholestetoma; Perforation 0% (0/86) 0% (0/75) 0% 

of MEE, Presence of middle ear effusion (MEE), N=87 Healthcare utilization Serous OM 12% (10/86) 11% (8/75) 1% (-9, 11) 

S&S of Bulging tympanic membrane [TM], Phenoxymethylpenicillin 

MEI Erythematous TM, Outcome: Signs or symptoms at Day3-7 

Pneumatic otoscopy/tympanometry PcV Wait-and-see Diff (95%CI) 

(limited or absent mobility of TM), Pain severity 2-3 

S&S of middle ear inflammation (MEI) 2% (2/76) 5% (4/87) -3% (-9, 3) 

Analgesics use 

Exclusion: 3% (3/76) 10% (8/87) -7%(-15, 1) 

Penicillin/beta-lactams, Fever>38oC 

Concomitant/Concurrent infection 3% (3/76) 6% (5/87) -3%(-9, 3) 

needing 

antibiotic treatment, Outcome: Economic 

Recurrent AOM (>2 episodes in 6 PcV Wait-and-see Diff (95%CI) 

months), Parents at home 

Chronic suppurative OM, 56% (49/76) 53% (42/87) 3%(-12, 18) 

TM perforation/Otorrhea, Days at home from work (median, range) 

Neurological disease/impairment, 1.2 (0-7) 1.2 (0-7) 0.90 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Noel 

2008123 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45 mg/kg/day 

Study Time: 

10/2002-5/2005 

Influencing 

factors: 

Age 

Treatment failure; 

By Pneumatic 

otoscopy/tympanometry; 

Outcome: Clinical success (cure and improved) at 2-5 days 

Age Levofloxacin Amox-clav Diff (95%CI) 

0.5-<5yr 94% (592/630) 91% (613/675) -3.2 (-6.0,-0.3) 

Page 1 of 2 (0-5):3 = bid for 10 days Place: Signs or symptoms of 0.5-2yr 92% (327/357) 88% (347/394) -3.5 (-7.3, 0.8) 

[1,0,1,1,0] Multicenter: MEI; >2-<5yr 97% (265/273) 95% (266/281) -2.4 (-5.7, 0.9) 

vs. 66 centers Entering: By symptoms 

N=1650 (otalgia, ear fullness); Outcome: Clinical success (cure and improved) at 10-17 days 

Definition: Levofloxacin Inclusion: N=823 Amoxicillin- By otoscopy Age Levofloxacin Amox-clav Diff (95%CI) 

Presence 10 mg/kg/day >6 mo, clavulanate (distinct TM erythema); 0.5-<5yr 84% (585/700) 80% (578/719) -3.2 (-7.2, 0.8) 

of MEE, = bid for 10 days Bulging tympanic membrane [TM], N=827 Levofloxacin Other symptoms: fever; 0.5-2yr 79% (318/404) 76% (315/417) -3.2 (-8.9, 2.6) 

S&S of Cloudy TM, Adverse effects of >2-<5yr 90% (267/296) 87% (263/302) -3.1 (-8.2, 2.0) 

MEI Erythematous TM, Completing: treatment 

Otorrhea, N=1435 Outcome: Clinical cure (not including improved) at 2-5 days 

Pneumatic otoscopy/tympanometry N=721 Amoxicillin- Age Levofloxacin Amox-clav Diff (95%CI) 

(limited or absent mobility of TM), clavulanate 0.5-<5yr 72% (456/630) 70% (472/675) -2.5 (-7.4, 2.5) 

Otalgia within last 24 hours, N=714 Levofloxacin 0.5-2yr 69% (246/357) 66% (261/394) -2.7 (-9.4, 4.0) 

Otoscopy (distinct TM erythema), >2-<5yr 77% (210/273) 75% (211/281) -1.8 (-8.9, 5.3) 

Recurrent AOM, Analyzed: 

Persistent AOM N=1305 Outcome: Clinical cure (not including improved) at 10-17 days 

N=675 Amoxicillin- Age Levofloxacin Amox-clav Diff (95%CI) 

Exclusion: clavulanate 0.5-<5yr 75% (524/700) 74% (531/719) -1.0 (-5.6, 3.5) 

Penicillin/beta-lactams, N=630 Levofloxacin 0.5-2yr 70% (284/404) 70% (291/417) -0.5 (-6.7, 5.8) 

Any antibiotic, >2-<5yr 81% (240/296) 80% (240/302) -1.6 (-8.0, 4.8) 

Any antibiotic during present illness, 

Concomitant/Concurrent infection Outcome: Adverse events 

needing Levofloxacin Amox-clav Diff (95%CI) 

antibiotic treatment, 1 or more up to visit 4 

PE tubes/history of PE tubes, 54% (448/827) 58% (475/823) -4%(-8,1.3) 

Major Systemic disease/ condition, Arthralgia 1.5% (12/827) 0.7%(6/823) 0.8%(-0.2,1.8) 

medical problem, Arthralgia disorder 

On other medication/treatment 1.2% (10/827) 0.6% (5/823) 0.6%(-0.3,1.5) 

Arthritis disorder 

0.2% (2/827) 0% (0/823) 0.2%(-0.1,0.5) 

Arthropathy 

0% (0/827) 0.2% (2/823) -0.2%(-0.5,0.1) 

Dermatitis 13% (108/827) 16% (129/823) -3%(-6, 0.8) 

Diarrhea 13% (108/827) 20% (161/823) -7%(-10, -3) 

Fever 7% (60/827) 8% (64/823) -1%(-3, 2) 

Gait abnormality disorder 

0.1% (1/827) 0% (0/823) 0.1%(-0.1,0.3) 

Muscle weakness 

0% (0/827) 0.1% (1/823) -0.1%(-0.3,0.1) 

Otitis media not related to treatment failure 

5% (45/827) 4% (34/823) 1% (-0.8, 3.4) 

Pathologic fracture 

0% (0/827) 0.5% (4/823) -0.5%(-1, 0) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Noel 

2008123 

Levofloxacin Amox-clav 

Musculoskeletal disorder (DSMC) 

Diff (95%CI) 

1.5% (12/827) 0.6% (5/823) 1%(-0.1, 1.9) 

Page 2 of 2 Muscoskeletal adverse events 

2.8% (23/827) 2.3% (19/823) 0.5%(-1, 2) 

Rhinitis 5% (43/827) 5% (39/823) 0.5%(-1.6,2.6) 

Synovitis 0.1% (1/827) 0% (0/823) 0.1%(-0.1,0.3) 

URI 6% (53/827) 9% (78/823) -3%(-5.7,-0.5) 

Vomiting 10% (81/827) 7% (61/823) 2%(-0.3, 5.1) 

Oguz 

200382 

Jadad 

quality 

score 1 

Cefaclor 

40 mg/kg/day 

/ tid for 10 days 

Study Time: 

1/1998-5/2000 

Entering: 

N=78 

N=37 Cefaclor 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success (cure + improvement) 

Cefaclor Azithromycin 

Day3-5 100% (33/33) 98% (39/40) 

Diff (95%CI) 

2%(-2.8, 6.8) 

(0-5):3 Place: N=41 Azithromycin OME]; Day10 97% (32/33) 97% (38/39) 0%(-8, 8) 

[1,0,1,1,0] vs. Turkey, Disease recurrence; Day30 91% (30/33) 94% (33/35) -3%(-15, 10) 

Turkey Completing: Antibiotic resistance; 

Azithromycin Hospital clinic/ N=73 Adverse effects of Outcome: Clinical cure 

Definition: 10 mg/kg/day outpatient N=33 Cefaclor treatment Cefaclor Azithromycin Diff (95%CI) 

Presence = qd for 3 days N=40 Azithromycin Day3-5 36% (12/33) 32% (13/40) 4%(-18, 26) 

of MEE Inclusion: Day10 85% (28/33) 77% (30/39) 8%(-10, 26) 

6 mo-12 yr, Analyzed: Day30 82% (27/33) 91% (32/35) -9%(-25, 7) 

Presence of middle ear effusion (MEE), N=73 

Bulging tympanic membrane [TM], N=33 Cefaclor Outcome: Persistence of MEF 

Cloudy TM, N=40 Azithromycin Cefaclor Azithromycin Diff (95%CI) 

Erythematous TM, Day10 12% (4/33) 21% (8/39) -9%(-26, 8) 

Otorrhea, Day30 3% (1/33) 9% (3/35) -6%(-17, 5) 

Diagnosis by ENT 

Outcome: Adverse events 

Exclusion: Cefaclor Azithromycin Diff (95%CI) 

Any antibiotic, Diarrhea and vomiting 

Antibiotic within 2 weeks, 3% (1/37) 2% (1/41) 1%(-5.9, 8) 

Long acting antibiotic within 6 weeks, 

Chronic suppurative OM, 

TM perforation/Otorrhea, 

Respiratory Illness, 

Renal Disorders, 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Paradise 

199926 

Jadad 

quality 

score 1 

Placebo 

vs. 

Study Time: 

4/1980-4/1994 

Entering: 

N=461 

N=181 Placebo 

Disease recurrence; 

Adverse effects of 

treatment; 

Outcome: Success rate (% with no AOM episode) in 1 year in patients 

with no tonsil-related indications 

Adenoidectomy Placebo Diff (95%CI) 

Page 1 of 2 (0-5):3 Place: N=100 Adenoid PE tube placement; 31% (19/61) 22% (17/79) 10% (-5, 24) 

[1,0,1,1,0] Adenoidectomy United States N=180 Adenoid/tonsil Days of ear pain; 

Hospital Days of Abx Tx; Outcome: Success rate (% with<=1 AOM episode) in 1 year in patients 

vs. Completing: Duration of AOM with no tonsil-related indications 

Definition: Inclusion: N=410 Adenoidectomy Placebo Diff (95%CI) 

Other Adenoidectomy 3-15 yr, N=177 Placebo 48% (29/61) 51% (40/79) -3% (-20, 14) 

and/or Recurrent AOM N=79 Adenoid Outcome: Success rate (% with no AOM episode) in 1 year in patients 

tonsillectomy N=154 Adenoid/tonsil with no tonsil-related indications 

Exclusion: Adenoidectomy Adenotonsillectomy: Diff (95%CI) 

PE tubes/history of PE tubes, 31% (19/61) 37% (26/71) -6% (-22, 11) 

Cranio-facial 

Outcome: Success rate (% with<=1 AOM episode) in 1 year in patients 

with no tonsil-related indications 

Adenoidectomy Adenotonsillectomy: Diff (95%CI) 

48% (29/61) 59% (42/71) -12% (-29, 5) 

Outcome: Success rate (% with no AOM episode) in 1 year in patients 

with no tonsil-related indications 

Adenotonsillectomy Placebo Diff (95%CI) 

37% (26/71) 22% (17/79) 15% (0.6, 30) 

Outcome: Success rate (% with<=1 AOM episode) in 1 year in patients 

with no tonsil-related indications 

Adenotonsillectomy Placebo Diff (95%CI) 

59% (42/71) 51% (40/79) 9% (-7, 25) 

Outcome: Adverse events 

Adenoidectomy Placebo Diff (95%CI) 

Erythematous rashes during treatment 

7.2% (6/83) 3.9% (7/181) 3%(-2.3,9) 

Adenoidectomy Adenotonsillectomy: Diff (95%CI) 

Erythematous rashes during treatment 

7.2% (6/83) 2.2% (4/178) 5%(0,10) 

Hemorrhage after hospital discharge 

0% (0/83) 2.2% (4/178) -2%(-5.4,1) 

Incipient malignant hyperthermia 

1.2% (1/83) 0.6% (1/178) 0.6%(-1.7,1) 

Perioperative and postoperative complications 

4.8% (4/83) 14.6% (26/178) -10%(-18,-1.5) 

Postoperative pneumonia 

1.2% (1/83) 0% (0/178) 1.2%(-0.4,2.8) 

Postoperative velopharyngeal insufficiency - persistent (9mo) 

0% (0/83) 0.6% (1/178) -0.6%(-2.3,1.1) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Author 

Year 

Quality 

& AOM 

definition Intervention 

Time, Place, Inclusion, Exclusion 

Criteria 

Influencing 

Factors and 

Sample Size Outcomes Findings 

Paradise 

199926 

Page 2 of 2 

Adenoidectomy Adenotonsillectomy: Diff (95%CI) 

Postoperative velopharyngeal insufficiency-transient (<=43 d) 

2.4% (2/83) 5.1% (9/178) -2.7%(-8,2.6) 

Retained in hospital 1 additional day and/or readmitted to hospital due to 

fever, poor fluid intake orally, vomiting, and/or dehydration 

0% (0/83) 6% (11/178) -6%(-11,-0.8) 

Serum sickness during antimicrobial treatment 

0% (0/83) 0.6% (1/178) -0.6%(-2.3,1.1) 

Adenotonsillectomy Placebo Diff (95%CI) 

Erythematous rashes during treatment 

2.2% (4/178) 3.9% (7/181) -1.7%(-5.3,1.9) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Pessey 

199979 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

40 mg/kg/day 

Place: 

France 

Multicenter: 

Influencing 

factors: 

Age 

Treatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Satisfactory clinical response post-treatment ­

A-C10d vs. CAE 

(0-5):2 / tid for 10 days 50 centers Bacteriologic cure/failure; A-C10d CAE Diff (95%CI) 

[1,0,1,0,0] Adverse effects of Total 88% (181/205) 86% (175/203) 2% (-4.5, 8.5) 

vs. Inclusion: Entering: treatment <1.5 yrs 89% (116/131) 83% (111/134) 6% (-2.4, 14) 

6-36 mo, N=716 1.5-3yrs 88% (65/74) 93% (64/69) -5% (-15, 4.7) 

Definition: Amoxicillin- Presence of middle ear effusion (MEE), N=255 AmoxicillinPresence clavulanate Bulging tympanic membrane [TM], clavulanate 40 mg 10 days Outcome: Satisfactory clinical response post-treatment ­

of MEE, 80 mg/kg/day Cloudy TM, N=209 Amoxicillin­ A-C8d vs. CAE 

S&S of / tid for 8 days Loss of landmarks, clavulanate 80 mg 8 days 

MEI Erythematous TM, N=252 Cefuroxime A-C8d CAE Diff (95%CI) 

vs. Pneumatic otoscopy/tympanometry Total 88% (145/165) 86% (175/203) 2% (-4.9, 9) 

(limited or absent mobility of TM), <1.5 yrs 84% (83/99) 83% (111/134) 1% (-9, 11) 

Cefuroxime Otalgia, 1.5-3yrs 94% (62/66) 93% (64/69) 1% (-7, 9) 

30 mg/kg/day Decreased hearing, 

/ bid for 5 days Fever, Outcome: Satisfactory clinical response post-treatment -

Tympanocentesis preformed Not A-C10d vs. A-C8d 

Specified 

Outcome: Adverse events 

Exclusion: A-C10d A-C8d Diff (95%CI) 

Penicillin/beta-lactams, Total 88% (181/205) 88% (145/165) 0% (-7, 7) 

Antibiotic within 72 hours, <1.5 yrs 89% (116/131) 84% (83/99) 5% (-3.8, 14) 

Concomitant/Concurrent infection 1.5-3yrs 88% (65/74) 94% (62/66) -6% (-16, 4) 

needing 

antibiotic treatment, Outcome: Adverse events 

TM perforation/Otorrhea, A-C10d CAE Diff (95%CI) 

PE tubes/history of PE tubes, Any 22% (57/255) 15% (37/252) 8%(1,14) 

GI disorders/Liver, Diarrhea 18% (46/255) 10% (25/252) 8%(2, 14) 

Renal Disorders, 

Immunosuppressed A-C8d CAE Diff (95%CI) 

/compromised/deficient, Any 16% (33/209) 15% (37/252) 1%(-5.5,8) 

Major Systemic disease/ condition, Diarrhea 10% (21/209) 10% (25/252) 0.1%(-5.4,5.6) 

medical problem, 

Investigational drug within 3 months A-C10d A-C8d Diff (95%CI) 

Any 22% (57/255) 16% (33/209) 7%(-0.6,14) 

Diarrhea 18% (46/255) 10% (21/209) 8%(1.6,14) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Roland 

2003126 

Jadad 

quality 

score 1 

Cipro otic 3% 

3 drops 

= bid for 7 days 

Study Time: 

3/2000-2/2001 

Influencing 

factors: 

Age 

Treatment failure; 

Bacteriologic cure/failure; 

Adverse effects of 

Outcome: Clinical success (cure and improve) on day 8 (post-therapy) 

Cipro alone Cipro+Dex Diff (95%CI) 

(0-5):3 Place: treatment Total 91.2% (73/80) 94.2% (82/87) -3% (-11, 4.9) 

[1,0,1,1,0] vs. Multicenter: 

18 centers Entering: No data by age groups were reported. 

Ciprodex drops N=201 

Definition: 3 drops Inclusion: N=98 Cipro otic Outcome: Clinical success (cure and improve) on day 14 (test-of-cure) 

Not = bid for 7 days 6 mo-12 yr, N=103 Ciprodex Cipro alone Cipro+Dex Diff (95%CI) 

specified Otorrhea, Total 93.8% (75/80) 98.9% (86/87) -5% (-11, 0.5) 

AOM < 3 weeks, Completing: 

Patent tympanostomy tubes N=167 No data by age groups were reported. 

N=80 Cipro otic 

Exclusion: N=87 Ciprodex Outcome: Adverse event 

Antibiotic within 2 days, Cipro alone Cipro+Dex Diff (95%CI) 

Long acting antibiotic within 2 weeks, Analyzed: Excessive crying 

Complication of OM, N=167 1% (1/98) 1% (1/103) 0% (-2.8, 2.8) 

Cranio-facial, N=80 Cipro otic Burning 1% (1/98) 2% (2/103) -1%(-4.2,2.4) 

Endocrine disorders (diabetes), N=87 Ciprodex Pain 1% (1/98) 2% (2/103) -1%(-4.2,2.4) 

GI disorders/Liver, Precipitate 3% (3/98) 0% (0/103) 3%(-0.3,6.5) 

Renal Disorders, Pruritus 1% (1/98) 1% (1/103) 0%(-2.8,2.8) 

Immunosuppressed Taste perversion 

/compromised/deficient, 0% (0/98) 1% (1/103) -1%(-3, 1) 

Other Infectious diseases (meningitis), 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Roland 

2004127 

Jadad 

quality 

score 1 

Ciprodex drops 

4 drops 

= bid for 7 days 

Place: 

United States, 

Canada 

Entering: 

N=599 

N=297 Ciprodex 

Treatment failure; 

By otoscopic findings:; 

Otorrhea; 

Outcome: clinical cure at test-of-cure visit day 18-21 

Ciprodex Ofloxacin Diff (95%CI) 

Total 90% (162/180) 78.2% (133/170) 12%(4.2, 19) 

(0-5):1 Multicenter: N=302 Ofloxacin Other symptoms: Outcome: Clinical success (cured or improved) 

[1,0,0,0,0] vs. 39 centers decreased hearing; Ciprodex Ofloxacin Diff (95%CI) 

Completing: Bacteriologic cure/failure; Day 3 93.7% (194/207) 79.6% (172/216) 14%(7.6, 21) 

Ofloxacin drops Inclusion: N=423 Adverse effects of Day 11 96.1% (199/207) 89.8% (194/216) 6%(1.4, 11) 

Definition: 5 drops 6 mo-12 yr, N=207 Ciprodex treatment; Day 18 93.7% (194/207) 88.4% (191/216) 5%(-0.2, 11) 

Not = bid for 10 days Otorrhea, N=216 Ofloxacin Other antibiotic: No new Outcome: Absence of otorrhea 

specified Onset of AOM symptoms within 21 abx Rx/no change in abx Ciprodex Ofloxacin Diff (95%CI 

days before entry, Analyzed: Rx Day 3 32.2% (67/207) 18.5% (40/216) 14%(5.4, 22) 

Patent tympanostomy tubes N=423 Day 11 84.6% (176/207) 63.4% (137/216) 21%(13, 30) 

N=207 Ciprodex Day 18 85.0% (176/206) 70.8% (153/216) 14%(6, 22) 

Exclusion: N=216 Ofloxacin 

Any antibiotic, Outcome: Adverse events 

Concomitant/Concurrent infection Ciprodex Ofloxacin Diff (95%CI 

needing Cough or crying or diarrhea or ear debris or edema eardrum or headache 

antibiotic treatment, or hyperemia eardrum 

Other antibiotic Tx, 0% (0/297) 0.3% (1/302) -0.3%(-0.9,0.3) 

Topical antibiotic drops prior to study, Discomfort ear: 

Otitis externa, 3.4% (10/297) 1% (3/302) 2.4%(0.1,4.7) 

TM perforation/Otorrhea >3 weeks, Dizziness or erythema or tinnitus or tympanostomy tube blockage 

Complication of OM, 0.3% (1/297) 0%(0/302) 0.3%(-0.3,0.9) 

History of otic/ME surgery (excluding Infection super ear or irritation ear or pruritus ear 

tubes), 0% (0/297) 0.7% (2/302) -0.7%(-1.6,0.2) 

Respiratory Illness, Irritability 0.7% (2/297) 0% (0/302) 0.7%(-0.2,1.6) 

Cranio-facial, Monilia oral 

Endocrine disorders (diabetes), 0.3% (1/297) 0.3% (1/302) 0%(-0.9,0.9) 

GI disorders/Liver, Pain ear 2.4% (7/297) 3.0% (9/302) -0.6%(-3.2,2) 

Renal Disorders, Precipitate ear 

Immunosuppressed 0.7% (2/297) 1.0% (3/302) -0.3%(-1.8,1.2) 

/compromised/deficient, Serious Tx related 

Other Infectious diseases (meningitis), 0% (0/297) 0% (0/302) 0% (0, 0) 

On other medication/treatment, Taste perversion 

Menarche 0.3% (1/297) 1% (3/302) -0.7%(-2,0.6) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Roos 

2000131 

Jadad 

quality 

score 1 

Ceftibuten 

9 mg/kg/day 

= qd for 10 days 

Enrollment 

Time: 

6/1995-6/1996 

Entering: 

N=180 

N=90 Ceftibuten 10 days 

Disease recurrence; 

Adverse effects of 

treatment; 

Outcome: Success rate (no recurrence after treatment ) up to day 14 from 

start of treatment 

Age Ceftibuten 5d Ceftibuten 10d Diff (95%CI) 

(0-5):2 N=90 Ceftibuten 5 days Bacteriologic outcomes All 79% (70/89) 96% (85/89) -16.8(-26.7,-7.0) 

[1,0,1,0,0] vs. Place: by nasopharyngeal cultures 

Sweden Completing: Outcome: Success rate (no recurrence after treatment ) up to day 40 from 

Ceftibuten Multicenter: N=178 start of treatment 

Definition: 9 mg/kg/day 6 centers N=89 Ceftibuten 10 days Age Ceftibuten 5d Ceftibuten 10d Diff (95%CI) 

Presence = qd for 5 days N=89 Ceftibuten 5 days All 65% (58/89) 70% (62/89) -5.0 (-18.8, 8.8) 

of MEE, Inclusion: 

S&S of 6 mo-8 yr, Analyzed: Outcome: Percent patients with adverse events 

MEI <45 kg, N=178 Ceftibuten 5d Ceftibuten 10d Diff (95%CI) 

Presence of middle ear effusion (MEE), N=89 Ceftibuten 10 days All 7% (6/90) 17% (15/90) -10.0(-19.4, -0.6) 

Bulging tympanic membrane [TM], N=89 Ceftibuten 5 days 

Erythematous TM, Outcome: Adverse events 

Otalgia, Ceftibuten 5d Ceftibuten 10d Diff (95%CI) 

Recurrent AOM, GI disturbance 

Weight of child Lower weight limit not 6.7% (6/90) 16.7% (15/900 -10%(-19,-0.6) 

specified 

Exclusion: 

Penicillin/beta-lactams, 

Complication of OM, 

PE tubes/history of PE tubes, 

Immunosuppressed 

/compromised/deficient 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Saez-Llorens 

2005121 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45/6.4 mg/kg/day 

Enrollment 

Time: 

5/2001-5/2002 

Influencing 

factors: 

Hearing deficit and severity, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success rate at day 3-10- all type of diagnoses 

Age Amox-clav Gatifloxacin Diff (95%CI) 

All 84% (102/121) 90% (222/246) -6%(-13, 1) 

Page 1 of 2 (0-5):2 / bid for 10 days Laterality, OME]; <2yrs 80% (36/45) 92% (81/88) -12%(-24,-0.3) 

[1,0,1,0,0] Place: Age, Signs or symptoms of 2-7yrs 87% (66/76) 89% (141/158) -2%(-11, 7) 

vs. Multicenter: Recurrent otitis media/ MEI; 

20 centers otitis prone Disease recurrence; Outcome: Success rate at day 3-10- Recurrent OM only 

Definition: Gatifloxacin Adverse effects of Age Amox-clav Gatifloxacin Diff (95%CI) 

Presence 10 mg/kg/day Inclusion: treatment All 81% (35/43) 89% (67/75) -8%(-21, 5.0) 

of MEE, = qd for 10 days 6 mo-7 yr, Entering: <2yrs 88% (14/16) 94% (30/32) -6%(-22, 10) 

S&S of Recurrent AOM, N=419 2-7yrs 78% (21/27) 86% (37/43) -8%(-26, 10) 

MEI Failed previous antibiotic N=139 Amoxicillinclavulanate Outcome: Success rate at day 3-10- AOM treatment failures only 

Exclusion: N=280 Gatifloxacin Age Amox-clav Gatifloxacin Diff (95%CI) 

Penicillin/beta-lactams, All 85% (62/73) 91% (140/154) -6%(-15, 2.7) 

Any antibiotic, Analyzed: <2yrs 73% (19/26) 89% (41/46) -16%(-34, 2) 

Antibiotic within 7 days, N=413 2-7yrs 92% (43/47) 92% (99/108) 0%(-9.3, 9.3) 

Concomitant/Concurrent infection N=136 Amoxicillinneeding clavulanate Outcome: Success rate at day 3-10- both ROM and AOM tx failures 

antibiotic treatment, N=277 Gatifloxacin Age Amox-clav Gatifloxacin Diff (95%CI) 

Otitis externa, All 100% (5/5) 88% (15/17) 12% (-17, 41) 

TM perforation/Otorrhea, <2yrs 100% (3/3) 100% (10/10) 0% 

PE tubes/history of PE tubes, 2-7yrs 100% (2/2) 71% (5/7) 29%(-37, 95) 

Cranio-facial, 

GI disorders/Liver, Outcome: Success rate at day 3-10- Unilateral cases 

Renal Disorders, Age Amox-clav Gatifloxacin Diff (95%CI) 

Major Systemic disease/ condition, All 91% (49/54) 92% (109/118) -1%(-10, 8) 

medical problem, <2yrs 86% (12/14) 98% (40/41) -12%(-25, 1.3) 

Metabolic/Inborn Errors of metabolism, 2-7yrs 92% (37/40) 90% (69/77) 2%(-9, 13) 

Investigational drug within 1 month, 

On other medication/treatment Outcome: Success rate at day 3-10- Bilateral cases 

Age Amox-clav Gatifloxacin Diff (95%CI) 

All 79% (53/67) 88% (113/128) -9%(-20, 1.6) 

<2yrs 77% (24/31) 87% (41/47) -10%(-27, 7) 

2-7yrs 81% (29/36) 89% (72/81) -8%(-21, 5.4) 

Outcome: Success rate at day 3-10- Mild/Moderate Severity cases 

Age Amox-clav Gatifloxacin Diff (95%CI) 

All 80% (33/41) 89% (83/93) -9%(-22, 4) 

<2yrs 67% (10/15) 87% (20/23) -20%(-46, 6) 

2-7yrs 88% (23/26) 90% (63/70) -2%(-16, 12) 

Outcome: Success rate at day 3-10- Severe Severity cases 

Age Amox-clav Gatifloxacin Diff (95%CI) 

All 86% (69/80) 91% (139/153) -5%(-13, 3.4) 

<2yrs 87% (26/30) 94% (61/65) -7%(-19, 4.9) 

2-7yrs 86% (43/50) 89% (78/88) -3%(-14, 8) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Author 

Year 

Quality 

& AOM 

definition Intervention 

Time, Place, Inclusion, Exclusion 

Criteria 

Influencing 

Factors and 

Sample Size Outcomes Findings 

Saez-Llorens 

2005121 

Page 2 of 2 

Outcome: Success rate (sustained cure) at day 21-28 

Age Amox-clav Gatifloxacin 

All 73% (88/121) 74% (183/246) 

<2yrs 64% (29/45) 70% (62/88) 

2-7yrs 78% (59/76) 77% (121/158) 

Outcome: Adverse events 

Amox-clav Gatifloxacin 

Any 59% (81/136) 55% (153/277) 

Arthralgia 2% ( 2/136) 2% ( 6/277) 

Drug-related 15% (20/136) 18% (49/277) 

Vomiting 5% ( 7/136) 8% (23/277) 

Diarrhea 7% (10/136) 3% ( 8/277) 

Abd pain 2% ( 2/136) 4% (11/277) 

Diaper rash 2% ( 3/136) 1% ( 2/277) 

Serious* 2% ( 2/136) 0% ( 0/277) 

* one was generalized seizure 

Diff (95%CI) 

-1%(-11, 9) 

-6%(-23, 11) 

1%(-10, 12) 

Diff (95%CI) 

4%(-6, 14) 

0%(-2.9, 2.9) 

-3%(-11,4.7) 

-3%(-8, 2.2) 

4%(-0.2, 8) 

-2%(-5.7, 1.7) 

1%(-1.4,3 .4) 

2%(0.3, 3.7) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Sarrell 

2001102 

Jadad 

quality 

score 1 

Topical anesthetic 

nos 

5 drops 

Study Time: 

1/1998-10/1999 

Completing: 

N=103 

N=42 Anesthetic drops 

Treatment failure; 

Signs or symptoms of 

MEI; 

Outcome: Improvement in ear pain score (use the measurements at 30 

minutes) 

Anesthetic Otikon 

(0-5):3 = tid Place: N=61 Otikon drops By symptoms (n=42) (n=61) 

[1,1,1,0,0] Office setting/ (otalgia, ear fullness); Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

vs. private practice, Analyzed: Adverse effects of Day 1 4.3+/-2.2 3.1+/-2.0 1.2 (0.37, 2.03) 0.005 

Pediatric practice N=103 treatment Day 2 2.1+/-1.0 1.4+/-0.8 0.7 (0.35, 1.05) 0.000 

Definition: Otikon drops Multicenter N=42 Anesthetic drops Day 3 1.4+/-0.6 1.1+/-0.5 0.3 (0.08, 0.52) 0.007 

Presence 5 drops N=61 Otikon drops 

of MEE, = tid Inclusion: Outcome: Adverse events 

S&S of 6-18 yr, Anesthetic Otikon Diff (95%CI) 

MEI Presence of middle ear effusion (MEE), Any 0% (0/42) 0% (0/61) 0% (0,0) 

Bulging tympanic membrane [TM], 

Cloudy TM, 

Erythematous TM, 

Air fluid level behind TM, 

Pneumatic otoscopy/tympanometry 

(limited or absent mobility of TM), 

S&S of middle ear inflammation 

(MEI), 

Otalgia, 

Otoscopy (distinct TM erythema), 

Ear fullness 

Exclusion: 

Allergic to other medication NOS, 

AOM within 2 weeks, 

TM perforation/Otorrhea, 

Complication of OM, 

PE tubes/history of PE tubes, 

Immunosuppressed 

/compromised/deficient, 

On other medication/treatment, 

Inability to do visual scale 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Sarrell 

2003103 

Jadad 

quality 

score 1 

Amoxicillin 

80 mg/kg/day 

/ tid, 

Study Time: 

1/1999-1/2001 

Entering: 

N=180 

N=45 Anesthetic 

By symptoms 

(otalgia, ear fullness); 

Adverse effects of 

Outcome: Improvement in ear pain score (use the measurements at 30 

minutes) 

NHED NHED+Amox 

(0-5):5 Topical anesthetic Place: with Amoxicillin treatment (n=44) (n=42) 

[1,1,1,1,1] nos Public health center/ N=45 NHED Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

5 drops clinic/CHC N=45 NHED Day 1 3.0+/-2.0 3.5+/-2.5 -0.5(-1.5, 0.5) 0.31 

= tid with Amoxicillin Day 2 1.3+/-2.3 1.8+/-2.3 -0.5(-1.5, 0.5) 0.32 

Definition: Inclusion: N=45 Anesthetic Day 3 0.3+/-0.6 0.8+/-2.1 -0.5(-1.2, 0.2) 0.13 

Presence vs. 5-18 yr, 

of MEE, Presence of middle ear effusion (MEE), Completing: NHED Anesthetic 

S&S of NHED Bulging tympanic membrane [TM], N=171 (n=44) (n=42) 

MEI 5 drops Erythematous TM, N=43 Anesthetic Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

= tid Air fluid level behind TM, with Amoxicillin Day 1 3.0+/-2.0 2.9+/-1.6 0.1(-0.7, 0.9) 0.80 

Pneumatic otoscopy/tympanometry N=44 NHED Day 2 1.3+/-2.3 1.4+/-0.8 -0.1(-0.8, 0.6) 0.79 

vs. (limited or absent mobility of TM), N=42 NHED Day 3 0.3+/-0.6 1.2+/-0.5 -0.9(-1.1, -0.7) 0.000 

S&S of middle ear inflammation with Amoxicillin 

Amoxicillin (MEI), N=42 Anesthetic NHED Anesthetic+Amox 

80 mg/kg/day Otalgia (n=44) (n=43) 

/ tid, Analyzed: Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

NHED Exclusion: N=171 Day 1 3.0+/-2.0 5.6+/-2.6 -2.6(-3.6, -1.6) 0.000 

5 drops TM perforation/Otorrhea, N=43 Anesthetic Day 2 1.3+/-2.3 2.7+/-2.6 -1.4(-2.4, -0.4) 0.009 

= tid Complication of OM, with Amoxicillin Day 3 0.3+/-0.6 2.0+/-2.0 -1.7(-2.3, -1.1) 0.000 

PE tubes/history of PE tubes, N=44 NHED 

vs. Cranio-facial, N=42 NHED NHED+Amox Anesthetic 

Immunosuppressed with Amoxicillin (n=42) (n=42) 

Topical anesthetic /compromised/deficient, N=42 Anesthetic Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

nos On other medication/treatment, Day 1 3.5+/-2.5 2.9+/-1.6 0.6(-0.3, 1.5) 0.19 

5 drops Allergy to other medications, Day 2 1.8+/-2.3 1.4+/-0.8 0.4(-0.4, 1.2) 0.29 

= tid A or B on Tympanogram, Day 3 0.8+/-2.1 1.2+/-2.0 -0.4(-1.3, 0.5) 0.37 

Inability to do visual scale 

NHED+Amox Anesthetic+Amox 

NHED=Naturopat (n=42) (n=43) 

hic Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

Herbal Extract Ear Day 1 3.5+/-2.5 5.6+/-2.6 -2.1(-3.2, -1.0) 0.000 

Drops Day 2 1.8+/-2.3 2.7+/-2.6 -0.9(-2.0, 0.2) 0.10 

Day 3 0.8+/-2.1 2.0+/-2.0 -1.2(-2.1, -0.3) 0.008 

Anesthetic Anesthetic+Amox 

(n=42) (n=43) 

Mean+/-SD Mean+/-SD Diff (95%CI) p-value 

Day 1 2.9+/-1.6 5.6+/-2.6 -2.7(-3.6, -1.8) 0.000 

Day 2 1.4+/-0.8 2.7+/-2.6 -1.3(-2.1, -0.5) 0.003 

Day 3 1.2+/-2.0 2.0+/-2.0 -0.8(-1.7, 0.06) 0.07 

Outcome: Adverse events 

All treatment options had 0 adverse events: Diff (95%CI): 0%(0,0) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Scholz 

19984 

Jadad 

quality 

score 1 

Amoxicillin 

50 mg/kg/day 

/ bid for 10 days 

Study Time: 

9/1995-1/1996 

Influencing 

factors: 

Otorrhea, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Clinical success on day 9-11 

Amoxicillin Erythromycin 

By drugs 96% (133/139) 94% (132/141) 

Diff (95%CI) 

2% (-3, 7) 

(0-5):5 Place: Laterality, OME]; 

[1,1,1,1,1] vs. Germany Age Signs or symptoms of Age<=2years Age>2years Diff (95%CI) 

Multicenter: MEI; By Age 89.7% (35/39) 95.4% (230/241) -5.7%(-13, 2) 

Erythromycin 19 centers Other symptoms: fever; 

Definition: 40 mg/kg/day Pediatric practice Entering: Other symptoms: Otorrhea at entry No Otorrhea at entry Diff (95%CI) 

Presence / bid for 10 days N=302 decreased hearing; By otorrhea 94.7% (36/38) 94.6% (229/242) 0.1%(-8, 8) 

of MEE, Inclusion: N=151 Amoxicillin Invasive infections, 

S&S of 6 mo-11 yr, N=151 Erythromycin e.g., mastoiditis, Bilateral Unilateral Diff (95%CI) 

MEI Presence of middle ear effusion (MEE), bacteremia; By Laterality 87.3% (69/79) 97.5% (196/201) -10%(-16, -4) 

Bulging tympanic membrane [TM], Completing: Disease recurrence; 

Cloudy TM, N=280 Adverse effects of Outcome: Free of recurrence 

Erythematous TM, N=139 Amoxicillin treatment Amoxicillin Erythromycin Diff (95%CI) 

Otorrhea, N=141 Erythromycin All pts 95.0% (132/139) 94.3% (133/141) 0.7%(-4.6, 6) 

Pneumatic otoscopy/tympanometry 31-40 d 97.8% (136/139) 97.2% (137/141) 0.6 %(-3, 4) 

(limited or absent mobility of TM), Analyzed: 

S&S of middle ear inflammation N=280 Outcome: Adverse events 

(MEI), N=139 Amoxicillin Amoxicillin Erythromycin Diff (95%CI) 

Otalgia, N=141 Erythromycin Tx-related or possibly tx-related 

Otoscopy (distinct TM erythema), 7% (11/151) 5% (8/151) 2% (-3.7,7.5) 

Decreased hearing, 

Ear fullness, 

Fever, 

Onset of AOM symptoms within 4 days 

before entry 

Exclusion: 

Penicillin/beta-lactams, 

Macrolides, 

Antibiotic within 7 days, 

Long acting antibiotic within 4 weeks, 

AOM within 4 weeks, 

Chronic suppurative OM, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

PE tubes/history of PE tubes, 

Cranio-facial, 

Immunosuppressed 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Sher 

2005122 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

90/6.4 mg/kg/day 

Enrollment 

Time: 

3/2001-6/2002 

Influencing 

factors: 

Laterality, 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success rate on day 10 (test of day visit) by age group 

Amox-clav Gatifloxacin Diff (95%CI) 

Total 79% (92/117) 85% (105/124) -6%(-16, 3.7) 

(0-5):2 / bid for 10 days Age, OME]; <2yrs 78% (45/58) 79% (49/62) -1%(-16, 14) 

[1,0,1,0,0] Place: Severity Signs or symptoms of >=2yrs 80% (47/59) 90% (56/62) -11%(-23,2.7) 

vs. United States, MEI; 

Costa Rica Bacteriologic cure/failure; Outcome: Success rate on day 10 (test of day visit) by laterality 

Definition: Gatifloxacin Multicenter: Entering: Adverse effects of Amox-clav Gatifloxacin Diff (95%CI) 

Presence 10 mg/kg/day 27 centers N=349 treatment Unilateral 82% (40/49) 84% (48/57) -3%(-17, 12) 

of MEE, = qd for 10 days N=173 Amoxicillin- Bilateral 76% (52/68) 85% (57/67) -9%(-22, 4.7) 

S&S of Inclusion: clavulanate 

MEI 6 mo-7 yr, N=176 Gatifloxacin Outcome: Success rate on day 10 (test of day visit) by SEVERITY 

Presence of middle ear effusion (MEE), Amox-clav Gatifloxacin Diff (95%CI) 

S&S of middle ear inflammation Completing: Mild/Mod 85% (45/53) 84% (47/56) 1%(-13, 15) 

(MEI), N=328 Bilateral 73% (47/64) 85% (58/68) -12(-26, 2) 

AOM treated with antibiotic at least 2 N=164 Amoxicillindays, clavulanate Outcome: Adverse events 

Recurrent AOM N=164 Gatifloxacin Amox-clav Gatifloxacin Diff (95%CI) 

Any 27% (46/173) 24% (42/176) 3%(-6, 12) 

Exclusion: Analyzed: Abd pain or diarrhea (severe in intensity) 

Antibiotic within 7 days, N=241 0.6% (1/173) 0% (0/176) 0.6(-0.4,1.7) 

Other antibiotic Tx, N=117 Amoxicillin- Anorexia 0% (0/173) 0.6% (1/176) -0.6%(-1.8,0.6) 

Otitis externa, clavulanate Arthralgia event unrelated to treatment 

TM perforation/Otorrhea, N=124 Gatifloxacin 1.2% (2/173) 0.5% (1/176) 0.6%(-1.4,2.6) 

PE tubes/history of PE tubes, Deaths or Serious drug related events 

Major Systemic disease/ condition, 0% (0/173) 0% (1/173) 0% (0, 0) 

medical problem, Diaper rash 

Failed previous antibotic 6.4% (11/173) 5.1% (9/176) 1.3%(-3.6,6) 

Diarrhea 18% (31/173) 10% (17/176) 8% (1, 15) 

Vomiting 6% (10/173) 7% (12/176) -1%(-6, 4) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Spiro 

200694 

Jadad 

quality 

score 1 

Antibiotic 

vs. 

Enrollment 

Time: 

7/2004-7/2005 

Entering: 

N=283 

N=145 Antibiotic 

Treatment failure; 

Adverse effects of 

treatment; 

Outcome: Healthcare utilization at day 4-6 

Antibiotic Rx RxHold Diff (95%CI) 

Not fill Rx 13% (17/133) 62% (82/132) -49%(-61, -37) 

(0-5):3 N=138 Prescription to hold Parent satisfaction; No analgesic 90% (120/133) 93% (123/132) -3%(-10, 3.7) 

[1,0,1,1,0] Prescription to Place: Cost outcomes; No MD visit 92% (125/133) 90% (110132) 2%(-4.9, 8.9) 

Hold Emergency room Completing: Healthcare utilization 

N=265 Outcome: Presence of symptoms and signs at day 4-6 

Definition: Inclusion: N=133 Antibiotic Antibiotic Rx RxHold Diff (95% CI) 

Not 6 mo-12 yr, N=132 Prescription to hold Otalgia 67% (89/133) 64% (85/132) 3%(-8, 14) 

specified AOM Fever 35% (46/133) 32% (42/132) 3%(-8, 14) 

Analyzed: Diarrhea 23% (31/133) 8% (10/132) 15%(6, 24) 

Exclusion: N=265 Vomiting 11% (15/133) 11% (15/132) 0%(-7.5, 7.5) 

Antibiotic within 1 week, N=133 Antibiotic 

Concomitant/Concurrent infection N=132 Prescription to hold Outcome: Healthcare utilization at day 11-14 

needing Antibiotic Rx RxHold Diff (95%CI) 

antibiotic treatment, No analgesic 11% (13/123) 5% (6/124) 6%(-18, 6) 

TM perforation/Otorrhea, No MD visit 89% (109/123) 85% (106124) 4%(-4.4, 12) 

PE tubes/history of PE tubes, 

Immunosuppressed Outcome: Presence of symptoms and signs at day 11-14 

/compromised/deficient, Antibiotic Rx RxHold Diff (95% CI) 

Hospitalization/need for admission, Otalgia 61% (75/123) 67% (83/124) -6%(-18, 6) 

In other studies/trials, Fever 31% (38/123) 32% (40/124) -1%(-13, 11) 

Unable/unlikely to return to follow-up, Diarrhea 24% (29/123) 12% (15/124) 12%(2.4, 22) 

No telephone, Vomiting 10% (12/123) 9% (11/124) 1%(-6, 8) 

Language barrier 

Outcome: Adverse event at 4-6 day follow-up 

Antibiotic Rx RxHold Diff (95%CI) 

Diarrhea 21% (31/145) 7% (10/138) 14%(6, 22) 

Otalgia 61% (89/145) 62% (85/138) -0.2%(-11,11) 

Vomiting 10% (15/145) 11% (15/138) -1%(-8, 7) 

Outcome: Adverse event at 11-14 day follow-up 

Diarrhea 20% (29/145) 11% (15/138) 9% (0.7, 18) 

Otalgia 52% (75/145) 60% (83/138) -8%(-20,3.2) 

Vomiting 8% (12/145) 8% (11/138) 0.3%(-6, 7) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Subba Rao 

19985 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

250 mg for > 6 y 

Study Time: 

9/1995-12/1996 

Entering: 

N=233 

N=114 AmoxicillinTreatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success at end of study day 28-34 

Amox-clav Cefaclor Diff((95%CI) 

Total 91.4% (96/105) 78.6%(88/112) 13%(3.2, 22) 

(0-5):3 = tid for 7 days, Place: clavulanate OME]; 

[1,0,1,1,0] --- 125 mg for < 6 India, N=119 Cefaclor Signs or symptoms of Outcome: Success at end of treatment on day 7 

y United Arab Emirates MEI; Amox-clav Cefaclor Diff((95%CI) 

= tid for 7 days Multicenter: Completing: Other symptoms: fever; Total 97.1% (102/105) 83.9% (94/112) 13%(5.3, 21) 

Definition: 6 centers N=183 Other symptoms: 

Presence vs. Hospital clinic/ N=93 Amoxicillin­ decreased hearing; Outcome: Absence of tympanic membrane indicators (redness, bulging, 

of MEE, outpatient clavulanate Bacteriologic cure/failure; loss of light reflex, rupture) 

S&S of Cefaclor N=90 Cefaclor Disease recurrence; Amox-clav Cefaclor Diff((95%CI) 

MEI 125 or 250 mg Inclusion: Adverse effects of Day7 62.9% (66/105) 44.6% (50/112) 18%(5.0, 32) 

= tid for 7 days 1-12 yr, Analyzed: treatment Day10-12 90.0%(90/100) 84.2% (85/101) 6%(-3.5, 15) 

Presence of middle ear effusion (MEE), N=217 Day28-34 93.8%(90/96) 91.6% (87/95) 2%(-5.2, 10) 

Bulging tympanic membrane [TM], N=105 AmoxicillinLoss of landmarks, clavulanate Outcome: Absence of signs and symptoms (ear pain, ear discharge, 

Erythematous TM, N=112 Cefaclor hearing loss) 

Otorrhea, Amox-clav Cefaclor Diff((95%CI) 

Pneumatic otoscopy/tympanometry Day7 99.0% (104/105) 83.9% (94/112) 15%(7.6, 23) 

(limited or absent mobility of TM), Day10-12 97.0% (97/100) 92.1% (93/101) 5%(-1.4, 11) 

S&S of middle ear inflammation Day28-34 97.9% (94/96) 94.7% (90/95) 3% (-2.1, 8) 

(MEI), 

Otalgia, Outcome: Adverse events 

Decreased hearing, Amox-clav Cefaclor Diff((95%CI) 

Fever Diarrhea 7% (8/114) 8.4% (10/119) -1.4%(-8,5.5) 

Fever 0% (0/114) 1.7% (2/119) -1.7%(-4, 0.7) 

Exclusion: Headache 0% (0/114) 2.5% (3/119) -2.5%(-5.4,0.4) 

Penicillin/beta-lactams, Vomiting 2.6% (3/114) 5% (6/119) -2.4%(-7.3,2.5) 

Antibiotic within 7 days, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem, 

Bowel function-altering meds, 

Concurrent use of antihistamine, 

On other medication/treatment 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Teele 

2000129 

Jadad 

quality 

score 1 

Placebo 

vs. 

Place: 

United States 

Multicenter: 

Entering: 

N=117 

N=41 Placebo 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success rate (none or 1 AOM episode in 6 months) 

Amoxicillin Sulfisoxazole Diff (95%CI) 

90% (36/40) 78% (28/36) 12% (-4, 29) 

(0-5):3 2 centers N=36 Sulfa OME]; 

[1,1,0,1,0] Sulfa alone N=40 Amoxicillin Disease recurrence Outcome Success rate (none or 1 AOM episode in 1 year) 

50 mg/kg/day Inclusion: Amoxicillin Sulfisoxazole Diff (95%CI) 

= qd Recurrent AOM Completing: 68% (27/40) 64% (23/36) 4% (-18, 25) 

Definition: N=117 

Acute vs. N=41 Placebo Outcome: Success rate (none or 1 AOM episode in 6 months) 

onset N=36 Sulfa Amoxicillin Placebo Diff (95%CI) 

of S&S, Amoxicillin N=40 Amoxicillin 90% (36/40) 71% (29/41) 19% (2, 37) 

Presence 20 mg/kg/day 

of MEE, = qd Analyzed: Outcome: Success rate (none or 1 AOM episode in 1 year) 

S&S of N=117 Amoxicillin Placebo Diff (95%CI) 

MEI N=41 Placebo 68% (27/40) 66% (27/41) 2% (-19, 22) 

N=36 Sulfa 

N=40 Amoxicillin Outcome: Success rate (none or 1 AOM episode in 6 months) 

Sulfisoxazole: Placebo Diff (95%CI) 

78% (28/36) 71% (29/41) 7% (-12, 27) 

Outcome: Success rate (none or 1 AOM episode in 1 year) 

Sulfisoxazole Placebo Diff (95%CI) 

64% (23/36) 66% (27/41) -2% (-23, 20) 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Tsai 

199886 

Jadad 

quality 

score 1 

Cefpodoxime 

10 mg/kg/day 

= qd for 10 days 

Study Time: 

1/1996-7/1997 

Entering: 

N=57 

N=23 Cefpodoxime 

Treatment failure; 

Presence of MEE 

[also persistent effusion, 

Outcome: Success (cured or improved) at end of treatment day 10-14 

Cefaclor Cefpodoxime Diff (95%CI) 

90.0% (27/30) 95.2% (20/21) -5%(-20, 10) 

(0-5):1 Inclusion: N=34 Cefaclor OME]; 

[1,0,1,0,0] vs. 3 mo-15 yr, Signs or symptoms of Outcome: Absence of middle ear effusion day 10-14 

Presence of middle ear effusion (MEE), Completing: MEI; Cefaclor Cefpodoxime Diff (95%CI) 

Cefaclor Bulging tympanic membrane [TM], N=51 Other symptoms: fever; 35.0% (7/20) 26.7% (4/15) 8%(-23, 39) 

Definition: 45 mg/kg/day Cloudy TM, N=21 Cefpodoxime Disease recurrence; 

Presence / tid for 10 days Loss of landmarks, N=30 Cefaclor Adverse effects of Outcome: Adverse events 

of MEE, Air fluid level behind TM, treatment Cefaclor Cefpodoxime Diff (95%CI) 

S&S of Pneumatic otoscopy/tympanometry Analyzed: Any 15% (5/34) 30% (7/23) -16(-37,5.9) 

MEI (limited or absent mobility of TM), N=51 Abdominal discomfort 

Otalgia, N=21 Cefpodoxime 3% (1/34) 9% (2/23) -6%(-18,6) 

Fever N=30 Cefaclor Diarrhea 3% (1/34) 17% (4/23) -14%(-30,0.5) 

Intolerable abd discomfort or intolerable urticaria leading to being 

Exclusion: switched to other tx group 

Penicillin/beta-lactams, 3% (1/34) 0% (0/23) 3%(-4, 10) 

Antibiotic within 48 hours, Pruritis 0% (0/34) 4% (1/23) -4%(-11, 3) 

TM perforation/Otorrhea, Skin rash 6% (2/34) 0% (0/23) 6%(-4,16) 

Immunosuppressed Sweating 3% (1/34) 0% (0/23) 3% (-4, 10) 

/compromised/deficient, 

Major Systemic disease/ condition, 

medical problem, 

Investigational drug within 2 weeks, 

Unable/unlikely to return to follow-up 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Turik 

1998125 

Jadad 

quality 

score 1 

Cefuroxime 

30 mg/kg/day 

/ bid for 10 days 

Study Time: 

2/1996-12/1996 

Entering: 

N=205 

N=101 Cefuroxime 

Treatment failure; 

Adverse effects of 

treatment 

Outcome: Clinical success (cured or improved) 

Cefaclor Cefuroxime axetil Diff (95%CI) 

Day 10 93.6% (73/78) 92.9% (65/70) 0.7%(-7, 9) 

(0-5):2 Place: N=104 Cefaclor Day20-26 85.9% (67/78) 87.1% (61/70) -1.2%(-12, 10) 

[1,0,1,0,0] vs. Multicenter: 

13 centers Completing: Outcome: Adverse events 

Cefaclor N=189 Cefaclor Cefuroxime axetil Diff (95%CI) 

Definition: 40 mg/kg/day Inclusion: N=91 Cefuroxime Any 31% (32/104) 36% (36/101) -5%(-18, 8) 

Presence / bid for 10 days 3 mo-12 yr, N=98 Cefaclor Asthma or Bronchospasm unrelated to study drug or respiratory disorder 

of MEE, >5.5 kg, or vomiting 

S&S of Presence of middle ear effusion (MEE), Analyzed: 0% (0/104) 1% (1/101) -1%(-2.9, 0.9) 

MEI Bulging tympanic membrane [TM], N=205 Diarrhea 2% (2/104) 1% (11/101) -9%(-16,-2.3) 

Cloudy TM, N=101 Cefuroxime Diarrhea during treatment 

Loss of landmarks, N=104 Cefaclor 0% (0/104) 8% (8/101) -8%(-13,-2.5) 

Erythematous TM, Increased cough 

Pneumatic otoscopy/tympanometry 7% (7/104) 0% (0/101) 7% (1.7,12) 

(limited or absent mobility of TM), Rhinitis 9% (9/104) 10% (10/101) -1%(-9, 7) 

S&S of middle ear inflammation 

(MEI), 

Decreased hearing, 

Ear fullness, 

Fever, 

AOM treated with antibiotic 2-10 days 

Exclusion: 

Penicillin/beta-lactams, 

Concomitant/Concurrent infection 

needing 

antibiotic treatment, 

OME (serous OM, nonsuppurative OM, 

mucoid OM 

secretory OM, glue ear), 

TM perforation/Otorrhea 24 hours, 

Complication of OM, 

PE tubes/history of PE tubes, 

GI disorders/Liver, 

Renal Disorders, 

Other Infectious diseases (meningitis), 

Major Systemic disease/ condition, 

medical problem, 

Investigational drug within 28 days, 

Menarche 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Wang 

200478 

Jadad 

quality 

score 1 

Amoxicillinclavulanate 

45 mg/kg/day 

Enrollment 

Time: 

2/2000-4/2002 

Entering: 

N=109 

N=55 AmoxicillinTreatment failure; 

Disease recurrence; 

Adverse effects of 

Outcome: Clinical cure rate on day 11 after 10-day treatment (per 

protocol) 

Amox-clav Ceftriaxon Diff (95%CI) 

(0-5):2 / tid for 10 days clavulanate treatment 

[1,0,1,0,0] Place: N=54 Ceftriaxone 78.1% (25/32) 75.6% (31/41) 2.5%(-22, 17) 

vs. China 

Completing: Outcome: Clinical cure rate on day 11 after 10-day treatment (intent to 

Definition: Ceftriaxone Inclusion: N=78 treat) 

Presence 50 mg/kg/day 3 mo-6 yr, N=35 Amoxicillin­ Amox-clav Ceftriaxon Diff (95%CI) 

of MEE, = qd for 1 day Presence of middle ear effusion (MEE), clavulanate 60.0% (27/45) 62.8% (32/51) 3% (-17, 22) 

S&S of Pneumatic otoscopy/tympanometry N=43 Ceftriaxone 

MEI (limited or absent mobility of TM), Outcome: Adverse events 

S&S of middle ear inflammation Analyzed: Amox-clav Ceftriaxon Diff (95%CI) 

(MEI), N=73 Any 36% (20/55) 24% (13/54) 12%(-5.0,30) 

Otalgia, N=32 Amoxicillin- Diarrhea 31% (17/55) 17% (9/54) 14%(-1.8,30) 

Otoscopy (distinct TM erythema), clavulanate GI 34% (19/55) 22% (12/54) 12%(-4.6,29) 

Decreased hearing, N=41 Ceftriaxone Skin & appendages or rash 

Fever >38 C 11% (6/55) 7% (4/54) 4%(-7, 14) 

Exclusion: 

Antibiotic within 7 days, 

TM perforation/Otorrhea, 

PE tubes/history of PE tubes 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Zhang 

200368 

Jadad 

quality 

score 1 

Amoxicillin 

40 mg/kg/day tid 

for 10 

Study Time: 

11/2001-4/2002 

Entering: 

N=236 

N=118 Ceftriaxone 

Treatment failure; 

By otoscopic findings:; 

Bulging tympanic 

Outcome: Success rate at 10-14 days (cured or improved): 

Amox Ceftriaxon Diff (95%CI) 

90.6% (96/106) 97.2% (103/106) -7%(-13, -0.2) 

(0-5):1 Place: N=118 Amoxicillin membrane [TM]; 

[1,0,1,0,0] vs. China Erythematous TM; Outcome: Adverse effects 

Multicenter: Completing: By Pneumatic Amox Ceftriaxon Diff (95%CI) 

Ceftriaxone 3 centers N=212 otoscopy/tympanometry; 1.9% (2/106) 1.9% (2/106) 0% 

Definition: 50 mg/kg/day for 1 Hospital, N=106 Ceftriaxone By symptoms 2/106 2/106 

Acute day University/ N=106 Amoxicillin (otalgia, ear fullness); 

onset academic, Other symptoms: fever; Adverse events not reported by drug arm. 

of S&S Children's Analyzed: Other symptoms: 

N=212 decreased hearing 

Inclusion: N=106 Ceftriaxone 

1-12 yr, N=106 Amoxicillin 

Acute onset S&S (parent/guardian 

report), 

Bulging tympanic membrane [TM], 

Erythematous TM, 

S&S of middle ear inflammation 

(MEI), 

Otoscopy (distinct TM erythema), 

Decreased hearing, 

Fever >38 C, 

Tympanocentesis preformed Not 

Specified, 

Weight of child Lower weight limit not 

specified, 

Weight of child Upper weight limit not 

specified 

Exclusion: 

Allergic to other medication NOS, 

Antibiotic within 7 days, 

AOM within 3 days, 

Recurrent AOM (>1 episodes in 6 

months), 

Otitis externa, 

TM perforation/Otorrhea, 

Renal Disorders, 

Major Systemic disease/ condition, 

medical problem 
Appendix C. Evidence Tables For Randomized Controlled Trials
 

Quality Influencing 

Author & AOM Time, Place, Inclusion, Exclusion Factors and 

Year definition Intervention Criteria Sample Size Outcomes Findings 

Zielnik- Jadad Amoxicillin Place: Entering: Otorrhea; In Polish. 

Jurkiewicz 

200565 

quality 

score 1 

80 mg/kg/day 

/ tid for 10 days 

Poland N=40 

N=20 Amoxicillin 

Signs or symptoms of 

MEI; Adverse events not reported 

(0-5):4 Inclusion: N=20 Amoxicillin/Fenspiride By symptoms 

[1,1,1,1,0] vs. Pneumatic otoscopy/tympanometry (otalgia, ear fullness); 

(limited or absent mobility of TM), Completing: Other symptoms: fever; 

Amoxicillin AOM, N=40 Other symptoms: 

Definition: 80 mg/kg/day Age of child Children, age not N=20 Amoxicillin decreased hearing 

Not / tid for 10 days, specified N=20 Amoxicillin/Fenspiride 

specified Fenspiride 

2 ml Exclusion: Analyzed: 

/ tid for 10 days Any antibiotic, N=40 

GI disorders/Liver, N=20 Amoxicillin 

Adenoid hypertrophy N=20 Amoxicillin/Fenspiride 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Legros JM, Hitoto H, Garnier F, Dagorne C, Parot-Schinkel E, Fanello S. Clinical 

qualitative evaluation of the diagnosis of acute otitis media in general practice. Int J 

Pediatr Otorhinolaryngol. Jan 2008;72(1):23-30. 

Design: Single cohort study (Before-After, 

Time series) 

Steinbach WJ, Sectish TC, Benjamin Jr DK, Chang KW, Messner AH. Pediatric residents' 

clinical diagnostic accuracy of otitis media. Pediatrics. Jun 2002;109(6):993-998. 

Design: Cross-sectional study 

Palmu A, Syrjanen R, Kilpi T, et al. Negative pressure tympanograms in children less than 

2 years of age--different bacterial findings in otitis media by tympanometric results. Int J 

Pediatr Otorhinolaryngol. Oct 19 2001;61(1):61-69. 

Published before 2002 

Johansen EC, Lildholdt T, Damsbo N, Eriksen EW. Tympanometry for diagnosis and 

treatment of otitis media in general practice. Fam Pract. Aug 2000;17(4):317-322. 

Published before 2002 

Palmu A, Puhakka H, Rahko T, Takala AK. Diagnostic value of tympanometry in infants 

in clinical practice. Int J Pediatr Otorhinolaryngol. Aug 20 1999;49(3):207-213. 

Published before 2002 

Jensen PM, Lous J. Criteria, performance and diagnostic problems in diagnosing acute 

otitis media. Fam Pract. Jun 1999;16(3):262-268. 

Published before 2002 

Kontiokari T, Koivunen P, Niemela M, Pokka T, Uhari M. Symptoms of acute otitis 

media. Pediatr Infect Dis J. Aug 1998;17(8):676-679. 

Design: Cross-sectional study 

Hemlin C, Hassler E, Hultcrantz M, Papatziamos G, Krakau I. Aspects of diagnosis of 

acute otitis media. Fam Pract. Apr 1998;15(2):133-137. 

Published before 2002 

McCormick DP, Lim-Melia E, Saeed K, Baldwin CD, Chonmaitree T. Otitis media: can 

clinical findings predict bacterial or viral etiology? Pediatr Infect Dis J. Mar 

2000;19(3):256-258. 

Published before 2002 

Rodriguez WJ, Schwartz RH. Streptococcus pneumoniae causes otitis media with higher 

fever and more redness of tympanic membranes than Haemophilus influenzae or 

Moraxella catarrhalis. Pediatr Infect Dis J. Oct 1999;18(10):942-944. 

Published before 2002 

Gonzalez-Vallejo C, Sorum PC, Stewart TR, Chessare JB, Mumpower JL. Physicians' 

diagnostic judgments and treatment decisions for acute otitis media in children. Med Decis 

Making. Apr-Jun 1998;18(2):149-162. 

Published before 2002 

D-1
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Pichichero ME, Casey JR, Hoberman A, Schwartz R. Pathogens Causing Recurrent and 

Difficult-to-Treat Acute Otitis Media, 2003-2006. Clin Pediatr (Phila). Jun 16 2008. 

Reject no kq or not valid pre/post vaccine 

datar data 

Benninger MS. Acute bacterial rhinosinusitis and otitis media: changes in pathogenicity 

following widespread use of pneumococcal conjugate vaccine. Otolaryngol Head Neck 

Surg. Mar 2008;138(3):274-278. 

Design 

Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal 

strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 

Oct 17 2007;298(15):1772-1778. 

Not valid pre/post vaccine study 

Pichichero ME, Casey JR. Evolving microbiology and molecular epidemiology of acute 

otitis media in the pneumococcal conjugate vaccine era. Pediatr Infect Dis J. Oct 

2007;26(10 Suppl):S12-16. 

Design 

Oosterhuis-Kafeja F, Beutels P, Van Damme P. Immunogenicity, efficacy, safety and 

effectiveness of pneumococcal conjugate vaccines (1998-2006). Vaccine. Mar 8 

2007;25(12):2194-2212. 

Design 

Brunton S. Current face of acute otitis media: microbiology and prevalence resulting from 

widespread use of heptavalent pneumococcal conjugate vaccine. Clin Ther. Jan 

2006;28(1):118-123. 

Design 

Arguedas A, Dagan R, Guevara S, et al. Middle ear fluid Streptococcus pneumoniae 

serotype distribution in Costa Rican children with otitis media. Pediatr Infect Dis J. Jul 

2005;24(7):631-634. 

Design 

Zissis NP, Syriopoulou V, Kafetzis D, et al. Serotype distribution and antimicrobial 

susceptibility of Streptococcus pneumoniae causing invasive infections and acute otitis 

media in children. Eur J Pediatr. Jul 2004;163(7):364-368. 

Design 

Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis 

GA. Pneumococcal vaccines for preventing otitis media. Cochrane Database Syst Rev. 

2004(1):CD001480. 

Design 

Kamiya H, Kato T. [Epidemiological survey of pneumococcus serotypes in pediatric 

patients with acute suppurative otitis media]. Kansenshogaku Zasshi. 2007;81(1):59-66. 

Not valid pre/post vaccine study 

D-2
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Straetemans M, Sanders EA, Veenhoven RH, Schilder AG, Damoiseaux RA, Zielhuis 

GA. Review of randomized controlled trials on pneumococcal vaccination for prevention 

of otitis media. Pediatr Infect Dis J. Jun 2003;22(6):515-524. 

Design 

McEllistrem MC, Adams J, Mason EO, Wald ER. Epidemiology of acute otitis media 

caused by Streptococcus pneumoniae before and after licensure of the 7-valent 

pneumococcal protein conjugate vaccine. J Infect Dis. Dec 1 2003;188(11):1679-1684. 

Reject at Duplicate data 

Hausdorff WP, Yothers G, Dagan R, et al. Multinational study of pneumococcal serotypes 

causing acute otitis media in children. Pediatr Infect Dis J. Nov 2002;21(11):1008-1016. 

Design 

Kilpi T, Herva E, Kaijalainen T, Syrjanen R, Takala AK. Bacteriology of acute otitis 

media in a cohort of Finnish children followed for the first two years of life. Pediatr Infect 

Dis J. Jul 2001;20(7):654-662. 

Not valid pre/post vaccine study 

Joloba ML, Windau A, Bajaksouzian S, Appelbaum PC, Hausdorff WP, Jacobs MR. 

Pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae isolates and the 

antimicrobial susceptibility of such isolates in children with otitis media. Clin Infect Dis. 

Nov 1 2001;33(9):1489-1494. 

Design 

Dagan R, Givon-Lavi N, Shkolnik L, Yagupsky P, Fraser D. Acute otitis media caused by 

antibiotic-resistant Streptococcus pneumoniae in southern Israel: implication for 

immunizing with conjugate vaccines. J Infect Dis. Apr 2000;181(4):1322-1329. 

Design 

Satran R, Leibovitz E, Raiz S, et al. Clinical/otologic score before and during treatment of 

acute otitis media. Acta Paediatr. Dec 2007;96(12):1814-1818. 

Design 

Bulut Y, Guven M, Otlu B, et al. Acute otitis media and respiratory viruses. Eur J Pediatr. 

Mar 2007;166(3):223-228. 

Design 

Williams JV, Tollefson SJ, Nair S, Chonmaitree T. Association of human 

metapneumovirus with acute otitis media. Int J Pediatr Otorhinolaryngol. Jul 

2006;70(7):1189-1193. 

Design 

Sakran W, Makary H, Colodner R, et al. Acute otitis media in infants less than three 

months of age: clinical presentation, etiology and concomitant diseases. Int J Pediatr 

Otorhinolaryngol. Apr 2006;70(4):613-617. 

Design 

D-3
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Yano H, Suetake M, Endo H, et al. Isolation of measles virus from middle ear fluid of 

infants with acute otitis media. J Infect. Nov 2005;51(4):e237-240. 

Design 

Sagai S, Suetake M, Yano H, et al. Relationship between respiratory syncytial virus 

infection and acute otitis media in children. Auris Nasus Larynx. Dec 2004;31(4):341-345. 

Design 

Huebner RE, Wasas AD, Hockman M, Klugman KP. Bacterial aetiology of non-resolving 

otitis media in South African children. J Laryngol Otol. Mar 2003;117(3):169-172. 

Design 

Dagan R, Leibovitz E, Cheletz G, Leiberman A, Porat N. Antibiotic treatment in acute 

Otitis Media promotes superinfection with resistant Streptococcus pneumoniae carried 

before initiation of treatment. J Infect Dis. Mar 15 2001;183(6):880-886. 

Design 

Yano H, Okitsu N, Hori T, et al. Detection of respiratory viruses in nasopharyngeal 

secretions and middle ear fluid from children with acute otitis media. Acta Otolaryngol. 

Jun 13 2008:1-6. 

Design 

Yano H, Okitsu N, Watanabe O, et al. Acute otitis media associated with cytomegalovirus 

infection in infants and children. Int J Pediatr Otorhinolaryngol. Sep 2007;71(9):1443-

1447. 

Design 

Ruohola A, Meurman O, Nikkari S, et al. Microbiology of acute otitis media in children 

with tympanostomy tubes: prevalences of bacteria and viruses. Clin Infect Dis. Dec 1 

2006;43(11):1417-1422. 

Not valid pre/post vaccine study 

Harimaya A, Takada R, Somekawa Y, Fujii N, Himi T. High frequency of Alloiococcus 

otitidis in the nasopharynx and in the middle ear cavity of otitis-prone children. Int J 

Pediatr Otorhinolaryngol. Jun 2006;70(6):1009-1014. 

Design 

Zielnik-Jurkiewicz B, Kolczynska M. [Bacterial flora in children with recurrent acute 

otitis media]. Pol Merkur Lekarski. Feb 2005;18(104):146-150. 

Design 

Segal N, Givon-Lavi N, Leibovitz E, Yagupsky P, Leiberman A, Dagan R. Acute otitis 

media caused by Streptococcus pyogenes in children. Clin Infect Dis. Jul 1 2005;41(1):35-

41. 

Design 

Hoberman A, Paradise JL, Greenberg DP, Wald ER, Kearney DH, Colborn DK. Penicillin 

susceptibility of pneumococcal isolates causing acute otitis media in children: seasonal 

variation. Pediatr Infect Dis J. Feb 2005;24(2):115-120. 

Not valid pre/post vaccine study 

D-4
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Hoberman A, Dagan RL, E. , Rosenblut A, et al. Large dosage amoxicillin/clavulanate, 

compared with azithromycin, for the treatment of bacterial acute otitis media in children. 

Pediatr Infect Dis J. Jun 2005;24(6):525-532. 

Design 

Shinogami M, Ishibashi T. Presence of human herpesviruses in young children with acute 

otitis media. Int J Pediatr Otorhinolaryngol. Feb 2004;68(2):205-210. 

Design 

Sakakura K, Chikamatsu K, Furukawa M, et al. Acute otitis media caused by drugresistant bacteria: correlation with antibiotic treatment. Acta Otolaryngol. Nov 

2004;124(9):1008-1014. 

Design 

Leskinen K, Hendolin P, Virolainen-Julkunen A, Ylikoski J, Jero J. Alloiococcus otitidis 

in acute otitis media. Int J Pediatr Otorhinolaryngol. Jan 2004;68(1):51-56. 

Not valid pre/post vaccine study 

Gene A, Garcia-Garcia JJ, Domingo A, Wienberg P, Palacin E. [Etiology of acute otitis 

media in a children's hospital and antibiotic sensitivity of the bacteria involved]. Enferm 

Infecc Microbiol Clin. Aug-Sep 2004;22(7):377-380. 

Design 

Monobe H, Ishibashi T, Nomura Y, Shinogami M, Yano J. Role of respiratory viruses in 

children with acute otitis media. Int J Pediatr Otorhinolaryngol. Jul 2003;67(7):801-806. 

Not valid pre/post vaccine study 

Leibovitz E, Greenberg D, Piglansky L, et al. Recurrent acute otitis media occurring 

within one month from completion of antibiotic therapy: relationship to the original 

pathogen. Pediatr Infect Dis J. Mar 2003;22(3):209-216. 

Not valid pre/post vaccine study 

Arguedas A, Dagan R, Soley C, et al. Microbiology of otitis media in Costa Rican 

children, 1999 through 2001. Pediatr Infect Dis J. Dec 2003;22(12):1063-1068. 

Not valid pre/post vaccine study 

Ako-Nai AK, Oluga FA, Onipede AO, Adejuyigbe EA, Amusa YB. The characterization 

of bacterial isolates from acute otitis media in Ile-Ife, southwestern Nigeria. J Trop 

Pediatr. Feb 2002;48(1):15-23. 

Design 

Wald ER, Mason Jr. EO, Bradley JS, Barson WJ, Kaplan SL. Acute otitis media caused 

by Streptococcus pneumoniae in children's hospitals between 1994 and 1997. Pediatr 

Infect Dis J. Jan 2001;20(1):34-39. 

Design 

Sih TM. Acute otitis media in Brazilian children: analysis of microbiology and 

antimicrobial susceptibility. Ann Otol Rhinol Laryngol. Jul 2001;110(7 Pt 1):662-666. 

Design 

D-5
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Rosenblut A, Santolaya ME, Gonzalez P, et al. Bacterial and viral etiology of acute otitis 

media in Chilean children. Pediatr Infect Dis J. May 2001;20(5):501-507. 

Not valid pre/post vaccine study 

Li WC, Chiu NC, Hsu CH, Lee KS, Hwang HK, Huang FY. Pathogens in the middle ear 

effusion of children with persistent otitis media: implications of drug resistance and 

complications. J Microbiol Immunol Infect. Sep 2001;34(3):190-194. 

Design 

Husson MO, Pierreti A, Quelquejay J, Vaneecloo FM, Courcol RJ, Vincent C. [Bacterial 

epidemiological study of acute otitis media in children observed at home in the Nord Pasde-Calais region]. Pathol Biol (Paris). Dec 2001;49(10):789-793. 

Design 

Gehanno P, Panajotopoulos A, Barry B, et al. Microbiology of otitis media in the Paris, 

France, area from 1987 to 1997. Pediatr Infect Dis J. Jun 2001;20(6):570-573. 

Design 

Block SL, Hedrick JA, Tyler RD, Smith RA, Harrison CJ. Microbiology of acute otitis 

media recently treated with aminopenicillins. Pediatr Infect Dis J. Nov 2001;20(11):1017-

1021. 

Design 

Commisso R, Romero-Orellano F, Montanaro PB, Romero-Moroni F, Romero-Diaz R. 

Acute otitis media: bacteriology and bacterial resistance in 205 pediatric patients. Int J 

Pediatr Otorhinolaryngol. Nov 30 2000;56(1):23-31. 

Design 

Brook I, Gober AE. Reliability of the microbiology of spontaneously draining acute otitis 

media in children. Pediatr Infect Dis J. Jun 2000;19(6):571-573. 

Design 

Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the 

middle ear during acute otitis media. N Engl J Med. Jan 28 1999;340(4):260-264. 

Design 

Haddad Jr. J, Saiman L, Chin NX, Della-Latta P. Penicillin-nonsusceptible pneumococcus 

in acute otitis media in New York City. Otolaryngol Head Neck Surg. Jul 1999;121(1):27-

30. 

Design 

Jacobs MR, Dagan R, Appelbaum PC, Burch DJ. Prevalence of antimicrobial-resistant 

pathogens in middle ear fluid: multinational study of 917 children with acute otitis media. 

Antimicrob Agents Chemother. Mar 1998;42(3):589-595. 

Design 

Gehanno P, N'Guyen L, Derriennic M, Pichon F, Goehrs JM, Berche P. Pathogens 

isolated during treatment failures in otitis. Pediatr Infect Dis J. Oct 1998;17(10):885-890. 

Not valid pre/post vaccine study 

D-6
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Brook I, Gober AE. Microbiologic characteristics of persistent otitis media. Arch 

Otolaryngol Head Neck Surg. Dec 1998;124(12):1350-1352. 

Design 

Arguedas A, Loaiza C, Perez A, et al. Microbiology of acute otitis media in Costa Rican 

children. Pediatr Infect Dis J. Aug 1998;17(8):680-689. 

Design 

Zielnik-Jurkiewicz B, Bielicka A. [Evaluation of antibiotic resistance in material isolated 

from the middle ear in children with acute otitis media not responding to standard 

antibiotic treatment]. Otolaryngol Pol. 2007;61(5):892-897. 

Design 

Zielnik-Jurkiewicz B, Kolczynska M. [Nasopharyngeal and middle ear flora in children 

with acute otitis media]. Otolaryngol Pol. 2005;59(4):537-542. 

Design 

Prymula R, Motlova J, Kriz P. Comparison of Streptococcus pneumoniae serotypes 

causing acute otitis media & invasive disease in young children in the Czech Republic. 

Indian J Med Res. May 2004;119 Suppl:168-170. 

Design 

Porat N, Barkai G, Jacobs MR, Trefler R, Dagan R. Four antibiotic-resistant 

Streptococcus pneumoniae clones unrelated to the pneumococcal conjugate vaccine 

serotypes, including 2 new serotypes, causing acute otitis media in southern Israel. J Infect 

Dis. Feb 1 2004;189(3):385-392. 

Design 

Nokso-Koivisto J, Raty R, Blomqvist S, et al. Presence of specific viruses in the middle 

ear fluids and respiratory secretions of young children with acute otitis media. J Med 

Virol. Feb 2004;72(2):241-248. 

Not valid pre/post vaccine study 

del Castillo F, Baquero-Artigao F, Garcia-Perea A. Influence of recent antibiotic therapy 

on antimicrobial resistance of Streptococcus pneumoniae in children with acute otitis 

media in Spain. Pediatr Infect Dis J. Feb 1998;17(2):94-97. 

Not valid pre/post vaccine study 

Shibata M. [Infant case of acute otitis media due to PISP not eradicated with double-dose 

of CDTR]. Jpn J Antibiot. May 2001;54 Suppl B:99. 

Design 

Hotomi M, Billal DS, Kamide Y, et al. Serotype distribution and penicillin resistance of 

Streptococcus pneumoniae isolates from middle ear fluids of pediatric patients with acute 

otitis media in Japan. J Clin Microbiol. Nov 2008;46(11):3808-3810. 

Design 

D-7
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Mahjoub-Messai F, Doit C, Mariani-Kurkdjian P, Francois M, Bingen E. [Epidemiology 

of acute otitis media caused by Streptococcus pneumoniae: emergence of serotype 19A]. 

Arch Pediatr. Nov 2008;15(11):1713-1716. 

Reject no kq or not valid pre/post vaccine 

datar data 

Lopez-Enriquez C, Blanco-Montero A, Espinosa-Monteros LE, Rodriguez R, De la Torre 

C, Gomez-Barreto D. Middle-ear fluid Streptococcus pneumoniae susceptibility and 

serotype and distribution in mexican children with acute otitis media. Pediatrics. Jan 

2008;121:S129-S129. 

Design 

Papavasileiou K, Papavasileiou H, Makri A, Varzakakos I, Nika E, Voyatzi A. Laboratory 

investigation of acute otitis media in children. International Journal of Antimicrobial 

Agents. Mar 2007;29:S431-S431. 

Design 

Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute 

otitis media six to eight years after introduction of pneumococcal conjugate vaccine. 

Pediatr Infect Dis J. Apr 2010;29(4):304-309. 

Reject at long for for no KQ 

Erramouspe J, Heyneman CA. treatment and prevention of otitis media. Ann 

Pharmacother. Dec 2000;34(12):1452-1468. 

Not RCT 

Foxlee R, Johansson A, Wejfalk J, Dawkins J, Dooley L, Del Mar C. Topical analgesia for 

acute otitis media. Cochrane Database Syst Rev. 2006;3:CD005657. 

Not RCT 

Degenhardt BF, Kuchera ML. Osteopathic evaluation and manipulative treatment in 

reducing the morbidity of otitis media: a pilot study. J Am Osteopath Assoc. Jun 

2006;106(6):327-334. 

Not RCT 

Valtonen H, Tuomilehto H, Qvarnberg Y, Nuutinen J. A 14-year prospective follow-up 

study of children treated early in life with tympanostomy tubes: Part 2: Hearing outcomes. 

Arch Otolaryngol Head Neck Surg. Apr 2005;131(4):299-303. 

Not RCT 

Nomura Y, Ishibashi T, Yano J, et al. Effect of myringotomy on prognosis in pediatric 

acute otitis media. Int J Pediatr Otorhinolaryngol. Jan 2005;69(1):61-64. 

Not RCT 

Marchetti F, Ronfani L, Nibali SC, Tamburlini G. Delayed prescription may reduce the 

use of antibiotics for acute otitis media: a prospective observational study in primary care. 

Arch Pediatr Adolesc Med. Jul 2005;159(7):679-684. 

Not RCT 

D-8
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Esposito S, Novelli A, Noviello S. [Treatment of acute otitis media in paediatrics: a metaanalysis]. Infez Med. Jun 2005;13(2):63-71. Not RCT 

Al-Shawwa BA, Wegner D. Trimethoprim-sulfamethoxazole plus topical antibiotics as 

therapy for acute otitis media with otorrhea caused by community-acquired methicillinresistant Staphylococcus aureus in children. Arch Otolaryngol Head Neck Surg. Sep 

2005;131(9):782-784. 

Not RCT 

Aggarwal M, Sinha R, Murali MV, Trihan P, Singhal PK. Comparative efficacy and 

safety evaluation of cefaclor vs amoxycillin + clavulanate in children with Acute Otitis 

Media (AOM). Indian J Pediatr. Mar 2005;72(3):233-238. 

Not RCT 

Wustrow TP. Alternative versus conventional treatment strategy in uncomplicated acute 

otitis media in children: a prospective, open, controlled parallel-group comparison. Int J 

Clin Pharmacol Ther. Feb 2004;42(2):110-119. 

Not RCT 

Gupta N, Bagga V, Parmar BJ, et al. Efficacy and tolerability assessment of cefprozil in 

children with acute otitis media. Indian J Pediatr. Apr 2004;71(4):319-324. 

Not RCT 

Siegel RM, Kiely M, Bien JP, et al. Treatment of otitis media with observation and a 

safety-net antibiotic prescription. Pediatrics. Sep 2003;112(3 Pt 1):527-531. 

Not RCT 

Piglansky L, Leibovitz E, Raiz S, et al. Bacteriologic and clinical efficacy of high dose 

amoxicillin for therapy of acute otitis media in children. Pediatr Infect Dis J. May 

2003;22(5):405-413. 

Not RCT 

Gryczynska D, Grzegorowski M, Hassman-Poznanska E, Niedzielska G. [Multicenter, 

open clinical investigation on using cefprozil in therapy of otitis media in children]. 

Otolaryngol Pol. 2003;57(1):99-101. 

Not RCT 

Arguedas A, Sher L, Lopez E, et al. Open label, multicenter study of gatifloxacin 

treatment of recurrent otitis media and acute otitis media treatment failure. Pediatr Infect 

Dis J. Nov 2003;22(11):949-956. 

Not RCT 

Richards M, Giannoni C. Quality-of-life outcomes after surgical intervention for otitis 

media. Arch Otolaryngol Head Neck Surg. Jul 2002;128(7):776-782. 

Not RCT 

D-9
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Mgbor NC, Umeh RE. A blind parallel comparative study of the efficacy and safety of 

rovamycin versus augmentin in the treatment of acute otitis media. West Afr J Med. AprJun 2002;21(2):117-120. 

Not RCT 

Leiberman A, Leibovitz E, Piglansky L, et al. Bacteriologic and clinical efficacy of 

trimethoprim-sulfamethoxazole for treatment of acute otitis media. Pediatr Infect Dis J. 

Mar 2001;20(3):260-264. 

Not RCT 

Frei H, Thurneysen A. Homeopathy in acute otitis media in children: treatment effect or 

spontaneous resolution? Br Homeopath J. Oct 2001;90(4):180-182. 

Not RCT 

Dagan R, Hoberman A, Johnson C, et al. Bacteriologic and clinical efficacy of high dose 

amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J. Sep 

2001;20(9):829-837. 

Not RCT 

Block SL, Hedrick JA, Kratzer J, Nemeth MA, Tack KJ. Five-day twice daily cefdinir 

therapy for acute otitis media: microbiologic and clinical efficacy. Pediatr Infect Dis J. 

Dec 2000;19(12 Suppl):S153-158. 

Not RCT 

Sox CM, Finkelstein JA, Yin R, Kleinman K, Lieu TA. Trends in otitis media treatment 

failure and relapse. Pediatrics. Apr 2008;121(4):674-679. 

Not RCT 

Heslop A, Ovesen T. Severe acute middle ear infections: microbiology and treatment. Int 

J Pediatr Otorhinolaryngol. Oct 2006;70(10):1811-1816. 

Not RCT 

Arguedas A, Dagan R, Pichichero M, et al. An open-label, double tympanocentesis study 

of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute 

otitis media. Pediatr Infect Dis J. Dec 2006;25(12):1102-1109. 

Not RCT 

Starostecka B. [Assessment of therapeutic effectiveness of Cefprozil in a short 5-day 

course of empirical antibiotic therapy in ambulatory patients with bacterial infections of 

the upper respiratory tract and otitis media]. Otolaryngol Pol. 2005;59(1):147-148. 

Not RCT 

Takenaka M, Morikawa Y, Nakagawa T, Takashima T, Haruta T, Tsuji T. [Causative 

organisms of acute otitis media and acute sinusitis in children and their susceptibility of 

oral beta-lactam antibiotics]. Jpn J Antibiot. Feb 1999;52(2):162-171. 

Not RCT 

Roger G, Carles P, Pangon B, et al. Management of acute otitis media caused by resistant 

pneumococci in infants. Pediatr Infect Dis J. Jul 1998;17(7):631-638. 

Not RCT 

D-10
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Quach C, Collet JP, LeLorier J. Effectiveness of amoxicillin, azithromycin, cefprozil and 

clarithromycin in the treatment of acute otitis media in children: a population-based study. 

Pharmacoepidemiol Drug Saf. Mar 2005;14(3):163-170. 

Not RCT 

Maruyama Y, Hoshida S, Furukawa M, Ito M. Effects of Japanese herbal medicine, 

Juzen-taiho-to, in otitis-prone children - a preliminary study. Acta Otolaryngol. Jun 12 

2008:1-5. 

Not RCT 

Coleman C, Moore M. Decongestants and antihistamines for acute otitis media in 

children. Cochrane Database Syst Rev. 2008(3):CD001727. 

Not RCT 

Sugita R, Yamanaka N, Kudo F, et al. [Efficacy and safety of potassium 

clavulanate/amoxicillin (CLAVAMOX) dry syrup in children with otitis media]. Jpn J 

Antibiot. Aug 2007;60(4):221-241. 

Not RCT 

Soley C, Arguedas A, Guevara S, et al. An open-label, double tympanocentesis, singlecenter study of trimethoprim sulfametoxasole in children with acute otitis media. Pediatr 

Infect Dis J. Mar 2007;26(3):273-274. 

Not RCT 

Chow Y, Wabnitz DA, Ling J. Quality of life outcomes after ventilating tube insertion for 

otitis media in an Australian population. Int J Pediatr Otorhinolaryngol. Oct 

2007;71(10):1543-1547. 

Not RCT 

Prim Espada MP, Perez Mora R, de Diego Sastre JI. [Comparative analysis of the 

therapeutic costs to control the recurrent acute otitis media]. An Otorrinolaringol Ibero 

Am. 2006;33(5):505-512. 

Not RCT 

Wustrow TP. [Naturopathic therapy for acute otitis media. An alternative to the primary 

use of antibiotics]. Hno. Aug 2005;53(8):728-734. 

Not RCT 

Valtonen H, Tuomilehto H, Qvarnberg Y, Nuutinen J. A 14-year prospective follow-up 

study of children treated early in life with tympanostomy tubes: Part 1: Clinical outcomes. 

Arch Otolaryngol Head Neck Surg. Apr 2005;131(4):293-298. 

Not RCT 

Pichichero ME, Arguedas A, Dagan R, et al. Safety and efficacy of gatifloxacin therapy 

for children with recurrent acute otitis media (AOM) and/or AOM treatment failure. Clin 

Infect Dis. Aug 15 2005;41(4):470-478. 

Not RCT 

D-11
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Mui S, Rasgon BM, Hilsinger Jr. RL, Lewis B, Lactao G. Tympanostomy tubes for otitis 

media: quality-of-life improvement for children and parents. Ear Nose Throat J. Jul 

2005;84(7):418, 420-412, 424. 

Not RCT 

Garashchenko TI, Denisova OA, Kotov RV. [Initial antibiotic therapy in acute otitis 

media and acute sinusitis in children]. Vestn Otorinolaringol. 2005(3):62-63. 

Not RCT 

Cotter CS, Kosko JR. Effectiveness of laser-assisted myringotomy for otitis media in 

children. Laryngoscope. Mar 2004;114(3):486-489. 

Not RCT 

Dunne MW, Khurana C, Mohs AA, et al. Efficacy of single-dose azithromycin in 

treatment of acute otitis media in children after a baseline tympanocentesis. Antimicrob 

Agents Chemother. Aug 2003;47(8):2663-2665. 

Not RCT 

Dasgupta KS, Deshpande AS, Vedi JN, Patel S. Evaluation of efficacy of nizer versus 

nimesulide tablets in otitis media. J Indian Med Assoc. Oct 2002;100(10):619. 

Not RCT 

Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Francis AB, Green JL. A 

prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis 

media. Otolaryngol Head Neck Surg. Apr 2001;124(4):381-387. 

Not RCT 

Uno Y. [Retrospective studies of penicillin-resistant pneumococcal acute otitis media in 

infants and children--the treatment of tympanostomy tube insertion]. Kansenshogaku 

Zasshi. Sep 2000;74(9):703-708. 

Not RCT 

Reilly JS, Deutsch ES, Cook S. Laser-assisted myringotomy for otitis media: a feasibility 

study with short-term followup. Ear Nose Throat J. Aug 2000;79(8):650-652, 654-657. 

Not RCT 

Glasziou PP, Hayem M, Del Mar CB. Antibiotics for acute otitis media in children. 

Cochrane Database Syst Rev. 2000(2):CD000219. 

Not RCT 

Valtonen H, Qvarnberg Y, Nuutinen J. Tympanostomy in young children with recurrent 

otitis media. A long-term follow-up study. J Laryngol Otol. Mar 1999;113(3):207-211. 

Not RCT 

Thompson D, Oster G, McGarry LJ, Klein JO. Management of otitis media among 

children in a large health insurance plan. Pediatr Infect Dis J. Mar 1999;18(3):239-244. 

Not RCT 

Sugita R, Harada S, Deguchi K, et al. [A clinicobacteriologic study on clavulanic 

acid/amoxicillin in pediatric acute otitis media]. Jpn J Antibiot. Oct 1999;52(10):595-612. 

Not RCT 

D-12
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Hueston WJ, Ornstein S, Jenkins RG, Pan Q, Wulfman JS. Treatment of recurrent otitis 

media after a previous treatment failure. Which antibiotics work best? J Fam Pract. Jan 

1999;48(1):43-46. 

Not RCT 

Gehanno P, Nguyen L, Barry B, et al. Eradication by ceftriaxone of Streptococcus 

pneumoniae isolates with increased resistance to penicillin in cases of acute otitis media. 

Antimicrob Agents Chemother. Jan 1999;43(1):16-20. 

Not RCT 

Leibovitz E, Piglansky L, Raiz S, et al. Bacteriologic efficacy of a three-day intramuscular 

ceftriaxone regimen in nonresponsive acute otitis media. Pediatr Infect Dis J. Dec 

1998;17(12):1126-1131. 

Not RCT 

Franklin JH, Marck PA. Outcome analysis of children receiving tympanostomy tubes. J 

Otolaryngol. Oct 1998;27(5):293-297. 

Not RCT 

Kim CW, Jin JW, Rho YS. Tuberculous otitis media developing as a complication of 

tympanostomy tube insertion. Eur Arch Otorhinolaryngol. Mar 2007;264(3):227-230. 

Not RCT 

Steppberger K, Adams I, Deutscher J, Muller H, Kiess W. Meningitis in a girl with 

recurrent otitis media caused by Streptococcus pyogenes--otitis media has to be treated 

appropriately. Infection. Oct 2001;29(5):286-288. 

Not RCT 

Garcia-Lopez M, Martinez-Blanco M, Martinez-Mir I, Palop V. Amoxycillin-clavulanic 

acid-related tooth discoloration in children. Pediatrics. Sep 2001;108(3):819. 

Not RCT 

Spandow O, Gothefors L, Fagerlund M, Kristensen B, Holm S. Lateral sinus thrombosis 

after untreated otitis media. A clinical problem--again? Eur Arch Otorhinolaryngol. 

2000;257(1):1-5. 

Not RCT 

Little JP, Tunkel DE, Marsh BR. Foreign body aspiration: an unusual complication of 

antibiotic therapy. Arch Pediatr Adolesc Med. Mar 2000;154(3):313-314. 

Not RCT 

Vega C, Quinby PM, Aspy CB. Hepato-biliary abnormalities secondary to ceftriaxone 

use: a case report. J Okla State Med Assoc. Aug 1999;92(8):432-434. 

Not RCT 

Grouhi M, Hummel D, Roifman CM. Anaphylactic reaction to oral cefaclor in a child. 

Pediatrics. Apr 1999;103(4):e50. 

Not RCT 

Benjamin S, Mueller BA. Erythema multiforme secondary to amoxicillin/clavulanic acid 

exposure. Ann Pharmacother. Jan 1999;33(1):109-110. 

Not RCT 

D-13
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Beghetti M, Wilson GJ, Bohn D, Benson L. Hypersensitivity myocarditis caused by an 

allergic reaction to cefaclor. J Pediatr. Jan 1998;132(1):172-173. 

Not RCT 

Kawalec P, Cel M, Glogowski C. Cost-effectiveness of augmentin esovs azithromycin 

forthetreatment of paediatric acute otitis media (AOM) in Poland. Value in Health. NovDec 2007;10(6):A440-A440. 

Not RCT 

Leach AJ, Morris PS. Antibiotics for the prevention of acute and chronic suppurative otitis 

media in children. Cochrane Database Syst Rev. 2006(4):CD004401. 

Not RCT 

McDonald S, Langton Hewer CD, Nunez DA. Grommets (ventilation tubes) for recurrent 

acute otitis media in children. Cochrane Database Syst Rev. 2008(4):CD004741. 

Not RCT 

Williams RL, Chalmers TC, Stange KC, Chalmers FT, Bowlin SJ. Use of antibiotics in 

preventing recurrent acute otitis media and in treating otitis media with effusion. A metaanalytic attempt to resolve the brouhaha. JAMA. Sep 15 1993;270(11):1344-1351. 

Not RCT 

Thanaviratananich S, Laopaiboon M, Vatanasapt P. Once or twice daily versus three times 

daily amoxicillin with or without clavulanate for the treatment of acute otitis media. 

Cochrane Database Syst Rev. 2008(4):CD004975. 

Not RCT 

Wall GM, Stroman DW, Roland PS, Dohar J. Ciprofloxacin 0.3%/dexamethasone 0.1% 

sterile otic suspension for the topical treatment of ear infections: a review of the literature. 

Pediatr Infect Dis J. Feb 2009;28(2):141-144. 

Not RCT 

Bonati M, Marchetti F, Pistotti V, et al. Metaanalysis of antimicrobial prophylaxis for 

recurrent acute otitis-media. Clinical Trials and Meta-Analysis. 1992;28(1):39-50. 

Not RCT 

Rovers MM, Glasziou P, Appelman CL, et al. Antibiotics for acute otitis media: a metaanalysis with individual patient data. Lancet. Oct 21 2006;368(9545):1429-1435. Not RCT 

Spurling GK, Del Mar CB, Dooley L, Foxlee R. Delayed antibiotics for respiratory 

infections. Cochrane Database Syst Rev. 2007(3):CD004417. 

Not RCT 

Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, et al. Short course antibiotics for acute 

otitis media. Cochrane Database Syst Rev. 2000(2):CD001095. 

Not RCT 

Takata GS, Chan LS, Shekelle PG, Morton SC, Mason W, Marcy SM. Evidence 

assessment of management of acute otitis media: I. The role of antibiotics in treatment of 

uncomplicated acute otitis media. Pediatrics. Aug 2001;108(2):239-247. 

}Not RCT 

D-14
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Bezakova N, Damoiseaux RA, Hoes AW, Schilder AG, Rovers MM. Recurrence up to 3.5 

years after antibiotic treatment of acute otitis media in very young Dutch children: survey 

of trial participants. BMJ. 2009;338:b2525. 

Rejected, does not answer KQ 

Abba K, Garner P. Zinc supplements for preventing otitis media [Protocol]. Cochrane 

Database of Systematic Reviews(3). 

Not RCT 

Azarpazhooh A, Lawrence HP. Xylitol for preventing acute otitis media in children up to 

12 years of age [Protocol]. Cochrane Database of Systematic Reviews(3). 

Not RCT 

Kay ES, Ng K. "Influenza vaccine for preventing acute otitis media in infants and children 

[Protocol]." Cochrane Database of Systematic Reviews(3). 

Not RCT 

Koopman L, Hoes AW, Glasziou PP, et al. Antibiotic therapy to prevent the development 

of asymptomatic middle ear effusion in children with acute otitis media: a meta-analysis 

of individual patient data. Arch Otolaryngol Head Neck Surg. Feb 2008;134(2):128-132. 

Not RCT 

Rahlfs VW. Brodimoprim in upper respiratory tract infections: two meta-analyses of 

randomised, controlled clinical trials in acute sinusitis and otitis media (Structured 

abstract). Clin Drug Invest. 1996;11(2):65-. 

Not RCT 

Sanders S, Glasziou P. Antibiotics for acute otitis media in children [Systematic 

Review]." Cochrane Database of Systematic Reviews(3). 

Not RCT 

Vouloumanou EK, Karageorgopoulos DE, Kazantzi MS, Kapaskelis AM, Falagas ME. 

Antibiotics versus placebo or watchful waiting for acute otitis media: a meta-analysis of 

randomized controlled trials. J Antimicrob Chemother. Jul 2009;64(1):16-24. 

Not RCT 

Gunasekera H, Morris PS, Daniels J, Couzos S, Craig JC. Management of children with 

otitis media: a survey of Australian Aboriginal Medical Service practitioners. J Paediatr 

Child Health. Jul-Aug 2009;45(7-8):457-463. 

Not RCT 

Abba K, Gulani A, Sachdev HS. Zinc supplements for preventing otitis media. Cochrane 

Database Syst Rev. 2010;2:CD006639. 

Not RCT 

Courter JD, Baker WL, Nowak KS, et al. Increased clinical failures when treating acute 

otitis media with macrolides: a meta-analysis. Ann Pharmacother. Mar 2010;44(3):471-

478. 

Not RCT 

D-15
 
Appendix D. List of Excluded studies
 

References Reason for Exclusion 

Gulani A, Sachdev HP, Qazi SA. Efficacy of short course (<4 days) of antibiotics for 

treatment of acute otitis media in children: a systematic review of randomized controlled 

trials. Indian Pediatr. Jan 7 2010;47(1):74-87. 

Not RCT 

D-16
 
Appendix E. List of Peer Reviewers
 

Name Contact Info 

Carmen C. Brewer National Institute on Deafness and Other 

Communication Disorders 

9000 Rockville Pike 

Building 10/5C306 

Bethesda, MD 20892 

Phone: 301-496-5294 

Fax: 301-402-0409 

brewerc@nidcd.nih.gov 

Anne Marie Tharpe Vanderbilt University 

1215 21st Ave South 

6301 MCE South Tower 

Nashville, TN 37232-8718 

Phone: 615-936-5001 

Fax: 615-936-5014 

anne.m.tharpe@vanderbilt.edu 

Jonathan Finkelstein, MD, MPH Harvard Medical School 

133 Brookline Ave., 6th Floor, 

Boston, MA 02215 

Phone: 617-509-9898 

Fax: 617-5099845 

Jonathan_finkelstein@harvardpilgrim.org 

Kathleen Daly University of Minnesota 

Dept of Otolaryngology 

MMC 396 

420 Delaware St SE 

Minneapolis, MN 55455 

Phone: 612-625-3259 

Fax: 612-625-2101 

dalyx002@umn.edu 

Allan Stuart Lieberthal MD, FAAP Kaiser-Permanente 

13652 Cantara St S1-101B 

Panorama City, CA 91402-5423 

Phone: 818-375-2412 

Fax: 818-375-4073 

allan.s.lieberthal@kp.org 

Aaron Carroll Indiana University-Purdue University 

Indianapolis 

410 W. 10thSt 

HITS 1020 

E-1
 
Appendix E. List of Peer Reviewers
 

Indianapolis, IN 46202 

Phone: 317-278-0552 

Fax: 317-278-0456 

aaecarro@iupui.edu 

Pauline Thomas New Jersey Medical School 

MSB F 506, 

185 South Orange Ave, 

Newark, NJ 

Phone: 973 972 9384 

Fax: 973 972 7625 

thomasp1@umdnj.edu 

Theodore G. Ganiats MD University of California San Diego 

9500 Gilman Drive-0628 

La Jolla, CA 92093-0628 

Phone: 858-534-6085 

Fax: 858-534-7517 

tganiats@ucsd.edu 

Richard Rosenfeld SUNY Health Science Center at Brooklyn 

134 Atlantic Avenue 

Brooklyn, NY 11201 

Maroeska M. Rovers UMC Utrecht, Julius Center for 

Care, PO Box 8550 

3508 GA Utrecht 

The Netherlands 

Phone: +31 88 7559399 

Fax: +31 88 7568099 

m.rovers@umcutrecht.nl 

Katherine Finn Davis Center for Pediatric Nursing Research & 

Evidence Based Practice, Children’s 

Hospital of Philadelphia 3535 Market St, 

Ste 1317 

Philadelphia, PA 19104 

Phone: 267-426-6966 

Fax: 267-426-0875 

kfinndavis@yahoo.com 

Lawrence C. Kleinman Mt. Sinai Medical Center 

E-2
 
Appendix E. List of Peer Reviewers
 

One Gustave L Levy Place 

Box 1077 

New York, NY 10029 

Phone: 212-659-9556 

Fax: 212-423-2998 

Lawrence.kleinman@mountsinai.org 

Tasnee Chonmaitree, M.D. Department of Pediatrics, Division of 

Infectious Doseases, University of Texas 

Medical Branch, 301 University Blvd., 

Galveston, TX 77555-0371 

Phone: (409) 772-2798 

Fax: (409) 747-1753 

Tchonmai@utmb.edu 

Donald T. Miller MD MPH FAAP 4610 Trieste Drive 

Carlsbad, CA 92010 

Phone: 760-207-0773 

Fax: 760-757-3004 

dtmillermd@gmail.com 

E-3
 
Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

Table F-1. Technical Expert Panel Composition 

Name, Affiliation, Contact information/ Nominating Organization 

Margaretha Casselbrant, MD, PhD 

Chair, Dept of Pediatric Otolaryngology 

University of Pittsburgh 

Childrens Hospital of Pittsburgh 

Dept of Pediatric Otolaryngology 

3705 5th Ave Ste 1650 

Pittsburgh, PA 15213-2524 

Email: cassml@chp.edu 

Society for Ear Nose Throat Advances in Children 

Tasnee Chonmaitree, M.D. University of Texas Medical Branch 

Professor, Pediatrics and Pathology 301 University Blvd. 

Director, Pediatric Infectious Disease Fellowship Galveston, TX 77555-0371 

Program Phone: (409) 772-4876 

Associate Director, UTMB Clinical Research Fax: (409) 747-1753 

Education Office E-mail: Tchonmai@utmb.edu 

University of Texas Medical Branch Pediatric Infectious Disease Society 

Katherine Finn Davis, PhD 

Coordinator for Nursing Research and Practice 

Center for Pediatric Nursing Research & Evidence 

Based Practice, Children’s Hospital of Philadelphia 

E-mail: kfinndavis@yahoo.com 

cc correspondance to: 

pnp.representative@napnap.org 

National Association of Pediatric Nurse 

Practitioners, 20 Brace Road, Suite 200, Cherry 

Hill, NJ 08034-1600 

National Association of Pediatric Nurse Associates 

and Practitioners 

Ted Ganiats, MD 

Professor and Interim Chair, 

Dept. of Family and Preventive Medicine 

University of California at San Diego 

University of California, San Diego 

Dept. of Family & Preventive Medicine 

9500 Gilman Drive, 0628 

La Jolla, CA 92093-0628 

Tel: (858) 534-6058 

Fax: (858) 534-7517 

email: tganiats@ucsd.edu 

American Academy of Family Physicians 

Mary Goessler, MD, MPM 

Medical Director of Quality 

Highmark, Inc. 

120 Fifth Avenue Ste P4501 

Pittsburgh, PA 15222-3099 

Phone: (412) 544 - 2629 

Fax: (412) 544 - 2695 

E-mail: mary.goessler@highmark.com 

America’s Health Insurance Programs 

Diane Sabo, PhD 

Director of Audiology and Communication 

Disorders, Department of Audiology and 

Communication Disorders, Children's Hospital of 

Pittsburgh 

Children's Hospital of Pittsburgh, Department of 

Audiology and 

Communication Disorders, 3705 Fifth Avenue, 

Pittsburgh PA 15213 

Phone: (412) 692-5576 

Fax: 412 692-7717 

E-mail: DLS1@pitt.edu 

American Speech-Language Hearing Association 

F-1
 
Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

Alison Grimes, AudD UCLA 

Head, Audiology Dept. 200 Medical Plaza, #540 

UCLA Medical Center Los Angeles, CA 90095 

E-mail: agrimes@mednet.ucla.edu 

American Academy of Audiology 

Lawrence Kleinman, MD, MPH Mount Sinai School of Medicine One Gustave L. 

Vice Chair for Research and Education, Levy Place New York, NY 10029 

Department of Health Policy 212 659-9556 

Mount Sinai School of Medicine fax 212 423-2998 

E-mail: lawrence.kleinman@mountsinai.org 

Academic Pediatric Association 

Linda Landry 

Council Member 

Family Voices of California 

323-255-0354 (office) 

323-717-7411 (cell) 

E-mail: lindajoyla@aol.com 

Family Voices LA 

Allan Lieberthal, MD 13652 Cantara Street. 

Clinical Professor of Pediatrics, USC and Panorama City, CA 91402. 

Chief of Immunization Team, Kaiser Permanente (818) 375-2412 Fax: 818/375-3870 

Hospital, Panorama City CA E-mail: Allan.S.Lieberthal@kp.org 

American Academy of Pediatrics 

Richard Rosenfeld, MD, MPH 134 Atlantic Avenue 

Professor of Clinical Otolaryngology, Brooklyn, NY 11201 

SUNY Health Science Center at Brooklyn, E-mail: richrosenfeld@msn.com 

Brooklyn, NY 

American Academy of Otolaryngology-Head and 

Neck Surgery 

Pauline Thomas, MD 

Associate Professor 

New Jersey Medical School 

New Jersey Medical School 

MSB F 506 

185 South Orange Avenue 

Newark, NJ 07103 

Phone: 973 972 9384 (office) 

Cell: 908 403 1615 

Fax: 973 972 7625 

E-mail: pthomas22@aol.com 

American Academy of Pediatrics 

AOM TEP Meeting 9/26/08 

Attendance: Tasnee Chonmaitree, Katherine Finn Davis, Ted Ganiats, Mary Goessler, Lawrence 

Kleinman, Linda Landry, Allan Lieberthal, Richard Rosenfeld, Pauline Thomas, Caryn 

Davidson, Paul Shekelle, Glen Takata, Linda Chen, Tumaini Coker, Mary Ann Limbos, Sydne 

Newberry, Tina Murray) 

Paul Shekelle introduced the role of the EPC and its responsibility for THE 2001 REPORT: 

The EPC team includes some clinicians, methodologists. However, the TEP consists of subject 

matter experts, consumers (and other end users), and representatives of the sponsoring 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

organization/partner (AAP). The TEP’s role today is to help clarify key questions and enunciate 

the sponsoring organization’s and others’ needs. 

Tina Murray described the role of the Task Order Officer (TOO): 

The TOO’s role is to try to maintain timeliness, address administrative issues. The TOO tries to 

make sure the TEP is broadly representative, including end-users. AHRQ looks to TEP to help 

ensure report is useful to them. 

Allan Lieberthal (representing AAP) 

This TEP includes many veterans of the original EPC AOM report in 2001. 

Following publication of that report, it took over four years to develop and approve new 

guidelines (2004).There were many controversies, including the right definition, the guideline 

regarding observation, first line antibiotics (AB), and dose. For the 2001 report, they were just 

beginning to get data on Prevnar. Now there are many more data on its efficacy as well as the 

role of viruses in OM. An important and final point to make is that AAP requested that AHRQ 

add recurrent AOM to the scope. This was a gap in the 2001 report. 

Discussion of the Definition of AOM 

The definition of AOM was something the research team wrestled with in the 2001 report. 

The definitions proposed by the research team were distributed for the TEP’s consideration (see 

attached file or insert as footnote). The team also wanted to know how the TEP would 

operationalize the definitions and what to do about studies that provide little or no information 

on how they defined AOM for enrollment. 

Rosenfeld said that part of accepting a definition is whether it is more inclusive or exclusive. . 

For our purposes, we want to err on the side of a few false positives rather than avoiding all false 

negatives. Thus a tight definition is better. 

Three criteria should be considered individually: Time course, rapidity of onset, middle ear 

effusion (MEE). 

But having said that, we can’t restrict the literature search to those that meet all three criteria. We 

can evaluate a study’s quality based on how closely it adheres to our definition, but don’t 

exclude studies on this basis. Paul rephrased: “So basically include any studies but conduct a 

sensitivity analysis that considers the number of criteria adhered to.” 

Rosenfeld pointed out that a big problem is documenting MEE. How well is it documented? This 

is an overwhelming cause of false positives. 

Lieberthal pointed out that a minimum criterion should be that authors define what THEY 

considered AOM 

Shekelle asked if we want to be stricter regarding diagnosis questions, especially given that there 

is a gold standard diagnostic method, but be more inclusive and relaxed regarding treatment 

questions. 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

Kleinman responded that if our aim is to guide practice, we need to consider the implications for 

practice, especially in the inner city. Considering only AOM, in isolation, is fine, but if we are 

guiding practice, we need to consider the spectrum of otitis, and once we propose a definition, 

we need to consider the implications for other ME disease. 

Ganiats said that an issue that came up last time (and was the subject of a minority report) was 

that studies that show the disease remits spontaneously did not have a good definition of AOM. 

The implication is that these spontaneous remissions didn’t really have the disease in the first 

place. He proposed the possibility of dividing evidence by studies that fulfill two criteria vs.. 

studies that fulfill all 3. 

Thus, basically the TEP agreed with the following approach: “...accept any study purporting 

to study AOM or ROM and compare the trial definition to our study definition, report that 

analysis, and attempt to analyze results by adherence to our study definition, if sufficient data 

are available” and sensitivity analysis based on definition quality. 

KQ1. Validity of clinical symptoms... 

What is the validity of clinical symptoms and otoscopic findings such as a bulging tympanic 

membrane to diagnose AOM? Do these clinical findings aid physicians in distinguishing AOM 

from OME? 

a. What should be the gold standard? E.g. tympanocentesis for middle ear effusion (MEE), 

microbiologic agent isolation, rectal temperature as opposed to oral or axillary temperature, etc. 

Rosenfeld stated there is no gold standard. He also stated that if a child had a 

tympanocentesis that showed an infectious agent but had no clinical symptoms, he would 

not call that AOM. Consensus by a panel of MDs would be the only gold standard. 

Someone suggested developing a composite gold standard (a set of criteria). 

Again, tympanometry (as well as acoustic reflectometry) are useful in research but not the 

doctor’s office. Tympanometers used by general clinicians are not the same quality as those used 

in the research setting. Chonmaitree pointed out that the studies reviewed will have to have a 

definition of AOM and they may use tympanometry. Another issue is that instruments don’t 

always work well in very young children, the most important group. 

It was felt that it should be noted whether a study included tympanometry. The team noted 

they have already been noting this. 

b. Which clinical symptoms and otoscopic findings are of particular interest that we should make 

every effort to report on, even if data are not available or already known to refute their use? 

The discussion did not reach this level of detail. 

c. Should any other diagnostic tests other than otoscopy be included in the review? E.g. 

tympanometry, acoustic reflectometry, oto-acoustic emissions, et cetera 

The TEP agreed that clinical symptoms and otoscopic findings should be the focus. The 

focus should be on diagnostic criteria that must include MEE but differentiate AOM 

from OME. The TEP agreed that the review could include tympanometry for diagnosis 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

of MEE. The TEP did not feel acoustic reflectometry was worth evaluating; in
 

particular published studies were lacking.
 

d. In a prior systematic review, the TEP for the otitis media with effusion (OME) panel decided 

that diagnosing MEE in a child with OME was different from diagnosing MEE in a child with 

AOM, so we did not use AOM MEE studies for the OME review of MEE diagnosis. Should the 

same logic apply to this AOM review if MEE is decided by the TEP to be an integral component 

of diagnosing AOM? 

The TEP did not discuss this issue. 

e. Other specifications? 

None were discussed. 

KQ2. What organisms (bacterial and viral) are associated with otitis media since the 

introduction of PNC7? 

What are the patterns of antimicrobial resistance since the introduction of PNC7? 

New infections 

Recurrent infections 

a.	 Should KQ2 include the effectiveness of the vaccine for preventing AOM? 

In general, the TEP felt we should address vaccine effectiveness only if time is available. 

b.	 Are “New infections” initial episodes of AOM? 

No, they are generally regarded as episodes of AOM that occur after some elapsed 

period of time since the previous episode. The question is whether the bacteriology of 

the “new” infection is distinct from the previous infection. 

c.	 Are “Recurrent infections” episodes of ROM? If so, which episode? 

The TEP seemed to want to re-phrase “New infections” and “Recurrent infections” to 

something related to the “antibiotic milieu,” i.e., whether or not the child had ever been 

exposed to an antibiotic, whether for AOM or any other condition. Some TEP members also 

expressed the desire to retain the concept of recurrent infection with the addition of persistent 

AOM and AOM relapse. See KQ4 for further discussion. 

d.	 If possible, we will analyze by antibiotic use pattern in the trial region. Are there any other 

factors apart from PNC7 and antibiotic use patterns that should be included in the analysis? 

This issue was not discussed. 

e.	 Other specifications? 

See “c”. 

KQ3. What is the comparative effectiveness of different treatment options (defined 

below) for treating AOM in average risk children ages <2 years, ages 2 years to <5years 

and ages ≥ 5 years? 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

Treatment options include but not limited to:
 

Amoxicillin (including high dose versus low dose)
 

Amox-clav (including high dose versus low dose)
 

Cephalosporins (e.g. ceftriaxone, cefdinir, cefixime)
 

“Wait and see approach” 

Placebo
 

Duration of treatment
 

Outcomes to consider but not limited to: 

Parent satisfaction 

Duration of symptoms/illness 

Treatment failure, mastoiditis, bacteremia, clinical cure, bacteriologic cure 

Disease recurrence 

a.	 Any other antibiotics should be included that we should make every effort to report on, even 

if data are not available or already known to refute their use?? 

The TEP was amenable to adding any FDA-approved antibiotic (especially erythromycin). 

b.	 What is the definition of the “Wait and see approach”? e.g. AAP/AAFP Guidelines, Dutch 

guidelines, et cetera? 

Use the AAP/AAFP AOM guideline for observational treatment. Rosenfeld felt most of the 

new AOM studies would be on this issue: the “delayed treatment” approach, which is 

distinct from the “wait and see” approach. The delayed treatment approach is in contrast to 

immediate treatment. 

c.	 Should analgesics be separated as an intervention? Oral versus topical? 

Initially there seemed to be a divergence of opinion, but the TEP seemed to be interested in 

studying analgesics. 

d.	 Are we interested in dual treatment? E.g. antibiotic plus analgesic? 

This issue was not addressed. 

e.	 What specific durations of treatment are of interest that we should make every effort to report 

on, even if data are not available or already known to refute their use? 

Rosenfeld believes no new studies of significance on short-duration therapy have been 

published since the Kozyrskyj (1998) publication of their systematic review. He treats 

children <2 years old for 7-10 days and children >5 years old for 3-5 days. He stated 

that for 2-5 years of age, some controversy exists. 

f.	 Any other outcomes that we should make every effort to report on, even if data are not 

available? 

Lieberthal stated he was interested in bacteriologic as well as clinical outcomes. Ganiats 

stated that clinical outcomes were more important, especially for guideline development. 

Kleinman brought up the need for quality of life and functional status outcomes. 

Cost outcomes were also discussed, including days of school or daycare missed and days of 

parental work missed. Landry noted that parents need to pay for daycare regardless of 

whether child attends, which makes cost an even more compelling issue. 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

g.	 What is the definition of disease recurrence? E.g. is this in relation to the otitis-prone child? 

The TEP agreed that recurrence is defined as AOM relapse within 30 days. Kleinman 

recommended that we gather specific time to relapse information, as most relapse may 

actually occur much earlier than 30 days (might be worth assessing whether it should be 15 

days). 

KQ4. What is the comparative effectiveness of different management options for recurrent 

otitis media? 

Management options include but not limited to: 

Amox-clav 

Cephalosporins (e.g. ceftriaxone, cefuroxime) 

Quinolones 

Antibiotic prophylaxis 

Outcomes to consider but not limited to: 

Parent satisfaction 

Duration of symptoms/illness 

Treatment failure, mastoiditis, bacteremia/Cure rates 

a.	 Same questions as for KQ3. 

In essence “yes;” however, the major issue is discussed in “c”. 

b. Are there any procedural interventions we should include that we should make every effort to 

report on, even if data are not available or already known to refute their use? 

Tympanostomy tubes were mentioned. Rosenfeld stated that antibiotic prophylaxis is 

already known not to be effective, though Kleinman stated the opposite later in the 

discussion. 

c. KQ4 currently addresses ROM? What definitions of chronic suppurative and/or persistent OM 

should be used to differentiate from ROM? 

Lieberthal stated that the AAP intended KQ4 to address ROM, i.e. the otitis-prone 

child. However, many of the TEP members voiced uncertainty over the present 

usefulness of the terms ROM and otitis prone The TEP seemed to agree that KQ4 

should address ROM but also acute recurrence of AOM within 30-60 days, i.e. persistent 

AOM or AOM relapse (Rosenfeld and Chonmaitree mentioned that Dagan and 

Arguedas are doing interesting studies on persistent AOM in South America). 

Coker noted that the definition and distinction (between recurrent, persistent/relapse, 

and otitis prone) has not been clear among the studies they have reviewed so far. 

Shekelle recommended determining how big a problem it would pose in analyzing the 

literature and then going back to the TEP. (Kleinman noted that OME and AOM can 

present in the same kids, that management may differ when kids show up acutely. He 

said this is something they need to consider). 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

KQ5: What is the evidence that the comparative effectiveness of different treatment options in 

KQ #3 differs in subpopulations of patients? 

Subpopulations to include (but not limited to): 

Bilateral disease 

Comorbidities (e.g. asthma –will need to define further) 

Age groups (e.g., <1 month, 1-<2 months, 2-<6 mos, 6mos-<2 years, 2-5 years) 

Race/Ethnicity 

Day care attendance 

a.	 What are other comorbidities in addition to asthma? Will any subpopulations be excluded 

such as those with craniofacial anomalies, immunodeficiencies, genetic disorders, et cetera? 

The TEP felt that most studies would exclude these comorbidities but did not state if we 

should a priori exclude studies on certain populations. They recommended referring to the 

Guidelines. [Bilateral disease was also mentioned as a comorbidity but it was unclear 

whether it should be excluded] 

b.	 Are the proposed age intervals appropriate? 

Rosenfeld proposed not studying <6 month olds. 

c.	 What is meant by race and ethnicity? Will we analyze the interaction? 

This issue was not discussed. 

d.	 What are thresholds of daycare attendance the review should focus upon? 

This issue was not discussed. 

e.	 What additional subpopulations should be considered for KQ5? E.g., AOM with perforation 

or otorrhea versus no perforation or no otorrhea, et cetera? 

Rosenfeld proposed analyzing by severity rating, e.g., the AAP/AAFP AOM Guideline 

severity rating. 

f.	 Should a similar subpopulation analysis be done for KQ4 on ROM? 

This issue was not discussed. 

KQ6. What are the comparative harms of different treatment options? 

Outcomes to consider (but not limited to): 

Antibiotic resistance 

Diarrhea/vomiting 

a. What other harm outcomes should be included that we should make every effort to report on, 

even if data are not available or are already known not to be significant issues? 

Shekelle explained the research team would list all harms reported but wondered if we 

need to consider any in particular. Kleinman wondered if we need to consider the 

harms of withholding treatment (e.g., increased risk of suppurative complications); 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

however this question was assessed in the first report. Only one study, a Dutch study, 

assessed it and it was done poorly. 

Responses to Query Regarding Nasopharyngeal Swabs as Proxy for Ear Fluid
 

November 18, 2008
 

Lieberthal: NP swabs do not accurately identify the organisms in the middle ear. They may 

reflect organisms that the child carries and may or may not be the same as the organism causing 

AOM. 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

Studies have looked at both clinical cure and bacteriologic cure. If there is bacteriologic cure 

there is more certainty of clinical cure. However clinical cure-the practical end point for 

providers-can occur without having sterilized the middle ear at the time of follow-up. 

Rosenfeld: 

1.	 Nasopharyngeal (NP) culture: This has been used as a surrogate for middle ear (ME) 

aspirates in some studies but the accuracy is poor. A negative NP culture for a particular 

pathogen has good predictive value for a negative ME culture for the same pathogen, but 

the value of a positive NP culture is no better than a coin toss at predicting ME results. 

The main value of NP cultures in OM studies has been to track changes in susceptibility 

of host organisms after antimicrobial therapy or vaccination. 

2.	 Bacteriologic vs.. clinical efficacy: The primary endpoint relevant to clinical decision 

making for AOM is clinical response, since about 70-80% of bacteriologic “failures” are 

nonetheless clinical “successes.” The value of bacteriologic endpoints is in assessing 

new antimicrobials, or in teasing out subtle differences in comparative efficacy of 

existing antimicrobials for specific pathogens. We can certainly use this as a secondary 

endpoint if enough data exist, but it takes a distant second place to clinical efficacy for 

everyday management decisions. 

Kleinman: I agree with Allan and would add that I am unaware of evidence that suggests that NP eradication improves long or short term course. 

Goessler: I also concur. 

Casselbrant: I have no further comments. 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

AOM TEP Meeting 2 Summary 

TEP Discussants: Tasnee Chonmaitree; Katherine Finn Davis; Diane Sabo; Allan Lieberthal; 

Richard Rosenfeld; Pauline Thomas 

AAP Staff Representative: Caryn Davidson 

AHRQ Representative: Lt. Commander Carmen Kelly 

SCEPC Staff Discussants: Linda Chan; Tumaini Coker; Mary Ann Limbos; Sydne Newberry; 

Paul Shekelle; Glenn Takata 

Date/Time: Tuesday 3/10/2009, 11:30 am to 12:40 pm 

1.	 Project Update: 

a.	 KQ1 Diagnosis: Identified recent systematic review and updated search. Screening titles. 

b.	 KQ2 Microbiology: Identified 70 articles. Conducted second level of screening. 

c.	 KQ3-6 Treatment and adverse effects: Screening and abstraction complete for original 

search and updated search; beginning pooling and data analysis. 

2.	 Additional feedback on the list of articles included for treatment and adverse event 

questions: Anything we’ve omitted? 

The panel was asked to review the lists of articles reviewed for the treatment questions to let 

us know if we have missed anything important. The searches date from 1998 (when the last 

AHRQ systematic review ended, allowing for some overlap, although older articles are being 

considered for recurrent/persistent OM). The search strategy builds on that of THE 2001 

REPORT with the addition of new terms, e.g., watchful waiting. PubMed and Web of 

Science were searched for the update, as well as reference mining systematic reviews and 

accepted articles. 

Dr. Chonmaitree noted that she had identified several more articles (including back-to-back 

articles by Hoberman in the January 2009 PID) in addition to a couple by her group 

(McCormick et al) that seemed to be missing from our lists. The panel suggested we try to 

determine how we had missed these articles.1 [Dr. Chonmaitree had also sent an email the 

previous day regarding Hotomi, Cates, and two Vernacchio articles.] 

3.	 Including Observational Studies? 

We also presented the strategy of including observational studies on treatment issues only 

when controlled trial data were lacking as recommended by current systematic review 

guidelines. Paul Shekelle clarified that we are focusing on clinical trial comparisons of 

antibiotics and other treatments. We’re now in the pooling stage. If we find cells with no 

data, we will look to observational studies or we will ask the panel if observational studies 

will be of use in this analysis. The panel briefly reviewed the frequency table. 

1 It turns out the McCormick et al article pertaining to treatment was identified but then inadvertently 

excluded when duplicate articles were being eliminated from a list of titles. 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

There was a discussion of whether to examine each antibiotic separately or to pool. Dr. 

Rosenfeld suggested doing two sets of analysis: 1) drug a vs.. drug b (specific agents) and 2) 

combine all antibiotics, i.e. drug A vs.. all comparators. For the immediate vs.. deferred 

question, it is all right to pool different antibiotics for that comparison. Also, for the primary 

empiric decision - to treat or not – it is all right to pool. But when looking at treatment 

failures, we want to look separately. 

4. Overall Scope 

Finally, we asked for comments on the overall scope for this review: are we missing anything 

crucial? There was general agreement that it was a good summary. 

Clarification was requested for the difference between practitioner and examiner in 

influencing factors. Several participants noted that sometimes the examiner in a study is not 

the patient’s practitioner, and sometimes the examiner is blinded, whereas the practitioner 

may not be blinded. 

It was suggested we add the cost of antibiotics to the cost of outcomes, although there was 

discussion about the recent development that Walmart now carries an inexpensive generic 

amoxicillin-clavulanate. Someone mentioned that the amoxicillin-clavulanate ratio is lower 

in the generics, which can result in diarrhea. 

Should we include cholesteatoma development as an otological complication? Other panel 

members felt the incidence was too low and the onset time too long. The term “ear fullness” 

needs to be corrected. 

As a result of this discussion, the research team will provide definitions for each of the scope 

items. 

Other Business 

AOM Definition. Are we devising a definition of AOM? Paul Shekelle noted that we’re 

documenting elements of definitions used in articles for potential sensitivity analysis. More 

restrictive definitions result in smaller numbers of trials. 

Timeline. The panel asked about the timeline for the report (draft due week of April 12). The 

AAP expressed interest in having the report available for a June 30 meeting of the AAP AOM 

Guideline panel. Although the report may not be final by then, the panel should at least have the 

information they need. 

Considering generalizability of findings. Richard Rosenfeld recommended that the 

generalizability of results needs to be emphasized in the write-up. For example, with respect to 

pneumatic otoscopy, the concern is that it has to be done with fairly well trained otoscopists and 

that the validity in trials is not applicable to the average primary care physician, who may be 

more skilled at other diagnostic techniques. It will be useful to document and comment on the 

circumstances to which the findings apply with respect to characteristics of the examiner. Also, 

with regard to the concept of watchful waiting/deferred antibiotic observation and management 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

options, there is concern with the types of children involved in the clinical trials of this treatment 

option and the potentially poor quality of studies. The research team was advised to be attentive 

to studies that propose a reductionist approach: we need to define which patients these results 

can be extrapolated to. He emphasized that generalizability may be even more important than 

effect size. 

Report format. A question was raised about the report’s format. The report will include text as 

well as evidence tables and flow charts. The link was sent to the panel. 

Reporting effect sizes as risk ratios or odds ratios? The question was raised about how effect 

sizes were expressed in the first report. Dr. Shekelle responded that we mostly report RRs, 

which can be converted to the number needed to treat (NNT) or the number needed to harm. RR 

provides relative risk. According to Dr. Rosenfeld, Cochrane prefers to use odds ratios. Dr. 

Shekelle said that RRs are preferred, and Linda Chan noted that one can be converted to the 

other. Dr. Rosenfeld reported that risk ratios result in small differences in NNT, and that it is 

sometimes helpful to see absolute differences as well as relative differences. Dr. Takata noted 

that THE 2001 REPORT reported rate differences. Dr. Shekelle assured the panel that we can be 

flexible, but that we tend to avoid reporting odds ratios because of the tendency to overestimate 

what they mean. 

Reporting failure rates or success rates? Dr. Rosenfeld asked whether we would report failure 

rates or success rates. Cochrane reports failure rates. The problem is that with self-limiting 

conditions, failure rates are fairly small. Doubling still produces a small failure rate, so it is 

deceptive. Reporting success rates may be preferable if one is anticipating a robust success rate. 

Dr. Lieberthal noted that the first AOM report used NNT. For the clinician, NNT is one of the 

easier statistics to understand. Also, success rate is preferable for clinicians, as differences are 

not inflated. There was general agreement that success rates are simpler to understand. Dr. 

Takata suggested that maybe this distinction of reporting failure versus success should be made 

in the guideline discussions. The front-line clinician is more likely to read the guideline than the 

technical report. 

Zone of Indifference. Dr. Chan then raised the issue of the zone of indifference. A difference 

may be statistically significant but not clinically important. There are confidence intervals for 

failure rates as well as success rates. D r. Rosenfeld agreed that the zone of indifference is an 

important concept, equally so for adverse events, especially since AOM is a self-limiting disease. 

Thus adverse effects (AEs) may be the driving force in many treatment decisions. Much harm is 

done with well-meaning therapies and not enough has been done in previous reports to highlight 

AEs of treatment. Some discussion ensued about the degree to which AOM is self-limiting and 

the risk for severe complications like mastoiditis. (Dr. Rosenfeld cited a recent article by 

Thompson out of the UK in Pediatrics that showed a very low incidence of acute mastoiditis in 

AOM.) Regardless, the panel wants to see the same clarity and thoroughness in AE reporting as 

in the reporting of disease-related outcomes. 

Definition of persistent OM: AOM or OME? Dr. Davis asked whether persistent OM (as 

defined in the scope) refers to AOM or OME. Dr. Takata said it is AOM and that we will clarify 

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Appendix F. Technical Expert Panel Composition and 

Meeting Summaries 

the definitions. Dr. Davis also noted that the definition should include middle ear inflammation, 

not infection (however Pichicero’s definition of “persistent” specifies infection, not 

inflammation). 

This discussion raised questions about the definitions of recurrence and persistence. Is 

persistence relapse within a month or failure of symptoms to resolve within a month: These are 

two different conditions. Dr. Thomas asked “At what point is something a new episode as 

opposed to a continuation of the original episode?” Dr. Chonmaitree noted that Pichicero has 

apparently studied this question. In fact, it is his definition (from Pediatric Infectious Disease 

(2000) that we have adopted (the term is Persistent Otitis Media/Relapse of Acute Otitis Media)2

. 

Dr. Lieberthal noted that recurrence would be characterized by clear evidence of prior resolution. 

Wrap-up 

We may be contacting the panel before the report draft is sent out, for resolution of the need for 

including observational studies. 

2 Pichicero ME. Recurrent and persistent otitis media. Pediatr Infect Dis J 2000;19:911-916 

F-14
 
APPENDIX G. Summary Tables for Studies Included in Comparisons 

Table G.1 Comparisons for AOM1 Key Question 3 and AOM2 Key Question 3 on Antibiotics versus No Antibiotics 

The general principle agreed upon was to separate amoxicillin-clavulanate, penicillin G, penicillin V, erythromycin estolate, triple 

sulfonamide, and erythromycin estolate-triple sulfonamide from ampicillin/amoxicillin and each other. Penicillin G is oxidized in the 

stomach and not well absorbed. Penicillin V does not cover Haemophilus influenza well. Erythromycin estolate is quite different 

from the other antibiotics. Triple sulfonamide is no longer in common usage. 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Ampicillin or amoxicillin Placebo 5 2 7 

Amoxicillin-clavulanate Placebo 1 

Penicillin G plus sulfisoxazole Placebo 1 

Penicillin V Placebo 2 

Erythromycin estolate Placebo 1 

Triple sulfonamide Placebo 1 

Erythromycin estolate-triple sulfonamide Placebo 1 

Table G.2 Comparisons for AOM1 Key Question 4a and AOM2 Key Question 3 on 

Amoxicillin or Trimethoprim-Sulfamethoxazole versus Other Antibiotics 

The general principle agreed upon was to compare by individual antibiotic rather than by antibiotic class, spectrum, or 

pharmacokinetics. 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Amoxicillin or ampicillin Penicillin 3 

Amoxicillin or ampicillin Amoxicillin-clavulanate 0 

Amoxicillin or ampicillin Cephalexin 2 

G-1
 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

Amoxicillin or ampicillin Cephradine 1 

Amoxicillin or ampicillin Cefuroxime axetil 2 

Amoxicillin or ampicillin Cefaclor 5 

Amoxicillin or ampicillin Loracarbef 1 

Amoxicillin or ampicillin Cefixime 5 

Amoxicillin or ampicillin Ceftriaxone 3 1 4 

Amoxicillin or ampicillin Erythromycin estolate 2 

Amoxicillin or ampicillin Clarithromycin 2 

Amoxicillin or ampicillin Clindamycin 1 

Amoxicillin or ampicillin Penicillin V and sulfisoxazole 2 

Amoxicillin or ampicillin Triple sulfonamide 1 

Amoxicillin or ampicillin Penicillin G plus triple sulfonamide 1 

Amoxicillin or ampicillin Erythromycin ethylsuccinatesulfisoxazole 1 

Amoxicillin or ampicillin Oxytetracycline and procaine penicillin 

plus benzathine penicillin G injection plus 

sulfisoxazole 

1 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Trimethoprim-sulfamethoxazole Amoxicillin-clavulanate 1 

Trimethoprim-sulfamethoxazole Cephalexin 0 

Trimethoprim-sulfamethoxazole Cephradine 0 

Trimethoprim-sulfamethoxazole Cefuroxime axetil 0 

G-2
 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

Trimethoprim-sulfamethoxazole Cefaclor 3 

Trimethoprim-sulfamethoxazole Loracarbef 0 

Trimethoprim-sulfamethoxazole Cefixime 0 

Trimethoprim-sulfamethoxazole Ceftriaxone 1 

Trimethoprim-sulfamethoxazole Erythromycin estolate 0 

Trimethoprim-sulfamethoxazole Erythromycin ethylsuccinate 0 

Trimethoprim-sulfamethoxazole Clarithromycin 0 

Trimethoprim-sulfamethoxazole Clindamycin 0 

Trimethoprim-sulfamethoxazole Penicillin-sulfasoxazole 0 

Trimethoprim-sulfamethoxazole Erythromycin ethylsuccinatesulfisoxazole 0 

Trimethoprim-sulfamethoxazole Erythromycin ethylsuccinate-acetyl 

sulfafurazole 

0 

Table G.3 Comparisons for AOM1 Key Question 4e and AOM2 Key Question 3 on 

Short-term versus Long-term Antibiotic Therapy 

The general principle agreed upon was to compare by individual antibiotic stratified by therapy duration, <5days versus 5days. 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Amoxicillin (<5d) amoxicillin (7-10d) 3 

Penicillin V (<5d) penicillin V (7-10d) 1 

Penicillin V (5d, either 25mg/kg/d or 

50mg/kg/d) 

penicillin V (7-10d) 1 (two 5-

day arms) 

Benthazine penicillin G/procaine penicillin 

G/potassium penicillin G (Bicillin) (1 dose) 

tetracycline (7-10d) 1 

G-3
 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

Benthazine penicillin G/procaine penicillin 

G/potassium penicillin G (Bicillin) (1 dose) 

benthazine penicillin/procaine penicilliln 

G/potassium penicillin G (Bicillin) (1 

dose) plus triple sulfonamide (7d) 

2 

Amoxicillin-clavulanate (5d, either 45mg/kg/d 

or 80 mg/kg/d) 

amoxicillin-clavulanate (7-10d, either 

40mg/kg/d or 45mg/kg/d or 80mg/kg/d) 

2 

Cefaclor (<5d) cefaclor (7-10d) 1 

Cefaclor (5d) amoxicillin (7-10d) 1 

Cefaclor (5d) cefaclor (7-10d) 1 

Cefuroxime axetil (5d) amoxicillin-clavulanate (7-10d) 1 1 2 

Cefuroxime axetil (5d) cefixime (7-10d) 1 

Cefpodoxime proxetil (5d) amoxicillin-clavulanate (7-10d) 2 

Cefpodoxime proxetil (5d) cefaclor (7-10d) 1 

Cefpodoxime proxetil (5d) cefixime (7-10d) 1 

Cefprozil (5d) cefprozil (7-10d) 1 

Ceftibuten (5d) ceftibuten (10d) 1 

Ceftriaxone (1 dose) amoxicillin (7-10d) 3 

Ceftriaxone (1 dose) amoxicillin-clavulanate (7-10d) 2 3 5 

Ceftriaxone (1 dose) cefaclor (7-10d) 1 

Ceftriaxone (1 dose) cefuroxime axetil (7-10d) 1 

Ceftriaxone (1 dose) trimethroprim-sulfamethoxazole (7-10d) 1 

Azithromycin (<5d) amoxicillin-clavulanate (7-10d, either 

40mg/kg/d or 45mg/kg/d) 

5 4 9 

Azithromycin (<5d) cefaclor (7-10d) 2 2 4 

Azithromycin (<5d) clarithromycin (7-10d) 1 

G-4
 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

Azithromycin (5d) amoxicillin-clavulanate (7-10d) 3 

Cefdinir (5d) amoxicillin-clavulanate (10d) 0 2 2 

Cefprozil (10d) cefdinir (5d) 0 1 1 

Cefpodoxime (5d) cefpodoxime (10d) 0 1 1 

Table G.4 Comparisons for AOM2 Key Question 3 But Not in AOM1 

(i) For Uncomplicated Acute Otitis Media 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Amoxicillin-clavulanate Amoxicillin Sulbactam 0 1 1 

Amoxicillin-clavulanate Cefaclor 0 1 1 

Amoxicillin-clavulanate Cefdinir: 14 mg 0 2 2 

Amoxicillin-clavulanate Cefdinir: 7 mg 0 2 2 

Amoxicillin-clavulanate Cefprozil 0 1 1 

Amoxicillin-clavulanate Ciprodex drops 0 1 1 

Amoxicillin-clavulanate: 40 mg 10 d Amoxicillin-clavulanate: 80 mg 8 d 0 1 1 

Amoxicillin-clavulanate: 40/10 mg Amoxicillin-clavulanate: 45/6.4 mg 0 1 1 

Amoxicillin-clavulanate: 45/6.4 mg 10 d Amoxicillin-clavulanate: 90/6.4 mg 10 d 0 1 1 

Amoxicillin-clavulanate: 80 mg Cefuroxime 0 1 1 

Amoxicillin Azithromycin 0 1 1 

Amoxicillin Prescription to Hold 0 2 2 

Amoxicillin Wait and see 0 1 1 

Amoxicillin/NHED Amoxicillin/Topical anesthetic nos 0 1 1 

Amoxicillin/NHED NHED 0 1 1 

Amoxicillin/NHED Topical anesthetic nos 0 1 1 

Amoxicillin/Topical anesthetic nos NHED 0 1 1 

Amoxicillin/Topical anesthetic nos Topical anesthetic nos 0 1 1 

Amoxicillin: 40-45 mg Amoxicillin: 80-90 mg 0 1 1 

Amoxicillin: 80 mg Amoxicillin: 80 mg/Fenspiride 0 1 1 

G-5
 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

Antibiotic Prescription to Hold 0 1 1 

Antihistamine/Ceftriaxone Antihistamine/Ceftriaxone/Prednisolone 0 1 1 

Antihistamine/Ceftriaxone Ceftriaxone 0 1 1 

Antihistamine/Ceftriaxone Ceftriaxone/Prednisolone 0 1 1 

Antihistamine/Ceftriaxone/Prednisolone Ceftriaxone 0 1 1 

Antihistamine/Ceftriaxone/Prednisolone Ceftriaxone/Prednisolone 0 1 1 

Aqueous lidocaine Placebo 0 1 1 

Azithromycin Cefdinir 0 1 1 

Azithromycin Ceftriaxone 0 1 1 

Cefaclor Cefpodoxime 0 1 1 

Cefaclor Cefprozil 0 1 1 

Cefaclor Cefuroxime 0 1 1 

Cefdinir: 14 mg Cefdinir: 7 mg 0 2 2 

Ceftriaxone Ceftriaxone/Prednisolone 0 1 1 

Ciprofloxacin otic 3% Ciprodex drops 0 1 1 

Ciprodex drops Ofloxacin drops 0 1 1 

Homeopathic NOS Placebo 0 1 1 

NHED Topical anesthetic nos 0 1 1 

Otikon drops Topical anesthetic nos 0 1 1 

Phenoxymethylpenicilin Wait and see 0 1 1 

Prescription to Hold Wait and see 0 1 1 

(ii) For Treatment of Acute Otitis Media in Recurrent Otitis Media 

Treatment A Treatment B # Studies 

in AOM1 

# Studies 

in AOM2 

Total 

Amoxicillin-clavulanate Azithromycin 0 1 1 

Amoxicillin-clavulanate Gatifloxacin 0 2 2 

Amoxicillin-clavulanate Levofloxacin 0 1 1 

G-6
 

(iii) For Prevention of Acute Otitis Media in Recurrent Otitis Media 

Treatment A Treatment B # Studies # Studies Total 
APPENDIX G. Summary Tables for Studies Included in Comparisons
 

in AOM1 in AOM2 

Adenoidectomy Adenoidectomy and/or tonsillectomy 0 1 1 

Adenoidectomy Placebo 0 2 2 

Adenoidectomy Sulfa alone 0 1 1 

Adenoidectomy and/or tonsillectomy Placebo 0 1 1 

Adenoidectomy/Tympanostomy tubes Tympanostomy tubes 0 1 1 

Amoxicillin Azithromycin 0 1 1 

Amoxicillin Placebo 0 1 1 

Amoxicillin Sulfa alone 0 1 1 

Ceftibuten: 9 mg - 10 days Ceftibuten: 9 mg - 5 days 0 1 1 

Probiotic bacteria Placebo 0 1 1 

Sulfa alone Placebo 0 2 2 

G-7
 
Appendix H. Conceptual Framework for the Report
 

H-1
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Summary.......................................................................................................................................I-2
 

Key Question 1 ...........................................................................................................................I-18
 

Key Question 3 ...........................................................................................................................I-26
 

Key Question 4 ...........................................................................................................................I-45
 

I-1
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews
 

Relevant to Management of Acute Otitis Media Update:
 Southern California Evidence-based Practice Center (RAND) 9/25/2008 

The document is a summary of the systematic reviews that have relevance to any of the key 

questions in the present Workplan. It consists of 3 parts: Part 1 contains the characteristics of the 

systematic reviews and the highlighted conclusions; Part 2 contains our assessment of the quality 

of the systematic reviews using AMSTAR quality indicators; and Part 3 provides representative 

quantitative outcomes of the comparisons contained in the systematic reviews. Finally, we 

include references and the AMSTAR instrument. 

We searched Medline and the Cochrane review database from 1998 through the present and 

identified reviews that have relevance to any of the key questions for the AOM update. We also 

included one review from 1994. 

Based on the general conclusions of these reviews, we would say that we are well justified in redoing systematic reviews for KQ3-KQ6. In addition, since we did not identify any systematic 

review relevant to KQ1 or KQ2, those must be addressed, as well. 

I-2
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-3
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-4
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-5
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-6
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-7
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-8
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-9
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-10
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-11
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-12
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-13
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-14
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update: 

Southern California Evidence-based Practice Center (RAND) 9/18/2008 

References 

Coleman, C. and M. Moore (2008). "Decongestants and 

antihistamines for acute otitis media in children." Cochrane 

Database Syst Rev(3): CD001727. 

Damoiseaux, R. A., F. A. van Balen, A. W. Hoes and R. A. 

de Melker (1998). "Antibiotic treatment of acute otitis 

media in children under two years of age: evidence based?" 

Br J Gen Pract 48(437): 1861-1864. 

Foxlee R., A. Johansson, J. Wejfalk, J. Dawkins, L. 

Dooley, C. B. Del Mar (2006). “Topical analgesia for acute 

otitis media.” Cochrane Database Syst Rev(3): CD005657. 

Glasziou, P. P., C. B. Del Mar, S. L. Sanders, and M. 

Hayem (2004). "Antibiotics for acute otitis media in 

children." Cochrane Database Syst Rev(1): CD000219. 

Kozyrskyj, A. L., G. E. Hildes-Ripstein, S. E. Longstaffe, J. 

L. Wincott, D. S. Sitar, T. P. Klassen and M. E. Moffatt 

(2000). "Short course antibiotics for acute otitis media." 

Cochrane Database Syst Rev(2): CD001095. 

Oxman, A. D. and G. H. Guyatt (1991). “Validation of an 

index of the quality of review articles.” J Clin Epidemiol 

44(11): 1271-1278. 

Rosenfeld, R. M., J. E. Vertrees, J. Carr, R. J. Cipolle, D. L. 

Uden, G. S. Biebink and D. M. Canafax. “Clinical efficacy 

of antimicrobial drugs for acute otitis media: metaanalysis 

of 5400 children from thirty-three randomized trials.” J 

Pediatr 1994;124:355-367. 

Rovers, M. M., P. Glasziou, C. L. Appelman, P. Burke, D. 

P. McCormick, R. A. Damoiseaux, I. Gaboury, P. Little 

and A. W. Hoes (2006). "Antibiotics for acute otitis media: 

a meta-analysis with individual patient data." Lancet 

368(9545): 1429-1435. 

Shea, B. J., J. M. Grimshaw, G. A. Wells, M. Boers, N. 

Anderson, C. Hamel, A. C. Porter, P. Tugwell, D. Moher, 

L. M. Bouter. “Development of AMSTAR: a measurement 

tool to assess the methodologic quality of systematic 

reviews.” BMC Med Res Methodol 2007;7:10. 

Spurling, G. K., C. B. Del Mar, L. Dooley and R. Foxlee 

(2007). "Delayed antibiotics for respiratory infections." 

Cochrane Database Syst Rev(3): CD004417. 

Takata, G. S., L. S. Chan, P. Shekelle, S. C. Morton, W. 

Mason and S. M. Marcy. “Evidence assessment of 

management of acute otitis media: I. The role of antibiotics 

in treatment of uncomplicated acute otitis media.” 

Pediatrics 2001;108:239-247. 

Whitlock, E. P., J. S. Lin, R. Chou, P. Shekelle, K.A. 

Robinson. “Using existing systematic reviews in complex 

systematic reviews.” Ann Intern Med. 148(10):776-782. 

I-15
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update: 

Southern California Evidence-based Practice Center (RAND) 9/18/2008 

Appendix: AMSTAR Quality Indicators (Shea, Grimshaw, Wells, et al, 2007) 

1. Was an ‘a priori’ design provided? 

The research question and inclusion criteria should be established before the 

conduct of the review. 

2. Was there duplicate study selection and data extraction? 

There should be at least two independent data extractors and a consensus 

procedure for disagreements should be in place. 

3. Was a comprehensive literature search performed? 

At least two electronic sources should be searched. The report must include 

years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words 

and/or MESH terms must be stated and where feasible the search strategy 

should be provided. All searches should be supplemented by consulting 

current contents, reviews, textbooks, specialized registers, or experts in the 

particular field of study, and by reviewing the references in the studies found. 

4. Was the status of publication (i.e. grey literature) used as an inclusion 

criterion? 

The authors should state that they searched for reports regardless of their 

publication type. The authors should state whether or not they excluded any 

reports (from the systematic review), based on their publication status, 

language etc. 

5. Was a list of studies (included and excluded) provided? 

A list of included and excluded studies should be provided. 

6. Were the characteristics of the included studies provided? 

In an aggregated form such as a table, data from the original studies should be 

provided on the participants, interventions and outcomes. The ranges of 

characteristics in all the studies analyzed e.g. age, race, sex, relevant 

socioeconomic data, disease status, duration, severity, or other diseases 

should be reported. 

7. Was the scientific quality of the included studies assessed and 

documented? 

‘A priori’ methods of assessment should be provided (e.g., for effectiveness 

studies if the author(s) chose to include only randomized, double-blind, 

placebo controlled studies, or allocation concealment as inclusion criteria); for 

other types of studies alternative items will be relevant. 

I-16
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

8. Was the scientific quality of the included studies used appropriately in 

formulating conclusions? 

The results of the methodological rigor and scientific quality should be 

considered in the analysis and the conclusions of the review, and explicitly 

stated in formulating recommendations. 

9. Were the methods used to combine the findings of studies 

appropriate? 

For the pooled results, a test should be done to ensure the studies were 

combinable, to assess their homogeneity (i.e. Chi-squared test for 

homogeneity, I2). If heterogeneity exists a random effects model should be applicable 

used and/or the clinical appropriateness of combining should be taken into 

consideration (i.e. is it sensible to combine?). 

10. Was the likelihood of publication bias assessed? 

An assessment of publication bias should include a combination of graphical 

aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger 

regression test). 

11. Was the conflict of interest stated? 

Potential sources of support should be clearly acknowledged in both the 

systematic review and the included studies. 

ot applicable 

I-17
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media Diagnosis Systematic Reviews
 

Relevant to Management of Acute Otitis Media Update:
 Southern California Evidence-based Practice Center (RAND) 

This document is a summary of the systematic reviews that have relevance to Key Question 1 

(KQ1) regarding diagnosis of acute otitis media in the present Workplan. It consists of 3 parts: 

Part 1 contains the characteristics of the systematic reviews and the highlighted conclusions; Part 

2 contains our assessment of the quality of the systematic reviews using AMSTAR quality 

indicators; and Part 3 provides representative quantitative outcomes of the comparisons 

contained in the systematic reviews. Finally, we include references and the AMSTAR 

instrument. 

We searched Medline from 1998 through the present and identified reviews that have relevance 

to KQ1 for the AOM update. We searched the Cochrane Review database to the present. We 

also searched the Web of Science 1980-1997 and did hand searches of reference lists of study 

articles identified for inclusion in the AOM update. 

Based on the general conclusions of these reviews we believe that we are justified in doing a 

systematic review for KQ1. We have also noted the studies included in these systematic reviews 

for possible inclusion in the present systematic review. 

I-18
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-19
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-20
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-21
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-22
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Systematic Reviews Relevant to Management of Acute Otitis 

Media Update: 

Southern California Evidence-based Practice Center (RAND) 2/24/2009 

References 

Heikkinen T, Ruuskanen O. Signs and symptoms 

predicting acute otitis media. Arch Pediatr Adolesc Med. 

1995;149:26-29 

Ingvarsson L. Acute otalgia in children – findings and 

diagnosis. Acta Paediatr Scand. 1982;71:705-710. 

Karma PH, Penttila MA, Sipila MM, Kataja MJ. Otoscopic 

diagnosis of middle ear effusion in acute and non-acute 

otitis media. I: the value of different otoscopic findings. Int 

J Pediatr Otorhinolaryngol. 1989;17:37-49. 

Kontiokari T, Koivunen P, Niemela M, Pokka T, Uhari M. 

Symptoms of acute otitis media. Pediatr Infect Dis J. 

1998;17:676-679. 

Niemela M, Uhari M, Juunio-Ervasti K, Luotonen J, Alho 

OP, Vierimaa E. Lack of specific symptomatology in 

children with acute otitis media. Pediatr Infect Dis J. 

1994;13:765-768. 

Oxman, AD, Guyatt GH. “Validation of an index of the 

quality of review articles.” J Clin Epidemiol 

1991;44(11):1271-1278. 

Rothman R, Owens T, Simel DL. Does this child have 

acute otitis media? JAMA 2003;290:1633-1640. 

Shea, BJ, Grimshaw JM, Wells GA, Boers M, Anderson N, 

Hamel C, Porter AC, Tugwell P, Moher D, Bouter LM. 

“Development of AMSTAR: a measurement tool to assess 

the methodologic quality of systematic reviews.” BMC 

Med Res Methodol 2007;7:10. 

Whitlock, EP, Lin JS, Chou R, Shekelle P, Robinson KA. 

“Using existing systematic reviews in complex systematic 

reviews.” Ann Intern Med 2008;148(10):776-782. 

I-23
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Systematic Reviews Relevant to Management of Acute Otitis 

Media Update: 

Southern California Evidence-based Practice Center (RAND) 2/24/2009 

Appendix: AMSTAR Quality Indicators (Shea, Grimshaw, Wells, et al, 2007) 

1. Was an ‘a priori’ design provided? 

The research question and inclusion criteria should be established before the 

conduct of the review. 

2. Was there duplicate study selection and data extraction? 

There should be at least two independent data extractors and a consensus 

procedure for disagreements should be in place. 

3. Was a comprehensive literature search performed? 

At least two electronic sources should be searched. The report must include 

years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words 

and/or MESH terms must be stated and where feasible the search strategy 

should be provided. All searches should be supplemented by consulting 

current contents, reviews, textbooks, specialized registers, or experts in the 

particular field of study, and by reviewing the references in the studies found. 

4. Was the status of publication (i.e. grey literature) used as an inclusion 

criterion? 

The authors should state that they searched for reports regardless of their 

publication type. The authors should state whether or not they excluded any 

reports (from the systematic review), based on their publication status, 

language etc. 

5. Was a list of studies (included and excluded) provided? 

A list of included and excluded studies should be provided. 

6. Were the characteristics of the included studies provided? 

In an aggregated form such as a table, data from the original studies should be 

provided on the participants, interventions and outcomes. The ranges of 

characteristics in all the studies analyzed e.g. age, race, sex, relevant 

socioeconomic data, disease status, duration, severity, or other diseases 

should be reported. 

7. Was the scientific quality of the included studies assessed and 

documented? 

‘A priori’ methods of assessment should be provided (e.g., for effectiveness 

studies if the author(s) chose to include only randomized, double-blind, 

placebo controlled studies, or allocation concealment as inclusion criteria); for 

other types of studies alternative items will be relevant. 

I-24
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

8. Was the scientific quality of the included studies used appropriately in 

formulating conclusions? 

The results of the methodological rigor and scientific quality should be 

considered in the analysis and the conclusions of the review, and explicitly 

stated in formulating recommendations. 

9. Were the methods used to combine the findings of studies 

appropriate? 

For the pooled results, a test should be done to ensure the studies were 

combinable, to assess their homogeneity (i.e. Chi-squared test for 

homogeneity, I2). If heterogeneity exists a random effects model should be applicable 

used and/or the clinical appropriateness of combining should be taken into 

consideration (i.e. is it sensible to combine?). 

10. Was the likelihood of publication bias assessed? 

An assessment of publication bias should include a combination of graphical 

aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger 

regression test). 

11. Was the conflict of interest stated? 

Potential sources of support should be clearly acknowledged in both the 

systematic review and the included studies. 

ot applicable 

I-25
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Systematic Reviews Relevant to Management of Acute Otitis 

Media Update: 

Southern California Evidence-based Practice Center (RAND) 2/24/2009 

This document is a summary of the systematic reviews that have relevance to Key Question 3 

(KQ3) regarding treatment of acute otitis media in the present Workplan. It consists of 3 parts: 

Part 1 contains the characteristics of the systematic reviews and the highlighted conclusions; Part 

2 contains our assessment of the quality of the systematic reviews using AMSTAR quality 

indicators; and Part 3 provides representative quantitative outcomes of the comparisons 

contained in the systematic reviews. Finally, we include references and the AMSTAR 

instrument. 

We searched Medline from 1998 through the present and identified reviews that have relevance 

to KQ3 for the AOM update. We searched the Cochrane Review database to the present. We 

also searched the Web of Science 1980-1997 and did hand searches of reference lists of study 

articles identified for inclusion in the AOM update. 

Based on the general conclusions of these reviews we believe that we are justified in doing a 

systematic review for KQ3. We have also noted the studies included in these systematic reviews 

for possible inclusion in the present systematic review. 

I-26
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-27
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-28
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-29
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-30
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-31
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-32
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-33
 
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Analyses 

I-34
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-35
 
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Analyses 

I-36
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-37
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-38
 
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Analyses 

I-39
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-40
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-41
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-42
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update: 

Southern California Evidence-based Practice Center (RAND) 9/18/2008 

References 

Abes G, Espallardo N, Tong M, Subramaniam KN, 

Hermani B, Lasiminigrum L, Anggraeni R. “A systematic 

review of the effectiveness of ofloaxin otic solution for the 

treatment of suppurative otitis media.” ORL 2003;65:106-

116. 

Coleman, C, Moore M (2008). "Decongestants and 

antihistamines for acute otitis media in children." Cochrane 

Database Syst Rev(3): CD001727. 

Damoiseaux RA, van Balen FA, Hoes AW, de Melker RA. 

(1998). "Antibiotic treatment of acute otitis media in 

children under two years of age: evidence based?" “Br J 

Gen Pract” 1998;48(437):1861-1864. 

Foxlee R, Johansson A, Wejfalk J, Dawkins J, Dooley L, 

Del Mar CB (2006). “Topical analgesia for acute otitis 

media.” Cochrane Database Syst Rev(3): CD005657. 

Glasziou PP, Del Mar CB, Sanders SL, Hayem M (2004). 

"Antibiotics for acute otitis media in children." Cochrane 

Database Syst Rev(1): CD000219. 

Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, 

Wincott JL, Sitar DS, Klassen TP, Moffatt ME (2000). 

"Short course antibiotics for acute otitis media." Cochrane 

Database Syst Rev(2): CD001095. 

Oxman AD, Guyatt GH. “Validation of an index of the 

quality of review articles.” J Clin Epidemiol 

1991:44(11):1271-1278. 

Rosenfeld RM, Vertrees JE, Carr J, Cipolle RJ, Uden DL, 

Biebink GS, Canafax DM. “Clinical efficacy of 

antimicrobial drugs for acute otitis media: metaanalysis of 

5400 children from thirty-three randomized trials.” J 

Pediatr 1994;124:355-367. 

Rovers MM, Glasziou P, Appelman CL, Burke P, 

McCormick DP, Damoiseaux RA, Gaboury I, Little P, 

Hoes AW. "Antibiotics for acute otitis media: a metaanalysis with individual patient data." Lancet 

2006;368(9545):1429-1435. 

Shea BJ, Grimshaw JM, Wells GA, Boers M, Anderson A, 

Hamel C, Porter AC, Tugwell P, Moher D, Bouter LM. 

“Development of AMSTAR: a measurement tool to assess 

the methodologic quality of systematic reviews.” BMC 

Med Res Methodol 2007;7:10. 

Spurling,GK, Del Mar CB, Dooley L, Foxlee R (2007). 

"Delayed antibiotics for respiratory infections." Cochrane 

Database Syst Rev(3): CD004417. 

Takata, GS, Chan LS, Shekelle P, Morton SC, Mason W, 

Marcy SM. “Evidence assessment of management of acute 

otitis media: I. The role of antibiotics in treatment of 

uncomplicated acute otitis media.” Pediatrics 

2001;108:239-247. 

Thanaviratananich S, Laopaiboon M, Vatanasapt P. “Once 

or twice daily versus three times daily amoxicillin with or 

without clavulanate for the treatment of acute otitis media. 

Cochrane Database of Systematic Reviews 2008, Issue 4. 

Art. No.: CD004975. DOI: 

10.1002/14651858.CD004975.pub2. 

Wall GM, Stroman DW, Roland PS, Dohar J. 

Ciprofloxacin 0.3%/desamethasone 0.1% sterile otic 

suspension for the topical treatment of ear infections: a 

review of the literature. Pediatr Infect Dis J 2009;28:141-

144. 

Whitlock EP, Lin JS, Chou R, Shekelle P, Robinson KA. 

“Using existing systematic reviews in complex systematic 

reviews.” Ann Intern Med 2008;148(10):776-782 

I-43
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update: 

Southern California Evidence-based Practice Center (RAND) 9/18/2008 

Appendix: AMSTAR Quality Indicators (Shea, Grimshaw, Wells, et al, 2007) 

1. Was an ‘a priori’ design provided? 

The research question and inclusion criteria should be established before the 

conduct of the review. 

2. Was there duplicate study selection and data extraction? 

There should be at least two independent data extractors and a consensus 

procedure for disagreements should be in place. 

3. Was a comprehensive literature search performed? 

At least two electronic sources should be searched. The report must include 

years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words 

and/or MESH terms must be stated and where feasible the search strategy 

o 

able 

should be provided. All searches should be supplemented by consulting 

current contents, reviews, textbooks, specialized registers, or experts in the 

particular field of study, and by reviewing the references in the studies found. 

4. Was the status of publication (i.e. grey literature) used as an inclusion 

criterion? 

The authors should state that they searched for reports regardless of their 

publication type. The authors should state whether or not they excluded any 

reports (from the systematic review), based on their publication status, 

language etc. 

5. Was a list of studies (included and excluded) provided? 

A list of included and excluded studies should be provided. 

6. Were the characteristics of the included studies provided? 

In an aggregated form such as a table, data from the original studies should be 

provided on the participants, interventions and outcomes. The ranges of 

characteristics in all the studies analyzed e.g. age, race, sex, relevant 

socioeconomic data, disease status, duration, severity, or other diseases 

should be reported. 

7. Was the scientific quality of the included studies assessed and 

documented? 

‘A priori’ methods of assessment should be provided (e.g., for effectiveness 

studies if the author(s) chose to include only randomized, double-blind, 

placebo controlled studies, or allocation concealment as inclusion criteria); for 

other types of studies alternative items will be relevant. 

I-44
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

8. Was the scientific quality of the included studies used appropriately in 

formulating conclusions? 

The results of the methodological rigor and scientific quality should be 

considered in the analysis and the conclusions of the review, and explicitly 

stated in formulating recommendations. 

9. Were the methods used to combine the findings of studies 

appropriate? 

For the pooled results, a test should be done to ensure the studies were 

combinable, to assess their homogeneity (i.e. Chi-squared test for 

homogeneity, I2). If heterogeneity exists a random effects model should be applicable 

used and/or the clinical appropriateness of combining should be taken into 

consideration (i.e. is it sensible to combine?). 

10. Was the likelihood of publication bias assessed? 

An assessment of publication bias should include a combination of graphical 

aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger 

regression test). 

11. Was the conflict of interest stated? 

Potential sources of support should be clearly acknowledged in both the 

systematic review and the included studies. 

ot applicable 

I-45
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update:
 Southern California Evidence-based Practice Center (RAND) 9/18/2008 

This document is a summary of the systematic reviews that have relevance to Key Question 4 

(KQ4) in the present Workplan. It consists of 3 parts: Part 1 contains the characteristics of the 

systematic reviews and the highlighted conclusions; Part 2 contains our assessment of the quality 

of the systematic reviews using AMSTAR quality indicators; and Part 3 provides representative 

quantitative outcomes of the comparisons contained in the systematic reviews. Finally, we 

include references and the AMSTAR instrument. 

We searched Medline from 1998 through the present and identified reviews that have relevance 

to KQ4 for the AOM update. We searched the Cochrane Review database to the present. We 

also searched the Web of Science 1980-1997 and did hand searches of reference lists of study 

articles identified for inclusion in the AOM update. 

Based on the general conclusions of these reviews we believe that we are justified in doing a 

systematic review for KQ4. We have also noted the studies included in these systematic reviews 

for possible inclusion in the present systematic review 

I-46
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-47
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-48
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-49
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-50
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-51
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-52
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-53
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

-

I-54
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-55
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-56
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-57
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

I-58
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Review of Acute Otitis Media (AOM) Systematic Reviews 

Relevant to Management of Acute Otitis Media Update: 

Southern California Evidence-based Practice Center (RAND) 9/18/2008 

References 

Bonati M, Marchetti F, Pistotti V, Agostini M, Bisogno G, 

Bussi R, Davico S, De Santis M, Forno S, Gangemi M, 

Merlin D, Merlo M, Murgia V, Pivetta S, Raimo F, 

Tamburlini G. “Metaanalysis of antimicrobial prophylaxis 

for recurrent acute otitis-media.” Clinical Trials and MetaAnalysis 1992;28(1):39-50. 

Leach AJ, Morris PS. “Antibiotics for the prevention of 

acute and chronic suppurative otitis media in children.” 

Cochrane Database of Systematic Reviews 2006, Issue 4. 

Art. No.: CD004401. DOI: 

10.1002/14651858.CD004401.pub2. 

McDonald S, Langton Hewer CD, Nunez DA. “Grommets 

(ventilation tubes) for recurrent acute otitis media in 

children.” Cochrane Database of Systematic Reviews 2008, 

Issue 4. Art. No.: CD004741. DOI: 

10.1002/14651858.CD004741.pub2. 

Oxman, AD, Guyatt GH. “Validation of an index of the 

quality of review articles.” J Clin Epidemiol 

1991;44(11):1271-1278. 

Shea, BJ, Grimshaw JM, Wells GA, Boers M, Anderson N, 

Hamel C, Porter AC, Tugwell P, Moher D, Bouter LM. 

“Development of AMSTAR: a measurement tool to assess 

the methodologic quality of systematic reviews.” BMC 

Med Res Methodol 2007;7:10. 

Straetemans M, Sanders EAM,Veenhoven RH, Schilder 

AGM, Damoiseaux RAMJ, Zielhuis GA. “Pneumococcal 

vaccines for preventing otitis media.” Cochrane Database 

of Systematic Reviews 2004, Issue 1. Art.No.: CD001480. 

DOI: 10.1002/14651858.CD001480.pub2. 

Whitlock, EP, Lin JS, Chou R, Shekelle P, Robinson KA. 

“Using existing systematic reviews in complex systematic 

reviews.” Ann Intern Med 2008;148(10):776-782. 

Williams, RL, Chalmers TC, Stange KC, Chalmers FT, 

Bowlin SJ. "Use of antibiotics in preventing recurrent acute 

otitis-media and in treating otitis-media with effusion - a 

metaanalytic attempt to resolve the brouhaha.” JAMA 

1993;270:1344-1351. 

I-59
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

Appendix: AMSTAR Quality Indicators (Shea, Grimshaw, Wells, et al, 2007) 

1. Was an ‘a priori’ design provided? 

The research question and inclusion criteria should be established before the 

conduct of the review. 

2. Was there duplicate study selection and data extraction? 

There should be at least two independent data extractors and a consensus 

procedure for disagreements should be in place. 

ot applicable 

3. Was a comprehensive literature search performed? 

At least two electronic sources should be searched. The report must include 

years and databases used (e.g. Central, EMBASE, and MEDLINE). Key words 

and/or MESH terms must be stated and where feasible the search strategy 

should be provided. All searches should be supplemented by consulting 

current contents, reviews, textbooks, specialized registers, or experts in the 

particular field of study, and by reviewing the references in the studies found. 

4. Was the status of publication (i.e. grey literature) used as an inclusion 

criterion? 

The authors should state that they searched for reports regardless of their 

publication type. The authors should state whether or not they excluded any 

reports (from the systematic review), based on their publication status, 

language etc. 

5. Was a list of studies (included and excluded) provided? 

A list of included and excluded studies should be provided. 

6. Were the characteristics of the included studies provided? 

In an aggregated form such as a table, data from the original studies should be 

provided on the participants, interventions and outcomes. The ranges of 

characteristics in all the studies analyzed e.g. age, race, sex, relevant 

socioeconomic data, disease status, duration, severity, or other diseases 

should be reported. 

7. Was the scientific quality of the included studies assessed and 

documented? 

‘A priori’ methods of assessment should be provided (e.g., for effectiveness 

studies if the author(s) chose to include only randomized, double-blind, 

placebo controlled studies, or allocation concealment as inclusion criteria); for 

other types of studies alternative items will be relevant. 

8. Was the scientific quality of the included studies used appropriately in 

formulating conclusions? 

The results of the methodological rigor and scientific quality should be 

considered in the analysis and the conclusions of the review, and explicitly 

stated in formulating recommendations. 

I-60
 
Appendix I. Summaries of Systematic Reviews Included in 

Analyses 

9. Were the methods used to combine the findings of studies 

appropriate? 

For the pooled results, a test should be done to ensure the studies were 

combinable, to assess their homogeneity (i.e. Chi-squared test for 

homogeneity, I2). If heterogeneity exists a random effects model should be applicable 

used and/or the clinical appropriateness of combining should be taken into 

consideration (i.e. is it sensible to combine?). 

10. Was the likelihood of publication bias assessed? 

An assessment of publication bias should include a combination of graphical 

aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger 

regression test). 

11. Was the conflict of interest stated? 

Potential sources of support should be clearly acknowledged in both the 

systematic review and the included studies. 

ot applicable 

I-61
 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Abes J, Jamir J, Gloria-Cruz MT, Gumban V, 

Seredrica G: Comparative efficacy and safety of ofloxacin and polymixin otic drops for chronic suppurative otitis media. UPM J 1998;4:59-70. Incl 

Abramson M. Topical anesthesia of the tympanic membrane. Archives of Otolaryngology 1969;90(2):147-9 

excl 

Adam D Five-day therapy with cefpodoxime versus ten-day treatment with cefaclor in infants with acute otitis media. Infection 

1995; 23:398 400 

Incl 

Adam D. Five-day therapy with cefpodoxime versus ten-day treatment with cefaclor in infants with acute otitis media. Infection 1995;23:398 99 

Incl 

Agro AS, Garner ET, Wright JW, De Escobar IC, Villeda B, Seidlin M: Clinical trial of ototopical ofloxacin for treatment of chronic suppurative otitis media. Clin Ther 

1998;20:744 758 Incl ALHO OP What is the natural history of recurrent acute otitis media in infancy? JOURNAL OF FAMILY PRACTICE 43 : 258 1996 

Ref 

ALTMAN DG Better reporting of randomised controlled trials: The CONSORT statement -Authors must provide enough information for 

readers to know how the trial was performed BRITISH MEDICAL JOURNAL 313 : 570 

1996 

Ref 

American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics 2004;113:1451­65 

Ref Ref 

Appelman CL, Claessen JQ, Touw Otten FW, Hordijk GJ, de Melker RA. Severity of inflammation of tympanic membrane as predictor of clinical course of recurrent acute otitis media BMJ 1993;306:895 

Incl 

APPELMAN CLM CO-AMOXICLAV IN RECURRENT ACUTE OTITIS-MEDIA -PLACEBO CONTROLLED-STUDY BRITISH 

MEDICAL JOURNAL 303 : 1450 1991 

Incl Incl Incl Incl Incl Ref 

Appelman CLM, van Balen FAM, van de Lisdonk EH,van Weert HCPM, Eizenga WH. NHG–Standaard Otitis Media Acuta. Huisarts en Wetenschap 1999; 42: 362 66 Arason A, Kristinsson KG, Sigurdson JA, Stefansdottir G, Molstad S, Gudmundsson S. Do antimicrobials increase the carriage rate of penicillin resistant pneumoccci in children? Cross sectional prevalence study. B iti h M di l J l 1996 313 387 91 

Ref 

Arguedas A, Loaiza C, Herrara M, Mohs E. Comparative trial of 3-day azithromycin versus 10-day amoxycillin/clavulante potassium in the treatment of children with acute otitis media with effusion. Int J 

A ti i bi l A t 1996 6 233 8 

Incl Incl Ref 

Arguedas A, Loaiza C, Rodriguez F, Herrera 

ML, et al. Comparative trial of 3 days of azithromycin versus 10 days of clarithromycin in the treatment of children with acute otitis media with effusion. J 

Ch th 1997 9 44 50 

Incl Incl Ref 

Aronovitz G A multi-center, open label trial of azithromycin vs. amoxicillin/clavulanate for the management of acute otitis media in children. Pediatr Infect Dis J 1996; 15:S15­S19 

Incl Incl Ref 

Arroll B, Goodyear-Smith F, Thomas D, KerseN. Delayed antibiotic prescriptions: What are the experiences and attitudes of physicians and patients?. The Journal of Family Practice 2002;51(11):954 9 

Ref 

Arroll B, Kenealy T, Kerse N. Do delayed prescriptions reduce antibiotic use in respiratory tract infections? A systematic review. British Journal of General Practice 

2003;53:871 7 

Ref 

Arroll B, Kenealy T, Kerse N. Do delayed prescriptions reduce the use of antibiotics for the common cold? A single-blind controlled trial. Journal of Family Practice 

2002;51(4):324 8 

Incl 

ArrollB, Kenealy T. Antibiotics for the common cold and acute purulent rhinitis. Cochrane Database of Systematic Reviews 2005, Issue 3.Art.No.: CD000247. 

DOI:10 1002/14651858 CD000247 pub2 

Ref 

BABA S A parallel comparative double blind study of cefixime with cefaclor in the treatment of acute suppurative otitis media 

in children JPN J ANTIBIOT 40 : 1 1987 

Incl 

BAIN J ACUTE OTITIS-MEDIA - CLINICAL COURSE AMONG CHILDREN WHO RECEIVED A SHORT COURSE OF HIGHDOSE ANTIBIOTIC BRITISH MEDICAL JOURNAL 291 : 1243 1985 

Incl excl Incl Ref 

Barnett ED, Teele DW, Klein JO, Cabral HJ, Kharasch SJ. Comparison of ceftriaxone and trimethoprim-sulfamethoxazole for acute otitis media Pediatrics 1997;99:23 8 

Incl Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Bass JW, Cashman TM, Frostad AL, Yamaoka M, Schooler RA, Dierdorff EP Antimicrobials in the treatment of acute otitis 

media. A second clinical trial. Am J Dis 

Child 1973; 125:397 402 

Incl Ref 

Bass JW, Cohen SH, Corless JD, Mamunes P. Ampicillin compared to other antimicrobials in acute otitis media. JAMA. 1967;202;697 702 

Incl Ref 

Bauchner H, Adams W, Barnett E, Klein J Therapy for acute otitis media. Preference of parents for oral or parenteral antibiotic. Arch Pediatr Adolesc Med 1996; 150:396 399 

Incl Ref 

BEGG CB A MEASURE TO AID IN THE INTERPRETATION OF PUBLISHED CLINICAL-TRIALS STATISTICS IN MEDICINE4:1 1985 

Ref 

BEGUE P ACUTE OTITIS-MEDIA IN CHILDREN - A RANDOMIZED OPEN CLINICAL-TRIAL OF EFFECTIVENESS OF 2 MAJOR ANTIBIOTICS -(ERYTHROMYCIN ETHYLSUCCINATE ACETYL-SULFAFURAZOLE VERSUS AMOXICILLIN CLAVULANIC ACID 

Incl 

Behre U, Burow HM, Quinn P, Cree F, Harrison HE. Efficacy of twice-daily dosing of amoxycillin/clavulanate in acute otitis media in children. Infection 1997;25(3):163­

6 BERGERON MG COMPARATIVE EFFICACIES OF ERYTHROMYCINSULFISOXAZOLE AND CEFACLOR IN ACUTE OTITIS-MEDIA - A DOUBLE-BLIND RANDOMIZED TRIAL PEDIATRIC INFECTIOUS DISEASE JOURNAL 6 : 654 

Incl 

Berlin JA. Does blinding of readers affect the results of meta-analyses? Lancet 1997 1997;350:185-6 

Ref 

Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D. Otitis mediarelated antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid 

population Pediatrics 1997;100(4):585 92 

Ref 

Berman S, Lauer BA A controlled trial of cefaclor versus amoxicillin for treatment of acute otitis media in early infancy. Pediatr 

Infect Dis J 1983; 2:30 33 

Ref 

Berman S. Otitis media in developing countries. Pediatrics 1996;96:126-31. 

Ref Ref Ref 

Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatric Infectious Disease Journal Incl 

BLUESTONE CD CURRENT THERAPY FOR OTITIS-MEDIA AND CRITERIA FOR EVALUATION OF NEW ANTIMICROBIAL AGENTS CLINICAL INFECTIOUS DISEASES 14 : S197 1992 

Ref 

Blumer JL, Bertino JS Jr, Husak MP Comparison of cefaclor and trimethoprimsulfamethoxazole in the treatment of acute 

otitis media Pediatr Infect Dis 1984; 3:25 29 

Incl Ref 

BODOR FF SYSTEMIC ANTIBIOTICS FOR TREATMENT OF THE CONJUNCTIVITIS OTITIS MEDIA SYNDROMEPEDIATRIC INFECTIOUS DISEASE JOURNAL 8 : 287 1989 

Ref 

Boesoirie T: A comparative study between ofloxacin ear drops and neomycin-polymixin b-hydrocortisone ear drops on the chronic suppurative otitis media. Department of ENT Head and Neck Surgery, University of Padjajaran, Bandung, Indonesia. Incl 

BOISSEL JP CONSIDERATIONS FOR THE METAANALYSIS OF RANDOMIZED CLINICAL-TRIALS - SUMMARY OF A PANEL DISCUSSION CONTROLLED CLINICAL TRIALS 10 : 254 1989 

Ref 

Bollag U, Bollag-Albrecht E Recommendations derived from practice audit for the treatment of acute otitis media. 

Lancet 1991; 338:96 99 

Incl Ref 

Borzak S, Ridker PM. Discordance between meta-analyses and large-scale randomized, controlled trials. Ann Intern Med 1995;123:873 7 

Ref 

Bottenfield GW, Burch DJ, Hedrick JA, Schaten R, Rowinski CA, Davies JT Safety and tolerability of a new formulation (90 mg/kg/day divided every 12 h) of amoxicillin/clavulanate (Augmentin) in the empiric treatment of pediatric acute otitis media caused by drugresistantStreptococcus pneumoniae. Pediatr 

Incl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Boulesteix J, Begue P, Dubreuil C, Acute otitis media in children: a study of nasopharyngeal carriage of potential pathogens and therapeutic efficacy of cefixime and amoxicillin-clavulanate. I f ti 1995 23 S79 S82 Boulesteix J, Dubreuil C, Moutot M, Rezvani Y, Rosembaum. Cefpodoxime proxetil 5 jours versus cefixime 8 jours, dans le traitement des otites moyennes aigues de l'enfant Med Mal Infect 1995;25:534 9 

Incl Ref 

Britten N, Ukoumunne O. The infl uence of patients’ hopes of receiving a prescription on doctors’ perceptions and the decisionto prescribe: a questionnaire survey. BMJ 1997; 315: 1506 10 Brodie DP, Griggs JV, Cunningham K Comparative study of cefuroxime axetil suspension and amoxicillin syrup in the treatment of acute otitis media in general practice J Int Med Res 1990; 18:235 239 

Ref 

Brook I.Microbiology of common infections in the upper respiratory tract. Primary Care 1998;25(3):633–48 

Ref 

Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false- positives and false-negatives.Health Technol Assess 

2001 5 1 56 BROWNING GG CONTROVERSIES IN THERAPEUTICS - CHILDHOOD OTALGIA -ACUTE OTITIS-MEDIA .1. ANTIBIOTICS NOT NECESSARY IN MOST CASES BRITISH MEDICAL JOURNAL 300 : 1005 1990 

Ref 

BRUIJNZEELS MA Everyday symptoms in childhood: occurrence and general practitioner consultation rates BRITISH JOURNAL OF GENERAL PRACTICE 48 : 

880 1998 

Ref 

Brunet J, Cozette P. [Clinical study of Otipax in infectious and barotraumatic pathology of the middle ear]. Therapeutique 1970;46(4):399 401 

excl 

Burke P, Bain J, Robinson D, Dunleavey J Acute red ear in children: controlled trial of non-antibiotic treatment in general practice. 

BMJ 1991; 303:558 562 

Ref Incl Ref Incl Incl Incl Ref 

Busmann GJ. [Local therapy of diseases of the middle ear]. Therapie der Gegenwart 1967;106(10):1326-9 

excl 

CALLAHAN CW COST-EFFECTIVENESS OF ANTIBIOTIC-THERAPY FOR OTITISMEDIA IN A MILITARY PEDIATRICCLINICPEDIATRIC INFECTIOUS DISEASE 

JOURNAL 7 : 622 1988 

Ref 

CAMERON GG Comparative efficacy of ampicillin and trimethoprimsulfamethoxazole in otitis media CAN MED 

ASSOC J 112 : 87 1975 

Incl 

Canafax DM, Giebink GS. Clinical and pharmacokinetic basis for the antimicrobial treament of acute otitis media. Otolaryngol Clin North Am 1991;24:859 74 

Ref 

CARLIN SA EARLY RECURRENCES OF OTITIS-MEDIA - REINFECTION OR RELAPSE JOURNAL OF PEDIATRICS 110 

: 20 1987 

Ref 

Casselbrant ML, Kaleida PH, Rockette HE, Paradise JL, Bluestone CD, Kurs-Lasky M, et al. Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media: results of a randomized clinical trial. Incl Incl 

Cates C. An evidence based approach to reducing antibiotics use in children with acute otitis media: controlled before and after study. British Medical Journal 1999;318:715 6 

Ref excl 

Chalmers I, Adams M, Dickersin K, Hetherington J, Tarnow-Mordi W, Meinert C, et al. A cohort study of summary reports of controlled trials. The Journal of the 

American Medical Association 

Ref Ref Ref 

CHALMERS TC A METHOD FOR ASSESSING THE QUALITY OF A RANDOMIZED CONTROL TRIAL CONTROLLED CLINICAL TRIALS 2 : 31 

1981 

Ref 

CHALMERS TC DATA ANAL CLIN MED Q : 85 1988 

Ref 

CHALMERS TC METAANALYSIS OF CLINICAL-TRIALS AS A SCIENTIFIC DISCIPLINE .1. CONTROL OF BIAS AND COMPARISON WITH LARGE COOPERATIVE TRIALS STATISTICS IN 

MEDICINE 6 315 1987 

Ref 

CHALMERS TC PROBLEMS INDUCED BY META-ANALYSES STATISTICS IN 

MEDICINE 10 : 971 1991 

Ref 

Chalmers TC, Celano P, Sacks HS, Smith Jr H. Bias in treatment assignment in controlled clinical trials. N Engl J Med 

1983;309:1358 61 

Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Chamberlain JM, Boenning DA, Waisman Y, Ochsenschlager DW, Klein BL Single-dose ceftriaxone versus 10 days of cefaclor for otitis media Clin Pediatr 1994; 33:642 646 

Incl Incl Ref 

Chaput de Saintonge DM, Levine DF, Temple Savage IT, Burgess GW, Sharp J, Mayhew SR, et al. Trial of three-day and tenday courses of amoxycillin in otitis media. BMJ Clinical Research Edition 1982 284(6322) 1078 81 

excl Incl Incl Ref 

Charles J, Pan Y, Britt H. Trends in childhood illness and treatment in Australian general practice, 1971-2001. Medical Journal of Australia 2004;180:216 9 

Ref 

CHONMAITREE T RESPIRATORY VIRUSES INTERFERE WITH BACTERIOLOGICAL RESPONSE TO ANTIBIOTIC IN CHILDREN WITH ACUTE OTITIS-MEDIA JOURNAL OF INFECTIOUS 

DISEASES 162 546 1990 

Ref 

Claessen JQ, Appelman CL, Touw Otten FW, de Melker RA, Hordijk GJ. Persistence of middle ear dysfunction after recurrent acute otitis media. Clinical Otolaryngology 

1994;19:35 40 

Incl Incl Ref 

CLAESSEN JQPJ A REVIEW OF CLINICALTRIALS REGARDING TREATMENT OF ACUTE OTITIS-MEDIA CLINICAL OTOLARYNGOLOGY 17 : 251 1992 

Ref 

Cohen ML. Epidemiology of drug resistance:implications for a postantimicrobial era Science 1992;257:1050-5 Ref 

COHEN R RANDOMIZED OPEN STUDY OF PEDIAZOLE VERSUS CEFACLOR IN CHILDREN WITH ACUTE OTITIS-MEDIA 

ANNALES DE PEDIATRIE 38 : 115 1991 

Incl 

Cohen R, de La Rocque F, Boucherat M, Levy C, Langue J, Bourrillon A Randomized trial comparing 5-day cefpodoxime proxetil and 8-day amoxicillin-clavulanate treatment of acute otitis media in children [Étude randomisée cefpodoxime proxetil 5 jours versus amoxicilline-acide clavulanique 8 jours dans le traitement de l'otite moyenne 

Incl Ref 

Cohen R, Levy C, Boucherat M, Levy C, Langue J, de La Rocque F A multi-center, randomized, double-blind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children. J Pediatr 1998; 133 634 639 

Incl Ref 

Coles SJ, Addlestone MB, Kamdar MK, Macklin JL A comparative study of clarithromycin and amoxicillin suspensions in the treatment of pediatric patients with acute otitis media Infection 1993; 21:272 

Ref 

Comeau M, Brummett R. Anesthesia of the human tympanic membrane by iontophoresis of a local anesthetic. The laryngoscope 1978;88(2 Pt 1):277 85 

excl 

Cook DJ, Sackett DL, Spitzer WO. Methodologic guidelines for systematic review of randomized control trials in health care from the Potsdam Consulation. J Clin 

Epidemiol 1995;48:161 71 

Ref 

Cruze, E.; Weldon, J. Minitab Reference Manual, Release 7; Minitab Inc: Forge 

Valley PA 1989 

Ref 

Dagan R, Sikuler-Cohen M, Zamir O, Janco J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatric Infectious Disease Journal Incl 

DALY KA EPIDEMIOLOGY OF OTITISMEDIA OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA 24 : 775 1991 

Ref 

Damoiseaux RA, van Balen FA, Hoes AW, Verheij TJ,de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitus media in children aged under 2 years. BMJ 

2000 320 350 54 

Incl 

Damoiseaux RAMJ, van Balen FAM, Hoes AW, Verheij TJM and de Melker RA (2000) Primary care based randomised, double blind trial of amoxycillin versus placebo for acute otitis media in children aged under 2 

B iti h M di l J l 320 330 

Ref 

Damrikarnlert L, Jauregui AC, Kzadri M. Efficacy and safety of amoxycillin/clavulanate (Augmentin) twice daily versus three times daily in the treatment of acute otitis media in children. 

Th A ti 454 St d G J l f Daniel RR Comparison of azithromycin and co-amoxiclav in the treatment of otitis media in children. J Antimicrob Chemother 1993; 31:65 71 

Incl Incl Incl Ref 

Del Mar C, Glasziou P, Hayem M Are antibiotics indicated as initial treatment for children with acute otitis media? A metaanalysis BMJ 1997; 314:1526 1529 

Ref Ref excl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat.Cochrane Database of Systematic Reviews 2006, Issue 4.Art. No.:CD000023. DOI:10 1002/14651858 CD000023 pub3 Department of Health Standing Medical Advisory Committee Subgroup on Antimicrobial Resistance 2000 Department of Health Standing Medical Advisory Committee Subgroup on Antimicrobial Resistance. The path of least resistanceRef DERSIMONIAN R METAANALYSIS IN CLINICAL-TRIALS CONTROLLED CLINICAL TRIALS 7 : 177 1986 

Ref Ref Ref 

DESAINTONGE DMC TRIAL OF 3-DAY 

AND 10-DAY COURSES OF AMOXYCILLIN 

IN OTITIS-MEDIA BRITISH MEDICAL 

JOURNAL 284 : 1078 1982 

Ref 

DICKERSIN K FACTORS INFLUENCING PUBLICATION OF RESEARCH RESULTS -FOLLOW-UP OF APPLICATIONS SUBMITTED TO 2 INSTITUTIONAL REVIEW BOARDS JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 

Ref 

Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic 

reviews BMJ 1994;309(6964):1286-91 

Ref Ref 

Dohar J, Garner E, Nielsen R, Biel MA, Seidlin M: Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg 

1999;125:537 545 Incl Dohar J, Giles W, Roland RS, et al. Topical ciprofloxacin/dexamethasone superior to oral amoxicillin/clavulanic acid in acute otitis media with otorrhea through tympanostomy tubes Pediatrics 2006;118:e561 e569 Douglas RM, Miles HB. Vaccination against Streptococcus pneumoniae in childhood: lack of demonstrable benefit in young Australian children. Journal Infectious Disease 1984;149(6):861 9 Incl Douglas RM, Hansman D, McDonald B, Paton J, Kirke K. Pneumococcal vaccine in aboriginal children - a randomized controlled trial involving 60 children. Community Health Study 1986;10(2):189 96 Incl Dowell J, Pitkethy M, Bain J, Martin S. A randomised controlled trial of delayed antibiotic prescribing as a strategy for managing uncomplicated respiratory tract infection in primary care. British Journal of G l P ti 2001 51 200 5 

Ref 

Dowell SF, Butler JC, Giebink GS, Acute otitis media: management and surveillance in an era of pneumococcal resistancea report from the Drug-Resistant Streptococcus pneumoniae Therapeutic 

W ki G P di t I f t Di J 1999 

Incl 

EASTERBROOK PJ PUBLICATION BIAS IN CLINICAL RESEARCH LANCET 337 : 867 

1991 

Ref 

Egger M, Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, 

graphical test BMJ 1997;315:629-34 

Ref 

El-Daher N, Rawashedeh N, Al-Khalil I, Abuektaish F. Immediate versus delayed treatment of Group A beta-haemolytic streptococcal pharyngitis with penicillin V. Pediatric Infectious Disease 

J l1991 10(2) 126 30 El-Sayed Y. Treatment of recurrent acute otitis media chemoprophylaxis versus ventiliation tube. Australian Journal of Otolaryngology 1996;2(4):352 5 Incl Engelhard D, Cohen D, Strauss N, Randomised study of myringotomy, amoxicillin/clavulanate, or both for acute otitis media in infants Lancet 1989; 2:141 

Incl excl Ref Incl 

Eppes SC, Klein JD, Lewis LL. Ceftriaxone for acute otitis media. Pediatrics 

1997;100:157 

Ref 

Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al. Efficacy of a Pneumococcal Conjugate Vaccine against Acute Otitis Media. New England Journal of 

Medicine 8 2 2001;344(6):403 9 Incl Everitt H, Little P, Smith P. A randomised controlled trial of managementstrategies for acute infective conjunctivitis in general practice.British Medical Journal 2006;333(7563):321 

excl 

FADEN H NASOPHARYNGEAL FLORA IN THE 1ST 3 YEARS OF LIFE IN NORMAL AND OTITIS-PRONE CHILDREN ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY 100 : 612 1991 

Ref 

Faden H, Bernstein J, Brodsky L, et al. Effect of prior antibiotic treatment on middle ear disease in children. Ann Otol Rhinol 

Laryngol 1992;101:87 91 

Ref Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Fahey T, Smucny J, Becker L, Glazier R. Antibiotics for acute bronchitis.CochraneDatabase of Systematic Reviews 2004, Issue 1.Art.No.:CD000245. DOI:10 1002/14651858 CD000245 pub2 

Ref 

Fay DL, Schellhase KG, Wujek D. Naturopathic ear drops minimally effective for acute otitis media. The Journal of Family 

Practice 2003;52(9):673 676 

excl 

FAYELUND H ACUTE AND LATENT MASTOIDITIS JOURNAL OF LARYNGOLOGY AND OTOLOGY 103 : 

1158 1989 

Ref 

FEDER HM COMPARATIVE TOLERABILITY OF AMPICILLIN, AMOXICILLIN, AND TRIMETHOPRIMSULFAMETHOXAZOLE SUSPENSIONS IN CHILDREN WITH OTITIS-MEDIA 

ANTIMICROBIAL AGENTS AND 

excl 

Feigin RD, Keeney RE, Nusrala J, Shackelford PG, Lins RD Efficacy of clindamycin therapy for otitis media. Arch 

Otolaryngol 1973; 98:27 31 

Ref Ref 

FELDMAN S SIMILAR HEMATOLOGIC CHANGES IN CHILDREN RECEIVING TRIMETHOPRIM-SULFAMETHOXAZOLE OR AMOXICILLIN FOR OTITIS-MEDIA JOURNAL OF PEDIATRICS 106 : 995 1985 

excl 

FELDMAN W TRIMETHOPRIMSULFAMETHOXAZOLE V AMOXICILLIN IN THE TREATMENT OF ACUTE OTITISMEDIA CANADIAN MEDICAL 

ASSOCIATION JOURNAL 139 : 961 1988 

Incl 

Feldman W, Sutcliffe T, Dulberg C Twicedaily antibiotics in the treatment of acute otitis media: trimethoprim-sulfamethoxazole versus amoxicillin-clavulanate [see comments] Can Med Assoc J 1990; 

Incl Ref 

Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media Pediatric Infectious Disease Journal Incl Fort G. Analgesia in otorhinolaryngological diseases: Lysine clonixinate versus ibuprofen [Analgesia en afecciones otorrinolaringologicas Clonixinato de Lisina vs. Ibuprofeno]. Prensa Medica Argentina 2000 87(4) 409 418 

excl 

Foshee WS Loracarbef (LY163892) versus amoxicillin-clavulanate in the treatment of bacterial acute otitis media with effusion. J 

Pediatr 1992; 120:980 986 Francois M. [Efficacy and tolerance of a local application of phenazone and chlorhydrate lidocaine (Otipax) in infants and children with congestive otitis]. Annales de Pediatrie 1993;40(7):481 4 

excl 

Francois M. [Treatment of acute otitis 

media]. Archives de Pediatrie 1995;2(1):86­

excl 

FRENKEL M ACUTE OTITIS-MEDIA -DOES THERAPY ALTER ITS COURSE POSTGRADUATE MEDICINE 82 : 84 1987 

Ref 

Froom J, Culpepper L, Grob P, Diagnosis and antibiotic treatment of acute otitis media: report from International Primary 

Care Network BMJ 1990; 300:582 586 

Ref Ref Ref Ref Ref 

Froom J, Culpepper L, Jacobs M. Antimicrobials for acute otitis media? A review from the International Primary Care Network. The British Medical Journal 1997;315:98 102 

Ref Incl 

FRY J ANTIBIOTICS IN ACUTE TONSILLITIS AND ACUTE OTITIS MEDIA 

BRITISH MEDICAL JOURNAL 2 : 883 1958 

Ref 

Gaskins JD, Holt J, Kyong CU, Weart CW, Ward J. Chemoprophylaxis of recurrent otitis media using 

trimethoprim/sulfamethoxazole Drug Intell Incl Incl Incl Gates GA. Cost-effectiveness considerations in otitis media treatment. In: Lim D, Bluestone CD, Casselbrant M, Klein J, Ogra P, eds. Proceedings of the Sixth International Symposium: Recent Advances in Otitis Media; June 4-8, 1995; Fort Gebhart DE. Tympanostomy tubes in the otitis media prone child. Laryngoscope 1981;91(6):849-66 incl Gehanno P, Taillebe M, Denis P, Jacquet P, Hoareau J, Gojon D, et al. Short-course cefotaxime compared with five-day coamoxyclav in acute otitis media in children. J Antimicrob Chemother 1990;26 Suppl A:29­36 

excl 

Gendeh S: A comparative study of ofloxacin otic drops vs. framycetin sulfatedexamethasone-gramicidin otic drops in the medical treatment of otitis externa and chronic suppurative otitis media. Department of ORL, Hospital University Kabangsaan Malaysia, Kuala Lumpur, Incl 

Gerber M, Randolph M, DeMeo K, Kaplan E. Lack of impact of early antibiotic therapy for streptococcal pharyngitis on recurrence rates. The Journal of Pediatrics 1990;December:853 8 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

GIEBINK GS Otitis media update: pathogenesis and treatment. ANN OTOL RHINOL LA S 155 : 21 1992 

Ref 

GIEBINK GS ANTIMICROBIAL TREATMENT OF ACUTE OTITIS-MEDIA 

JOURNAL OF PEDIATRICS 119 : 495 1991 

Ref 

Giebink GS, Batalden PB, Russ JN, Le CT. Cefaclor v amoxicillin in treatment of acute otitis media Am J Dis Child 1984; 138:287­

292 

Incl Incl Ref 

Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children. The Cochrane Database of Systematic Reviews 2003, Issue 4.Art. No.: CD000219. DOI: 10 1002/14651858 CD000219 b2 

Ref Ref 

Goldblatt E, Dohar J, Nozza R, Nielsen RW, Goldberg T, Sidman JM, Seidlin M: Topical versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr 

Ot hi l l 1998 46 91 101 

Incl 

Gonzalez C, Arnold JE, Woody EA, Erhardt JB, Pratt SR, Getts A, Kueser TJ, Kolmer JW. Prevention of recurrent acute otitis media: chemoprophylaxis versus tympanostomy tubes. Laryngoscope 1986; 96 1330 1334 

Incl Incl Incl 

Gooch WM III, Blair E, Puopolo A, Effectiveness of five days of therapy with cefuroxime axetil suspension for treatment of acute otitis media. Pediatr Infect Dis J 1996; 15:157 164 

Incl Ref Incl Ref 

Gray B. Controlled trial of sulfamethoxazoletrimethoprim for the prevention of recurrent acute otitis media in young children. Current Chemotherapy & Immunotherapy. Proceedings of the 12th International Congress of Chemotherapy. Florence, Italy, Incl Green SM, Rothrock SG. Single-dose intramuscular ceftriaxone for acute otitis media in children Pediatrics 1993;91:23-30 

Incl Ref 

Greenland S, Finkle WD. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 1995; 142: 1255 64 Gregoire G, Derderian F, Le Lorier J. Selecting the language of the publications included in a meta-analysis:is there a tower of babel bias? J Clin Epidemiol 1995;48:159­63 

Ref 

Guillemot D, Carbon C, Balkau B, Geslin P, Lecoeur H, Vauzelle-Kervroedan F, et al. Low dosage and long treatment duration of B-lactam: Risk factors for carriage of penicillin-resistant Streptococcus 

i JAMA 1997 279 365 70 

Ref 

Halsted C, Lepow ML, Balassanian N, Emmerich J, Wolinsky E Otitis media: microbiology and evaluation of therapy. Ann 

N Y Acad Sci 1967; 145:372 378 

Ref 

Halsted C, Lepow ML, Balassanian N, Emmerich J, Wolinsky E.Otitis media: clinical observation, microbiology and evaluation of therapy Am J Dis Child 1968; 

Incl Incl Incl Incl Ref 

Harrison CJ, Chartrand SA, Pichichero ME. Microbiologic and clinical aspects of a trial of once daily cefixime compared with twice daily cefaclor for treatment of acute otitis media in infants and children. Pediatr Infect Di J 1993 12 62 9 

excl 

Harrison CJ, Marks MI, Welch DF. Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatr Infect Dis 

1985;4:641 6 

Ref Ref 

HATHAWAY TJ ACUTE OTITIS-MEDIA -WHO NEEDS POSTTREATMENT FOLLOWUP PEDIATRICS 94 : 143 1994 Ref 

Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media. Arch Pediatr Adolesc Med 1995;149:26-29 Incl Helmi A, Ratna D, Zainul A, Sosialisman E, Alfian FH, Bambang H: The efficacy and safety of ofloxacin otic solution for active suppurative otitis media. Faculty of Medicine, University of Indonesia, Jakarta, I d i U bli h d 2000 

Incl 

Hendrickse WA, Kusmiesz H, Shelton S, Nelson JD Five vs. ten days of therapy for acute otitis media. Pediatr Infect Dis J 1988; 7:14 23 

Incl excl Incl Ref 

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses BMJ 2003; 327: 557–60 Hoberman A, Paradise JL, Burch DJ, Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children. Pediatr Infect Dis J 1997; 

Incl Incl Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Hoberman A, Paradise JL, Reynolds EA, Urkin J. Efficacy of Auralgan for treating ear pain in children with acute otitis media. Archives of Pediatrics & Adolescent Medicine 1997;151(7):675 8 

Incl 

HOWARD JE OTITIS MEDIA OF INFANCY AND EARLY-CHILDHOOD - DOUBLEBLIND-STUDY OF 4 TREATMENT REGIMENS AMERICAN JOURNAL OF 

DISEASES OF CHILDREN 130 : 965 1976 

excl 

HOWIE VM The "otitis-prone" condition.AM 

J DIS CHILD 129 : 676 1975 

Ref 

HOWIE VM BACTERIOLOGICAL AND CLINICAL EFFICACY OF CEFIXIME COMPARED WITH AMOXICILLIN IN ACUTE OTITIS-MEDIA PEDIATRIC INFECTIOUS DISEASE JOURNAL 6 : 989 

excl 

HOWIE VM EFFICACY OF FIXED COMBINATION ANTIBIOTICS VERSUS SEPARATE COMPONENTS IN OTITIS MEDIA - EFFECTIVENESS OF ERYTHROMYCIN ESTOLATE, TRIPLE SULFONAMIDE, AMPICILLIN, ERYTHROMYCIN ESTOLATE-TRIPLE SULFONAMIDE, AND PLACEBO IN 280 PATIENTS WITH ACUTE OTITIS MEDIA UNDER 2 1/2 YEARS OF AGE CLINICAL 

Incl Incl excl excl Incl Ref 

Howie VM, Dillard R, Lawrence B In vivo sensitivity test in otitis media: efficacy of antibiotics Pediatrics 1985; 75:8-13 

Ref 

Howie VM, Ploussard JH. The "In Vitro Sensitivity Test'-Bacteriology of middle ear exudate Pediatrics 1969;44:940-4 

Ref 

Huwiler-Muntener K, Juni P, Junker C, EggerM. Quality of reporting of randomized trials as a measure of methodologic quality. 

JAMA 2002;287(21):2801 4 IINO Y PROGNOSTIC FACTORS FOR PERSISTENT MIDDLE-EAR EFFUSION AFTER ACUTE OTITIS-MEDIA IN CHILDREN ACTA OTO-LARYNGOLOGICA 113 : 761 1993 

Ref 

Ingvarsson L. Acute otalgia in children—findings and diagnosis. Acta Paediatr Scand 1982;71:705-710 Incl Ingvarsson L, Lundgren K Penicillin treatment of acute otitis media in children. A study of the duration of treatment. Acta Otolaryngol 1982; 94:283 287 

Incl Ref Incl Ref 

Jacobson JA, Metcalf TJ, Parkin JL, Wenerstrom LG. Evaluation of cefaclor and amoxycillin in the treatment of acute otitis media. Postgrad Med J 1979;55(Suppl 4):39­41 

excl Incl Ref 

JACOBY GA MECHANISMS OF DISEASE -NEW MECHANISMS OF BACTERIALRESISTANCE TO ANTIMICROBIAL AGENTS NEW ENGLAND JOURNAL OF MEDICINE 324 : 601 1991 

Ref 

Jadad AR, Moore R, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials:is blinding 

necessary? Control Clin Trials 1996;17:1 

Ref 

JENNER PN A GENERAL-PRACTICE STUDY OF A NEW APPROACH TO THE USE OF ANTIBIOTICS IN THE TREATMENT OF ACUTE OTITIS-MEDIA IN CHILDREN AGED 3 AND OVER BRITISH JOURNAL OF CLINICAL PRACTICE 41 : 

excl Incl 

JOHN WRB TREATMENT OF OTITISMEDIA IN CHILDREN - A COMPARISON BETWEEN CEFACLOR AND 

AMOXYCILLIN PRACTITIONER 227 : 1805 

Incl 

JOHNSON CE CEFIXIME COMPARED WITH AMOXICILLIN FOR TREATMENT OF ACUTE OTITIS-MEDIA JOURNAL OF PEDIATRICS 119 : 117 1991 

excl Incl Ref 

JONES R 3-DAY AND 7-DAY TREATMENT IN ACUTE OTITIS-MEDIA - A DOUBLEBLIND ANTIBIOTIC TRIALJOURNAL OF THE ROYAL COLLEGE OF GENERAL PRACTITIONERS 36 : 356 1986 

Incl Ref Incl Ref 

Juni P,Witschi A, Bloch R, EggerM. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999;282(11):1054 9 Kafetzis DA Multi-investigator evaluation of the efficacy and safety of cefprozil, amoxicillin-clavulanate, cefixime and cefaclor in the treatment of acute otitis media. Eur J Clin Microbiol Infect Dis 1994; 13:857 865 

Ref Incl 

Kafetzis DA, Astra H, Mitropoulos L. Fiveday versus ten-day treatment of acute otitis media with cefprozil. Eur J Clin Microbiol 

Infect Dis 1997;16:283 6 

Incl Ref 

KALEIDA PH AMOXICILLIN OR MYRINGOTOMY OR BOTH FOR ACUTE OTITIS-MEDIA - RESULTS OF A RANDOMIZED CLINICAL-TRIAL PEDIATRICS 87 : 466 1991 

Incl Incl Ref Ref Ref Incl Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

KALEIDA PH AMOXICILLINCLAVULANATE POTASSIUM COMPARED WITH CEFACLOR FOR ACUTE OTITISMEDIA IN INFANTS AND CHILDREN PEDIATRIC INFECTIOUS DISEASE JOURNAL 6 265 1987 

Incl 

Kaprio E, Haapaniemi J, Bondesson G. Clinical efficacy of amoxycillin/clavulanic acid and cefaclor in acute otitis media. Acta Otolaryngol Suppl 1988;449:45 6 

Incl 

Kara CO, Ozuer MZ, Kilic I, Yalcin AN, Ergin H Comparison of amoxicillin with second and third generation cephalosporins in the treatment of acute otitis media. Infez Med 1998; 6:93 95 

Ref 

Karma P, Luotonen J, Timonen M, Pontynen S, Pukander J, Herva E. Efficacy of pneumococcal vaccination against recurrent otitis media. Preliminary results of a field trial in Finland. Annals Otology Rhinology Laryngology Supplement 1980;89(3 Pt Incl Karma PH, Penttila MA, Sipila MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media, I: the value of different otoscopic findings. Int J Pediatr Otorhinolaryngol 1989;17:37 Incl Karma P, Pukander J, Sipila M, Timonen M, Pontynen S. Herva E, et al. Prevention of otitis media in children by pneumococcal vaccination. American Journal of Otolaryngology 1985;6(3):173 84 Incl KENNA MA CEFIXIME VS CEFACLOR IN THE TREATMENT OF ACUTE OTITISMEDIA IN INFANTS AND CHILDREN PEDIATRIC INFECTIOUS DISEASE JOURNAL 6 : 992 1987 

Incl 

Khurana CM. A multi-center, randomized, open label comparison of azithromycin and amoxicillin/clavulanate in acute otitis media among children attending day care or school Pediatr Infect Dis J 1996;15 

Incl Incl Ref 

KIM HKC COMPARISON OF BACAMPICILLIN AND AMOXICILLIN IN ACUTE OTITIS-MEDIA WITH EFFUSION BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE 59 : 515 1983 

Incl 

Klein JO, Teele DW, Rosner BA, et al. Epidemiology of acute otitis media in Boston children from birth to seven years of age. Recent Advances in Otitis Media with Effusion. Proceedings of the Fourth I t ti l S i 1988 6 8 

Ref 

Klein JO. Epidemiology of otitis media. Pediatric Infectious Disease Journal 

1989;8(Suppl 1):89 

Ref Ref 

Klein JO. Protecting the therapeutic advantage of antimicrobial agents used for otitis media. Pediatr Infect Dis 

J 1998;17:571 575 discussion 580 Klein JO. The burden of otitis media. Vaccine 2001;19(Suppl):2-8. 

Ref 

KLIGMAN EW TREATMENT OF OTITISMEDIA .1. AMERICAN FAMILY PHYSICIAN 

45 : 242 1992 

Ref 

Koeppel FW. [Treatment of diseases of the ear canal and middle ear with Otobacid]. Munchener Medizinische Wochenschrift 

1970;112(17):806 9 

excl 

Kontiokari T, Koivunen P, Niemela M, Pokka T, Uhari M. Symptoms of acute otitis media. 

Pediatr Infect Dis J 1998;17:676-679 Incl Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SEA, Wincott JL, Sitar DS, Klassen TP, et al. Treatment of acute otitis media with a Shortened Course of Antibiotics JAMA 1998;279:1736 42 

Ref 

Kumar S, Little P, Britten N. Why do general practitioners prescribe antibiotics for sore throat?. British Medical Journal 

2003;326:138 43 

Ref 

Kurbasci M, Jones VF, Badgett JT, Thomas A. Two-week vs. six-week followup for acute otitis media [abstract]. Arch Pediatr Adolesc 

Med 1996;150:P19 

Ref 

Lacher G. [Clinical trial of Otipax: auricular pulverizations]. Revue de Laryngologie, D' Otologie et de Rhinologie 1969;90(11):719­

22 

excl 

Landis B, Koch GG. The measurement of observer agreement for categorical data. 

Biometrics 1977;3:159-74 

Ref 

Laszlo I, Pupp L. Anaesthesia of tympanic membrane with lidocaine. Therapia 

Hungarica 1981;29(4):176-9 

excl 

LAUPACIS A AN ASSESSMENT OF CLINICALLY USEFUL MEASURES OF THE CONSEQUENCES OF TREATMENT NEW ENGLAND JOURNAL OF MEDICINE 318 : 

1728 1988 

Ref Ref Ref 

Laxdal OE, Merida J, Jones RH Treatment of acute otitis media: a controlled study of 142 children. Can Med Assoc J 1970; 102:263 268 

Incl excl Incl Incl excl Incl Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Le Saux N, Gaboury I, Baird M, et al. A randomized, double-blind,placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age. CMAJ 2005; 172: 335 41 

Incl 

Leigh AP, Robinson D, Millar ED A general practice comparative study of a new thirdgeneration oral cephalosporin, cefixime, with amoxicillin in the treatment of acute 

paediatric otitis media Br J Clin Pract 1989; 

Incl Ref 

Lenoski EF, Wingert WA, Wehrle PF Drug trials in acute otitis media. Curr Ther Res Clin Exp 1968; 10:631-639 

Incl Ref 

LIGHT RJ SUMMING UP SCI REV R : 3 1984 

Ref 

LISBYSUTCH SM THERAPY OF OTITISMEDIA CLINICAL PHARMACY 9 : 15 1990 Ref LISTON TE THE BACTERIOLOGY OF RECURRENT OTITIS-MEDIA AND THE EFFECT OF SULFISOXAZOLE CHEMOPROPHYLAXIS PEDIATRIC INFECTIOUS DISEASE JOURNAL 3 : 20 

1984 

Ref 

Liston TE, Foshee WS, Pierson MWD Sulfisoxazole chemoprophylaxis for frequent 

otitis media Pediatrics 1983; 71:524-530 Incl Incl incl Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J.Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media BMJ 2001; 322:336 42 

excl Incl Incl 

Little P, Moore M, Warner G, Dunleavy J, Williamson I. Longer term outcomes from a randomised trial of prescribing strategies in otitis media. British Journal of General Practice 2006;56(524):176– 82. [MEDLINE: 16536953] 

Ref 

Little P, Rumsby K, Kelly J, Watson L, Moore M, Warner G, et al.Information leaflet and antibiotic prescribing strategies for acute lower respiratory infection. Journal of the American Medical Association 

2005 293 3029 35 

Incl 

Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. Open randomised trial of prescribing strategies inmanaging sore throat. British Medical Journal 

1997;314(7082):722 7 

Incl 

Little P. Delayed prescribing of antibiotics for upper respiratory tract infection. British 

Medical Journal 2005;331:301–2 

Ref 

LOFTIN LH Current treatment of otitis media 

in children. ALA MED 60 : 24 1991 

Ref 

LORENTZEN P TREATMENT OF ACUTE SUPPURATIVE OTITIS-MEDIA JOURNAL OF LARYNGOLOGY AND OTOLOGY 91 : 

331 1977 

Ref 

Macfarlane J, Holmes W, Macfarlane R, Britten N. Influence of patient’s expectations on antibiotic management of acute lower respiratory tract illness in general practice: questionnaire study. British Medical Journal 1997 315 1211 4 

Ref 

MacLoughlin GJF, Barreto DG, de la Torre C, Pinetta EA, del Castilllo F, Palma L. Cefpodoxime proxetil suspension compared with cefaclor suspension for treatment of acute otitis media in paediatric patients. J 

A ti i bi l Ch th 1996 37 565 

excl 

MacPhail E. Acute otitis media. Canadian 

Pharmaceutical Journal 1996;129(1):29-31. 

excl 

Makela PH, Leinonen M, Pukander J, Karma P. A study of the pneumococcal vaccine in prevention of clinically acute atttacks of recurrent otitis media. Review Infectious 

Disease 1981;3 Suppl:124 32 Incl Makela PH, Sibakov M, Herva E, Henrichsen J, Luotonen J, Timonen M, et al. Pneumococcal vaccine and otitis media. Lancet 1980;2(8194):547 51 Incl MANDEL EM DURATION OF EFFUSION AFTER ANTIBIOTIC-TREATMENT FOR ACUTE OTITIS-MEDIA - COMPARISON OF 

CEFACLOR AND AMOXICILLIN PEDIATRIC INFECTIOUS DISEASE 

JOURNAL 1 310 1982 

Incl 

MANDEL EM EFFICACY OF 20- VERSUS 10-DAY ANTIMICROBIAL TREATMENT FOR ACUTE OTITIS-MEDIA PEDIATRICS 96 : 5 1995 

Ref excl 

Mandel EM, Casselbrant ML, Rockette HE, Bluestone CD, Kurs-Lasky M. Efficacy of antimicrobial prophylaxis for recurrent middle ear effusion. Pediatric Infectious Diseases Journal 1996:15(12):1074 82 Incl Mangione-Smith R,McGlynn E, ElliotM. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behaviour. Pediatrics 1999;103:711 8 

Ref 

MARCHANT CD A RANDOMIZED CONTROLLED TRIAL OF AMOXICILLIN PLUS CLAVULANATE COMPARED WITH CEFACLOR FOR TREATMENT OF ACUTE OTITIS-MEDIA JOURNAL OF PEDIATRICS 

109 891 1986 

Incl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

MARCHANT CD A RANDOMIZED CONTROLLED TRIAL OF CEFACLOR COMPARED WITH TRIMETHOPRIMSULFAMETHOXAZOLE FOR TREATMENT OF ACUTE OTITIS-MEDIA JOURNAL OF PEDIATRICS 105 633 1984 

excl 

MARCHANT CD ANTIBACTERIAL THERAPY FOR ACUTE OTITIS-MEDIA - A CRITICAL ANALYSIS REVIEWS OF 

INFECTIOUS DISEASES 4 : 506 1982 

Ref 

MARCHANT CD MEASURING THE COMPARATIVE EFFICACY OF ANTIBACTERIAL AGENTS FOR ACUTE OTITIS-MEDIA - THE POLLYANNA PHENOMENON JOURNAL OF 

PEDIATRICS 120 72 1992 

Ref 

MARCHANT CD RECENT ADV OTITIS ME 

: 281 1984 

excl 

Marcy M, Takata G, Shekelle P, et al. Management of Acute Otitis Media. Evidence Report/Technology Assessment No. 15. (Prepared by the Southern California Evidence-based Practice Center under Contract No. 290-97-0001). 2001 AHRQ 

Ref 

Mathews JR, McGrath PJ, Pigeon H. Assessment and measurement of pain in children. Pain in Infants, Children, and 

Adolescents Williams and Wilkins 1993 

Ref 

Matz PS, Batista D, Vivier P, Alario AJ. Can a topical otic anesthetic reduce the need for antibiotics in acute otitis media? Pediatric 

Research 2001;49:131A 

excl 

Matz PS, Webster RA, Vivier P, Alario A. Use of a Topical Otic Analgesic as a Treatment Strategy for Acute Otitis Media. Unpublished manuscript presented at the Pediatric Academic Society Meeting; 2001; Baltimore:Pediatric Academic Society 

excl 

Maynard JE, Fleshman JK, Tschopp CF. Otitis media in Alaskan Eskimo children. Prospective evaluation of chemoprophylaxis. 

JAMA 1972;219(5)597 9 Incl Incl McAuley L, Pham B, Tugwell P, Moher D Does the inclusion of grey literature influence the estimates of intervention effectiveness reported in meta-analyses? Lancet 2000; 356:1228 1231 McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among officebased physicians JAMA 1995;273:214-9 Ref McConaghy JR. The evaluation and 

treatment of children with acute otitis media. The Journal of Family Practice 

2001;50(5):457 9 463 5 

excl 

McCormick DP, Chonmaitree T, Pittman C, et al. Nonsevere acute otitis media: a clinical trial comparing outcomes of watchful waiting versus immediate antibiotic 

treatment Pediatrics 2005;115: 1455 65 

Incl 

MCCRACKEN GH SELECTION OF ANTIMICROBIAL AGENTS FOR TREATMENT OF ACUTE OTITIS-MEDIA WITH EFFUSION PEDIATRIC 

INFECTIOUS DISEASE JOURNAL 6 : 985 

Ref 

McCracken GH Treatment of acute otitis media in an era of increasing microbial resistance. Pediatr Infect Dis J 1998; 17:576­

579 McLinn S A multi-center, double blind comparison of azithromycin and amoxicillin/clavulanate for the treatment of acute otitis media in children. Pediatr Infect Dis J 1996; 15:S20 S23 

Incl Incl Ref 

MCLINN SE CEFACLOR IN TREATMENT OF OTITIS-MEDIA AND PHARYNGITIS IN CHILDREN AMERICAN JOURNAL OF DISEASES OF CHILDREN 134 : 560 1980 

excl Ref 

MCLINN SE CURRENT CHEMOTHERAPY 1 : 123 1978 

excl 

McLinn SE Randomized open label multicenter trial of cefixime compared with amoxicillin for treatment of acute otitis media with effusion. Pediatr Infect Dis 1987; 6:997­1001 

Ref 

McLinn SE Recurrence of otitis media after antibiotic therapy: comparison of cephradine and amoxicillin. J Int Med Res 1979; 7:546­550 

Ref 

Mehta C, Patel N. StatXact. Statistical software for exact nonparametric inference. Version 2.0. Cambridge, MA: Cytel Software Corporation 1991 

Ref 

Meistrup-Larsen KI, Mygind N, Thomsen J, Sorensen H, Vesterhauge S Penicillin therapy in acute otitis media. Report of a double-blind, placebo-controlled clinical trial. [Penicillin therapy of acute otitis media. A double-blind placebo-controlled study.] 

Incl 

Meistrup-Larsen KI, Sorensen H, Johnsen NJ, Thomsen J, Mygind N, Sederberg-Olsen J Two versus seven days penicillin treatment for acute otitis media. A placebo controlled trial in children. Acta Otolaryngol 

1983 96 99 104 

Incl Incl Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Menshikov NM. The use of lyase and desoxyribonuclease in acute otitis in children. Zhurnal Ushnykh, Nosovykh i Gorlovykh Boleznei 1968;28(2):77 9 

excl 

Millard J. [On the local treatment of infections of the ear canal and middle ear]. 

Deutsches Medizinisches Journal 

excl 

Mills R, Uttley A, McIntyre M. Relationship between acute suppurative otitis media and chronic secretory otitis media:role of 

antibiotics J R Soc Med 1984;77:754 7 

Ref 

Moher D, Jadad AR, Nichol G, Penman M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials:an annotated bibliography of scales and checklists. 

Control Clin Trials 1995;16:62 73 

Ref 

Mohs E, Rodriguez-Solares A, Rivas E, Hoshy ZE. A comparative study of azithromycin and amoxycillin in paediatric patients with acute otitis media. J Antimicrob 

Chemother 1993;31 Suppl E:73 9 

Incl 

Murph JR, Dusdieker LB, Booth B, Murph WE. Is treatment of acute otitis media with once-a-day amoxicillin feasible? lin Pediatr 

1993;32:528 34 

excl 

Murray BE. Can antibiotic resistance be controlled? Engl J Med 1994;330:1229-30. 

Ref 

MYGIND N PENICILLIN IN ACUTE OTITISMEDIA - A DOUBLE-BLIND PLACEBOCONTROLLED TRIALCLINICAL 

OTOLARYNGOLOGY6:5 1981 

Incl Incl Ref Incl Ref Incl Ref 

NADAL D ACUTE MASTOIDITIS -CLINICAL, MICROBIOLOGICAL, AND THERAPEUTIC ASPECTS EUROPEAN JOURNAL OF PEDIATRICS 149 : 560 1990 

Ref 

Nasrin D, Collignon PJ, Roberts L, Wilson EJ, Pilotto LS, Douglas RM. Effect of beta lactam antibiotic use in children on pneumococcal resistance to penicillin: prospective cohort study. The British 

M di l J l 2002 324(7328) 324 8 

Ref 

Nassar WY, Allen BM A double-blind comparative clinical trial of cephalexin and ampicillin in the treatment of childhood acute otitis media. Curr Med Res Opin 1974; 

2:198 203 

Ref 

NATIONAL DISEASE THE : 1992 Ref Niemela M, Uhari M, Mottonen M, Pokka T. Costs arising from otitis media. Acta Paediatrica 1999;88(5):553–6 

Ref 

Niemela M, Uhari M, Jounio-Ervasti K, Luotonen J, Alho OP, Vierimaa E. Lack of specific symptomatology in children with acute otitis media. Pediatr Infect Dis J. 

1994;13:765 768 Incl NILSON BW ACUTE OTITIS MEDIA -TREATMENT RESULTS IN RELATION TO BACTERIAL ETIOLOGY PEDIATRICS 43 : 351 1969 

Incl Ref 

ODIO CM COMPARATIVE TREATMENT TRIAL OF AUGMENTIN VERSUS CEFACLOR FOR ACUTE OTITIS-MEDIA WITH EFFUSION PEDIATRICS 75 : 819 1985 

Incl 

O'Doherty B. An open comparative study of azithromycin versus cefaclor in the treatment of patients with upper respiratory tract infections. J Antimicrobial Chemotherapy 1996;37 Suppl C:71 81 

excl 

Ostfeld E, Segal J, Kaufstein M, Gelernter I. Management of acute otitis media without primary administration of systemic antimicrobial agents. In: Lim DJ, Bluestone CD, Klein JO,Nelson JD, eds. Recent advances in otitis media. Proceedings of the Fourth International Symposium. Toronto: 

excl Ref excl Incl Ref 

Owen MJ, Anwar R, Nguyen HK, Swank PR, Bannister ER, Howie VM Efficacy of cefixime in the treatment of acute otitis media in children Am J Dis Child 1993; 147:81 86 

Ref 

Oxman A. Preparing and maintaining systematic reviews. Cochrane Reviewers' Handbook Oxford: Update Software 1995 

Ref 

Palmu AA, Herva E, Savolainen H, Karma P, Makela PH, Kilpi TM.Association of Clinical Signs and Symptoms with Bacterial Findings in Acute Otitis Media. Clin Infect Dis 2004; 

38: 234 42 

Ref 

Paradise JL. Managing otitis media:a time for change. Pediatrics 1995;96:712-5. 

Ref 

Paradise JL. Short-course antimicrobial treatment for acute otitis media. Not best for infants and young children. JAMA 

1997;278:1640 42 

Ref 

Perrin JM, Charney E., MacWhinney JB, McInerny TK Miller RL, Nazarian LF. Sulfisoxazole as chemoprophylaxis for recurrent otitis media: A double-blind crossover study in pediatric practice. N Engl 

J M d 1974 291 664 667 

Incl Incl Incl 

Persico M, Podoshin L, Fradis M, Grushka M, Golan D, Foltin V, Wellisch G, Chahaza Z, Kolin A, Winter S. Recurrent acute otitis media - prophylactic penicillin treatment: a prospective study - Part I. Int J Pediatr Ot hi l l 1985 10 37 46 

Incl Incl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Pestalozza G, Cioce C, Facchini M Azithromycin in upper respiratory tract infections: a clinical trial in children with otitis media. Scand J Infect Dis Suppl 1992; 83:22 25 

Incl Incl Ref 

PICHICHERO M COMPARISON OF CEFUROXIME AXETIL, CEFACLOR, AND AMOXICILLIN-CLAVULANATE POTASSIUM SUSPENSIONS IN ACUTE OTITIS-MEDIA IN INFANTS AND CHILDREN SOUTHERN MEDICAL 

Incl 

Pichichero ME, Cohen R. Shortened course of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis. Pediatr Infect Dis J 1997;16:680 95 

Ref 

PichicheroM,Disney F, TalpeyW,Green J, Francis A, Roghmann K,et al.Adverse and beneficial effects of immediate treatment of Group A beta-haemolytic streptococcal pharyngitis with penicillin. PediatricInfectious 

Di J l 1987 6 635 43 

Incl 

PIIPPO T DOUBLE-BLIND COMPARISON OF CEFIXIME AND CEFACLOR IN THE TREATMENT OF ACUTE OTITIS-MEDIA IN CHILDREN SCANDINAVIAN JOURNAL OF 

INFECTIOUS DISEASES 23 : 459 1991 

Incl 

Pirozzo S, Del Mar C. Otitis media. In: Evidence-based Pediatrics and Child Health. 2nd Edition BMJ Books 2004 

Ref 

PLOUSSARD JH EVALUATION OF 5 DAYS OF CEFACLOR VS 10 DAYS OF 

AMOXICILLIN THERAPY IN ACUTE OTITISMEDIA CURRENT THERAPEUTIC RESEARCH-CLINICAL AND EXPERIMENTAL 36 641 1984 

Incl excl Incl Ref 

Polyakova TS, Voznesensky NL, Mironov AA, Al Sakir M. Otinum in the therapy of middle ear diseases. Vestnik-Oto-RinoLaringologii 1991;53(2):56 58 

excl 

POOLE JM Cefprozil vs. Cefixime and Cefaclor in Otitis Media in Children. 

INFECTIONS MED SE 9 : 21 1992 

Incl 

PRELLNER K Is beta-lactamase-producing bacteria of major importance for unfavourable development of acute otitis media? ACTA OTOLARYNGOL STO 493 : 

Ref 

Principi N Multicentre comparative study of the efficacy and safety of azithromycin compared with amoxicillin/clavulanic acid in the treatment of paediatric patients with otitis media. Eur J Clin Microbiol Infect Dis. 

1995 14 669 676 

Incl Incl Ref 

Principi N, Marchisio P Cefixime vs amoxicillin in the treatment of acute otitis media in infants and children. Drugs 1991; 42:25 29 

Incl Ref 

Principi N, Marchisio P, Massironi E, Grasso RM, Filiberti G. Prophylaxis of recurrent acute otitis media and middle-ear effusion. Comparison of amoxicillin with sulfamethoxazole and trimethoprim. Am J Di Child 1989 143 1414 1418 

Incl Incl Incl 

Principi N, Marchisio P, Bigalli L, Massironi E Amoxicillin twice daily in the treatment of acute otitis media in infants and children. Eur J Pediatr 1986; 145:522 525 

Ref Incl Ref 

Puczynski MS, Stankiewicz JA, O'Keefe JP Single dose amoxicillin treatment of acute otitis media Laryngoscope 1987;97:16-18 

Incl Ref

 PUHAKKA H, VIROLAINEN E, AANTAA E. TREATMENT OF ACUTE OTITIS-MEDIA IN CHILDREN - PENICILLIN-V OR AMOXICILLIN? ACTA OTOLARYNGOLOGICA 1982; Suppl. 386:108­111 

excl 

Pukander JS, Jero JP, Kaprio EA, Sorri MJ Clarithromycin vs. amoxicillin suspensions in the treatment of pediatric patients with acute otitis media. Pediatr Infect Dis J 1993; 

12:S118 S121 

Ref 

Reiss G, Reiss M. [Otorhinolaryngology--4: Pro and contra of ear drops]. Pflege Zeitschrift 2002;55(2):86-8 

excl 

Roark R, Berman S. Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media. Pediatric Infectious Disease Journal 1997;16(4)376­

81 

Incl 

ROBINS J A GENERAL ESTIMATOR FOR THE VARIANCE OF THE MANTELHAENSZEL ODDS RATIO AMERICAN JOURNAL OF EPIDEMIOLOGY 124 : 719 1986 

Ref 

Rodriguez AF An open study to compare azithromycin with cefaclor in the treatment of children with acute otitis media. J Antimicrob Chemother 1996; 37:63 69 

Incl Incl Ref 

Rodriguez WJ, Schwartz RH, Sait T, Erythromycin-sulfisoxazole vs amoxicillin in the treatment of acute otitis media in children. A double-blind, multiple-dose comparative study Am J Dis Child 1985; 

Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Roland RS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tube. L 2003 113 2116 2122 Roland RS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tube. Pediatrics. ROSEN C ACUTE OTITIS-MEDIA IN OLDER CHILDREN AND ADULTS TREATED WITH PHENOXYMETHYL PENICILLIN OR ERYTHROMYCIN STEARATE - BACTERIOLOGICAL AND IMMUNOLOGICAL ASPECTS ACTA OTOexcl Rosen C, Christensen P, Henrichsen J, Hovelius B, Prellner K. Beneficial effect of pneumococcal vaccination on otitis media in children over two years old. International Journal Pediatric Otorhinolaryngology 1984 7(3) 239 46 

Incl 

Rosen C, Christensen P, Hovelius B, Prellner K. Effect of pneumococcal vaccination on upper respiratory tract infections in children. Design of a follow-up study. Scandinavian Journal Infectious Di S l t 1983 39 39 44 

Incl 

Rosenfeld R. Personal communication 2005. Ref ROSENFELD RM CLINICAL EFFICACY OF ANTIMICROBIAL DRUGS FOR ACUTE OTITIS-MEDIA - METAANALYSIS OF 5400 CHILDREN FROM 33 RANDOMIZED TRIALS JOURNAL OF PEDIATRICS 124 : 355 1994 

Ref Ref Ref 

Rosenfeld RM. An evidence-based approach to approach to treating otitis media Ped Clin NA 1996;43:1165-81 

Ref 

Rosenfeld RM. Natural history of untreated otitis media. In: Rosenfeld RM, Bluestone CD, eds. Evidence-Based Otitis Media. St 

Louis MO: BC Decker Inc; 1999:157 177 Rosenfeld RM. Natural history of untreated otitis media. Laryngoscope 2003;113:1645­57 

Ref 

Rosenfeld RM. What to expect from medical therapy. In: Rosenfeld RM, Bluestone CD, eds. Evidence-Based Otitis Media. St Louis, 

MO: BC Decker Inc; 1999:179 205 Rothman R, Owens T, Simel D. Does this child have acute otitis media? JAMA 2003;290(12):1633-1640 

Ref 

Rovers MM, Schilder AG, Zielhuis GA, Rosenfeld RM. Otitis media. Lancet 2004; 

363: 465–73 RUBENSTEIN MM TREATMENT OF ACUTE OTITIS MEDIA IN CHILDREN .3. A 3RD CLINICAL TRIAL AMERICAN JOURNAL OF DISEASES OF CHILDREN 109 : 308 1965 

excl excl Incl Ref 

Rudberg RD. Acute otitis media: comparative therapeutic results of sulphonamide and penicillin administered in various forms Acta Otolaryngology 1954; 

excl Ref excl 

Ruohola A, Heikkinen T, Meurman O, Puhakka T, Lindblad N, Ruuskanen O. Antibiotic treatment of acute otorrhea through tympanostomy tube: Randomized double-blind placebo-controlled study with d il f ll P di t i 2003 111 

excl excl 

Sano F, Sole D, Naspitz CK, Takara CK. Otitis media in children. Brasileira-deMedicina 1995;52:113-122 excl 

Sarrell EM, Cohen HA, Kahan E. Naturopathic treatment for ear pain in 

children Pediatrics 2003a;111(5 Pt 1):574­

Incl 

Sarrell EM, Mandelberg A, Cohen HA. Efficacy of naturopathic extracts in the management of ear pain associated with acute otitis media. Archives of Pediatrics & 

Adolescent Medicine 2001;155(7):796 9 

Incl 

Schaad UB Multicentre evaluation of azithromycin in comparison with coamoxiclav for the treatment of acute otitis media in children. J Antimicrob Chemother 

1993; 31:81 88 

Incl Incl Ref 

Schappert SM. Office Visits for Otitis Media: United States, 1975-90. Advance Data from Vital and Health Statistics. Hyattsville, MD: National Center for Health Statistics; 1992 Schecter NL. Management of common pain problems in the primary care pediatric setting. Pain in infants, children and adolescents 2nd Edition Lippincott 

Ref 

Schentag JJ. Antibiotic treatment of acute otitis media in children:dosing 

considerations Pediatr Infect Dis J 

Ref 

Scholz H, Noack R multi-center, randomized, double-blind comparison of erythromycin estolate versus amoxicillin for the treatment of acute otitis media in children. AOM Study Group. Eur J Clin 

Mi bi l I f t Di 1998 17 470 478 

Ref 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Schuller DE. Prophylaxis of otitis media in asthmatic children. Pediatric Infectious Disease 1983;2(4):280-3 Incl Incl incl Schulz KF, Chalmers I, Hayes R, Altman DG. Empirical evidence of bias:dimensions of methodological quality associated with estimates of treatment effects in controlled trials JAMA 1995;273:408 12 [ 

Ref 

SCHUTZMAN SA BACTEREMIA WITH 

OTITIS-MEDIA PEDIATRICS 87 : 48 1991 

Ref 

SCHWARTZ RH AMOXICILLIN AS THE DRUG OF CHOICE FOR ACUTE OTITISMEDIA - ISNT IT TIME FOR ITS REASSESSMENT IN SOME AREAS OF THE COUNTRY PEDIATRIC INFECTIOUS 

DISEASE JOURNAL 8 806 1989 

Ref 

Schwartz RH, Puglise J. Rodriguez WJ. Sulfamethoxazole prophylaxis in the otitisprone child Arch Dis Child 1982;57:590-593 Incl Incl Scott HV, Pannowitz D, Ketelbey JW. 

Cefixime:clinical trial against otitis media and tonsillitis N Z Med J 1990;103:25-6 

excl 

Scottish Intercollegiate Guidelines Network. Guideline 66: Diagnosis and management of childhood otitis media in primary care: a national clinical guideline. http://www.sign.ac.uk/guidelines/fulltext/66/i 

d ht l (A d 16 A t 2005) 2003 

Ref 

Sharland M, Kendall H, Yeates D, Randall A, Hughes G, Glasziou P, et al.Antibiotic prescribing in general practice and hospital admissions for peritonsillar abscess,mastoiditis and rheumatic fever in children:time trend analysis. British Medical 

Ref 

Shikowitz MJ. Otitis media. Children'sHospital-Quarterly 1989;1(4):289-299. excl 

Sih T, Moura R, Caldas S, Schwartz B. Prophylaxis for recurrent acute otitis media: a Brazilian study. International Journal of Pediatric Otorhinolaryngology 1993;25(1­

3):19 24 Incl Silverstein H, Call DL. Tetracaine base. An effective surface anesthetic for the tympanic membrane. Archives of Otolaryngology 1969;90(2):150 1 

excl 

Simon MW Five- vs 10-day treatment of acute otitis media with ceftibuten in infants 

and children Adv Ther 1997; 14:312-317 

Incl Ref 

Sloyer JL, Jr, Ploussard JH, Howie VM. Efficacy of pneumococcal polysaccharide vaccine in preventing acute otitis media in infants in Huntsville, Alabama. Review Infectious Disease 1981;3 Suppl:119 23 Incl Spencer RC, Hannington J, Fraser S, Mason T. Cefpodoxime proxetil versus coamoxiclav in the treatment of acute infections of the ear, nose and throat in children-a multicentre randomized study ( b t t 851) 18th I t ti l C 

excl 

Spicer WJ, Christiansen K, Currie BJ, Dartnell JGA, Ferguson JK, Garland SM. Therapeutic Guidelines: Antibiotic. Version 12. North Melbourne: Therapeutic 

Guidelines Limited 2003 

Ref 

Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-see prescription for the treatment of acute otitis media:a randomized controlled trial. Journal of the American Medical Association 

2006 296(10) 1235 41 

Incl 

Stechenberg BW, Anderson D, Chang MJ, Cephalexin compared to ampicillin treatment 

of otitis media Pediatrics 1976; 58:532-536 

Ref 

STICKLER GB TREATMENT OF ACUTE OTITIS MEDIA IN CHILDREN .2. SECOND CLINICAL TRIAL JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 187 : 85 1964 

excl excl 

STICKLER GB TREATMENT OF ACUTE OTITIS MEDIA IN CHILDREN .4. A 4TH CLINICAL TRIAL AMERICAN JOURNAL 

OF DISEASES OF CHILDREN 114 : 123 

excl excl Incl Ref 

Stool SE, Berg AO, Berman S, et al. Otitis Media With Effusion in Children. Guideline Technical Report, No. 12. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services; Stool SE, Field MJ. The impact of otitis media. Pediatic Infectious Disease Journal 1989;8(1 Suppl):11-4 

Ref Ref Ref 

Subramaniam K, Jalaludin M, Krishnan G: Comparative study of ofloxacin otic drops versus neomycin-polymixin b-hydrocortisone in the medical management of chronic suppurative otitis media. Department of ORL University Malaya Medical Center, Kuala Incl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Supiyaphun P, Kerekhanjanarong V, Koransophonepun J, Sastarasadhit V: Comparison of ofloxacin otic solution with oral amoxycillin plus chloramphenicol ear drop in treatment of acute exacerbation of chronic suppurative otitis media. Department of ORL, Chulalongkorn Hospital, Faculty of Medicine, Incl Takata, GS, Chan LS, Ernst R, Shekelle PG, Marcy SM. Management of Acute Otitis Media. Final Evidence Report. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US D t t f H lth d H S i Teele DW, Klein JO, Word BM, Rosner BA, Starobin S., Earle R Jr. et al. Antimicrobial prophylaxis for infants at risk for recurrent acute otitis media. Vaccine 2000;19(Suppl 1):140 3 Incl TEELE DW BACTERIOLOGY OF ACUTE OTITIS-MEDIA UNRESPONSIVE TO INITIAL ANTI-MICROBIAL THERAPY JOURNAL OF PEDIATRICS 98 : 537 1981 Teele DW, Klein JO, Bratton L, Fisch GR, Mathieu OR, Porter PJ, et al. Use of pneumococcal vaccine for prevention of recurrent acute otitis media in infants in Boston. The Greater Boston Collaborative Otitis Media Study Group. Review Infectious Incl Thalin A, Densert 0, Larsson A, Lyden E, Ripa T. Is penicillin necessary in the treatment of acute otitis media? In: Sade J, ed. Proceedings of the International Conference on Acute and Secretory Otitis Media; 1985; Jerusalem. Amsterdam: Kugler 

Ref 

THOENE DE PHARMACOTHERAPY OF OTITIS-MEDIA PHARMACOTHERAPY 11 : 212 1991 

Incl excl Ref Incl Ref 

Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated? BMJ 1994;309:1351-5 

Ref 

Thomsen J, Meistrup-Larsen KI, Sorensen H, Larsen PK, Mygind N. Penicillin and acute otitis: short and long term results. Annals of Otology, Rhinology and 

Laryngology Supplement 1980;89:271 4 

Ref 

Tilyard MW, Dovey SM, Walker SA Otitis media treatment in New Zealand general 

practice N Z Med J 1997; 110:143-145 

Incl 

Tong M, Woo J, Van Hasselt A: A doubleblind comparative study of ofloxacin otic drops versus neomycin-polymixin bhydrocortisone otic drops in the medical treatment of chronic suppurative otitis 

di L l Ot l 1996 110 309 314 

Incl 

TOWNSEND E OTITIS MEDIA IN PEDRIATRIC PRACTICE NEW YORK STATE JOURNAL OF MEDICINE 64 : 1591 1964 

Incl Ref 

UK Department of Health. The path of least resistance - main report. Department of Health Standing Medical Advisory Committee Sub-group on Antimicrobial resistance.www.advisorybodies.doh.gov.uk/ 

1 ht (A d J 3 2007) 

Ref Incl Ref 

United Kingdom Department of Health. PRODIGY guidance: Otitis media–acute. 2004. http://www.prodigy.nhs.uk (accessedSept 14 2006) 

Ref 

van Buchem F, Peeters M, Van’ t Hof M. Acute otitis media: a new treatment 

strategy Br Med J (Clin Res Ed) 1985; 290: Van Buchem FL, Dunk JH, van 't Hof MA Therapy of acute otitis media: myringotomy, antibiotics, or neither? A double-blind study in children Lancet 1981; 2:883 887 

Ref Ref excl Ref excl Incl Ref 

Van ZuijlenDA, Schilder AG,Van Balen FA,Hoes AQ.National differences in incidences of acutemastoiditis: relationship to prescribing patterns for acute otitis media Pediatric Infectious Disease 

Incl Ref excl Ref Incl Ref 

Varsano I, Frydman M, Amir J, Alpert G. Single intramuscular dose of ceftriaxone as compared to 7-day amoxicillin therapy for acute otitis media in children. Chemotherapy 1988;34 Suppl 1:39 46

 Ref 

Varsano I, Volovitz B, Horev Z, et al. Single IM dose of ceftriaxone (CRO) compared to 10 days amoxicillin-clavulanate augmentin (AUG) for therapy of acute otitis media (AOM) in children (abstract 1059). 

P t d t th Si th I t ti l 

Incl Ref 

Varsano I, Volovitz B, Horev Z. Intramuscular ceftriaxone compared with oral amoxicillin-clavulanate for treatment of acute otitis media in children Eur J Pediatr 

excl 

Varsano I, Volovitz B, Mimouti F. Sulfisoxazole prophylaxis of middle ear effusion and recurrent acute otitis media. 

Am J Dis Child 1985; 139:632 635 

Incl Ref 

Incl Incl 
Incl = Included 

Ref = In Reference List, but not specifically included excl = Excluded 

Damoiseaux 1998 -

"Antibiotic treatment 

of acute otitis media 

in children under 2 

years of age" 

Br.J.Gen.Prac. 

48(437): 1861-1864 

Foxlee 2006 -

"Topical analgesia for 

acute otitis media" 

Cochr. Database 

Syst Revs (3) 

Glasziou 2004 -

"Antibiotics for acute 

otitis media in 

children" Cochr. 

Database Syst Revs 

(1) 

Kozyrskyj 2000 -

"Short course 

antibiotics for acute 

otitis media" Cochr. 

Database Syst Revs 

(2) 

Rosenfeld 1994 -

"Clinical efficacy of antimicrobial drugs 

for acute otitis media: 

metaanalysis..." J. 

Pediatrics 124:355­

367 

Rovers 2006 -

"Antibiotics for acute 

otitis media: a metaanalysis..." Lancet 

368(9545): 1429­

1435 

Spurling 2007 -

"Delayed antibiotics 

for respiratory 

infections" Cochr. 

Database Syst Revs 

(3) 

Takata 2001 -

"Evidence 

assessment of 

management of 

acute otitis media: I. 

The role of 

antibiotics..." 

Pediatrics 108:239­

247 

AHRQ Report No. 15 

- "Management of 

Acute Otitis Media" -

References 

Bonati 1992 ­

"Metaanalysis of 

antimicrobial 

prophylaxis for 

recurrent acute otitsmedia" Clinical 

Trials and MetaAnalysis 28(1):39-50 

Leach 2006 -

"Antibiotics for the 

prevention of acute 

and chronic 

suppurative otitis 

media in children" 

Cochrane 

Collaboration 2009, 

Issue 1 

McDonald 2008 -

"Grommets 

(ventiliation tubes) for 

recurrent acute otitis 

media in children 

(Review)." The 

Cochrane 

Collaboration, 2009, 

Issue 1 

Straetemans 2004 -

"Pnemococcal 

vaccines for 

preventing otitis 

media (Review)", 

Cochrane 

Collaboration 

2008(3). 

Williams 2003 - " 

Use of antibiotics in 

preventing recurrent 

otitis media and in 

treating otitis media 

with effusion: A metaanalytic attempt to 

resolve the 

brouhaha," JAMA 

270(11):1344-1351. 

Rothman 2003 -

"Does this child have 

acute otitis media?" 

JAMA 2003; 

290(12):1633-1640 

Ab

syste

the e

oflox

t

sup

m

Oto

R

200

Veenhoven R, Bogaert D, Uiterwaal C, Brouwer C, Kiezebrink H, Bruin J, et al. Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a 

d i d t d Th L t 

Incl 

Verkatesum P, Innes JA. Antibiotic resistance in common acute respiratory pathogens Thorax 1995;50:481–3 Incl Incl VITAL HLTH STATIS 10 176 : 1990 Ref Watson PD, Mortensen ME. Pharmacokinetics of common analgesics, antiinflammatories and antipyretics in children. Clinical Pharmacokinetics 1989;17:116 137 

Ref 

Weippl G, Michos N, Stocker H. Clinical experience and results of treatment with suprofen in pediatrics. 4th communication: Assessment of pain in babies and infants/Analgesic effect of suprofen syrup in otitis media. Arzneimittelforschung 

Ref 

WEISS JC COST-EFFECTIVENESS IN THE CHOICE OF ANTIBIOTICS FOR THE INITIAL TREATMENT OF OTITIS-MEDIA IN CHILDREN - A DECISION-ANALYSIS APPROACH PEDIATRIC INFECTIOUS 

DISEASE JOURNAL 7 23 1988

 excl 

Westert GP, Schellevis FG, de Bakker DH, Groenewegen PP,Bensing JM, van der Zee J. Monitoring health inequalities through General Practice: the Second Dutch National Survey of General Practice. Eur J P bli H lth 2005 15 59 65 

Ref 

WHO/CIBA Foundation Workshop. Prevention of hearing impairment from 

chronic otitis media WHO/PDH/98 4 1996 Willenberg W. [New preparation for the treatment of inflammatory ear diseases]. Zeitschrift fur Allgemeinmedizin 1975;51(16):759 62 

Ref 

WILSON A PRINCIPLES BEHIND PRACTICE .10. METAANALYSIS .2. ASSESSING THE QUALITY OF PUBLISHED META-ANALYSES MEDICAL 

JOURNAL OF AUSTRALIA 156 : 173 1992

 excl 

Woldman S. Treating ear pain in children with acute otitis media. Archives of Pediatrics & Adolescent Medicine 

Ref 

Yuen P, Lau S, Chau P, Hui Y, Wong SF, Wong S, Wei WI: Ofloxacin eardrop treatment for active chronic suppurative otitis media: Prospective randomized study. 

Am J Otol 1994;15:670 673 Incl ZENK KE Pharmacologic treatment of otitis media and sinusitis in pediatrics J PEDIAT HLTH CARE 4 : 297 1990 excl 

Ref