Complicated Intra-
Abdominal Infections:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2018 
Clinical/Antimicrobial 
Revision 1 
   
Complicated Intra-
Abdominal Infections:  
Developing Drugs for 
Treatment 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2018 
Clinical/Antimicrobial 
Revision 1 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEVELOPMENT PROGRAM ....................................................................................... 2 
A.  General Considerations .................................................................................................................2 
1. Early Phase Clinical Development Considerations .........................................................................2 
2. Drug Development Population .........................................................................................................2 
3. Efficacy Considerations ...................................................................................................................3 
4. Safety Considerations .......................................................................................................................3 
B.  Specific Efficacy Trial Considerations .........................................................................................3 
1. Trial Design ......................................................................................................................................3 
2. Trial Population ...............................................................................................................................3 
3. Inclusion and Exclusion Criteria .....................................................................................................3 
4. Clinical Microbiology Considerations .............................................................................................4 
5. Randomization, Stratification, and Blinding ....................................................................................5 
6. Specific Populations .........................................................................................................................5 
7. Dose Selection ..................................................................................................................................5 
8. Choice of Comparators ....................................................................................................................6 
9. Concomitant Antibacterial Therapy .................................................................................................6 
10.  Prior Nontrial Antibacterial Drugs .............................................................................................6 
11.  Efficacy Endpoints .......................................................................................................................6 
12.  Trial Procedures and Timing of Assessments ..............................................................................7 
a.  Entry visit ..................................................................................................................................7 
b.  On-therapy and end-of-therapy visit .........................................................................................7 
c.  Visit at day 28 ............................................................................................................................7 
13.  Statistical Considerations ............................................................................................................7 
a.  Analysis populations ..................................................................................................................7 
b.  Noninferiority margins ..............................................................................................................8 
c.  Sample size ................................................................................................................................8 
C.  Other Considerations .....................................................................................................................8 
1. PK/PD Considerations .....................................................................................................................8 
2. Labeling Considerations ..................................................................................................................9 
REFERENCES ............................................................................................................................ 10 
APPENDIX A:  JUSTIFICATION FOR NONINFERIORITY MARGIN FOR 
COMPLICATED INTRA-ABDOMINAL INFECTIONS ...................................................... 11 
APPENDIX B:  LIST OF REFERENCES USED IN THE NONINFERIORITY  
MARGIN JUSTIFICATION FOR THE ESTIMATE OF THE  PLACEBO/NO 
TREATMENT RESPONSE RATE........................................................................................... 15 
 
 
 
  Contains Nonbinding Recommendations 
 
Complicated Intra-Abdominal Infections:  
Developing Drugs for Treatment 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
treatment of complicated intra-abdominal infections (cIAIs).2  Specifically, this guidance 
addresses the Food and Drug Administrations (FDAs) current thinking regarding the overall 
development program and clinical trial designs for drugs to support an indication for the 
treatment of cIAI.   
 
This guidance does not contain discussion of the general issues of statistical analysis or clinical 
trial design.  Those topics are addressed in the ICH guidances for industry E9 Statistical 
Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical 
Trials, respectively.3   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
 
 
                                                 
1 This guidance has been prepared by the Division of Anti-Infective Products in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  You may submit comments on this guidance at any time.  
Submit comments to Docket No. FDA-2012-D-0973-0009 (available at 
https://www.regulations.gov/document?D=FDA-2012-D-0973-0009). 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Intra-abdominal infections are common in clinical practice and comprise a wide variety of 
clinical presentations and differing sources of infection.  A cIAI extends beyond the hollow 
viscus of origin into the peritoneal space and is associated with either abscess formation or 
peritonitis (Solomkin et al. 2010).  Different bacterial pathogens are responsible for cIAIs, 
including gram-negative aerobic bacteria, gram-positive bacteria, and anaerobic bacteria, and 
there are also mixed infections.  Uncomplicated intra-abdominal infections and complicated 
intra-abdominal infections may be difficult to distinguish, but in general cIAIs extend beyond 
local viscera into peritoneal or retroperitoneal spaces and are associated with systemic signs and 
symptoms of illness.  When patients are diagnosed with cIAI, antibacterial drug therapy is 
recommended before, during, and after the planned surgical procedure (e.g., open laparotomy, 
laparoscopy, percutaneous drainage of an abscess).   
 
 
III.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
 
1.  Early Phase Clinical Development Considerations 
 
The wide variety of bacterial pathogens responsible for cIAIs represents a challenging aspect for 
clinical development.  Before sponsors start phase 3 clinical trials, an investigational drugs 
antibacterial activity should be characterized (e.g., information on the spectrum of activity of the 
investigational drug against bacteria that cause cIAIs).    
 
2.  Drug Development Population  
 
The clinical diagnoses and brief descriptions that define the population of patients with cIAIs 
include, but are not limited to, the following: 
 
  Intra-abdominal abscess:  one or more abscesses surrounding diseased or perforated 
viscera often characterized by nonspecific abdominal pain  
 
  Perforation of intestine:  an acute perforation of the intestine associated with diffuse 
infection of the peritoneum, often characterized by nonspecific abdominal pain 
 
  Peritonitis:  a diffuse infection of the peritoneum, often characterized by nonspecific 
abdominal pain 
 
  Appendicitis with perforation or periappendiceal abscess:  an acute infection of the 
appendix characterized by colicky abdominal pain often localized to the right lower 
quadrant 
 
  Cholecystitis with perforation or abscess:  an acute infection extending beyond the 
gallbladder wall, often accompanied by right upper quadrant abdominal pain 
2  Contains Nonbinding Recommendations 
 
 
  Diverticulitis with perforation, peritonitis, or abscess:  an acute infection of a 
diverticula (herniation of mucosa or submucosa through the muscularis propria of the 
colon), most often characterized by left lower quadrant abdominal pain 
 
3.  Efficacy Considerations 
 
Noninferiority trials are interpretable and appropriate for the indication of the treatment of cIAI.  
A showing of superiority is also readily interpretable.   
 
A single adequate and well-controlled trial supported by other independent evidence, such as a 
trial in another infectious disease indication, can provide evidence of effectiveness.4  Sponsors 
should discuss with the FDA the other independent evidence that would be used to support the 
findings from a single trial in cIAI. 
 
4.  Safety Considerations 
 
In general, we recommend a preapproval safety database of approximately 700 patients.  If the 
same dose and duration of therapy for treatment of cIAI were used in clinical trials for other 
infectious disease indications, the safety information from those clinical trials can be part of the 
overall preapproval safety database.  For new drugs that have an important clinical benefit 
compared to existing therapies, a smaller preapproval safety database may be appropriate.  
Sponsors should discuss the appropriate size of the preapproval safety database with the FDA 
during clinical development. 
 
B.  Specific Efficacy Trial Considerations 
 
1.  Trial Design 
 
Trials in cIAI should be randomized, double blind, and active controlled using a noninferiority or 
superiority design.  Placebo-controlled trials are not appropriate for this indication except when 
they are add-on superiority trials in which patients receive either placebo or investigational drug 
added to standard-of-care antibacterial drug treatment. 
 
2.  Trial Population 
 
Trials should have a patient population with a variety of cIAI diagnoses as described in section 
III.A.2., Drug Development Population.  The proportion of patients who have cIAI caused by 
appendicitis with perforation or periappendiceal abscess should not exceed approximately 50 
percent in a cIAI trial. 
 
3.  Inclusion and Exclusion Criteria 
 
The following are recommendations for inclusion criteria: 
                                                 
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products. 
3  Contains Nonbinding Recommendations 
 
 
  Operative procedure for the current diagnosis and management of cIAI planned or 
completed within 24 hours of the first dose of an antibacterial drug  
 
  Procedures include open laparotomy, laparoscopy, and percutaneous drainage of 
intra-abdominal abscess 
 
  One or more systemic signs or symptoms that accompany cIAI, such as fever, 
hypotension, abdominal pain, nausea/vomiting, abdominal mass on clinical examination, 
altered mental status 
 
The following are recommendations for exclusion criteria: 
 
  Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of more 
than 24 hours during the previous 72 hours5 
 
  Upper gastrointestinal perforations unless clear evidence exists of an established 
secondary infection within the abdominal cavity 
 
4.  Clinical Microbiology Considerations 
 
An adequate clinical specimen for microbiologic evaluation should be obtained from all patients 
and sent to the laboratory for microscopic evaluation (e.g., Gram stain), culture, and in vitro 
antibacterial susceptibility testing performed on appropriate bacteria isolated from the specimen.  
Specimens should be processed according to recognized methods.6  The FDA also recommends 
that aerobic and anaerobic blood cultures be taken at two separate venipuncture sites before 
initiation of antibacterial drug therapy for cIAI.  All isolates considered to be possible pathogens 
should be saved in the event that additional testing of an isolate is needed (e.g., pulse field gel 
electrophoresis for strain identification).  Bacterial pathogens should have in vitro susceptibility 
testing using standardized methods.7 
 
Even though most patients will have a bacterial pathogen identified on routine cultures, 
development of new rapid diagnostic tests may facilitate future clinical trial design and 
potentially benefit patients by providing earlier diagnosis of causative organisms.  Clinical trials 
of a new antibacterial drug for treatment of cIAI may provide an opportunity to contribute to the 
evaluation of a new diagnostic test.  Sponsors interested in the development of a new rapid 
diagnostic test should discuss this with the FDA. 
 
                                                 
5 Patients who received an antibacterial drug for surgical prophylaxis and then developed cIAI, or patients who have 
objective documentation of clinical progression of cIAI while on antibacterial drug therapy, may be appropriate for 
enrollment. 
 
6 For examples, see the most current editions of the publications from the American Society for Microbiology, such 
as Manual of Clinical Microbiology and Clinical Microbiological Procedures Handbook. 
 
7 Standard methods for in vitro susceptibility testing are developed by organizations such as the Clinical and 
Laboratory Standards Institute, Wayne, PA. 
4  Contains Nonbinding Recommendations 
 
5.  Randomization, Stratification, and Blinding 
 
Trials should be randomized, multicenter, and double-blind unless there is a compelling reason 
for single-blind or open-label trials.  If trials are single-blind or open-label, sponsors should 
discuss potential biases with the FDA and how these biases will be addressed.  Sponsors should 
consider a stratification strategy to avoid enrollment of an excessive number of patients with 
cIAI associated with appendicitis (see section III.B.2., Trial Population).   
 
6.  Specific Populations 
 
The trials should include patients of both sexes and all races, as well as geriatric patients.8  
Patients with renal or hepatic impairment can be enrolled, provided the pharmacokinetics of the 
drug have been evaluated in these patients and appropriate dosing regimens have been defined.   
 
The FDA encourages sponsors to begin discussions about their pediatric clinical development 
plans as early as is feasible because pediatric studies are a required part of the overall drug 
development program and sponsors are required to submit pediatric study plans no later than 60 
days after an end-of-phase 2 meeting.9 
 
7.  Dose Selection 
 
To choose the dose or doses to be evaluated in phase 3 clinical trials, sponsors should integrate 
the findings from nonclinical toxicology studies, animal models of infection, pharmacokinetics, 
safety and tolerability information from phase 1 clinical trials, and safety and efficacy 
information from phase 2 dose-ranging clinical trials.  An assessment of drug penetration into 
certain tissues can be used as supportive evidence that the selected doses are likely to achieve 
drug concentrations sufficient to exert both an antimicrobial and clinical effect for cIAI.   
 
In general, patients with cIAI will begin treatment with an antibacterial drug given by 
intravenous (IV) administration.  Guidelines recommend 4 to 7 days of therapy for cIAI 
(Solomkin et al. 2010).  Because nausea and vomiting are frequently associated with cIAI and 
patients may require complete bowel rest for several days, patients are often hospitalized and 
cannot eat food or take oral mediations (e.g., a physician order for nil per os or NPO) while 
being treated for cIAI.  Therefore, it may be possible to conduct clinical trials using IV 
antibacterial drug therapy for 4 to 7 days without a switch to oral drug therapy.  However, 
patients who demonstrate improvement and can tolerate an oral diet may have completion of 
treatment with an orally administered drug (Solomkin et al. 2010).  Sponsors should discuss with 
                                                 
8 See the ICH guidances for industry E7 Studies in Support of Special Populations:  Geriatrics and E7 Studies in 
Support of Special Populations:  Geriatrics:  Questions and Answers. 
 
9 See the Pediatric Research Equity Act (Public Law 108-155; section 505B of the Federal Food, Drug, and 
Cosmetic Act; 21 U.S.C. 355c) as amended by the Food and Drug Administration Safety and Innovation Act of 
2012 (Public Law 112-144) and the draft guidance for industry Pediatric Study Plans:  Content of and Process for 
Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.  When final, this guidance will 
represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
5  Contains Nonbinding Recommendations 
 
the FDA the timing of a switch from an investigational IV drug to oral drug during therapy for 
cIAI or the development of an oral drug for treatment of cIAI. 
 
8.  Choice of Comparators 
 
In general, the active comparator used in clinical trials should be considered standard of care in 
the United States for this indication.  When evaluating the current standard of care, we consider 
recommendations by authoritative scientific bodies (e.g., the Surgical Infection Society, 
Infectious Diseases Society of America) based on clinical evidence and other reliable 
information that reflects current clinical practice.  
 
9.  Concomitant Antibacterial Therapy 
 
An investigational drugs in vitro antibacterial activity can encompass the full spectrum of 
bacterial pathogens implicated in cIAI.  However, an investigational drug may not have a full 
spectrum of activity and the addition of concomitant antibacterial therapy may be necessary to 
complete the antibacterial spectrum for empirical treatment of cIAI.  The spectrum of 
antibacterial activity of the investigational drug should not be similar to the spectrum of the 
concomitant drug, so that the effect of the investigational antibacterial drug can be isolated and 
fully assessed.   
 
10.  Prior Nontrial Antibacterial Drugs 
 
Patients who have cIAIs should receive effective antibacterial drug therapy before, during, and 
after the operative procedure as part of standard of care (Solomkin et al. 2010; Bratzler et al. 
2013).  Based on available data, we were not able to determine the effect that prior antibacterial 
drug therapy would have on the assessment of an investigational drugs efficacy.  Attempts 
should be made to minimize prior nontrial antibacterial drug therapy to the extent possible.  
Patients who receive up to 24 hours of prior nontrial antibacterial drug therapy should be eligible 
for enrollment.  For patients who are enrolled in the trial after the surgical procedure, only one 
dose of effective antibacterial drug therapy should be administered postoperatively before 
randomization.  The results in the subgroups of patients who did and did not receive prior 
effective antibacterial drug therapy should be analyzed.   
 
11.  Efficacy Endpoints 
 
The primary endpoint of clinical success is defined as resolution of the baseline signs and 
symptoms of cIAI based on objective assessments of events from randomization until 
approximately day 28.  A patient should be characterized as having a primary endpoint of 
clinical failure based on any of the following events that occur from randomization until 
approximately day 28: 
 
  Death 
 
  Surgical site wound infection 
 
6  Contains Nonbinding Recommendations 
 
  Unplanned surgical procedures or percutaneous drainage procedures for complication or 
recurrence of cIAI based on documented worsening symptoms or signs of cIAI 
 
  Initiation of nontrial antibacterial drug therapy for treatment of cIAI based on 
documented worsening symptoms or signs of cIAI 
 
12.  Trial Procedures and Timing of Assessments 
 
a.  Entry visit 
 
At the entry visit, baseline demographic and clinical information should be collected and should 
include clinical signs and symptoms, microbiologic specimens (Gram stain and culture of intra-
abdominal specimen and/or blood), radiographic or ultrasound imaging results, and laboratory 
tests, as appropriate. 
 
b.  On-therapy and end-of-therapy visit 
 
Patients should be evaluated at least once during therapy and at the end of prescribed therapy.  
Clinical and laboratory assessments for safety should be performed as appropriate.  If it is 
possible that the trial drug would need to be continued beyond the protocol-specified duration, 
objective criteria for extending the therapy should be prespecified in the protocol.   
 
c.  Visit at day 28 
 
At approximately day 28 following randomization, patients should be evaluated for safety and 
for the occurrence of an event at or before the visit at day 28 that characterizes clinical failure 
(see section III.B.11., Efficacy Endpoints). 
 
13.  Statistical Considerations 
 
In general, sponsors should provide a detailed statistical analysis plan stating the trial hypotheses 
and the analysis methods before trial initiation.  The primary efficacy analysis should be based 
on the difference in the proportions of patients achieving a successful clinical response. 
 
a.  Analysis populations 
 
The FDA considers the following to be the definitions for the statistical analysis populations: 
 
  Intent-to-treat (ITT) population  All patients who were randomized 
 
  Safety population  All patients who received at least one dose of drug during the trial 
 
  Microbiological intent-to-treat (micro-ITT) population  All patients randomized to 
treatment who have a baseline bacterial pathogen known to cause cIAI 
 
7  Contains Nonbinding Recommendations 
 
  Per-protocol populations  Patients who follow important components of the trial can 
then be defined as part of a per-protocol population 
 
  Microbiologically evaluable population  Patients who follow important components of 
the trial and who have a baseline bacterial pathogen known to cause cIAI 
 
In general, a bacterial pathogen (or bacterial pathogens) should be identifiable in a majority of 
enrolled patients such that the ITT and micro-ITT populations will be similar.  The micro-ITT 
population should be considered as the primary analysis population.  Generally, it is not 
appropriate to consider analyses of the per-protocol population as primary because that 
population is based on postrandomization events or characteristics of patients.  However, 
consistency of the results should be evaluated in all populations. 
 
b.  Noninferiority margins 
 
Noninferiority trials are considered appropriate and recommended if there is reliable and 
reproducible evidence of a treatment effect for the comparator drug.10  For a cIAI trial, a 
noninferiority margin of 10 percent is supported by the historical evidence (see Appendix A).  
Sponsors should discuss with the FDA the selection of a proposed margin greater than 10 
percent. 
 
c.  Sample size 
 
An estimate of an appropriate sample size for the primary micro-ITT analysis population for a 
noninferiority trial with 1:1 randomization is approximately 337 patients per group based on a 
noninferiority margin selection of 10 percent and a clinical success rate of 80 percent in the 
control group.  Approximately 90 percent of patients enrolled in the trial should have a bacterial 
pathogen identified by culture (the ITT population would consist of approximately 375 patients 
per group).  The trial should rule out a greater than 10 percent inferiority of the investigational 
drug to control drug (upper bound of the two-sided 95 percent confidence interval for the clinical 
success rate of control drug minus investigational drug). 
 
C.  Other Considerations 
 
1.  PK/PD Considerations 
 
The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the drug should be evaluated 
using in vitro models or animal models of infection.  The results from PK/PD assessments should 
be integrated with the findings from phase 1 PK assessments to help identify appropriate dosing 
regimens for evaluation in phase 2 and phase 3 clinical trials.  
 
Sponsors should consider a sparse sampling strategy in all patients in phase 2 and phase 3 
clinical trials to allow for the estimation of drug exposure in each patient.  Collection of PK data 
in phase 2 clinical trials can be used to explore the exposure-response relationship and to confirm 
that the proper dose and dosing regimen are selected for further evaluation in phase 3 clinical 
                                                 
10 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness. 
8  Contains Nonbinding Recommendations 
 
trials.  Collection of PK data in phase 3 clinical trials may help to address potential questions 
regarding efficacy or safety that might arise from the clinical trials.  
 
A retrospective exposure-response analysis based on the population PK model from patients in 
phase 3 clinical trials should be performed to assess the relationship between PK/PD indices and 
observed clinical and microbiologic outcomes.  The relationship between drug exposure or 
different dosing regimens and clinically relevant adverse events also should be explored to 
identify potential risks.  Additionally, these relationships should be explored for specific patient 
populations (e.g., patients with renal impairment). 
 
2.  Labeling Considerations 
 
The labeled indication should be for the treatment of cIAI caused by specific bacteria identified 
in patients in the clinical trials.  For example: 
 
Drug X is indicated for the treatment of complicated intra-abdominal infections due to.... 
 
 
9  Contains Nonbinding Recommendations 
 
REFERENCES 
 
Altemeier, WA, 1949, The Treatment of Acute Peritonitis, JAMA, 139(6):347352. 
 
Bratzler, DW, EP Dellinger, KM Olsen, et al., 2013, Clinical Practice Guidelines for 
Antimicrobial Prophylaxis in Surgery, Am J Health Syst Pharm, 70:195283. 
 
DerSimonian, R and N Laird, 1986, Meta-Analysis in Clinical Trials, Control Clin Trials, 7:177
187. 
 
Donovan, IA, D Ellis, D Gatehouse, et al., 1979, One-Dose Antibiotic Prophylaxis Against 
Wound Infection After Appendectomy:  A Randomized Trial of Clindamycin, Cefazolin Sodium 
and a Placebo, Br J Surg, 66:193196. 
 
Maluch, RW and RM Simon, 1980, Sample Size Considerations for Non-Randomized 
Comparative Studies, J Chron Dis, 33:175181. 
 
Montravers, P, R Gauzit, C Muller, et al., 1996, Emergence of Antibiotic-Resistant Bacteria in 
Cases of Peritonitis After Intra-abdominal Surgery Affects the Efficacy of Empirical 
Antimicrobial Therapy, Clin Infect Dis, 23:48694. 
 
Morris, WT, DB Innes, RA Richardson, AJ Lee, and RB Ellis-Pegler, 1980, The Prevention of 
Post-Appendectomy Sepsis by Metronidazole and Cefazolin:  A Controlled Double-Blind Trial, 
Aust NZ J Surg, 50:429433 
 
Mosdell, DM, DM Morris, A Voltura, et al., 1991, Antibiotic Treatment for Surgical Peritonitis, 
Ann Surg, 214:543549. 
 
Solomkin, JS, JE Mazuski, JS Bradley et al., 2010, Diagnosis and Management of Complicated 
Intra-Abdominal Infection in Adults and Children:  Guidelines by the Surgical Infection Society 
and the Infectious Disease Society of America, Clin Infect Dis, 50:133164. 
 
10  Contains Nonbinding Recommendations 
 
APPENDIX A:  JUSTIFICATION FOR NONINFERIORITY MARGIN FOR 
COMPLICATED INTRA-ABDOMINAL INFECTIONS 
 
A literature search found no placebo-controlled trials in patients with complicated intra-
abdominal infections (cIAIs).  Observational-cohort and retrospective chart-review studies show 
that effective antibacterial drugs for treatment of cIAIs are associated with shorter hospital stays, 
fewer unplanned re-operations, and lower mortality rates (Montravers et al. 1996; Mosdell et al. 
1991), but an estimate of a treatment effect of an antibacterial drug could not be derived from 
these nonrandomized studies.  Because all patients in these studies had appropriate surgical 
procedures for cIAIs, the studies suggest that effective antibacterial drugs have an added benefit 
to the benefits of the surgical procedures for cIAIs. 
 
We evaluated a cross-study comparison of success rates described in recently conducted trials 
and success rates described before the availability of antibacterial drugs.  However, in the 
historical papers before the availability of antibacterial drugs, there was uncertainty as to whether 
events labeled as clinical success were actual clinical successes (e.g., continued drainage of pus 
for more than 28 days following insertion of a drainage tube was considered a clinical success in 
one historical paper).  Therefore, it was not possible to estimate the proportion of patients with a 
true clinical success before the availability of antibacterial drugs. 
 
Approximately 40 placebo-controlled surgical prophylaxis trials are published in the more recent 
literature.  These trials evaluated the effect of antibacterial drugs administered as prophylaxis; 
patients about to undergo elective intra-abdominal surgeries were randomized to antibacterial 
drug or to placebo/no treatment.  Of these, 36 trials provided enough data to characterize the 
clinical events among patients who were randomized to placebo/no treatment or receiving 
antibacterial drug treatment.  For these trials, we excluded patients who were undergoing 
procedures for simple appendicitis without abscess formation.  In general, patients were followed 
postoperatively in a hospitalized setting and then evaluated in an outpatient clinic setting after 
trial completion, usually within a 1-month time period.  Therefore, the event rates can be 
considered as events that occurred within approximately 1 month following the surgical 
procedure.  In addition, the rates of day 28 clinical success outcomes were evaluated among 
recently conducted active-controlled clinical trials in patients who have cIAIs.   
 
In this appendix, we describe two approaches to quantifying an estimate of the treatment effect 
of antibacterial drugs for cIAIs in patients who have appropriate surgical procedures. 
 
The first approach to understanding the effect of an antibacterial drug for treatment of cIAIs is to 
evaluate the risk differences of event rates in the surgical prophylaxis trials.  Figure 1 shows the 
forest plot of the differences in event rates of death or development of an intra-abdominal or 
surgical wound infection. 
11  Contains Nonbinding Recommendations 
 
Figure 1.  Forest Plot of the Risk Differences in Event Rates (Death or Intra-Abdominal or 
Surgical Infection) Between Recipients of Antibacterial Drug Prophylaxis and Recipients of 
Placebo/No Treatment in the Trials of Antibacterial Drug Prophylaxis1 
  y
 
Model Study name Statistics for each study Risk difference and 95% CI
Risk  Lower  Upper 
difference limit limit
Bates (1980) -0.064 -0.423 0.296
Bauer (1989) -0.223 -0.341 -0.105
Bjerkeset (1980) -0.098 -0.309 0.113
Burdon - trial 1(1977) -0.181 -0.468 0.107
Burdon - trial 2 (1977) -0.101 -0.375 0.173
Burton (1975) 0.034 -0.171 0.239
Clarke (1977) -0.261 -0.403 -0.119
Eykyn (1979) -0.346 -0.548 -0.143
Feathers (1977) -0.444 -0.652 -0.237
Foster (1981) -0.259 -0.477 -0.042
Galland (1977) -0.340 -0.520 -0.160
Gillespie (1978) -0.342 -0.535 -0.148
Glenhill (1983) 0.026 -0.279 0.331
Goldring (1975) -0.360 -0.582 -0.138
Gordon (1965) 0.149 -0.034 0.332
Gottrup (1985) -0.200 -0.357 -0.043
Griffiths (1976) -0.295 -0.483 -0.106
Hagen (1980) -0.263 -0.521 -0.005
Hojer (1978) -0.296 -0.446 -0.146
Hughes (1970) -0.150 -0.303 0.003
Hunt (1979) -0.280 -0.467 -0.093
Keighley (1976) -0.232 -0.454 -0.010
Kjellgren (1977) -0.355 -0.526 -0.184
Matheson (1978) -0.208 -0.377 -0.039
Nichols (1973) -0.300 -0.602 0.002
Nygaard (1980) -0.089 -0.204 0.025
Persson (1981) -0.387 -0.603 -0.172
Polk (1969) -0.234 -0.339 -0.129
Rosenberg (1971) -0.170 -0.366 0.025
Rubbo (1965) -0.163 -0.349 0.023
Schiessel (1984) -0.318 -0.513 -0.123
Soderquist (1995) -0.095 -0.190 -0.001
Ulrich (1981) -0.587 -0.803 -0.370
Utley (1984) -0.255 -0.406 -0.105
Washington (1974) -0.382 -0.515 -0.250
Wetterfors (1980) -0.313 -0.461 -0.166
Fixed -0.227 -0.255 -0.198
Random -0.235 -0.279 -0.191
-0.50 -0.25 0.00 0.25 0.50
FFavaovuorrss T Treraetamtemnte nt  FavFoauvros rPsl aPcleabcoebo 
 
   
The random effects meta-analysis (DerSimonian and Laird 1986) shows a treatment benefit of 
antibacterial drug prophylaxis at 19.1 percent (the lowest absolute numerical value of the two-
sided 95 percent confidence interval of the risk difference).  At randomization, patients in these 
studies did not yet have an infection, and many patients undoubtedly did not develop an 
infection, limiting the potential benefit of an anti-infective agent.  The treatment difference 
between treated and untreated patients who have established infection is likely to be larger than 
                                                 
1 A list of these references can be found in Appendix B of the guidance for industry Complicated Intra-Abdominal 
Infections:  Developing Drugs for Treatment. 
12  Contains Nonbinding Recommendations 
 
the observed effect of prophylaxis.  M can be defined at 19.1 percent, a conservative estimate, 
1 
using the prophylaxis results. 
 
The second approach is to evaluate the event rates of death or development of an intra-abdominal 
or surgical wound infection among patients randomized to receive placebo/no treatment in the 
antibacterial drug prophylaxis trials, and compare these rates to the event rates in recently 
conducted trials among patients receiving appropriate antibacterial drug therapy for cIAIs.  
Figure 2 describes the event rates of death or development of an intra-abdominal or surgical 
wound infection. 
 
Figure 2.  Forest Plot of the Event Rates (Death or Intra-Abdominal or Surgical Infection) 
in the Trials of Antibacterial Drug Prophylaxis Among Recipients of Placebo or 
Randomized to Receive No Antibacterial Drug Treatment2 
 
Study name  Statistics for each study  Event rate and 95% CI 
#Events /   Event   Lower   Upper  
Total  rate  limit  limit 
Bates (1980)  5 / 12  0.417  0.185  0.692 
Bauer (1989)  22 / 72  0.306  0.210  0.421 
Bjerkeset (1980)  8 / 31  0.258  0.135  0.437 
Burdon-trial 1(1977)  11 / 24  0.458  0.275  0.654 
Burdon-trial 2 (1977)  13 / 23  0.565  0.363  0.748 
Burton (1975)  12 / 39  0.308  0.184  0.467 
Clarke (1977)  21 / 60  0.350  0.241  0.478 
Eykyn (1979)  25 / 39  0.641  0.481  0.775 
Feathers (1977)  12 / 25  0.480  0.296  0.669 
Foster (1981)  19 / 27  0.704  0.510  0.844 
Galland (1977)  16 / 38  0.421  0.276  0.581 
Gillespie (1978)  17 / 37  0.459  0.308  0.619 
Glenhill (1983)  9 / 20  0.450  0.253  0.664 
Goldring (1975)  11 / 25  0.440  0.263  0.634 
Gordon (1965)  2 / 17  0.118  0.030  0.368 
Gottrup (1985)  13 / 41  0.317  0.194  0.473 
Griffiths (1976)  12 / 33  0.364  0.219  0.537 
Hagen (1980)  8 / 21  0.381  0.203  0.598 
Hojer (1978)  25 / 60  0.417  0.299  0.544 
Hughes (1970)  11 / 44  0.250  0.144  0.397 
Hunt (1979)  11 / 31  0.355  0.209  0.534 
Keighley (1976)  12 / 29  0.414  0.252  0.596 
Kjellgren (1977)  26 / 49  0.531  0.392  0.665 
Matheson (1978)  25 / 59  0.424  0.305  0.552 
Nichols (1973)  3 / 10  0.300  0.100  0.624 
Nygaard (1980)  8 / 49  0.163  0.084  0.294 
Persson (1981)  12 / 26  0.462  0.284  0.650 
Polk (1969)  26 / 90  0.289  0.205  0.391 
Rosenberg (1971)  17 / 43  0.395  0.262  0.546 
Rubbo (1965)  19 / 40  0.475  0.327  0.627 
Schiessel (1984)  12 / 31  0.387  0.235  0.565 
Soderquist (1995)  6 / 50  0.120  0.055  0.242 
Ulrich (1981)  16 / 24  0.667  0.461  0.824 
Utley (1984)  15 / 47  0.319  0.202  0.464 
Washington (1974)  27 / 63  0.429  0.313  0.553 
Wetterfors (1980)  25 / 60  0.417  0.299  0.544 
Weighted Analysis  0.392  0.351  0.434 
-1.00  -0.50  0.00  0.50  1.00 
Event Rate 
 
A random effects meta-analysis (DerSimonian and Laird 1986) showed the point estimate for the 
event rate among placebo/no treatment recipients at 39.2 percent, with a two-sided 95 percent 
confidence interval of 35.1 percent and 43.4 percent.  The rate of a clinical success outcome was 
computed by 1 minus the event rate.  Thus, an estimate of the placebo/no treatment successful 
response rate is 60.8 percent, with a two-sided 95 percent confidence interval of 56.6 percent and 
64.9 percent.   
                                                 
2 A list of these references can be found in Appendix B of the guidance for industry Complicated Intra-Abdominal 
Infections:  Developing Drugs for Treatment. 
13  Contains Nonbinding Recommendations 
 
 
We evaluated the rate of day 28 clinical success outcomes among recently conducted active-
controlled clinical trials in cIAI.  All trials evaluated patients during antibacterial drug treatment 
for cIAI and observed patients for differing periods of time after completion of antibacterial 
drugs (e.g., observations from day 14 to day 60). 
 
The results from the datasets available for review at the FDA are displayed in Table 1. 
 
Table 1.  Clinical Response Cure Rate at Day 28 in the  
Micro-ITT Population 
 
Trial  Study Group  Clinical Response Rate at Day 28 
n/N (%) 
1  A  157/194 (80.9) 
1  B  159/191 (83.2) 
2  C  157/199 (78.9) 
2  D  157/186 (84.4)) 
 
The meta-analysis for the clinical response rates among patients treated with an antibacterial 
drug showed a point estimate of 81.7 percent and a two-sided 95 percent confidence interval of 
78.8 percent and 84.3 percent (DerSimonian and Laird 1986). 
 
An estimate of the treatment effect based on the difference in the clinical response rates can be 
derived by comparing the rate of successful clinical responses of recently conducted clinical 
trials in infected patients and the rate of successful clinical responses of placebo or no treatment 
among patients undergoing intra-abdominal surgery.  This gives a conservative estimate of the 
difference in rates because the patients undergoing surgery did not yet have an infection when 
randomized.  Therefore, the difference between treated and untreated patients with an established 
infection should be larger than the difference observed here.  Using an approach of the lower 
bound two-sided 95 percent confidence interval for antibacterial drug treatment estimate minus 
the upper bound of the two-sided 95 percent confidence interval for the placebo/no treatment 
estimate, a treatment difference is estimated to be 13.9 percent (78.8 percent minus 64.9 
percent).   
 
As noted, the comparison of the upper bound 95 percent confidence interval for the within-trial 
risk difference in the surgical prophylaxis trials, and the comparison of the lower bound 95 
percent confidence interval for antibacterial drug therapy and the upper bound of the 95 percent 
confidence interval for placebo/no treatment are conservative estimates of the treatment 
difference.  Therefore, there is little reason to consider discounting the treatment difference.  M  
1
is defined at 13.9 percent using this second approach and was defined at 19.1 percent using the 
first approach.  Because it is important to preserve the treatment effect when selecting a 
noninferiority margin, regardless of either approach there is support for a noninferiority margin 
of 10 percent for active-controlled trials of cIAI for an endpoint of clinical success at 28 days.  
Sponsors should discuss with the FDA the choice of a noninferiority margin greater than 10 
percent. 
 
14  Contains Nonbinding Recommendations 
 
APPENDIX B:  LIST OF REFERENCES USED IN THE NONINFERIORITY  
MARGIN JUSTIFICATION FOR THE ESTIMATE OF THE  
PLACEBO/NO TREATMENT RESPONSE RATE 
 
Bates, T, VLR Touquet, MK Tutton, SE Mahmoud, and WA Reuther, 1980, Prophylactic 
Metronidazole in Appendectomy:  A Controlled Trial, BrJ Surg, 67:547550. 
 
Bauer, T, BO Vennits, B Holm, et al., 1989, Antibiotic Prophylaxis in Acute Nonperforated 
Appendicitis, Ann Surg, 209(3):307311. 
 
Bjerkeset, T and A Digranes, 1980, Systemic Prophylaxis With Metronidazole (Flagyl) in 
Elective Surgery of the Colon and Rectum, Surgery, 87(5):560566. 
 
Burdon, JGW, PJ Morris, P Hunt, and JM Watts, 1977, A Trial of Cephalothin Sodium in Colon 
Surgery to Prevent Wound Infection, Arch Surg, 112:11691173-Trial 1. 
 
Burdon, JGW, PJ Morris, P Hunt, and JM Watts, 1977, A Trial of Cephalothin Sodium in Colon 
Surgery to Prevent Wound Infection, Arch Surg, 112:11691173-Trial 2. 
 
Burton, RC, ESR Hughes, and AM Cuthbertson, 1975, Prophylactic Use of Gentamycin in 
Colonic and Rectal Surgery, Med J Aust, 2:597599. 
 
Clarke, JS, RE Condon, JH Bartlett, SL Gorbach, RL Nichols, and S Ochi, 1977, Preoperative 
Oral Antibiotics Reduce Septic Complications of Colon Operations:  Results of Prospective, 
Randomized, Double-Blind Clinical Study, Ann Surg, 186:251259. 
 
Eykyn, SJ, HE Lockhart-Mummery, BT Jackson, and II Phillips, 1979, Prophylactic 
Preoperative Intravenous Metronidazole in Elective Colorectal Surgery, Lancet, 2(8146):761
764. 
 
Feathers, RS, AAM Lewis, GR Sagor, ID Amirak, and P Noone, 1977, Prophylactic Systemic 
Antibiotics in Colorectal Surgery, Lancet, 2:761764. 
 
Foster, GE, JB Bourke, J Bolwell, et al., 1981, Clinical and Economic Consequences of Wound 
Sepsis After Appendicectomy and Their Modification by Metronidazole or Povidone Iodine, 
Lancet, 1(8223):769771. 
 
Galland, RB, JH Saunders, JH Mosley, and JH Darrell, 1977, Prevention of Wound Infection in 
Abdominal Operations by Preoperative Antibiotics or Povidone-Iodine:  A Controlled Trial, 
Lancet, 2:10431045. 
 
Gillespie, G and W McNaught, 1978, Prophylactic Oral Metronidazole in Intestinal Surgery, J 
Antimicrob Chemother, 4(suppl c):2932. 
 
15  Contains Nonbinding Recommendations 
 
Glenhill, T, A Odurny, and PC Weaver, 1983, A Controlled Study of Single Dosage 
Cefamandole in the Prophylaxis of Wound Infections in Appendectomy, Surg Gynaecol Obstetr, 
156(3):295297. 
 
Goldring, J, A Scott, W McNaught, and G Gillespie, 1975, Prophylactic Oral Antimicrobial 
Agents in Elective Colonic Surgery:  A Controlled Trial, Lancet, 2:9971000. 
 
Gordon, HE, DW Gaylor, DM Richmond, et al., 1965, Operations on the Colon:  The Role of 
Antibiotics in Preoperative Preparation, Calif Med, 103:243246. 
 
Gottrup, F, P Diederich, K Sorensen, et al., 1985, Prophylaxis With Whole Gut Irrigation and 
Antimicrobials in Colorectal Surgery:  A Prospective, Randomized Double-Blind Clinical Trial, 
Am J Surg, 149(March):317322. 
 
Griffiths, DA, RA Simpson, BA Shorey, DCE Speller, and NB Williams, 1976, Single-Dose 
Preoperative Antibiotic Prophylaxis in Gastrointestinal Surgery, Lancet, 2(7981):325328. 
 
Hagen, TB, T Bergan, I Liavag, 1980, Prophylactic Metronidazole in Elective Colon-Rectal 
Surgery, Acta Chir Scand, 146:7175. 
 
Hojer, H and J Wetterfors, 1978, Systemic Prophylaxis With Doxycycline in Surgery of the 
Colon and Rectum, Ann Surg, 187(4):362368. 
 
Hughes, ESR, KJ Hardy, AM Cuthbertson, and SD Rubbo, 1970, Chemoprophylaxis in Large 
Bowel Surgery.  1. Effect of Intravenous Administration of Penicillin on Incidence of 
Postoperative Infection, Med J Aust, 1:305308. 
 
Hunt, PS, JK Francis, G Peck, et al., 1979, Tinidazole in the Prevention of Wound Infection 
After Elective Colorectal Surgery, Med J Aust, 1:107109. 
 
Keighley, MRB, AR Crapp, DW Burdon et al., 1976, Prophylaxis Against Anaerobic Sepsis in 
Bowel Surgery, Br J Surg, 63:538541. 
 
Kjellgren, K and H Sellstrom, 1977, Effect of Prophylactic Systemic Administration of 
Cephalothin in Colorectal Surgery, Acta Chir Scand, 143:473477. 
 
Matheson, DM, Y Arabi, D Baxter-Smith, et al., 1978, Randomized Multicentre Trial of Oral 
Bowel Preparations and Antimicrobials for Elective Colorectal Operations, Br J Surg, 65:597
600. 
 
Nichols, RL, P Broido, RE Condon, et al., 1973, Effect of Preoperative Neomycin-Erythromycin 
Intestinal Preparation on the Incidence of Infectious Complications Following Colon Surgery, 
Ann Surg, 178:453459. 
 
Nygaard, K and J Hognestad, 1980, Infection Prophylaxis With Doxycycline in Colorectal 
Surgery, A Preliminary Report, Scand J Gastroenterol Suppl, 59:3739. 
16  Contains Nonbinding Recommendations 
 
 
Persson, S and H Gnarpe, 1981, Tinidazole as Preventive Treatment in Elective Colonic Surgery, 
Scand J Infect Dis, 13:137140. 
 
Polk, HC Jr and JF Lopez-Major, 1969, Postoperative Wound Infection:  A Prospective Study of 
Determinant Factors and Prevention, Surgery, 66:97103. 
 
Rosenberg, IL, NG Graham, FT deDombal, and JC Goligher, 1971, Preparation of the Intestine 
in Patients Undergoing Major Large-Bowel Surgery, Mainly for Neoplasms of the Colon and 
Rectum, Br J Surg, 58:266269. 
 
Rubbo, SD, ESR Hughes, B Blainey, and IS Russell, 1965, Role of Preoperative 
Chemoprophylaxis in Bowel Surgery, Antimicrob Agents Chemother, 5:649658. 
 
Schiessel, R, I Huk, M Wunderlich, et al., 1984, Postoperative Infections in Colonic Surgery 
After Enteral Bacitracin-Neomycin-Clindamycin or Parenteral Mezlocillin-Oxacillin 
Prophylaxis, J Hosp Infect, 5:289297. 
 
Soderquist-Elinder, C, K Hirsch, S Bergdahl, et al., 1995, Prophylactic Antibiotics in 
Uncomplicated Appendicitis During Childhood  A Prospective Randomised Study, Eur J 
Pediatr Surg, 5:282285. 
 
Ulrich, C, 1981, 24-hour Systemic Antibiotic Prophylaxis in Large-Bowel Surgery, The 
Netherlands Journal of Surgery, 33(1):39. 
 
Utley, RJ and WAAG Macbeth, 1984, Peroperative Cefoxitin, A Double-Blind Prospective 
Study in the Prevention of Wound Infection, J R Coll Surg Edinb, 29(3):143146. 
 
Washington, JA, WH Dearing, ES Judd, and LR Elveback, 1974, Effect of Preoperative 
Antibiotic Regimen on Development of Infection After Intestinal Surgery, Prospective, 
Randomized, Double-Blind Study, Ann Surg, 180(4):567571. 
 
Wetterfors, J and H Hoejer, 1980, Prophylaxis With Doxycycline (Vibramycin) in Colorectal 
Surgery, Scand J Gastroenterol, Suppl 59:1216. 
17