# Presentation: 463011

## Design Issuesin Antimicrobial TreatmentTrials of AOM

**G. Scott Giebink, M.D.**
**Professor of Pediatrics and Otolaryngology**
**Director, Otitis Media Research Center**
**University of Minnesota School of Medicine**

## Markers of Antimicrobial Effectiveness

_**Bacteriologic cure**_** = sterilize middle ear fluid**
**On-therapy (double) tap: eradication vs. suppression**
_**Clinical cure**_** = resolve clinical symptoms & signs**
**EOT (2-5 days after treatment)**
**TOC (25-30 days after treatment)**
_**Pharmacokinetic surrogates**_** = T > MIC**
**Plasma vs. Middle ear fluid**

## Design Issues

**Double-tap design yields definitive bacteriological cure rate in a non-comparative setting.**
**Timing of 2****nd**** tap: eradication vs. suppression.**
**Enriching for PRSP biases for treatment failure.**
**Risk factors for PRSP = risk factors for recurrent AOM.**
**PK / PD surrogates are highly variable.**
**? Relatedness of murine models to OM**
**1****st**** dose PK studies miss accumulation over time**
**OM severity at entry correlates with bacteriological and clinical cure, and has implication for sample size.**

## Acute Otitis Media in the US

**> 24 million AOM office visits per year**** ****(1)**** **
**~ 80% of children have ******** 1 episode by age 3 ****(2)**** **
**~ 50% have > 3 episodes by age 3 ****(2)**** **
**~ 7–12 million cases caused by *****S.***** *****pneumoniae *****(1)**
**Small differences in treatment response rates can affect millions of children each year.**

***(1) MMWR. 1997;46:1-24******(2) Teele DW et al. J Infect Dis. 1989;160:83-94***

## Bacteriology of Severe and Mild AOM

***Kaleida, et al.  Pediatrics, 1991***

**Severity****	****Pnc****	****Hi****	****M cat****	****Mixed****	****Total**
**	****(# ears)**
**Mild****	****20****%****	****26****%**** ****	****7****%**** ****	****11****%**** ****	****65****%**
**	***(n=54)*** ****	**
**Severe****	****38****%**** ****	****18****%**** ****	****6****%**** ****	****10****%**** ****	****71****%**
**	***(n=175)*

***p*****=0.13**

## AOM: Clinical Responseto Placebo or Amoxicillin

**	****	****Placebo (mild)****	****	****	****or****	****Amoxicillin****	****Myringotomy (severe)****	****only**
**Mild AOM****	****92%****	****96%**
**Severe AOM****	****76%****	****90%**

***P*****=0.006**

***Kaleida et al. Pediatrics, 1991***

***P*****=0.009**

**% clinically cured / improved**

## OM Severity Affects Bacteriological& Clinical Cure Rates Without Treatment

**	****Pnc****	****Hi****	****Mcat****	****Mixed****	****NG****	****Total**
_**Mild**_**	****20%****	****26% ****	****7% ****	****11% ****	****40%****	**
**Spont cure****	****.2****	****.5****	****.7****	****.3****	****1.0**
**Bact cure****	****4%****	****12%****	****4%****	****3%****	****40%****	****63%**
**Clinical cure****	****	****	****	****	****	****	****92%**
**	**
_**Severe**_**	****40% ****	****20% ****	****5% ****	****10% ****	****25%****	**
**Spont cure****	****.2****	****.5****	****.7****	****.3****	****1.0**
**Bact cure****	****8%****	****10%****	****4%****	****3%****	****25%****	****50%**
**Clinical cure****	****	****	****	****	****	****	****76%**

****** ****= 13%**

****** ****= 16%**

**Sample size implications**

## Clinical vs. Bacteriologic Outcomesin 293 Children with Bacterial AOM

**	****	****                   ****Bacteriologic**
**Clinical****	****Failure****	****Success****	****Total**
**Failure****	****15****	****  17****	****  32**
**Success****	**_**25**_**	**_**236**_**	**_**261**_
**	****Total****	****40****	****253****	****293**

**Sensitivity ****of clinical outcome: ****236 / 253**** = ****93%**
**Specificity ****of clinical outcome: ****15 / 40**** = ****37%**

***Carlin, et al.  J Pediatrics, 1991***

## WHYBacteriological / Clinical Discordance?

_**Bacti success / Clinical failure (6%):**_
**Persistence of bacterial & host inflammatory mediators**
**Concurrent viral infection**
_**Bacti failure / Clinical success (9%):**_
**Low-grade pathogen / poor growth in MEF**

## Persistent Symptoms During Treatment

**Concurrent viral infection**
**Noncompliance**
**Resistant bacterial pathogen **
**Sensitive bacteria, but drug distribution failure  ****(eg, AOM complicating chronic mucoid OME)**
**Inflammation after clearing bacterial pathogens**
**Immune deficiency ****-- acquired, congenital**

## Respiratory Viruses Contributeto Bacterial AOM & Cause AOMIndependent of Bacterial Pathogens

***A Pitkaranta et al.***** *****Pediatrics 1998; 102: 291-5***

## The OM Continuum

**The OM Continuum**

**Acute**
**(purulent)**
**Otitis Media**

**Chronic**
**Otitis Media With**
**Effusion**** ****(OME)**
**Mucoid OM**
**Secretory OM**

_**NONSUPPURATIVE SEQUELAE**_
**TM atelectasis**
**Adhesive OM**
**Cholesteatoma**
**Ossicular erosion / fixation**
**Hearing loss**
**Conductive**
**Sensorineural**

_**SUPPURATIVE COMPLICATIONS**_
**Chronic suppurative OM**
**Mastoiditis**
**Meningitis**
**Facial nerve palsy**

**Enriching subject populations for rAOM & PRSP creates**
**a cohort not representative of uncomplicated AOM.**

## AOM Risk Factors

**For PRSP**
**Antibiotic ****within the last 1 month**
**Infection while on antibiotic prophylaxis**
**Persistent or recurrent AOM or sinusitis**
**Infection during Winter / Spring months**
**Age < 2 years**
**Day care attendance**

**For Treatment Failure / Recurrence**
**Antibiotic within the last 1 month**
_**ANY**_** OM diagnosis within the last 1 month**
**> 3 AOM episodes in last 6 months**
**Age < 2 years**
**Age at 1****st**** OM < 6 months**
**Day care **_**center**_** attendance (> 10 children)**
**Bilateral OM disease**

## Child Care Effect on OM:% URIs Complicated by OM

**Child Care Effect on OM:****% URIs Complicated by OM**

***Wald, et al. Pediatrics 1991;87:129***

## Prevalence of Pneumococcal CarriageAmong Day Care Center ChildrenWith 3 Cases of MDRSP-14 Meningitis (DCC-A)

***n=80***

***n=46***

***n=52***

***n=48***

***Craig et al. Clin Infect Dis 1999;29:1257***

## Risk Factors* for OME PersistenceAfter AOM Treatment* Bilateral AOM, Day care , OME > 4 weeks

***K Daly et al.  Pediatr Infect Dis J 1988;7:471-5***

## Pediatric Pneumococcal Carriage Rates

***Fedson DS et al. Vaccines (3rd ed) WB Saunders; 1999:553-607***

## Pneumococcal Susceptibility by Specimen Source

**	****	****Blood/CSF ****	****Respiratory ****	****Ear ****	****Eye**
**	****	*****(n=370)******	****** (n=682)******	****** (n=85) ******	****** (n=58)***
**Penicillin****	****77.8****	****60.9*****	****44.7*****	****65.5***
**Amoxicillin****	****89.7****	****79.0*****	****58.8*****	****82.5**
**Amox-Clav****	****87.2****	****76.3*****	****55.3*****	****78.9**
**Ceftriaxone****	****88.4****	****79.9*****	****60.0*****	****84.2**
**Erythromycin****	****85.4****	****72.9*****	****65.9*****	****79.3**
**Clindamycin****	****96.5****	****93.8****	****88.2*****	****87.9***
**TMP-SMX****	****92.7****	****86.6*****	****77.4*****	****93.0**
**Tetracycline****	****90.8****	****81.1*****	****76.2*****	****77.2***
*** % susceptible significantly lower (*****P*****<0.05) than that for blood/CSF.****	**

***Thornsberry et al. AAC 1999;43:2612***

## Pneumococcal Susceptibility by Age

**	****	********2 yr****	****3-12 yr****	********13 yr**
***	******	****** ******(n=284) ******	****** (n=134) ******	****** (n=813)***
**Penicillin****	****49****	****61*****	****70***
**Amoxicillin****	****68****	****74****	****85***
**Amox-Clav****	****62****	****73*****	****83***
**Ceftriaxone****	****67****	****77*****	****86***
**Erythromycin****	****63****	****75****	****80***
**Clindamycin****	****87****	****95*****	****96***
**TMP-SMX****	****82****	****81****	****91***
**Tetracycline****	****77****	****86*****	****85***
*** % susceptible significantly higher (*****P*****<0.05) than that for the ********2 yr group**

***Thornsberry et al. AAC 1999;43:2612***

## Pneumococcal Conjugate Vaccine Effect on PRSPPRSP by Serotype in Children <5 YearsU.S. 1998

**	****PCV-7****	****%****	****Non-PCV****	****%**
**	****types****	****resistant****	****types****	****resistant**
**	****4****	****1.6****	****1****	****0**
**	****6B****	****42.1****	****3****	****0**
**	****9V****	****60.8****	****6A****	****53.7**
**	****14****	****33.3****	****7F****	****0**
**	****18C****	****2.4****	****12F****	****0**
**	****19F****	****40.2****	****19A****	****65.5**
**	****23F****	****44.8****	****22F****	****0**
**	****	****	****All others****	****20.9**

***Whitney et al. NEJM 2001;343:1917***

**Routine PCV will greatly reduce the occurrence of PRSP AOM.**

## Conclusions

**Tightly control clinical definitions**
**Enrollment severity affects bacteriological & clinical cure rates**
**EOT cure**
**Eliminate TOC**
**Enriching for PRSP**
**Selects subjects with more chronic ME disease – not comparable to uncomplicated AOM**
**Selects younger, day care subjects**
**Increases reinfection rates**
**2****nd**** tap may measure suppression, not eradication**
**Routine PCV immunization will significantly reduce PRSP incidence in AOM.**