1. Giebink – FDA – 07/11/02 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

2. Giebink – FDA – 07/11/02 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

3. Giebink – FDA – 07/11/02 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.

4. Giebink – FDA – 07/11/02 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

5. Giebink – FDA – 07/11/02 Bacteriology of Severe and Mild AOM Kaleida, et al. Pediatrics, 1991 Severity PncHiM catMixedTotal (# ears) Mild 20 % 26 % 7 % 11 % 65 % (n=54) Severe 38 % 18 % 6 % 10 % 71 % (n=175) p=0.13

6. Giebink – FDA – 07/11/02 AOM: Clinical Response to Placebo or Amoxicillin Placebo (mild) orAmoxicillin Myringotomy (severe)only Mild AOM92%96% Severe AOM76%90% P=0.006 Kaleida et al. Pediatrics, 1991 P=0.009 % clinically cured / improved

7. Giebink – FDA – 07/11/02 OM Severity Affects Bacteriological & Clinical Cure Rates Without Treatment PncHiMcatMixedNGTotal Mild 20%26% 7% 11% 40% Spont cure.2.5.7.31.0 Bact cure4%12%4%3%40%63% Clinical cure92% Severe 40% 20% 5% 10% 25% Spont cure.2.5.7.31.0 Bact cure8%10%4%3%25%50% Clinical cure76%  = 13%  = 16% Sample size implications

8. Giebink – FDA – 07/11/02 Clinical vs. Bacteriologic Outcomes in 293 Children with Bacterial AOM Bacteriologic ClinicalFailureSuccessTotal Failure15 17 32 Success25236261 Total40253293 Sensitivity of clinical outcome: 236 / 253 = 93% Specificity of clinical outcome: 15 / 40 = 37% Carlin, et al. J Pediatrics, 1991

9. Giebink – FDA – 07/11/02 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

10. Giebink – FDA – 07/11/02 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

11. Giebink – FDA – 07/11/02 Respiratory Viruses Contribute to Bacterial AOM & Cause AOM Independent of Bacterial Pathogens A Pitkaranta et al. Pediatrics 1998; 102: 291-5

12. 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.

13. Giebink – FDA – 07/11/02 AOM Risk Factors For PRSP within the last 1 monthAntibiotic 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 monthAntibiotic within the last 1 month ANY OM diagnosis within the last 1 monthANY OM diagnosis within the last 1 month > 3 AOM episodes in last 6 months> 3 AOM episodes in last 6 months Age < 2 yearsAge < 2 years Age at 1 st OM < 6 monthsAge at 1 st OM < 6 months Day care center attendance (> 10 children)Day care center attendance (> 10 children) Bilateral OM diseaseBilateral OM disease

14. Child Care Effect on OM: % URIs Complicated by OM Wald, et al. Pediatrics 1991;87:129

15. Giebink – FDA – 07/11/02 Prevalence of Pneumococcal Carriage Among Day Care Center Children With 3 Cases of MDRSP-14 Meningitis (DCC-A) n=80n=46n=52n=48 Craig et al. Clin Infect Dis 1999;29:1257

16. Giebink – FDA – 07/11/02 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

17. Giebink – FDA – 07/11/02 Pediatric Pneumococcal Carriage Rates Fedson DS et al. Vaccines (3rd ed) WB Saunders; 1999:553-607

18. Giebink – FDA – 07/11/02 Pneumococcal Susceptibility by Specimen Source Blood/CSF Respiratory Ear Eye (n=370) (n=682) (n=85) (n=58) Penicillin77.860.9*44.7*65.5* Amoxicillin89.779.0*58.8*82.5 Amox-Clav87.276.3*55.3*78.9 Ceftriaxone88.479.9*60.0*84.2 Erythromycin85.472.9*65.9*79.3 Clindamycin96.593.888.2*87.9* TMP-SMX92.786.6*77.4*93.0 Tetracycline90.881.1*76.2*77.2* * % susceptible significantly lower (P<0.05) than that for blood/CSF. Thornsberry et al. AAC 1999;43:2612

19. Giebink – FDA – 07/11/02 Pneumococcal Susceptibility by Age  2 yr3-12 yr  13 yr (n=284) (n=134) (n=813) Penicillin4961*70* Amoxicillin687485* Amox-Clav6273*83* Ceftriaxone6777*86* Erythromycin637580* Clindamycin8795*96* TMP-SMX828191* Tetracycline7786*85* * % susceptible significantly higher (P<0.05) than that for the  2 yr group Thornsberry et al. AAC 1999;43:2612

20. Giebink – FDA – 07/11/02 Pneumococcal Conjugate Vaccine Effect on PRSP PRSP by Serotype in Children <5 Years U.S. 1998 PCV-7%Non-PCV% typesresistanttypesresistant 41.610 6B42.130 9V60.86A53.7 1433.37F0 18C2.412F0 19F40.219A65.5 23F44.822F0 All others20.9 Whitney et al. NEJM 2001;343:1917 Routine PCV will greatly reduce the occurrence of PRSP AOM.

21. Giebink – FDA – 07/11/02 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.