1. Giebink – FDA – 01/2001 Otitis Media Epidemiology and Drug-Resistant Streptococcus pneumoniae G. Scott Giebink, M.D. Professor of Pediatrics and Otolaryngology Director, Otitis Media Research Center University of Minnesota School of Medicine

2. Giebink – FDA – 01/2001 Acute Otitis Media in the US > 24 million acute otitis media office visits per year (1)  ~ 80% of children in the US have at least 1 episode of otitis media by age 3 (2)  ~ 50% have > 3 episodes by age 3 (2)  ~ 7–12 million cases are caused by S. pneumoniae (1) (1) MMWR. 1997;46:1-24 (2) Teele DW et al. J Infect Dis. 1989;160:83-94

3. Giebink – FDA – 01/2001 Bacteriology of AOM Mandel et al. Pediatr 1995 DelBeccaro et al. J Pediatr 1992

4. Giebink – FDA – 01/2001 Bacteriology of Severe and Mild AOM Kaleida, et al. Pediatrics, 1991 Severity PncHiMcatMixedTotal (# ears) Mild 20 % 26 % 7 % 11 % 65 % (n=54) Severe 38 % 18 % 6 % 10 % 71 % (n=175) p=0.13

5. Giebink – FDA – 01/2001 Viral-Bacterial Etiology of AOM A Pitkaranta et al. Pediatrics 1998; 102: 291-5

6. Giebink – FDA – 01/2001 Otitis Media Pathogenesis  Eustachian tube dysfunction / obstruction Respiratory virus infection Anatomic  Middle ear bacterial invasion  Inflammatory middle ear response

7. Consequences of Otitis Media 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

8. Giebink – FDA – 01/2001 Pneumococcal Disease in the US approximate cases per year Meningitis Bacteremia Pneumonia Otitis Media7,000,000 500,000 50,000 3,000 5% to 7% mortality, higher in elderly 20% mortality, higher in elderly Reduction in hearing & suppurative complications 30% mortality, higher in elderly

9. Giebink – FDA – 01/2001 Colonization Crossing of mucosal barrier Otitis media Sinusitis Non-bacteremic pneumonia Otitis media Sinusitis Non-bacteremic pneumonia Local invasion Pneumococcal Disease: Pathogenesis Meningitis Sepsis Invasion of bloodstream Bacteremic pneumonia

10. Giebink – FDA – 01/2001 Pediatric Carriage Rates Fedson DS et al. Vaccines (3rd ed) WB Saunders; 1999:553-607

11. Giebink – FDA – 01/2001 U.S. Antimicrobial Resistance Trends Among Respiratory Tract Pathogens Resistance mechanism: Beta-lactamase Altered PBPs M. catarrhalis H. influenzae S. pneumoniae

12. Giebink – FDA – 01/2001 Breiman RF et al. JAMA. 1994;271:1831-1835. Streptococcus pneumoniae: Patterns of Penicillin Nonsusceptibility Major resistance trends by serotype –6B, 9V, 14, 19A, 19F, 23F are most frequent Penicillin-susceptible strains may acquire resistance over time Resistant strains are often resistant to other classes of antibiotic s

13. Giebink – FDA – 01/2001 Penicillin Nonsusceptibility Among Isolates Causing Invasive Pneumococcal Disease* Spika JS et al. J Infect Dis. 1991;163:1273-8 Breiman RF et al. JAMA. 1994;271:1831-5 Butler JC et al. J Infect Dis. 1996;174:986-93 Cetron MS et al. ASM, 1997.Abstract MMWR. 1999;48:656-61 Whitney CG et al. NEJM 2001; 343:1917-24 *Isolates obtained from patients of all ages. 0 5 10 15 20 25 30 1979–871991–921993–941995–961997 Collection year Resistant isolates (%) 5.0 6.7 17.3 20.8 25.0 1998 24.0

14. Giebink – FDA – 01/2001 Penicillin Susceptibility by Region 68% 64% 61% 72%61% 74% 63% 43%56% 1996-97 2752 isolates 51 medical centers Thornsberry et al. AAC 1999;43:2612

15. Giebink – FDA – 01/2001 Pneumococcal Susceptibilities: US 1996-97 % Susceptible (NCCLS breakpoints) Pen SPen IPen R (n=820) (n=218) (n=238) Amoxicillin99.983.910.5 Amox-Clav99.977.90.8 Cefuroxime99.146.81.7 Cefotaxime99.985.35.9 Ceftriaxone99.985.810.1 Erythromycin93.561.930.7 Azithromycin93.764.231.2 Clarithromycin93.761.931.6 Thornsberry et al. AAC 1999;43:2612

16. Giebink – FDA – 01/2001 Pneumococcal Susceptibilities: US 1996-97 % Susceptible (NCCLS breakpoints) Pen SPen IPen R (n=820) (n=218) (n=238) Grepafloxacin99.999.599.5 Sparfloxacin99.899.599.2 Levofloxacin100.099.599.2 Ofloxacin99.899.599.2 Clindamycin98.886.781.9 Rifampin99.8100.099.6 Tetracycline96.072.048.7 TMP-SMX96.786.659.6 Vancomycin100.0100.0100.0 Thornsberry et al. AAC 1999;43:2612

17. Giebink – FDA – 01/2001 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 or CSF. Thornsberry et al. AAC 1999;43:2612

18. Giebink – FDA – 01/2001 Pneumococcal Susceptibility by Age 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

19. Giebink – FDA – 01/2001 Pneumococcal Susceptibilities: US 1998 CDC – 7 Cities – 16.5 million population % Susceptible (NCCLS breakpoints) Pen SPen IPen R (n=2636) (n=356) (n=483) Amoxicillin10098.217.8 Cefuroxime99.965.20 Cefotaxime99.985.35.9 Ceftriaxone10097.257.6 Erythromycin96.864.938.7 Tetracycline98.780.974.5 TMP-SMX93.450.67.7 Whitney et al. NEJM 2001;343:1917

20. Giebink – FDA – 01/2001 Pneumococcal Susceptibilities: US 1998 CDC – 7 Cities – 16.5 million population % Susceptible (NCCLS breakpoints) Pen SPen IPen R (n=820) (n=218) (n=238) Levofloxacin99.199.799.3 Chloramphenicol99.693.385.3 Clindamycin99.589.387.8 Rifampin99.810099.8 Synercid  10099.499.8 Vancomycin100100100 Whitney et al. NEJM 2001;343:1917

21. Giebink – FDA – 01/2001 Increasing Prevalence of Multidrug-Resistant Pneumococci in the US Whitney et al. NEJM 2001;343:1917

22. Giebink – FDA – 01/2001 Pneumococcal Resistance to Penicillin by Serotype in Children <5 Years: US 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

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

24. Giebink – FDA – 01/2001 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

25. Giebink – FDA – 01/2001 Distribution of Unique Pneumococcal Strains Among 264 Children in 8 Day Care Centers Beer-Sheva, Israel: 10/96 – 2/97 Day Care Center (% carrying strain at least once) SerotypeResistance12345678 6APen, Em--45--8199--3 15S31--8------135 15Pen--328--3----3 19FPen, Em,----------15---- T-S, Tet 19FTet--------22------ 23AS----3--9----21 23BS------16-------- Pen, penicillin; Em, erythromycin; T-S, trimethoprim-sulfamethoxazole; Tet, tetracycline; S, susceptible to all Givon-Lavi et al. Clin Infect Dis 1999;29:1274

26. Giebink – FDA – 01/2001 Chemoprophylaxis Effect on Pneumococcal Carriage Craig et al. Clin Infect Dis 1999;29:1257 No rif or clinda resistant strains

27. Giebink – FDA – 01/2001 Markers of Antibiotic Effectiveness Bacteriologic efficacy = sterilize middle ear fluid Clinical efficacy = resolve clinical symptoms & signs »Relapse with the same bacteria Pharmacokinetic surrogates = antibiotic concentration time over MIC »Middle ear fluid »Plasma

28. Giebink – FDA – 01/2001 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

29. Giebink – FDA – 01/2001 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

30. Giebink – FDA – 01/2001 Bacteriologic Failure in 2-Tap Studies Pneumococci H influenzae All Drug Pen-S Pen-I Pen-R  lac-  lac+ bacteria Amoxicillin0% (10) 29% (4) --21% (28) 60% (5) 25% (63) Cefuroxime9% (22) --21% (19) 15% (45) 16% (93) Cefaclor10% (41) --62% (29) 40% (85) 36% (171) Azithromycin0% (12) --100% (6) 71% (34) 47% (57) Ceftriaxone0% (8) --14% (29) 0% (45) 7% (75) (number of patients) R. Dagan (Mar 1997)

31. Giebink – FDA – 01/2001 The “Pollyanna Phenomenon” in AOM Treatment Trials Marchant et al. J Pediatr 1992; 120:72 No antibiotic treatment

32. Giebink – FDA – 01/2001 Antibiotic Treatment Failure Clinical and Bacteriologic Failure  Noncompliance  Resistant bacterial pathogen – inadequate T > MIC  Sensitive bacteria, but drug distribution failure (e.g., AOM complicating chronic mucoid OME; viral infection)  Immune deficiency -- acquired, congenital Bacteriologic Success / Clinical Failure  Concurrent viral infection  Persisting ME inflammation after clearing bacterial pathogen