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Otitis Media Epidemiology and Drug-Resistant Streptococcus pneumoniae

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. Acute Otitis Media in the US.

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Otitis Media Epidemiology and Drug-Resistant Streptococcus pneumoniae

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  1. Otitis Media Epidemiologyand Drug-ResistantStreptococcus pneumoniae G. Scott Giebink, M.D. Professor of Pediatrics and Otolaryngology Director, Otitis Media Research Center University of Minnesota School of Medicine

  2. 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. Bacteriology of AOM Mandel et al. Pediatr 1995 DelBeccaro et al. J Pediatr 1992

  4. Bacteriology of Severe and Mild AOM Severity Pnc Hi Mcat Mixed Total (# ears) Mild 20% 26% 7% 11% 65% (n=54) Severe 38% 18% 6% 10% 71% (n=175) p=0.13 Kaleida, et al. Pediatrics, 1991

  5. Viral-Bacterial Etiology of AOM A Pitkaranta et al.Pediatrics 1998; 102: 291-5

  6. Otitis Media Pathogenesis • Eustachian tube dysfunction / obstruction • Respiratory virus infection • Anatomic • Middle ear bacterial invasion • Inflammatory middle ear response

  7. Consequences of Otitis Media • Chronic • Otitis Media With • Effusion(OME) • Mucoid OM • Secretory OM Acute (purulent) Otitis Media • 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. Pneumococcal Disease in the USapproximate cases per year Meningitis 3,000 30% mortality, higher in elderly Bacteremia 50,000 20% mortality, higher in elderly 500,000 Pneumonia 5% to 7% mortality, higher in elderly Reduction in hearing & suppurative complications Otitis Media 7,000,000

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

  10. Pediatric Carriage Rates Fedson DS et al. Vaccines (3rd ed) WB Saunders; 1999:553-607

  11. U.S. Antimicrobial Resistance TrendsAmong Respiratory Tract Pathogens Resistance mechanism: Beta-lactamase Beta-lactamase Altered PBPs Altered PBPs M. catarrhalis H. influenzae S. pneumoniae

  12. 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 antibiotics Breiman RF et al. JAMA. 1994;271:1831-1835.

  13. Penicillin Nonsusceptibility Among Isolates CausingInvasive Pneumococcal Disease* 30 25.0 24.0 25 20.8 17.3 20 Resistant isolates (%) 15 10 6.7 5.0 5 0 1998 1979–87 1991–92 1993–94 1995–96 1997 Collection year * Isolates obtained from patients of all ages. 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;174:986-93Cetron MS et al. ASM, 1997.AbstractMMWR. 1999;48:656-61Whitney CG et al. NEJM 2001; 343:1917-24

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

  15. Pneumococcal Susceptibilities: US 1996-97 % Susceptible (NCCLS breakpoints) Pen S Pen I Pen R (n=820) (n=218) (n=238) Amoxicillin 99.9 83.9 10.5 Amox-Clav 99.9 77.9 0.8 Cefuroxime 99.1 46.8 1.7 Cefotaxime 99.9 85.3 5.9 Ceftriaxone 99.9 85.8 10.1 Erythromycin 93.5 61.9 30.7 Azithromycin 93.7 64.2 31.2 Clarithromycin 93.7 61.9 31.6 Thornsberry et al. AAC 1999;43:2612

  16. Pneumococcal Susceptibilities: US 1996-97 % Susceptible (NCCLS breakpoints) Pen S Pen I Pen R (n=820) (n=218) (n=238) Grepafloxacin 99.9 99.5 99.5 Sparfloxacin 99.8 99.5 99.2 Levofloxacin 100.0 99.5 99.2 Ofloxacin 99.8 99.5 99.2 Clindamycin 98.8 86.7 81.9 Rifampin 99.8 100.0 99.6 Tetracycline 96.0 72.0 48.7 TMP-SMX 96.7 86.6 59.6 Vancomycin 100.0 100.0 100.0 Thornsberry et al. AAC 1999;43:2612

  17. 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 or CSF. Thornsberry et al. AAC 1999;43:2612

  18. 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

  19. Pneumococcal Susceptibilities: US 1998CDC – 7 Cities – 16.5 million population % Susceptible (NCCLS breakpoints) Pen S Pen I Pen R (n=2636) (n=356) (n=483) Amoxicillin 100 98.2 17.8 Cefuroxime 99.9 65.2 0 Cefotaxime 99.9 85.3 5.9 Ceftriaxone 100 97.2 57.6 Erythromycin 96.8 64.9 38.7 Tetracycline 98.7 80.9 74.5 TMP-SMX 93.4 50.6 7.7 Whitney et al. NEJM 2001;343:1917

  20. Pneumococcal Susceptibilities: US 1998 CDC – 7 Cities – 16.5 million population % Susceptible (NCCLS breakpoints) Pen S Pen I Pen R (n=820) (n=218) (n=238) Levofloxacin 99.1 99.7 99.3 Chloramphenicol 99.6 93.3 85.3 Clindamycin 99.5 89.3 87.8 Rifampin 99.8 100 99.8 Synercid 100 99.4 99.8 Vancomycin 100 100 100 Whitney et al. NEJM 2001;343:1917

  21. Increasing Prevalence of Multidrug-ResistantPneumococci in the US Whitney et al. NEJM 2001;343:1917

  22. Pneumococcal Resistance to Penicillinby Serotype in Children <5 Years: US 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

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

  24. Prevalence of Pneumococcal CarriageAmong Day Care Center ChildrenWith 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

  25. Distribution of Unique Pneumococcal StrainsAmong 264 Children in 8 Day Care CentersBeer-Sheva, Israel: 10/96 – 2/97 Day Care Center (% carrying strain at least once) Serotype Resistance 1 2 3 4 5 6 7 8 6A Pen, Em -- 45 -- 8 19 9 -- 3 15 S 31 -- 8 -- -- -- 13 5 15 Pen -- 3 28 -- 3 -- -- 3 19F Pen, Em, -- -- -- -- -- 15 -- -- T-S, Tet 19F Tet -- -- -- -- 22 -- -- -- 23A S -- -- 3 -- 9 -- -- 21 23B S -- -- -- 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. Chemoprophylaxis Effecton Pneumococcal Carriage No rif or clinda resistant strains Craig et al. Clin Infect Dis 1999;29:1257

  27. 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. AOM: Clinical Responseto Placebo or Amoxicillin Placebo (mild) or Amoxicillin Myringotomy (severe) only Mild AOM 92% 96% Severe AOM 76% 90% % clinically cured / improved P=0.009 P=0.006 Kaleida et al. Pediatrics, 1991

  29. Clinical vs. Bacteriologic Outcomesin 293 Children with Bacterial AOM Bacteriologic Clinical Failure Success Total Failure 15 17 32 Success 25236261 Total 40 253 293 Sensitivity of clinical outcome: 236 / 253 = 93% Specificity of clinical outcome: 15 / 40 = 37% Carlin, et al. J Pediatrics, 1991

  30. Bacteriologic Failure in 2-Tap Studies Pneumococci H influenzae All Drug Pen-S Pen-I Pen-R lac- lac+ bacteria Amoxicillin 0% (10) 29% (4) -- 21% (28) 60% (5) 25% (63) Cefuroxime 9% (22) -- 21% (19) 15% (45) 16% (93) Cefaclor 10% (41) -- 62% (29) 40% (85) 36% (171) Azithromycin 0% (12) -- 100% (6) 71% (34) 47% (57) Ceftriaxone 0% (8) -- 14% (29) 0% (45) 7% (75) (number of patients) R. Dagan (Mar 1997)

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

  32. 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

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