# Presentation: 903788

## 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

**> 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***

## Bacteriology of AOM

***Mandel et al.  Pediatr 1995***
***DelBeccaro et al. J Pediatr 1992***

## Bacteriology of Severe and Mild AOM

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

**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**

## Viral-Bacterial Etiology of AOM

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

## Otitis Media Pathogenesis

**Eustachian tube dysfunction / obstruction**
**Respiratory virus infection**
**Anatomic**
**Middle ear bacterial invasion**
**Inflammatory middle ear response**

## Consequences of Otitis Media

**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**

## Pneumococcal Disease in the USapproximate cases per year

**Meningitis**

**Bacteremia**

**Pneumonia**

**Otitis Media**

**7,000,000**

**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**

## Pneumococcal Disease:  Pathogenesis

**Colonization**

- Crossing of mucosal barrier

**Otitis media****	**
**Sinusitis**
**Non-bacteremic pneumonia**

**Local invasion**

**Pneumococcal Disease:  Pathogenesis**

- Meningitis Sepsis

**Invasion of bloodstream**

- Bacteremic pneumonia

## Pediatric Carriage Rates

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

## U.S. Antimicrobial Resistance TrendsAmong Respiratory Tract Pathogens

**Resistance**
_**mechanism**_**:**
**Beta-lactamase**
**Beta-lactamase**
**Altered PBPs**
**Altered PBPs**

***M. catarrhalis***

***H. influenzae***

***S. pneumoniae***

##  Streptococcus pneumoniae:  Patterns of Penicillin Nonsusceptibility

** *****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**

## Penicillin Nonsusceptibility Among Isolates CausingInvasive Pneumococcal Disease*

**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**

**1979–87**

**1991–92**

**1993–94**

**1995–96**

**1997**

**Collection year**

**Resistant isolates (%)**

**5.0**

**6.7**

**17.3**

**20.8**

**25.0**

**1998**

**24.0**

## 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***

## 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***

## 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***

## 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***

## 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 Susceptibilities: US 1998CDC – 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***

## 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***

## Increasing Prevalence of Multidrug-ResistantPneumococci in the US

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

## Pneumococcal Resistance to Penicillinby 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***

## 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***

## 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)**
**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***

## Chemoprophylaxis Effecton Pneumococcal Carriage

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

**No rif or clinda**
**resistant strains**

## 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**

## 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**

## 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***

## 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)***

## The “Pollyanna Phenomenon”in AOM Treatment Trials

***Marchant et al. J Pediatr 1992; 120:72***

**No antibiotic treatment**

## 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**