Otitis Media Epidemiology and DrugResistant Streptococcus pneumoniae

1
Otitis Media Epidemiologyand Drug-ResistantStrep
tococcus 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)
• 712 million cases are caused by S. pneumoniae
  (1)

(1) MMWR. 1997461-24(2) Teele DW et al. J
Infect Dis. 198916083-94
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
• (n54)
• Severe 38 18 6 10 71
• (n175)

p0.13
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
1999553-607
11
U.S. Antimicrobial Resistance TrendsAmong
Respiratory Tract Pathogens
Resistance mechanism Beta-lactamase Beta-lacta
mase 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. 19942711831-1835.
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
197987
199192
199394
199596
1997
Collection year
Spika JS et al. J Infect Dis. 19911631273-8 Brei
man RF et al. JAMA. 19942711831-5 Butler JC et
al. J Infect Dis. 1996174986-93Cetron MS et
al. ASM, 1997.AbstractMMWR. 199948656-61Whitne
y CG et al. NEJM 2001 3431917-24
Isolates obtained from patients of all ages.
14
Penicillin Susceptibility by Region
72
61

• 1996-97
• 2752 isolates
• 51 medical centers

68
64
74
63
61
43
56
Thornsberry et al. AAC 1999432612
15
Pneumococcal Susceptibilities US 1996-97

• Susceptible (NCCLS breakpoints)
• Pen S Pen I Pen R
• (n820) (n218) (n238)
• 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 1999432612
16
Pneumococcal Susceptibilities US 1996-97

• Susceptible (NCCLS breakpoints)
• Pen S Pen I Pen R
• (n820) (n218) (n238)
• 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 1999432612
17
Pneumococcal Susceptibility by Specimen Source

• Blood/CSF Respiratory Ear Eye
• (n370) (n682) (n85) (n58)
• 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 (Pthat for blood or CSF.

Thornsberry et al. AAC 1999432612
18
Pneumococcal Susceptibility by Age

• 13 yr
• (n284) (n134) (n813)
• 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 (Pthan that for the

Thornsberry et al. AAC 1999432612
19
Pneumococcal Susceptibilities US 1998CDC 7
Cities 16.5 million population

• Susceptible (NCCLS breakpoints)
• Pen S Pen I Pen R
• (n2636) (n356) (n483)
• 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 20013431917
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Pneumococcal Susceptibilities US 1998 CDC 7
Cities 16.5 million population

• Susceptible (NCCLS breakpoints)
• Pen S Pen I Pen R
• (n820) (n218) (n238)
• 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 20013431917
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Increasing Prevalence of Multidrug-ResistantPneum
ococci in the US
Whitney et al. NEJM 20013431917
22
Pneumococcal Resistance to Penicillinby Serotype
in Children

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 20013431917
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Child Care Effect on OM URIs Complicated by OM
Wald, et al. Pediatrics 199187129
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Prevalence of Pneumococcal CarriageAmong Day
Care Center ChildrenWith 3 Cases of MDRSP-14
Meningitis (DCC-A)
n80
n46
n52
n48
Craig et al. Clin Infect Dis 1999291257
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 1999291274
26
Chemoprophylaxis Effecton Pneumococcal Carriage
No rif or clinda resistant strains
Craig et al. Clin Infect Dis 1999291257
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

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AOM Clinical Responseto Placebo or Amoxicillin
clinically cured / improved

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

P0.009
P0.006
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 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
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 Phenomenonin AOM Treatment Trials
No antibiotic treatment
Marchant et al. J Pediatr 1992 12072
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