Title: Otitis Media Epidemiology and DrugResistant Streptococcus pneumoniae
1Otitis 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
2Acute 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
3Bacteriology of AOM
Mandel et al. Pediatr 1995 DelBeccaro et al. J
Pediatr 1992
4Bacteriology 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
5Viral-Bacterial Etiology of AOM
A Pitkaranta et al. Pediatrics 1998 102 291-5
6Otitis Media Pathogenesis
- Eustachian tube dysfunction / obstruction
- Respiratory virus infection
- Anatomic
- Middle ear bacterial invasion
- Inflammatory middle ear response
7Consequences 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
8Pneumococcal 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
9Pneumococcal Disease Pathogenesis
Colonization
Crossing of mucosal barrier
Local invasion
Invasion of bloodstream
Otitis media Sinusitis Non-bacteremic pneumonia
Bacteremic pneumonia
Meningitis Sepsis
10Pediatric Carriage Rates
Fedson DS et al. Vaccines (3rd ed) WB Saunders
1999553-607
11U.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.
13Penicillin 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.
14Penicillin Susceptibility by Region
72
61
- 1996-97
- 2752 isolates
- 51 medical centers
68
64
74
63
61
43
56
Thornsberry et al. AAC 1999432612
15Pneumococcal 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
16Pneumococcal 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
17Pneumococcal 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
18Pneumococcal 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
19Pneumococcal 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
20Pneumococcal 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
21Increasing Prevalence of Multidrug-ResistantPneum
ococci in the US
Whitney et al. NEJM 20013431917
22Pneumococcal 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 20.9Whitney et al. NEJM 20013431917
23Child Care Effect on OM URIs Complicated by OM
Wald, et al. Pediatrics 199187129
24Prevalence 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
25Distribution 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
26Chemoprophylaxis Effecton Pneumococcal Carriage
No rif or clinda resistant strains
Craig et al. Clin Infect Dis 1999291257
27Markers 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
28AOM 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
29Clinical 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
30Bacteriologic 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)
31The Pollyanna Phenomenonin AOM Treatment Trials
No antibiotic treatment
Marchant et al. J Pediatr 1992 12072
32Antibiotic 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