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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
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
Giebink – FDA – 01/2001
Bacteriology of AOM
Mandel et al. Pediatr 1995DelBeccaro et al. J Pediatr 1992
No growth6%
Other6%
Strep. pyogenes
5%Moraxella catarrhalis
14%
Haemophilus influenzae
19%
Strep. pneumoniae
50%
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
Viral-Bacterial Etiology of AOM
23
7
16
10
12
5
22
30
5
10
15
20
25
30
35
40
Pneumococcus H influenzae M catarrhalis S pyogenes No bacteria
% o
f Mid
dle
Ear
Flu
ids
With virus
Without virus
A Pitkaranta et al. Pediatrics 1998; 102: 291-5
Giebink – FDA – 01/2001
Otitis Media PathogenesisEustachian tube dysfunction / obstruction
• Respiratory virus infection• Anatomic
Middle ear bacterial invasion Inflammatory middle ear response
Giebink – FDA – 01/2001
Consequences of Otitis Media
Acute(purulent)
Otitis Media
ChronicOtitis 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
Giebink – FDA – 01/2001
Pneumococcal Disease in the USapproximate 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
Giebink – FDA – 01/2001
ColonizationColonization
Crossing of mucosal barrierCrossing of mucosal barrier
Otitis media
Sinusitis
Non-bacteremic pneumonia
Otitis media
Sinusitis
Non-bacteremic pneumonia
Local invasionLocal invasion
Pneumococcal Disease: Pathogenesis
Meningitis Sepsis
Meningitis Sepsis
Invasion of bloodstreamInvasion of bloodstream
Bacteremic
pneumonia
Bacteremic
pneumonia
Giebink – FDA – 01/2001
Pediatric Carriage Rates
60
35
25
6
29
0
10
20
30
40
50
60
70
80
% c
olo
niz
ed
Preschool GrammarSchool
High School Adults w/oChildren
Adults w.Children
Fedson DS et al. Vaccines (3rd ed) WB Saunders; 1999:553-607
Giebink – FDA – 01/2001
U.S. Antimicrobial Resistance TrendsAmong Respiratory Tract Pathogens
0
25
50
75
100
1965 1970 1975 1980 1985 1990 1995 2000
% R
esis
tan
t
Resistancemechanism:
Beta-lactamase
Beta-lactamaseAltered PBPs
Altered PBPs
M. catarrhalis
H. influenzae
S. pneumoniae
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 antibiotics
Giebink – FDA – 01/2001
Penicillin Nonsusceptibility Among Isolates CausingInvasive Pneumococcal Disease*
Spika JS et al. J Infect Dis. 1991;163:1273-8Breiman RF et al. JAMA. 1994;271:1831-5
Butler JC et al. J Infect Dis. 1996;174:986-93Cetron MS et al. ASM, 1997.Abstract
MMWR. 1999;48:656-61Whitney 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 1997Collection year
Res
ista
nt
iso
late
s (%
)
5.06.7
17.320.8
25.0
1998
24.0
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
Giebink – FDA – 01/2001
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 31.6Thornsberry et al. AAC 1999;43:2612
Giebink – FDA – 01/2001
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 99.5Sparfloxacin 99.8 99.5 99.2Levofloxacin 100.0 99.5 99.2Ofloxacin 99.8 99.5 99.2
Clindamycin 98.8 86.7 81.9Rifampin 99.8 100.0 99.6Tetracycline 96.0 72.0 48.7TMP-SMX 96.7 86.6 59.6Vancomycin 100.0 100.0 100.0
Thornsberry et al. AAC 1999;43:2612
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
Increasing Prevalence of Multidrug-Resistant
Pneumococci in the US
0
5
10
15
20
25
30
35
40
Res
ista
nt Is
olat
es (%
)
1995
1996
1997
1998
Whitney et al. NEJM 2001;343:1917
Giebink – FDA – 01/2001
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 20.9Whitney et al. NEJM 2001;343:1917
Giebink – FDA – 01/2001
Child Care Effect on OM:% URIs Complicated by OM
0
5
10
15
20
25
30
35
40
45
0 - 1 year 1 -2 year 2 - 3 year
Home Care Group Care Center Care
Wald, et al. Pediatrics 1991;87:129
Giebink – FDA – 01/2001
Prevalence of Pneumococcal CarriageAmong Day Care Center Children
With 3 Cases of MDRSP-14 Meningitis (DCC-A)
0
10
20
30
40
50
60
70
% c
olo
niz
ed
DCC-A DCC-B DCC-C Ped Practice
Other Types
MDRSP-14
n=80 n=46 n=52 n=48
Craig et al. Clin Infect Dis 1999;29:1257
Giebink – FDA – 01/2001
Distribution of Unique Pneumococcal Strains
Among 264 Children in 8 Day Care CentersBeer-Sheva, Israel: 10/96 – 2/97Day 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
Giebink – FDA – 01/2001
Chemoprophylaxis Effecton Pneumococcal Carriage
0
10
20
30
40
50
60
0 20 40 60 80 100 120
Days after completing 7 days rifampin + clindamycin prophylaxis
% c
olo
niz
ed
MDRSP-14
Other Types
Craig et al. Clin Infect Dis 1999;29:1257
No rif or clindaresistant strains
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
Giebink – FDA – 01/2001
AOM: Clinical Responseto 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
Giebink – FDA – 01/2001
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
Giebink – FDA – 01/2001
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)
Giebink – FDA – 01/2001
The “Pollyanna Phenomenon”in AOM Treatment Trials
20
40
60
80
100
120
Bacteriologic Efficacyin Acute Bacterial OM
Clinical Efficacy inAcute Bacterial OM
Clinical Efficacy inAcute Clinical OM
% E
ffic
ac
y
Marchant et al. J Pediatr 1992; 120:72
No antibiotic treatment
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