Giebink – FDA – 01/2001 Otitis Media Epidemiology and Drug-Resistant Streptococcus pneumoniae G....

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


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 1995DelBeccaro et al. J Pediatr 1992

No growth6%

Other6%

Strep. pyogenes

5%Moraxella catarrhalis

14%

Haemophilus influenzae

19%

Strep. pneumoniae

50%


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

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


Otitis Media PathogenesisEustachian tube dysfunction / obstruction

• Respiratory virus infection• Anatomic

Middle ear bacterial invasion Inflammatory middle ear response


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


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


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


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


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


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


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 31.6Thornsberry 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 99.5Sparfloxacin 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



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.



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



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


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



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



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


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


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


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


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


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 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


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


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

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


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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