R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center

otitis/2002/Daganotitis/2002/Dagan

R. DaganR. DaganThe Pediatric Infectious Disease UnitThe Pediatric Infectious Disease Unit

Soroka University Medical CenterSoroka University Medical CenterBen-Gurion UniversityBen-Gurion University

Beer-Sheva, IsraelBeer-Sheva, Israel

Double Tympanocentesis Studies: Double Tympanocentesis Studies: Bridging from Bacteriological Outcome to Bridging from Bacteriological Outcome to

Studies with Clinical OutcomeStudies with Clinical Outcome


day 1day 1 day 4-6day 4-6 day 10-12day 10-12 Day 21-30Day 21-30

TREATMENTTREATMENT

CULTURECULTURE

TYMPANOCENTESISTYMPANOCENTESIS

aa bb


(1)(1)

In AOM, is there any difference In AOM, is there any difference between drugs in regard to between drugs in regard to

bacteriologic eradication on day 4-6?bacteriologic eradication on day 4-6?


S-PncNon-S-Pnc

HiHi BL+cefac

cefac (40)(40)

cef-axetcef-axet (40)

(40)am

ox/augm

amox/augm

(40-50)(40-50)

CROx1CROx1 (50)

(50)

CROx3CROx3 (50)

(50)

AzithAzith (3;5d)

(3;5d)TsTs

placebo placebo

** for amoxicilline only for amoxicilline only

84%84%

52%52%%

per

sist

ence

% p

ersi

sten

ce

AugAug ES-600

ES-600 (90)(90)

GatiGati (10)

(10)

**


placebo (1*)placebo (1*)

Failure rate (%)Failure rate (%)*Number of studies*Number of studies

Failure Rate to Eradicate H. influenzae in AOM: Studies Failure Rate to Eradicate H. influenzae in AOM: Studies with a 2with a 2ndnd Tympanocentesis Performed on Day 2-6 of Tx Tympanocentesis Performed on Day 2-6 of Tx

505000 100100clarithto (1)clarithto (1)erythro (1)erythro (1)azithro (2)azithro (2)

cefprozil (1)cefprozil (1)cefaclor (6)cefaclor (6)

amox/clav - 45 (4)amox/clav - 45 (4)amp/amox (7)amp/amox (7)cefur-axet (2)cefur-axet (2)TMP/SMX (2)TMP/SMX (2)cefpodox (1)cefpodox (1)

cefixime (2)cefixime (2)

ceftriaxone (4)ceftriaxone (4)

amox/clav - 90 (1)amox/clav - 90 (1)

gatifloxacin (1)gatifloxacin (1)


(2)(2)

Can double tap studies determine an MIC Can double tap studies determine an MIC concentration cut-off, above which a given concentration cut-off, above which a given drug is not bacteriologically efficacious ?drug is not bacteriologically efficacious ?


8484

Placebo

5252

Placebo

CEF - AXET CECL

Cefaclor vs. Cefuroxime-Axetil: Bacteriology and Cefaclor vs. Cefuroxime-Axetil: Bacteriology and Organism-specific Bacteriological Failure Organism-specific Bacteriological Failure

% b

acte

riolo

gic

failu

res

% b

acte

riolo

gic

failu

res

Dagan et al, J Infect Dis 176:1253-1259, 1997Dagan et al, J Infect Dis 176:1253-1259, 1997 Dagan et al AAC 44:43-50, 2000 Dagan et al AAC 44:43-50, 2000

99 1010

Pnc - S

4/412/22

2121

6262

Pnc - I, R

18/294/19

1515

4040

Hi

34/857/46

Pnc Pnc n=111n=111

HiHin=131n=131


000/28

000/9

8484

5252

Pnc Placebo Pnc Hi Placebo Hi

MIC<=0.5 mcg/mlMIC >0.5 mcg/ml

% b

acte

riolo

gic

failu

res

% b

acte

riolo

gic

failu

res

Bacteriologic Failure Rate (day 4-5) TMP/SMX Bacteriologic Failure Rate (day 4-5) TMP/SMX as an Example of “All-or-Non Phenomenon”as an Example of “All-or-Non Phenomenon”

7373

11/15

5050

6/12

Leiberman et al, Pediatr Infect Dis, 20:260-4, 2001Leiberman et al, Pediatr Infect Dis, 20:260-4, 2001


8484

5252

0010102020303040405050

6060707080809090

100100

PlaceboPlacebo PlaceboPlacebo

PncPnc HiHi

% w

ith b

acte

riolo

gica

l fai

lure

% w

ith b

acte

riolo

gica

l fai

lure

Azithromycin MIC (µg/ml)Azithromycin MIC (µg/ml)

Bacteriologic Failure Rate (day 4-6) Bacteriologic Failure Rate (day 4-6) for Azithromycinfor Azithromycin

For placebo - Howie, Clin Pediatr 11:205-14,1972For placebo - Howie, Clin Pediatr 11:205-14,1972

3 days 3 days ((Dagan et al AAC 44:43-50, 2000)Dagan et al AAC 44:43-50, 2000)

5 days 5 days ((Dagan et al PIDJ 19:95-104, 2000)Dagan et al PIDJ 19:95-104, 2000)

0088

<= 0.25<= 0.25

0/120/122/252/25

100100

6363

> 2.0> 2.0

6/66/6

5/85/8

56566161

0.5 - 10.5 - 1

5/95/9 11/1811/186464 6565

2.0 - 4.02.0 - 4.0

23/3623/36 11/1711/17

0.250.25 0.250.25


Bacteriological Failures of Pnc and Hi Treated by Bacteriological Failures of Pnc and Hi Treated by Augmentin ES-600 by MICAugmentin ES-600 by MIC Dagan et al, Pediatr Infect Dis, 20:829-37, 2001Dagan et al, Pediatr Infect Dis, 20:829-37, 2001

% w

ith b

acte

riolo

gica

l fai

lure

% w

ith b

acte

riolo

gica

l fai

lure

P = .004P = .004

0

5

14

0

5

10

15

20

<=1.0 2 4N = 87 N = 20 N = 14

Penicillin MIC (µg/ml)Penicillin MIC (µg/ml)

PncPnc

2

14

25

0

5

10

15

20

25

30

<=0.5 1 >=2.0N = 57 N = 22 N = 4

P = .036P = .036

Augmentin MIC (µg/ml)Augmentin MIC (µg/ml)

HiHi


(3)(3)

Is there a relation between Is there a relation between bacteriologic eradication on day 4-6 bacteriologic eradication on day 4-6

and clinical outcome ?and clinical outcome ?


Clinical FailureClinical Failure Clinical successClinical success

Culture-positiveCulture-positiveon day 3-7on day 3-7

21/57 21/57 (37%)(37%)

15/40 15/40 (38%)(38%)

Culture-negativeCulture-negativeon day 3-7on day 3-7

2/66 2/66 (3%)(3%)

P < 0.001P < 0.001

17/253 17/253 (7%)(7%)

P < 0.001P < 0.001Carlin et alCarlin et alJ Pediatr J Pediatr

118:178-83, 1991118:178-83, 1991

Dagan et alDagan et alPediatr Infect Dis J Pediatr Infect Dis J

17:776-82, 1998 17:776-82, 1998

Clinical vs. Bacteriological Outcome of Children with Clinical vs. Bacteriological Outcome of Children with AOM with Initial Positive MEF CxAOM with Initial Positive MEF Cx


0% 20% 40% 60% 80% 100%

Score distribution

≥ 42 - 40-1

score

Day 4-6

6 46 45Culture (-)(n = 33)

34 55 11Culture (+)(n = 35)

P < 0.001

BB

0 1 2 3TEMPERATURE (ºC) <38.0 38.0-38.5 38.6-39.0 >39.0IRRITABILITY absent mild moderate severeTUGGING absent mild moderate severeREDNESS absent mild moderate severeBULGING absent mild moderate severe*

AA

* * Including draining pusIncluding draining pus Dagan et al Pediatr Infect Dis J 17:776-82, 1998 Dagan et al Pediatr Infect Dis J 17:776-82, 1998


(4)(4)

Can we determine by double tap Can we determine by double tap studies if an organism is not studies if an organism is not

important in AOMimportant in AOM


H. Influenzae is deemed by some clinicians/antibiotic manufacturers as being not important, although

prevalent, in AOM


High Dose Amoxicillin (80mg/Kg/d): High Dose Amoxicillin (80mg/Kg/d): MEF Pathogens in Bacteriologic Failure

PRSPPRSP30%30%

MCMC2%2%

No. pathogens = 56No. pathogens = 56No. patients = 43No. patients = 43

1320

4

1711

Day 1Day 1

PSSPPSSP7%7%ßL (+) HIßL (+) HI

23%23%

ßL (-) HIßL (-) HI36%36%

GASGAS2%2%

P=0.04P=0.04

No. ßL (+) organisms = 14/56 (25%)No. ßL (+) organisms = 14/56 (25%) No. ßL (+) organisms = 9/16 (56%)No. ßL (+) organisms = 9/16 (56%)

8

31

4

Day 4-6Day 4-6

No. pathogens = 16No. pathogens = 16No. patients = 13No. patients = 13

PRSPPRSP25%25%

ßL (+) HIßL (+) HI50%50%

ßL (-) HIßL (-) HI19%19%

MCMC6%6%

Leibovitz et al, 40th ICAAC, 2000Leibovitz et al, 40th ICAAC, 2000


0 1 2 3TEMPERATURE (ºC) <38.0 38.0-38.5 38.6-39.0 >39.0IRRITABILITY absent mild moderate severeREDNESS absent mild moderate severeBULGING absent mild moderate severe*

* * Including draining pusIncluding draining pus

Modified from Dagan et al Pediatr Infect Dis J 17:776-82, 1998 Modified from Dagan et al Pediatr Infect Dis J 17:776-82, 1998

Maximal score = 12Maximal score = 12

Does NTHi Cause a Less Severe AOM?Does NTHi Cause a Less Severe AOM?

Clinical scoreClinical score


7.4 7.6 7.8 8 8.2 8.4 8.6

Cx (+)Cx (+) 8.21 8.21 2.17 2.17

7.73 7.73 2.32 2.32

P = 0.003P = 0.003

n = 762n = 762

n = 240n = 240 Cx (-)Cx (-)

Mean Clinical Score (Mean Clinical Score ( SD) Pre-Treatment SD) Pre-Treatment


7.4 7.6 7.8 8 8.2 8.4 8.6

NTHiNTHi

PncPnc

NTHi + PncNTHi + Pnc

NGNG

8.32 8.32 2.19 2.19

8.14 8.14 2.11 2.11

8.06 8.06 2.20 2.20

7.73 7.73 2.32 2.32

P = 0.018P = 0.018

n = 392n = 392

n = 240n = 240

n = 173n = 173

n = 198n = 198

Mean Clinical Score (Mean Clinical Score ( SD) Pre-Treatment SD) Pre-Treatment

otitis/2002/Daganotitis/2002/DaganMean (Mean ( SD) SD) Difference in Total ScoreDifference in Total Score Between 1Between 1st st & 2& 2ndnd Visit Visit

P = 0.0001P = 0.0001

P = 0.0034 P = 0.0034

P = 0.13 P = 0.13

Failure

5.75 5.75 3.08 3.08n=36

5.29 5.29 3.143.14

n=85

n=43 4.79 4.79 3.71 3.71

3

4

5

6

7

8

day 1 day 4-6

Clin

ical

sco

reC

linic

al s

core

NTHiNTHi

PncPnc

NTHiNTHi+ Pnc+ Pnc

44 4.54.5 55 5.55.5 66 6.56.5 77 7.57.5

ScoreScore

Eradication

6.55 6.55 2.79 2.79n=143

6.89 6.89 2.762.76

n=254

n=98 6.53 6.53 2.93 2.93

∆ ∆ be

twee

n da

y 1

and

day

4-6

betw

een

day

1 an

d da

y 4-

6


(5)(5)

Can we bridge between double Can we bridge between double tap studies and studies with tap studies and studies with

clinical outcome?clinical outcome?


00

1010

2020

3030

4040

50506060

7070

8080

909087%

Amox/clav45mg/Kg

48%

Placebo

Bac

teria

l era

dica

tion

rate

Bac

teria

l era

dica

tion

rate

NTHi Eradication Rate: Amox/Clav (45mg/kg) vs. NTHi Eradication Rate: Amox/Clav (45mg/kg) vs. AzithromycinAzithromycin

Dagan et al PIDJ 19:95-104, 2000Dagan et al PIDJ 19:95-104, 2000

39%

Azithro5 days

P < 0.001P < 0.001


Clinical Success: Amox/Clav (45mg/kg) vs. AzithromycinClinical Success: Amox/Clav (45mg/kg) vs. Azithromycin

AzithromycinAzithromycin


Hi aloneHi alone Pnc alonePnc alone TotalTotal

AugmentinAugmentin

P=0.023 P=0.023 8686

7070

% w

ith c

linic

al s

ucce

ss%

with

clin

ical

suc

cess 9191

6565

86868080P=0.01 P=0.01

87 39 90 68 83 49


Clinical Clinical efficacyefficacy

in bacterial in bacterial AOMAOM

20

30

40

50

60

70

80

90

100

Bacteriologic Bacteriologic efficacyefficacy


PlaceboPlacebo

Clinical Clinical efficacy in efficacy in

“clinical” AOM“clinical” AOM

% S

ucce

ss%

Suc

cess

Marchant et al, J Pediat 120:72-7, 1992Marchant et al, J Pediat 120:72-7, 1992

Clinical Success: Amox/Clav (45mg/kg) vs. AzithromycinClinical Success: Amox/Clav (45mg/kg) vs. Azithromycin


Azithro (Azithro (65%65%))

Amox/clav - 45mg/Kg (Amox/clav - 45mg/Kg (86%86%))

Azithro (Azithro (80%80%))

Amox/clav - 45mg/Kg (Amox/clav - 45mg/Kg (87%87%))

PncPncHiHi


otitis/2002/Daganotitis/2002/DaganStudy Study 10151015 (Single Dose Azithro 30 mg/kg) Conducted (Single Dose Azithro 30 mg/kg) Conducted by Pfizer by Penicillin Susceptibilityby Pfizer by Penicillin Susceptibility



20

30

40

50

60

70

80

90

100



PlaceboPlacebo



% S

ucce

ss%

Suc

cess


Pnc Pen-S (Pnc Pen-S (95%95%))

Pnc Pen-I (Pnc Pen-I (75%75%))Pnc Pen-R (Pnc Pen-R (67%67%))


otitis/2002/Daganotitis/2002/DaganClinical Success in Studies Conducted by Pfizer by by Clinical Success in Studies Conducted by Pfizer by by PathogensPathogens



20

30

40

50

60

70

80

90

100



PlaceboPlacebo



% S

ucce

ss%

Suc

cess


Single dose - Pnc (Single dose - Pnc (88%88%) ) 3 days - Pnc (3 days - Pnc (94%94%) )

Single dose - Hi (Single dose - Hi (64%64%) ) 3 days - Hi (3 days - Hi (69%69%) )


(6)(6)

How do double tap studies help in How do double tap studies help in understanding the best timing for understanding the best timing for clinical outcome determination? clinical outcome determination?


day 1day 1 day 4-6day 4-6 day 10-12day 10-12((EOTEOT))

Day 21-30Day 21-30((TOCTOC))

TREATMENTTREATMENT


CULTURECULTURE

aa bbcc


NG20 (18%)

True bacteriologic

relapse30 (28%)

New Infection58 (54%)

Clinical Recurrence After Completion of Rx vs Clinical Recurrence After Completion of Rx vs Bacteriologic RelapseBacteriologic Relapse

Clinical recurrenceClinical recurrenceAfter bacteriologicAfter bacteriologic

eradication N=108eradication N=108

Leibovitz et al, 40th ICAAC, Toronto. 2000Leibovitz et al, 40th ICAAC, Toronto. 2000

otitis/2002/Daganotitis/2002/DaganNew Acquisition vs Persistence of Pathogens in Clinical New Acquisition vs Persistence of Pathogens in Clinical Recurrence of AOM in Relation to Initial AOM Isolate*Recurrence of AOM in Relation to Initial AOM Isolate*

42%

58%

Pnc Pnc Pnc Pnc(n = 38)(n = 38)

44%

56%

Hi Hi Hi Hi (n = 34)(n = 34)

* * Verified by serotype and PFGE for Pnc and PFGE for HiVerified by serotype and PFGE for Pnc and PFGE for Hi

RelapseRelapseNewNew

Leibovitz et al, 40th ICAAC, Toronto. 2000Leibovitz et al, 40th ICAAC, Toronto. 2000


day 1day 1 day 4-6day 4-6 day 10-12day 10-12((EOTEOT))

Day 21-30Day 21-30((TOCTOC))

TREATMENTTREATMENT


CULTURECULTURE

aa bbcc


day 1day 1 day 4-6day 4-6

TREATMENTTREATMENT


CULTURECULTURE

aa bbEOT >>>>TOCEOT >>>>TOC


(7)(7)

Are the patients that are studied in Are the patients that are studied in double tap studies different than double tap studies different than those in purely clinical studies?those in purely clinical studies?


Yes,Yes, Patients that are Studied in Double Tap Studies Patients that are Studied in Double Tap Studies Are Different than Those in Pure Clinical StudiesAre Different than Those in Pure Clinical Studies

•Most are < 2yrs of ageMost are < 2yrs of age•Tympanic membrane bulging + pusTympanic membrane bulging + pus•Positive CxPositive Cx•Enriched for more complex AOMEnriched for more complex AOM

•Otitis proneOtitis prone•Recent antibiotic useRecent antibiotic use•DCC attendance DCC attendance •Older siblingsOlder siblings•geneticsgenetics

Patients in whom Patients in whom antibiotics are antibiotics are most neededmost needed


ConclusionsConclusions1)1) Double tap studies clearly demonstrate a Double tap studies clearly demonstrate a

considerable difference between drugs in regard to considerable difference between drugs in regard to their ability to eradicate the pathogens within 3-5 their ability to eradicate the pathogens within 3-5 daysdays

2)2) Double tap studies can determine an MIC Double tap studies can determine an MIC concentration cut-off, above which a given drug is concentration cut-off, above which a given drug is not bacteriologically efficaciousnot bacteriologically efficacious

3)3) Bacteriologic eradication within 3-5 days and Bacteriologic eradication within 3-5 days and clinical outcome correlateclinical outcome correlate


Conclusions Conclusions (cont’d)(cont’d)

4)4) Double tap studies demonstrate that Double tap studies demonstrate that H. influenzaeH. influenzae is an important pathogen in AOMis an important pathogen in AOM

5)5) We can bridge between double tap studies and We can bridge between double tap studies and studies with clinical outcomestudies with clinical outcome

6)6) Double tap studies help in understanding that the Double tap studies help in understanding that the best timing for clinical outcome determination is best timing for clinical outcome determination is EOT rather than TOC EOT rather than TOC

7)7) The patients that are studied in double tap studies The patients that are studied in double tap studies are those who need antibiotics more often than are those who need antibiotics more often than patients enrolled in purely clinical studiespatients enrolled in purely clinical studies

Documents

R. Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center