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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
otitis/2002/Daganotitis/2002/Dagan
day 1day 1 day 4-6day 4-6 day 10-12day 10-12 Day 21-30Day 21-30
TREATMENTTREATMENT
CULTURECULTURE
TYMPANOCENTESISTYMPANOCENTESIS
aa bb
otitis/2002/Daganotitis/2002/Dagan
(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?
otitis/2002/Daganotitis/2002/Dagan
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)
**
otitis/2002/Daganotitis/2002/Dagan
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)
otitis/2002/Daganotitis/2002/Dagan
(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 ?
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
(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 ?
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
(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
otitis/2002/Daganotitis/2002/Dagan
H. Influenzae is deemed by some clinicians/antibiotic manufacturers as being not important, although
prevalent, in AOM
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
(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?
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
Clinical Success: Amox/Clav (45mg/kg) vs. AzithromycinClinical Success: Amox/Clav (45mg/kg) vs. Azithromycin
AzithromycinAzithromycin
Dagan et al PIDJ 19:95-104, 2000Dagan et al PIDJ 19:95-104, 2000
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
otitis/2002/Daganotitis/2002/Dagan
Clinical Clinical efficacyefficacy
in bacterial in bacterial AOMAOM
20
30
40
50
60
70
80
90
100
Bacteriologic Bacteriologic efficacyefficacy
in bacterial in bacterial AOMAOM
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
Dagan et al PIDJ 19:95-104, 2000Dagan et al PIDJ 19:95-104, 2000
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/Dagan
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
Clinical Clinical efficacyefficacy
in bacterial in bacterial AOMAOM
20
30
40
50
60
70
80
90
100
Bacteriologic Bacteriologic efficacyefficacy
in bacterial in bacterial AOMAOM
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
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/Dagan
otitis/2002/Daganotitis/2002/DaganClinical Success in Studies Conducted by Pfizer by by Clinical Success in Studies Conducted by Pfizer by by PathogensPathogens
Clinical Clinical efficacyefficacy
in bacterial in bacterial AOMAOM
20
30
40
50
60
70
80
90
100
Bacteriologic Bacteriologic efficacyefficacy
in bacterial in bacterial AOMAOM
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
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%) )
otitis/2002/Daganotitis/2002/Dagan
(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?
otitis/2002/Daganotitis/2002/Dagan
day 1day 1 day 4-6day 4-6 day 10-12day 10-12((EOTEOT))
Day 21-30Day 21-30((TOCTOC))
TREATMENTTREATMENT
TYMPANOCENTESISTYMPANOCENTESIS
CULTURECULTURE
aa bbcc
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
day 1day 1 day 4-6day 4-6 day 10-12day 10-12((EOTEOT))
Day 21-30Day 21-30((TOCTOC))
TREATMENTTREATMENT
TYMPANOCENTESISTYMPANOCENTESIS
CULTURECULTURE
aa bbcc
otitis/2002/Daganotitis/2002/Dagan
day 1day 1 day 4-6day 4-6
TREATMENTTREATMENT
TYMPANOCENTESISTYMPANOCENTESIS
CULTURECULTURE
aa bbEOT >>>>TOCEOT >>>>TOC
otitis/2002/Daganotitis/2002/Dagan
(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?
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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
otitis/2002/Daganotitis/2002/Dagan
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