# Presentation: 463010

## R. Dagan
The Pediatric Infectious Disease Unit
Soroka University Medical Center
Ben-Gurion University
 Beer-Sheva, Israel

**The Pediatric Infectious Disease Unit**
**Soroka University Medical Center**
**Ben-Gurion University**
** ****Beer-Sheva, Israel**

**Double Tympanocentesis Studies: Bridging from Bacteriological Outcome to Studies with Clinical Outcome**

## TREATMENT

**day 1**

**day 4-6**

**day 10-12**

**Day 21-30**

**TREATMENT**

## (1)

***In AOM, is there any difference between drugs in regard to bacteriologic eradication on day 4-6?***

## * for amoxicilline only

**cefac**** ****(40)**

**cef-axet**** ****(40)**

**amox/augm**** ****(40-50)**

**CROx1**** ****(50)**

**CROx3**** ****(50)**

**Azith**** ****(3;5d)**

**Ts**

**placebo **

******* for amoxicilline only**

**84%**

**52%**

**% persistence**

**Aug****  ****ES-600**** ****(90)**

**Gati**** ****(10)**

*****

## Failure rate (%)

**placebo (1*)**

**Failure rate (%)**

***Number of studies**

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

**50**

**0**

**100**

## (2)

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

## Pnc 

**84**

**Placebo**

**CEF - AXET**

**CECL**

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

**% bacteriologic failures**

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

**Pnc **
**n=111**

**Hi**
**n=131**

## Bacteriologic Failure Rate (day 4-5) TMP/SMX 

**84**

**52**

**Pnc**

**Placebo Pnc**

**Hi**

**Placebo Hi**

**MIC<=0.5 mcg/ml**

**MIC >0.5 mcg/ml**

**% bacteriologic failures**

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

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

## Pnc

**84**

**52**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Placebo**

**Placebo**

**Pnc**

**Hi**

**% with bacteriological failure**

**Azithromycin MIC (μg/ml)**

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

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

## Bacteriological Failures of Pnc and Hi Treated by Augmentin ES-600 by MIC

**Dagan et al, Pediatr Infect Dis, 20:829-37, 2001**

**% with bacteriological failure**

## (3)

***Is there a relation between bacteriologic eradication on day 4-6 and clinical outcome ?***

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

**Clinical Failure**

**Clinical success**

**Carlin et al**
**J Pediatr **
**118:178-83, 1991**

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

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

## B

**B**

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

**A**

*** ****Including draining pus**

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

## Can we determine by double tap studies if an organism is not important in AOM

***Can we determine by double tap studies if an organism is not important 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): MEF Pathogens in Bacteriologic Failure

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

## Does NTHi Cause a Less Severe AOM?

**TEMPERATURE (oC)****	****<38.0****	****38.0-38.5****	****38.6-39.0****	****>39.0**
**IRRITABILITY****	****absent****	****mild****	****moderate****	****severe**
**REDNESS ****	****absent****	****mild****	****moderate****	****severe**
**BULGING****	**** ****absent****	****mild****	****moderate****	****severe***

*** ****Including draining pus**

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

**Maximal score = 12**

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

***Clinical score***

## Cx (+)

**Cx (+)**

**8.21 ******** 2.17**

**7.73 ******** 2.32**

***P = 0.003***

**n = 762**

**n = 240**

**Cx (-)**

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

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

**NTHi**

**Pnc**

**NTHi + Pnc**

**NG**

**8.32 ******** 2.19**

**8.14 ******** 2.11**

**8.06 ******** 2.20**

**7.73 ******** 2.32**

***P = 0.018***

**n = 392**

**n = 240**

**n = 173**

**n = 198**

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

## Mean ( SD) Difference in Total Score 

***Mean (************ SD) ******Difference in Total Score****** ***
***Between 1******st ******& 2******nd****** Visit ***

## Can we bridge between double tap studies and studies with clinical outcome?

***Can we bridge between double tap studies and studies with clinical outcome?***

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

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**Bacterial eradication rate**

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

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

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

**Azithromycin**

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

**Hi alone**

**Pnc alone**

**Total**

**Augmentin**

## % Success

**Clinical efficacy**
**in bacterial AOM**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Bacteriologic efficacy**
**in bacterial AOM**

**Clinical efficacy in ****“clinical” AOM**

**% Success**

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

## Slide 25

## Study 1015 (Single Dose Azithro 30 mg/kg) Conducted by Pfizer by Penicillin Susceptibility

**Clinical efficacy**
**in bacterial AOM**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Bacteriologic efficacy**
**in bacterial AOM**

**Clinical efficacy in ****“clinical” AOM**

**% Success**

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

## Slide 27

## Clinical Success in Studies Conducted by Pfizer by by Pathogens

**Clinical efficacy**
**in bacterial AOM**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Bacteriologic efficacy**
**in bacterial AOM**

**Clinical efficacy in ****“clinical” AOM**

**% Success**

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

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

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

## TREATMENT

**day 1**

**day 4-6**

**day 10-12**
**(****EOT****)**

**Day 21-30**
**(****TOC****)**

**TREATMENT**

## Clinical Recurrence After Completion of Rx vs Bacteriologic Relapse

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

**Clinical recurrence**
**After bacteriologic**** **
**eradication N=108**

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

## New Acquisition vs Persistence of Pathogens in Clinical Recurrence of AOM in Relation to Initial AOM Isolate*

**Pnc ******** Pnc**
**(n = 38)**

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

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

## TREATMENT

**day 1**

**day 4-6**

**day 10-12**
**(****EOT****)**

**Day 21-30**
**(****TOC****)**

**TREATMENT**

## EOT >>>>TOC

**day 1**

**day 4-6**

**TREATMENT**

**EOT >>>>TOC**

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

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

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

*** ***

**Most are < 2yrs of age**
**Tympanic membrane bulging + pus**
**Positive Cx**
**Enriched for more complex AOM**
**Otitis prone**
**Recent antibiotic use**
**DCC attendance **
**Older siblings**
**genetics**

## Conclusions

**1)****	****Double tap studies clearly demonstrate a considerable difference between drugs in regard to their ability to eradicate the pathogens within 3-5 days**
**2)****	****Double tap studies can determine an MIC concentration cut-off, above which a given drug is not bacteriologically efficacious**
**3)****	****Bacteriologic eradication within 3-5 days and clinical outcome correlate**

## Conclusions (cont’d)

**4)****	****Double tap studies demonstrate that *****H. influenzae***** is an important pathogen in AOM**
**5)****	****We can bridge between double tap studies and studies with clinical outcome**
**Double tap studies help in understanding that the best timing for clinical outcome determination is EOT rather than TOC **
**The patients that are studied in double tap studies are those who need antibiotics more often than patients enrolled in purely clinical studies**