# Presentation: 689549

## Ron Dagan MD

Professor of Pediatrics and Infectious Diseases
Director
The Pediatric Infectious Disease Unit
Soroka University Medical Center
Ben-Gurion University
 Beer-Sheva, Israel

**Professor of Pediatrics and Infectious Diseases**
**Director**
**The Pediatric Infectious Disease Unit**
**Soroka University Medical Center**
**Ben-Gurion University**
** ****Beer-Sheva, Israel**

***Getting Clear Answers -AOM Clinical Trials ***

## Abbreviations

**Pnc****	*****S. pneumoniae***
**Hi****	*****H. influenzae***
**MC****	*****M. catarrhalis***
***Pen******	******penicillin***
**Amox****	****amoxicillin**
**Amox/clav****	****amoxicillin/clavulanate**
**Cef-axet****	****cefuroxime axetil**
**Cecl****	****cefaclor**
**TMP/SMX****	****trimethoprim/sulfamethoxazole**
**DCC ****	****day care centers**
**NP****	****Nasopharyngeal**
**Pk/Pd****	****pharmacokinetics/pharmacodynamics**

## AOM studies may be 

**hand-tailored to **
**your needs**

## Which outcome to choose?

***(1)***

## The “Pollyanna Phenomenon”

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**% Success**

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

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

**84**

**52**

**Placebo Pnc**

**Placebo Hi**

**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**
**(for placebo - Howie, Clin Pediatr 11:205-14,1972)**** **

**Financial support: Glaxo; Pfizer**

## 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**
**(for placebo - Howie, Clin Pediatr 11:205-14,1972)**

**Financial support: none**

## Hi AOM Treated with Amoxicillin: Role of -lactamase

**52**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**Placebo**

**Howie et al,  Pediatr Infect Dis J, 1987; 6:989**
**Johnson et al,  J Pediatr, 1991; 119:117**
**Dagan et al - unpublished**

***Hi AOM Treated with Amoxicillin: Role of ************-lactamase***

**% of patients with **
**persistence of organisms  **

**Financial support: none**

## Bacteriologic Failure Rate (day 4-5)  

***for Azithromycin***

**84**

**52**

**Placebo**

**Pnc**

**Placebo**

**Hi**

**<= 0.125**

**Dagan et al AAC 44:43-50, 2000**
**(for placebo - Howie, Clin Pediatr 11:205-14,1972)**

**0.5**

**1**

**2.0 - 4.0**

**MIC (μg/ml)**

**>=32.0**

**% with failure**

**Pnc**

**Hi**

**Financial support: Pfizer**

## Which end-point to choose?

***(2) ***

## Severe AOM

**Kaleida et al, Pediatr 87:466-74, 1991**

**0**

**20**

**40**

**60**

**80**

**% with response**

** ****Age ≥ 2 yrs**

## Clinical Recurrence After Completion of Rx vs Bacteriologic Relapse

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

**Clinical recurrence**
**After bacteriologic**** **
**Eradication when followed to day 28**
**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**

## Who are the Patient’s contacts?

***(3) ***

## Outcome of Children with AOM (% Clinical Failures = End of Treatment) According to Day Care and Length of Treatment with Various Drugs

***Outcome of Children with AOM ******(% Clinical Failures = End of Treatment)****** According to Day Care and Length of Treatment with Various Drugs***

**Cohen et al, PIDJ (submitted)**

**n=166**

***P = .018 ***** for each **
**duration comparing**
**child care**

**% Clinical Failures **
**End of Treatment**** **

**n=238**

**n=223**

**n=274**

## Outcome of Children with AOM (% Clinical Recurrence = Test  of Cure) According to Day Care and Length of Treatment with Various Drugs

***Outcome of Children with AOM ******(% Clinical Recurrence = Test  of Cure)****** According to Day Care and Length of Treatment with Various Drugs***

**Cohen et al, PIDJ (submitted)**

**n=106**

***P = .018 ***** for each **
**duration comparing**
**child care**

**% Clinical recurrence **
**Test of Cure**

**n=150**

**n=173**

**n=245**

## NP Carriage of  Penicillin Non-susceptible Pneumococci According to Day Care Attendance 

**organisms**

**Cohen et al, PIDJ (submitted)**

**% of all Pnc that  were **
**penicillin non-susceptible**

**N - 404**

**N - 497**

***NP Carriage of  Penicillin Non-susceptible Pneumococci According to Day Care Attendance ***

## Carriage of Pnc, Hi and MC in Children Aged 3m-3yrs 

***Carriage of Pnc, Hi and MC in Children Aged 3m-3yrs ***
***According to the Presence or Absence of Siblings at Home***

**Varon et al, Clin Infect Dis 2000; 31:477 - 81**

**% of children who **
**are carriers**

***P < 0.001 for all ***
***comparisons***

## Age effect

***(4) ***

## Effect of Age on Outcome (End of Treatment) of  AOM

**% with non-satisfactory **
**outcome**

**Age**

*** ****Non “success”**

## Effect of severity

***(4) ***

## Non severe

**% with initial failure**
**(Tx  modified)**

**Non severe**

**Severe**

***Effect of Severity on Clinical Outcome at end of treatment**********

*** For patients  ****≥ 2 yrs old (no placebo was used for younger patients****).**
**This was a clinical study, and bacteriologic diagnosis and outcome was not determined**

## Effects of these  factors on AOM studies

**Effects of these  factors on AOM studies**

## The “Pollyanna Phenomenon”

***The “Pollyanna Phenomenon”***

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

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

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

**% Success**

## Efficacy in AOM 

**Basis for calculation**

## Efficacy in AOM 

**Factors that may reduce clinical efficacy**
**Young age**
**DCC attendance**
**older sibs at home**
**Previous otitis episodes**
**Previous antibiotic treatment**
**Bilateral otitis**
**NP colonization with non-susceptibles**

## Vs

***bacteriologic ***
***Efficacy***
**But: **
**convenient**
**well tolerated**

***A drug with ******good ***
***bacteriologic ***
***Efficacy***
**But: **
**less convenient**
**less well tolerated**

**Vs**

## “Hand Tailored” AOM Drugs Studies 

**	****	****Weak well tolerated****	****Strong, less well tolerated**

**Conclusions****	****based on equivalence****	****based on bacteriologic**
**	****	****of clinical outcome and****	****and clinical efficacy**
**	****	****superiority of tolerability/****	****in “difficult to treat”**
**	****	****convenience ****	****cases****	****	**

***“******Hand Tailored” AOM Drugs Studies ***

**Baseline****	****clinical diagnosis****	****Clinical with proven **
**	****	****	****bacterial etiology on tympano**

**Study population**
**	****Age****	****> 24m****	****< 24m**
**	****DCC****	****avoid****	****as many as you can**
**	****Older siblings at home****	****avoid****	****as many as you can**
**	****Recurrent/non-responsive****	**** ****avoid****	****as many as you can**

**Outcomes**
**	****Tolerability****	****much emphasis****	****less emphasis**
**	****Convenience****	**** much emphasis****	****less emphasis**
**	****Bacteriological efficacy****	****do not include****	****main outcome**
**	****Main clinical outcome****	****test of cure****	****end of Rx****	****	****	****(d = 28-42)****	****(d = 11-12)**

## Conclusion

**Most AOM with clinical outcome as currently conducted, are virtually guaranteed show no significant differences between agents, dosing, or duration of treatment**