Design Issues in Antimicrobial Treatment Trials of AOM

1
Design Issuesin Antimicrobial TreatmentTrials
of AOM

• G. Scott Giebink, M.D.
• Professor of Pediatrics and Otolaryngology
• Director, Otitis Media Research Center
• University of Minnesota School of Medicine

2
Markers of Antimicrobial Effectiveness

• Bacteriologic cure sterilize middle ear fluid
• On-therapy (double) tap eradication vs.
  suppression
  
• Clinical cure resolve clinical symptoms
  signs
  
• EOT (2-5 days after treatment)
• TOC (25-30 days after treatment)
• Pharmacokinetic surrogates T MIC
• Plasma vs. Middle ear fluid

3
Design Issues

• Double-tap design yields definitive
  bacteriological cure rate in a non-comparative
  setting.
  
• Timing of 2nd tap eradication vs. suppression.
• Enriching for PRSP biases for treatment failure.
• Risk factors for PRSP risk factors for
  recurrent AOM.
  
• PK / PD surrogates are highly variable.
• ? Relatedness of murine models to OM
• 1st dose PK studies miss accumulation over time
• OM severity at entry correlates with
  bacteriological and clinical cure, and has
  implication for sample size.

4
Acute Otitis Media in the US

• 24 million AOM office visits per year (1)
• 80 of children have ? 1 episode by age 3 (2)
• 50 have 3 episodes by age 3 (2)
• 712 million cases caused by S. pneumoniae (1)
• Small differences in treatment response rates can
  affect millions of children each year.

(1) MMWR. 1997461-24(2) Teele DW et al. J
Infect Dis. 198916083-94
5
Bacteriology of Severe and Mild AOM

• Severity Pnc Hi M cat Mixed Total
• ( ears)
• Mild 20 26 7 11 65
• (n54)
• Severe 38 18 6 10 71
• (n175)

p0.13
Kaleida, et al. Pediatrics, 1991
6
AOM Clinical Responseto Placebo or Amoxicillin
clinically cured / improved

• Placebo (mild) or Amoxicillin Myringotomy
  (severe) only
  
• Mild AOM 92 96
• Severe AOM 76 90

P0.009
P0.006
Kaleida et al. Pediatrics, 1991
7
OM Severity Affects Bacteriological Clinical
Cure Rates Without Treatment

• Pnc Hi Mcat Mixed NG Total
• Mild 20 26 7 11 40
• Spont cure .2 .5 .7 .3 1.0
• Bact cure 4 12 4 3 40 63
• Clinical cure 92
• Severe 40 20 5 10 25
• Spont cure .2 .5 .7 .3 1.0
• Bact cure 8 10 4 3 25 50
• Clinical cure 76

? 13
? 16
Sample size implications
8
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
9
WHYBacteriological / Clinical Discordance?

• Bacti success / Clinical failure (6)
• Persistence of bacterial host inflammatory
  mediators
  
• Concurrent viral infection
• Bacti failure / Clinical success (9)
• Low-grade pathogen / poor growth in MEF

10
Persistent Symptoms During Treatment

• Concurrent viral infection
• Noncompliance
• Resistant bacterial pathogen
• Sensitive bacteria, but drug distribution failure
  (eg, AOM complicating chronic mucoid OME)
  
• Inflammation after clearing bacterial pathogens
• Immune deficiency -- acquired, congenital

11
Respiratory Viruses Contributeto Bacterial AOM
Cause AOMIndependent of Bacterial Pathogens
A Pitkaranta et al. Pediatrics 1998 102 291-5
12
The OM Continuum

• Chronic
• Otitis Media With
• Effusion (OME)
• Mucoid OM
• Secretory OM

Acute (purulent) Otitis Media

• NONSUPPURATIVE SEQUELAE
• TM atelectasis
• Adhesive OM
• Cholesteatoma
• Ossicular erosion / fixation
• Hearing loss
• Conductive
• Sensorineural

• SUPPURATIVE COMPLICATIONS
• Chronic suppurative OM
• Mastoiditis
• Meningitis
• Facial nerve palsy

Enriching subject populations for rAOM PRSP
creates a cohort not representative of uncomplica
ted AOM.
13
AOM Risk Factors

• For Treatment Failure / Recurrence
• Antibiotic within the last 1 month
• ANY OM diagnosis within the last 1 month
• 3 AOM episodes in last 6 months
• Age
• Age at 1st OM
• Day care center attendance ( 10 children)
• Bilateral OM disease

• For PRSP
• Antibiotic within the last 1 month
• Infection while on antibiotic prophylaxis
• Persistent or recurrent AOM or sinusitis
• Infection during Winter / Spring months
• Age
• Day care attendance

14
Child Care Effect on OM URIs Complicated by OM
Wald, et al. Pediatrics 199187129
15
Prevalence of Pneumococcal CarriageAmong Day
Care Center ChildrenWith 3 Cases of MDRSP-14
Meningitis (DCC-A)
n80
n46
n52
n48
Craig et al. Clin Infect Dis 1999291257
16
Risk Factors for OME PersistenceAfter AOM
Treatment Bilateral AOM, Day care , OME 4
weeks
K Daly et al. Pediatr Infect Dis J 19887471-5
17
Pediatric Pneumococcal Carriage Rates
Fedson DS et al. Vaccines (3rd ed) WB Saunders
1999553-607
18
Pneumococcal Susceptibility by Specimen Source

• Blood/CSF Respiratory Ear Eye
• (n370) (n682) (n85) (n58)
• 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 (Pthat for blood/CSF.

Thornsberry et al. AAC 1999432612
19
Pneumococcal Susceptibility by Age

• ?2 yr 3-12 yr ?13 yr
• (n284) (n134) (n813)
• 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 (Pthan that for the ?2 yr group

Thornsberry et al. AAC 1999432612
20
Pneumococcal Conjugate Vaccine Effect on
PRSPPRSP by Serotype in Children 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 20.9

Routine PCV will greatly reduce the occurrence of
PRSP AOM.
Whitney et al. NEJM 20013431917
21
Conclusions

• Tightly control clinical definitions
• Enrollment severity affects bacteriological
  clinical cure rates
  
• EOT cure
• Eliminate TOC
• Enriching for PRSP
• Selects subjects with more chronic ME disease
  not comparable to uncomplicated AOM
  
• Selects younger, day care subjects
• Increases reinfection rates
• 2nd tap may measure suppression, not eradication
• Routine PCV immunization will significantly
  reduce PRSP incidence in AOM.