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Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on Resistance

Primary Purpose

Acute Otitis Media

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Amoxicillin-Clavulanate, 10 days
Amoxicillin-Clavulanate, 5 days
Sponsored by
Alejandro Hoberman
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Otitis Media focused on measuring acute otitis media, ear infection, antimicrobial therapy, antimicrobial resistance

Eligibility Criteria

6 Months - 23 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Aged 6 through 23 months

  2. Have evidence of AOM defined as:

    • recent (within 48 hours) onset of signs and symptoms as described in the Acute Otitis Media - Severity of Symptoms (AOM-SOS) Scale AND a score of ≥3 at the time of enrollment on the AOM-SOS scale
    • middle ear effusion evidenced by the presence of at least 2 of the following:
    • decreased or absent mobility of the tympanic membrane
    • yellow or white discoloration of the tympanic membrane
    • opacification of the tympanic membrane

    AND

    • acute inflammation evidenced by one of the following:
    • 1+ bulging of the tympanic membrane with either intense erythema or otalgia
    • 2+ or 3+ bulging of the tympanic membrane
  3. Has received at least 2 doses of pneumococcal conjugate vaccine
  4. Parent has provided informed consent

Exclusion Criteria:

  1. Toxic appearance [capillary refill >3 seconds, systolic blood pressure <60 mm Hg];
  2. Inpatient hospitalization
  3. Clinical or anatomical characteristics that might obscure response to treatment (tympanostomy tubes in place, cleft palate, or Down syndrome)
  4. Sensorineural hearing loss (unilateral or bilateral)
  5. Serious underlying systemic problems that might obscure response to infection (cystic fibrosis, neoplasm, juvenile diabetes)
  6. Concomitant infection that would preclude evaluation of the response of the child's AOM to study product (pneumonia, periorbital cellulitis)
  7. Acute wheezing exacerbation which may require treatment with systemic corticosteroids
  8. Known renal or hepatic dysfunction or insufficiency
  9. History of amoxicillin-clavulanate-associated cholestatic jaundice
  10. Immune dysfunction or receipt of immunosuppressive therapy; chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease)
  11. Co-medications (systemic corticosteroids, more than one dose of systemic antimicrobial therapy within 96 hours, receipt of any investigational drug or vaccine within 30 days)
  12. Hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or known hypersensitivity to aspartame
  13. Unable to complete study, or no access to phone
  14. Previously enrolled in this study or currently enrolled in another study

Sites / Locations

  • Kentucky Pediatric/Adult Research
  • Children's Hospital of Pittsburgh of UPMC

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Other

Arm Label

Amoxicillin-Clavulanate, 10 days

Amoxicillin-Clavulanate, 5 days

Arm Description

amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 10 days

amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 5 days plus placebo, 2 divided doses, 5 days

Outcomes

Primary Outcome Measures

The Distribution of Children Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit Specific to the Index Episode of AOM
Proportion of children initially diagnosed with AOM who experience treatment failure at or before the day 12-14 visit. TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of randomization, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the tympanic membrane (TM) or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.

Secondary Outcome Measures

The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit
Proportion of AOM recurrences resulting in treatment failure at or before the day 12-14 visit. TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of the recurrence, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the TM or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of Children Whose Nasopharyngeal (NP) Isolates at Enrollment Are Pathogen Negative or Positive Only for at Least One Susceptible Pathogen Who Become Colonized With Nonsusceptible Pathogens at Any Time Over the Course of Follow-up
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences. The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses within 60 days of enrollment by the number of months of follow-up within 60 days of enrollment.
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences. The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses by the number of months of follow-up.
The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season
Systemic antibiotics include the study product, Amoxicillin-Clavulanate, dispensed for either 10 or 5 days and various concomitant medications, i.e. Amoxicillin, Amox/Clav, Azithromycin, Cefdinir, Cefpodoxime, Ceftriaxone, Erythromycin, Trimethoprim-Sulfamethoxazole, Omnicef, Augmentin, Azithromycin, Cefazolin, Clarythromycin and Ciprofloxacin.
The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14
The AOM-SOS scale measures seven discrete items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. The parent rated each of these symptoms in comparison with the child's usual state, as "none," "a little," or "a lot," with corresponding scores of 0, 1, and 2, and recorded the ratings in a diary. Each set of ratings was summed to obtain an AOM-SOS score as a measure of symptom burden. Total scores range from 0 to 14, with higher scores indicating greater severity of symptoms. For instances in which the participant was declared a treatment failure, scores are included up to, but not including the day of the failure. Otherwise, scores day 6 to day 14 are included.
The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
Protocol-defined diarrhea is defined as the occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days and is limited to events associated with study product.
The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product
Diaper dermatitis is defined as dermatitis in the diaper area calling for prescription of a topical antifungal agent and is limited to events associated with study product.

Full Information

First Posted
January 10, 2012
Last Updated
October 5, 2017
Sponsor
Alejandro Hoberman
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01511107
Brief Title
Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on Resistance
Official Title
A Phase 2b, Multicenter, Randomized, Double Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy of Short-Course Antimicrobial Therapy for Young Children With Acute Otitis Media (AOM) and Impact on Antimicrobial Resistance
Study Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Terminated
Why Stopped
The primary objective of the study was met.
Study Start Date
January 2012 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Alejandro Hoberman
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators will study whether, in young children with acute otitis media (AOM), shortening length of antibiotic treatment as a strategy for reducing antimicrobial resistance provides satisfactory clinical outcome. This is a Phase 2b multicenter, randomized, double-blind, placebo-controlled clinical trial in 600 children aged 6 through 23 months comparing the efficacy of consistent reduced-duration antimicrobial treatment (5 days) with that of consistent standard-duration treatment (10 days) for each episode of AOM developing during a single respiratory season (October 1 through May 31).
Detailed Description
Eligible subjects will be randomized at the enrollment visit and will have a telephone call in the course of therapy, and a subsequent visit at the end of therapy. Thereafter, they will be followed through the end of the respiratory season, and their parents will be encouraged to bring their child when concerned about a potential recurrence of AOM. At each recurrence subjects will receive the treatment regimen (either standard- or reduced-duration) to which they were randomized at study entry (consistent treatment strategy). The recruitment of eligible children with AOM of varying degrees of severity from various primary care practices in 2 separate geographic regions, i.e. Western Pennsylvania and Kentucky, representing urban, suburban and rural demographics will enhance generalizability of study findings and encourage translation to clinical practice.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Otitis Media
Keywords
acute otitis media, ear infection, antimicrobial therapy, antimicrobial resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
520 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Amoxicillin-Clavulanate, 10 days
Arm Type
Active Comparator
Arm Description
amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 10 days
Arm Title
Amoxicillin-Clavulanate, 5 days
Arm Type
Other
Arm Description
amoxicillin-clavulanate, 90/6.4 mg/kg/day, 2 divided doses, 5 days plus placebo, 2 divided doses, 5 days
Intervention Type
Drug
Intervention Name(s)
Amoxicillin-Clavulanate, 10 days
Other Intervention Name(s)
augmentin, amox-clav
Intervention Description
Amoxicillin-clavulanate (90/6.4mg/kg/day in 2 divided doses) Days 1-10
Intervention Type
Drug
Intervention Name(s)
Amoxicillin-Clavulanate, 5 days
Other Intervention Name(s)
augmentin, amox-clav
Intervention Description
Amoxicillin-clavulanate (90/6.4mg/kg/day in 2 divided doses) Days 1-5 Plus Placebo Days 6-10
Primary Outcome Measure Information:
Title
The Distribution of Children Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit Specific to the Index Episode of AOM
Description
Proportion of children initially diagnosed with AOM who experience treatment failure at or before the day 12-14 visit. TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of randomization, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the tympanic membrane (TM) or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.
Time Frame
From 72 hours after randomization until day 21 of the index episode. The mean day for this visit was 13.2.
Secondary Outcome Measure Information:
Title
The Distribution of AOM Recurrences Categorized as Treatment Failure (TF) at or Before the Day 12-14 End-of-Treatment Visit
Description
Proportion of AOM recurrences resulting in treatment failure at or before the day 12-14 visit. TF is defined as substantial persistence or worsening of symptoms specifically attributable to AOM, or of otoscopic signs of AOM, after 72 hours from the time of the recurrence, such that additional antimicrobial therapy is deemed advisable. If a parent/legal guardian is unwilling to continue the assigned study product regimen, the participant will be categorized as TF. Should a participant be administered another systemic antibiotic while taking study medication or prior to Day 16, the participant will be considered a TF. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the TM or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable.
Time Frame
From 72 hours after the AOM recurrence was diagnosed until day 21 of the recurrence. The mean day for this visit was 13.3.
Title
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit. The mean day for this visit was 13.3.
Title
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Negative for AOM Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit. The mean day for this visit was 13.4.
Title
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit. The mean day for this visit was 13.2.
Title
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive Only for One or More Susceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit. The mean day for this visit was 13.9.
Title
The Distribution of Children With a Nasopharyngeal (NP) Culture at Enrollment That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The end-of-treatment visit. The mean day for this visit was 13.6.
Title
The Distribution of AOM Recurrences With a Nasopharyngeal (NP) Culture at Onset That is Positive for One or More Nonsusceptible Pathogens in Which the Follow-up NP Culture at Day 12-14 Yields a Nonsusceptible Pathogen
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The end-of-treatment visit. The mean day for this visit was 13.4.
Title
The Distribution of Children Whose Nasopharyngeal (NP) Isolates at Enrollment Are Pathogen Negative or Positive Only for at Least One Susceptible Pathogen Who Become Colonized With Nonsusceptible Pathogens at Any Time Over the Course of Follow-up
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
Day 1 of study entry until day 365
Title
The Distribution of 6 Week Follow-up, Non-Illness Visits During the Respiratory Season at Which a Nonsusceptible Pathogen is Recovered
Description
AOM pathogens are defined as Streptococcus pneumoniae (S pn) or Haemophilus Influenzae (H flu). In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm. In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Title
The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
Description
In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
Time Frame
The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
Title
The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Streptococcus Pneumoniae (S pn) Isolate
Description
In the case of S pn, susceptibility to penicillin was determined as follows: When minimum inhibitory concentration (MIC) was available, susceptible was defined as MIC <0.1 µg/mL, intermediate as MIC 0.1 to 1 µg/mL, and resistant as MIC >1 µg/mL. When MIC was not available, susceptible was defined as showing oxacillin disk zone size >20 mm, intermediate as zone size 9 to 20 mm, and resistant as zone size ≤8 mm.
Time Frame
The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
Title
The Distribution of Children for Whom the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit, Specific to the Index Episode, Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
Description
In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit specific to the index episode. The mean day for this visit was 13.4.
Title
The Distribution of AOM Recurrences for Which the Follow-up Nasopharyngeal (NP) Culture at the Day 12-14 Visit Yields a Nonsusceptible Haemophilus Influenzae (H Flu) Isolate
Description
In the case of H flu, susceptible was defined as beta-lactamase-negative and ampicillin E test MIC ≤1 µg/mL; nonsusceptible was defined as either beta-lactamase-positive or beta-lactamase-negative and ampicillin E test MIC >1 µg/mL.
Time Frame
The day 12-14 visit following a recurrence. The mean day for this visit was 13.6.
Title
The Distribution of Children With AOM Recurrences and Relapses Within 60 Days of Enrollment
Description
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
Time Frame
Day 1 of study entry until day 60.
Title
The Distribution of Children With AOM Recurrences and Relapses Within the Entire Respiratory Season
Description
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences.
Time Frame
Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Title
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within 60 Days of Enrollment
Description
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences. The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses within 60 days of enrollment by the number of months of follow-up within 60 days of enrollment.
Time Frame
Day 1 of study entry until day 60.
Title
The Mean Rate, Per Month, of Protocol AOM Recurrences and Relapses Within the Entire Respiratory Season
Description
An episode of AOM occurring after Day 16 will be considered a recurrence. Subjects seen after day 10 and categorized as clinical success who return for an interim/sick visit before day 17 and are found to have AOM will be categorized as a relapse. For secondary outcome analyses, relapses are combined with recurrences. The rate, expressed as a monthly rate, is calculated by dividing the total number of recurrences and relapses by the number of months of follow-up.
Time Frame
Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Title
The Mean Number of Days Systemic Antibiotics Were Received During the Entire Respiratory Season
Description
Systemic antibiotics include the study product, Amoxicillin-Clavulanate, dispensed for either 10 or 5 days and various concomitant medications, i.e. Amoxicillin, Amox/Clav, Azithromycin, Cefdinir, Cefpodoxime, Ceftriaxone, Erythromycin, Trimethoprim-Sulfamethoxazole, Omnicef, Augmentin, Azithromycin, Cefazolin, Clarythromycin and Ciprofloxacin.
Time Frame
Day 1 of study entry until day 244. The respiratory season is October 1 - May 31, inclusive.
Title
The Mean Acute Otitis Media - Severity of Symptom (AOM-SOS) Scores Days 6 to 14
Description
The AOM-SOS scale measures seven discrete items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. The parent rated each of these symptoms in comparison with the child's usual state, as "none," "a little," or "a lot," with corresponding scores of 0, 1, and 2, and recorded the ratings in a diary. Each set of ratings was summed to obtain an AOM-SOS score as a measure of symptom burden. Total scores range from 0 to 14, with higher scores indicating greater severity of symptoms. For instances in which the participant was declared a treatment failure, scores are included up to, but not including the day of the failure. Otherwise, scores day 6 to day 14 are included.
Time Frame
From day 6 of administration of study product until day 14 for all episodes
Title
The Distribution of Children for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
Description
Protocol-defined diarrhea is defined as the occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days and is limited to events associated with study product.
Time Frame
Day 1 of administration of study product until day 16 for all episodes
Title
The Distribution of Children for Whom Diaper Dermatitis Was Reported and Associated With Study Product
Description
Diaper dermatitis is defined as dermatitis in the diaper area calling for prescription of a topical antifungal agent and is limited to events associated with study product.
Time Frame
Day 1 of administration of study product until day 16 for all episodes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
23 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged 6 through 23 months Have evidence of AOM defined as: recent (within 48 hours) onset of signs and symptoms as described in the Acute Otitis Media - Severity of Symptoms (AOM-SOS) Scale AND a score of ≥3 at the time of enrollment on the AOM-SOS scale middle ear effusion evidenced by the presence of at least 2 of the following: decreased or absent mobility of the tympanic membrane yellow or white discoloration of the tympanic membrane opacification of the tympanic membrane AND acute inflammation evidenced by one of the following: 1+ bulging of the tympanic membrane with either intense erythema or otalgia 2+ or 3+ bulging of the tympanic membrane Has received at least 2 doses of pneumococcal conjugate vaccine Parent has provided informed consent Exclusion Criteria: Toxic appearance [capillary refill >3 seconds, systolic blood pressure <60 mm Hg]; Inpatient hospitalization Clinical or anatomical characteristics that might obscure response to treatment (tympanostomy tubes in place, cleft palate, or Down syndrome) Sensorineural hearing loss (unilateral or bilateral) Serious underlying systemic problems that might obscure response to infection (cystic fibrosis, neoplasm, juvenile diabetes) Concomitant infection that would preclude evaluation of the response of the child's AOM to study product (pneumonia, periorbital cellulitis) Acute wheezing exacerbation which may require treatment with systemic corticosteroids Known renal or hepatic dysfunction or insufficiency History of amoxicillin-clavulanate-associated cholestatic jaundice Immune dysfunction or receipt of immunosuppressive therapy; chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease) Co-medications (systemic corticosteroids, more than one dose of systemic antimicrobial therapy within 96 hours, receipt of any investigational drug or vaccine within 30 days) Hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or known hypersensitivity to aspartame Unable to complete study, or no access to phone Previously enrolled in this study or currently enrolled in another study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alejandro Hoberman, MD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Kentucky Pediatric/Adult Research
City
Bardstown
State/Province
Kentucky
ZIP/Postal Code
40004
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28002709
Citation
Hoberman A, Paradise JL, Rockette HE, Kearney DH, Bhatnagar S, Shope TR, Martin JM, Kurs-Lasky M, Copelli SJ, Colborn DK, Block SL, Labella JJ, Lynch TG, Cohen NL, Haralam M, Pope MA, Nagg JP, Green MD, Shaikh N. Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children. N Engl J Med. 2016 Dec 22;375(25):2446-2456. doi: 10.1056/NEJMoa1606043.
Results Reference
derived
PubMed Identifier
24911895
Citation
Martin JM, Hoberman A, Paradise JL, Barbadora KA, Shaikh N, Bhatnagar S, Shope T, Block SL, Haralam MA, Kurs-Lasky M, Colborn DK, Green M. Emergence of Streptococcus pneumoniae serogroups 15 and 35 in nasopharyngeal cultures from young children with acute otitis media. Pediatr Infect Dis J. 2014 Nov;33(11):e286-90. doi: 10.1097/INF.0000000000000445.
Results Reference
derived

Learn more about this trial

Efficacy of Short-Course Antimicrobial Treatment for Children With Acute Otitis Media and Impact on Resistance

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