Effect of Antimicrobial Treatment of Acute Otitis Media on the Intestinal Microbiome in Children

Study Overview
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Brief Summary
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This is a randomized, controlled trial studying the effects of various antimicrobial treatments on the intestinal microbiome of small children. The participating children with acute otitis media are treated wither with amoxicillin, amoxicillin-clavulanate or without antibiotics. The children with allergy to amoxicillin receive a course of macrolide and they will be monitored as a separate group. The main outcomes of this trial are the changes in the intestinal microbiome after the treatment.

Detailed Description
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Antimicrobial treatment of acute otitis media has been proven efficacious in children. It has been suggested that antimicrobial treatment makes a lot of harm to intestinal microbiome and may thus have effects on the child's health and wellbeing. However, data on these changes and their magnitude is scanty. This is a randomized, controlled trial studying the effects of various antimicrobial treatments on the intestinal microbiome of small children. The participating children with acute otitis media are treated wither with amoxicillin, amoxicillin-clavulanate or without antibiotics. The children with allergy to amoxicillin receive a course of macrolide and they will be monitored as a separate group. The main outcomes of this trial are the changes in the intestinal microbiome after the treatment.

Official Title
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Effect of Antimicrobial Treatment of Acute Otitis Media on the Intestinal Microbiome in Children: A Randomized Controlled Trial

Conditions
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Acute Otitis Media

Intervention / Treatment
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* Drug: Amoxicillin
* Drug: Amoxicillin-Potassium Clavulanate
* Drug: Macrolide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: acute symptoms of respiratory infection AND signs of inflammation on the tympanic membrane in otoscopy AND middle ear effusion found in pneumatic otoscopy Exclusion Criteria: Suspected or proven complication of acute otitis media (for example acute mastoiditis or perforated tympanic membrane) Severe acute otitis media: severe pain and fever > 39 degrees C Bilateral acute otitis media in a child younger than 2 years Primary or secondary immunodeficiency or Downs syndrome Impaired general condition or suspected severe bacterial infection Allergy to both amoxicillin and macrolide Acute otorrhea through tympanostomy tube Antimicrobial treatment ongoing or during previous 7 days

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Amoxicillin<br>The children with acute otitis media will be treated with amoxicillin mixture, 100mg/ml, 40mg/kg/d, divided to two daily doses for 7 days. | Drug: Amoxicillin<br>* The children with acute otitis media will be treated with amoxixillin mixture, 100mg/ml, 40mg/kg/d, divided to two daily doses for 7 days.<br>|
| Active Comparator: Amoxicillin-Potassium Clavulanate<br>The children with acute otitis media will be treated with amoxicillin-clavulanate mixture, 80mg/ml, 45mg/kg/d, divided to two daily doses for 7 days. | Drug: Amoxicillin-Potassium Clavulanate<br>* The children with acute otitis media will be treated with amoxixillin-clavulanate mixture, 80mg/ml, 45mg/kg/d, divided to two daily doses for 7 days.<br>|
| No Intervention: Wait and see<br>The children with acute otitis media will be monitored without antimicrobial treatment. | |
| Other: Macrolide<br>The children with acute otitis media with known allergy to amoxicillin or amoxicillin-clavulanate will be treated with macrolide and monitored as a separate group, outside randomization. | Drug: Macrolide<br>* The children with acute otitis media with a know allergy to amoxicillin or amoxicillin-clavulanate will be treated with macrolide and monitored separately<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the relative abundance of Firmicutes in stool samples | Change in the relative abundance of Firmicutes in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Principal coordinate analysis (PCA) of fecal samples | Principal coordinate analysis (PCA) of the microbiota of fecal samples 10 days after starting treatment to acute otitis media | 10 days | 
| Change in the relative abundance of Actinobacteria in stool samples | Change in the relative abundance of Actinobacteria in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Bacteroidetes in stool samples | Change in the relative abundance of Bacteroidetes in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Proteobacteria in stool samples | Change in the relative abundance of Proteobacteria in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Verrucomicrobia in stool samples | Change in the relative abundance of Verrucomicrobia in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Lactobacilli in stool samples | Change in the relative abundance of Lactobacilli in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Bifidobacteria in stool samples | Change in the relative abundance of Bifidobacteria in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the relative abundance of Faecalibacterium prausnitzii in stool samples | Change in the relative abundance of Faecalibacterium prausnitzii in stool samples obtained at baseline and at 10 days after the diagnosis of acute otitis media. | Change from baseline to 10 days | 
| Change in the diversity of fecal microbiota measured with the number of operational taxonomic units (OTUs) | Change in the diversity of fecal microbiota measured with the number of operational taxonomic units (OTUs) from baseline to 10 days after the diagnosis of acute otitis media | Change from baseline to 10 days | 
| Change in the diversity of fecal microbiota measured with Shannon index | Change in the diversity of fecal microbiota measured with Shannon index from baseline to 10 days after the diagnosis of acute otitis media | Change from baseline to 10 days | 
| Change in the diversity of fecal microbiota measured with Chao index | Change in the diversity of fecal microbiota measured with Chao index from baseline to 10 days after the diagnosis of acute otitis media | Change from baseline to 10 days | 
| Presence of antimicrobial genes measured with the means of metagenomics | Presence of antimicrobial genes measured with the means of metagenomics at 10 days after the diagnosis of acute otitis media | 10 days | 
| Proportion of Clostridium difficile -positive fecal samples | Occurrence of Clostridium difficile in fecal samples 10 days after the diagnosis of acute otitis media | 10 days | 
| Proportion of fecal samples with Extended Spectrum Beta-Lactamase -positive strains | Proportion of fecal samples with Extended Spectrum Beta-Lactamase -positive strains 10 days after the diagnosis of acute otitis media | 10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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children, intestinal microbiome, microbiota, antimicrobial course, amoxicillin, amoxicillin-clavulanate, macrolide