Antibiotic Resistance and Microbiome in Children Aged 6-59 Months in Nouna, Burkina Faso

Study Overview
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Brief Summary
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The use of antibiotics has saved millions of human lives, however consumption of antibiotics can select for antibiotic resistant organisms and may lead to changes in commensal microbiome. This study is designed to estimate the effect of antibiotic consumption on microbiome in a rural region of rural Burkina Faso. Changes in the intestinal and nasopharyngeal microbiome and resistome following a short course of antibiotics will be measured.

Detailed Description
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This study is designed to better understand the effect of a short course of antibiotics on changes in intestinal and nasopharyngeal microbiome on treated children and untreated household contacts. The investigators hypothesize that a short course of antibiotics will lead to decreased bacterial diversity shortly after completion of the antibiotic course, and higher probability of identification of bacterial resistance genes in rectal and nasopharyngeal samples. The investigators hypothesize that a 5-day course of antibiotics (azithromycin, amoxicillin, or co-trimoxazole) will lead to significantly decreased intestinal and nasopharyngeal bacterial diversity among children aged 6-59 months. Specific Aim 1. Determine the effect of treatment with antibiotics on microbiome diversity in children aged 6-59 months following a 5-day course of antibiotics. Specific Aim 1A. Determine the direct effect of a 5-day course of azithromycin, amoxicillin, or co-trimoxazole on intestinal and nasopharyngeal bacterial diversity in children aged 6-59 months compared to no treatment. Specific Aim 1B. Determine the indirect effect of antibiotic treatment of children in a household on intestinal and nasopharyngeal bacterial diversity in an untreated child aged 6-59 months. Specific Aim 1C. Assess the association between intestinal bacterial diversity and anthropometry in a population-based sample of children.

Official Title
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Antibiotic Resistance and Microbiome in Children Aged 6-59 Months in Nouna, Burkina Faso

Conditions
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Child Development

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Amoxicillin
* Drug: Cotrimoxazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Households will be eligible for inclusion in the study if they have 2 or more children aged 6 months to 59 months currently residing in the household. Children from the household will be eligible if they are 6-59 months of age and are not currently receiving antibiotic treatment Exclusion Criteria: Children who are allergic to any of the study antibiotics will be excluded. Individuals aged under 6 months and 5 years or older will be excluded. Children already receiving antibiotics for an ongoing disease will be excluded.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 59 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Households will be randomized to one of four treatment arms (azithromycin, cotrimoxazole, amoxicillin, or placebo), and each child age 6-59 months in the household will receive 5 days of treatment. One child within each of the antibiotic households will be randomly selected to receive placebo instead of the antibiotc, to allow for study of indirect effects of antibiotic use
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithromycin<br>Comparison of nasopharyngeal and rectal microbiome in children receiving Azithromycin versus children receiving placebo Children aged 6 months to 59 months will be measured and weighed then, they will be randomized to one of the study arm and treated for 5 days. Children will receive treatment everyday, once a day as is: Azithromycin: 10 mg/kg once daily on Day 1, then 5 mg/kg once daily Days 2-5 | Drug: Azithromycin<br>* Children in this arm will receive Azithromycin once a day.<br>* Other names: Zithromax;|
| Active Comparator: Amoxicillin<br>Comparison of nasopharyngeal and rectal microbiome in children receiving Amoxicillin versus children receiving placebo Children aged 6 months to 59 months will be measured and weighed then, they will be randomized to one of the study arm. Children will receive treatment everyday, twice a day as is: Amoxicillin: 25 mg/kg/day, divided into twice daily doses for Days 1-5 | Drug: Amoxicillin<br>* Children in this arm will receive Amoxicillin twice a day.<br>|
| Active Comparator: Cotrimoxazole<br>Comparison of nasopharyngeal and rectal microbiome in children receiving Cotri-moxazole versus children receiving placebo Children aged 6 months to 59 months will be measured and weighed then, they will be randomized to one of the study arm. Children will receive treatment everyday, once a day as is: Co-trimoxazole: 240 mg daily for Days 1-5 | Drug: Cotrimoxazole<br>* Children in this arm will receive co-trimoxazole once a day.<br>|
| Placebo Comparator: Placebo<br>Comparison of nasopharyngeal and rectal microbiome in children receiving placebo versus children receiving antibiotics Children aged 6 months to 59 months will be measured and weighed then, they will be randomized to one of the study arm. Children will receive Placebo everyday, once a day. | Drug: Placebo<br>* Children in this arm will receive Placebo once a day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Simpson's Index of Diversity (Alpha Diversity) in Intestinal Microbiome | The primary outcome of the study was pre-specified as α-diversity (inverse Simpson's) at the genus level, expressed in effective number. Simpson's Alpha Diversity were obtained at Baseline and Post-treatment in this study. The minimum of Simpson's index of diversity is 0, there is no maximum. Higher Simpson's index of diversity means more diverse. There are no subscales. | Baseline and Day 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Simpson's Index of Diversity (Alpha Diversity) in Microbiome | Direct and indirect effect of antibiotics on alpha diversity from rectal samples | Day 9 | 
| Weight-for-height Z-score | Nutritional status as determined by weight-for-height Z-score vs. Placebo household Weight-for-height Z-score in each antibiotic group compared with placebo 4 weeks after last antibiotic dose Weight-for-height Z (WHZ) scores were calculated based on the 2006 World Health Organization (WHO) standards. The mean of the 2006 population standards is 0. Lower standard deviations = worse outcomes. A cutoff of < -2 means moderately wasted (WHZ). A cutoff of < -3 means wasted (WHZ). | Day 35 | 
| Height-for-age Z-score | Nutritional status as determined by height-for-age Z-score Height-for-age Z-score in each antibiotic group compared with placebo 4 weeks after last antibiotic dose Height-for-age Z (HAZ) score were calculated based on the 2006 World Health Organization (WHO) standards. The mean of the 2006 population standards is 0. Lower standard deviations = worse outcomes. A cutoff of < -2 means moderately stunted (HAZ). A cutoff of < -3 means severely stunted (HAZ). | Day 35 | 
| Weight-for-age Z-score | Nutritional status as determined by weight-for-age Z-score vs. Placebo household Weight-for-age Z-score in each antibiotic group compared with placebo 4 weeks after last antibiotic dose Weight-for-age Z-score (WAZ) scores were calculated based on the 2006 World Health Organization (WHO) standards. The mean of the 2006 population standards is 0. Lower standard deviations = worse outcomes. A cutoff of < -2 means moderately underweight (WAZ). A cutoff of < -3 means severely underweight (WAZ). | Day 35 | 
| Mid-upper Arm Circumference | Nutritional status as determined by mid-upper arm circumference in each antibiotic group compared with placebo 4 weeks after last antibiotic dose Mid-upper arm circumference (MUAC) in each antibiotic group compared with placebo 4 weeks after last antibiotic dose. MUAC is a measure to assess nutritional status. It is measured on a straight left arm, mid-way between the tip of the shoulder and the tip of the elbow. It identifies acute malnutrition and is commonly used in children 6-59 months of age as well as pregnant women. MUAC less than 115 mm indicates severe wasting or severe acute malnutrition (SAM). MUAC greater than or equal to 115 mm and less than 125 mm indicates moderate wasting or moderate acute malnutrition (MAM). | Day 35 | 
| Shannon's Index of Diversity (Alpha Diversity) in Intestinal Microbiome | Shannon's Alpha Diversity at Baseline and Post-treatment. combines richness and diversity. Shannon's index of diversity (alpha diversity) measures both the number of species and the inequality between species abundances. A large value is given by the presence of many species with well balanced abundances. | Baseline and Day 9 (Post- Treatment) | 
| Shannon's Index of Diversity (Alpha Diversity) in Nasopharyngeal Microbiome | Direct and indirect effects of antibiotics on Shannon's index of bacterial diversity | Day 9 | 
| L1-norm Distance on Bacterial Reads (Intestinal) | L1-norm distance on bacterial reads (intestinal) - L1 norm is equivalent to Shannon's diversity. Shannon's Alpha Diversity combines richness and diversity. Shannon's index of diversity (alpha diversity) measures both the number of species and the inequality between species abundances. A large value is given by the presence of many species with well balanced abundances. | Baseline and Day 9 (Post- Treatment) | 
| L1-norm Distance on Bacterial Reads (Nasopharyngeal) | L1-norm distance on bacterial reads (nasopharyngeal) | Day 9 | 
| L2-norm Distance on Bacterial Reads (Intestinal) | L2-norm distance on bacterial reads (intestinal) - L2 norm is equivalent to Simpson's diversity. Simpson's Alpha Diversity were obtained at Baseline and Post-treatment in this study. The minimum of Simpson's index of diversity is 0, there is no maximum. Higher Simpson's index of diversity means more diverse. There are no subscales. | Baseline and Day 9 (Post- Treatment) | 
| L2-norm Distance on Bacterial Reads (Nasopharyngeal) | L2-norm distance on bacterial reads (nasopharyngeal) | Day 9 | 
| Number of Participants With Macrolide Resistance Genes | Prevalence of macrolide resistance genes measured using DNA-seq from rectal swabs. | 2 years | 
| Alpha Diversity in the Intestinal Microbiome | Alpha diversity in the intestinal microbiome using DNA-seq from rectal swabs | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infection, azithromycin, amoxicillin, co-trimoxazole, trachoma, mass treatment