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

Phase 4

Completed

Conditions: Child Development

Interventions: Drug: Cotrimoxazole
Drug: Placebo
Drug: Azithromycin
Drug: Amoxicillin

Registration Number: NCT03187834

Lead Sponsor: University of California, San Francisco

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 252

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cotrimoxazole	Cotrimoxazole	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
Placebo	Placebo	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.
Azithromycin	Azithromycin	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
Amoxicillin	Amoxicillin	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

Primary Outcome Measures

Name	Time	Method
Simpson's Index of Diversity (Alpha Diversity) in Intestinal Microbiome	Baseline and Day 9	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.

Secondary Outcome Measures

Name	Time	Method
Simpson's Index of Diversity (Alpha Diversity) in Microbiome	Day 9	Direct and indirect effect of antibiotics on alpha diversity from rectal samples
Weight-for-height Z-score	Day 35	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).
Height-for-age Z-score	Day 35	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).
Weight-for-age Z-score	Day 35	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).
Mid-upper Arm Circumference	Day 35	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).
Shannon's Index of Diversity (Alpha Diversity) in Intestinal Microbiome	Baseline and Day 9 (Post- Treatment)	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.
Shannon's Index of Diversity (Alpha Diversity) in Nasopharyngeal Microbiome	Day 9	Direct and indirect effects of antibiotics on Shannon's index of bacterial diversity
L1-norm Distance on Bacterial Reads (Intestinal)	Baseline and Day 9 (Post- Treatment)	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.
L1-norm Distance on Bacterial Reads (Nasopharyngeal)	Day 9	L1-norm distance on bacterial reads (nasopharyngeal)
L2-norm Distance on Bacterial Reads (Intestinal)	Baseline and Day 9 (Post- Treatment)	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.
L2-norm Distance on Bacterial Reads (Nasopharyngeal)	Day 9	L2-norm distance on bacterial reads (nasopharyngeal)
Number of Participants With Macrolide Resistance Genes	2 years	Prevalence of macrolide resistance genes measured using DNA-seq from rectal swabs.
Alpha Diversity in the Intestinal Microbiome	2 years	Alpha diversity in the intestinal microbiome using DNA-seq from rectal swabs