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

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.

Study Overview

• Status: Completed
• Conditions: Child Development
• Intervention / Treatment: Drug: Azithromycin; Drug: Amoxicillin; Drug: Cotrimoxazole; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 4

Contacts and Locations

Study Locations

• Burkina Faso
  • Nouna, Burkina Faso
    • Centre de recherche en Santé de nouna
• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Proctor Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 4 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Azithromycin; Children in this arm will receive Azithromycin once a day.; Other Names: Zithromax
Active Comparator: 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	Drug: Amoxicillin; Children in this arm will receive Amoxicillin twice a day.
Active Comparator: 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	Drug: Cotrimoxazole; Children in this arm will receive co-trimoxazole once a day.
Placebo Comparator: 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.	Drug: Placebo; Children in this arm will receive Placebo once a day.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Heidelberg University; Centre de Recherche en Sante de Nouna, Burkina Faso
• Investigators: Principal Investigator: Thomas M Lietman, MD, UCSF F.I. Proctor Foundation; Study Director: Catherine E Oldenburg, ScD, UCSF F.I. Proctor Foundation

Publications and helpful links

General Publications

• Oldenburg CE, Hinterwirth A, Worden L, Sie A, Dah C, Ouermi L, Coulibaly B, Zhong L, Chen C, Ruder K, Lietman TM, Keenan JD, Doan T. Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial. Int Health. 2021 Feb 24;13(2):130-134. doi: 10.1093/inthealth/ihaa029.
• Dennis EG, Sie A, Ouermi L, Dah C, Tapsoba C, Zabre P, Barnighausen T, O'Brien KS, Lebas E, Keenan JD, Oldenburg CE. Short-term weight gain among preschool children in rural Burkina Faso: a secondary analysis of a randomised controlled trial. BMJ Open. 2019 Jul 29;9(7):e029634. doi: 10.1136/bmjopen-2019-029634.
• Oldenburg CE, Sie A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, Barnighausen T, Lebas E, Arzika AM, Cummings S, Zhong L, Lietman TM, Keenan JD, Doan T. Indirect Effect of Azithromycin Use on the Intestinal Microbiome Diversity of Untreated Children: A Randomized Trial. Open Forum Infect Dis. 2019 Feb 6;6(3):ofz061. doi: 10.1093/ofid/ofz061. eCollection 2019 Mar.
• Oldenburg CE, Sie A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, Barnighausen T, Ray KJ, Zhong L, Cummings S, Lebas E, Lietman TM, Keenan JD, Doan T. Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial. Open Forum Infect Dis. 2018 Nov 2;5(11):ofy289. doi: 10.1093/ofid/ofy289. eCollection 2018 Nov.
• Sie A, Dah C, Ouermi L, Tapsoba C, Zabre P, Barnighausen T, Lebas E, Arzika AM, Snyder BM, Porco TC, Lietman TM, Keenan JD, Oldenburg CE. Effect of Antibiotics on Short-Term Growth among Children in Burkina Faso: A Randomized Trial. Am J Trop Med Hyg. 2018 Sep;99(3):789-796. doi: 10.4269/ajtmh.18-0342. Epub 2018 Jul 12.

Study record dates

Study Major Dates

• Study Start (Actual): July 4, 2017
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: June 12, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): March 2, 2023
• Last Update Submitted That Met QC Criteria: February 1, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: infection; azithromycin; amoxicillin; trachoma; co-trimoxazole; mass treatment
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anti-Infective Agents, Urinary; Renal Agents; Amoxicillin; Azithromycin; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: 17-22036

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No