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Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Nutrition and Clinical Services Division, International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh. Laboratory Sciences and Services Division, International Centre for Diarrheal Disease Research, Bangladesh, Dhaka, Bangladesh. Center for Public Health Kinetics, New Delhi, Delhi, India. Childhood Acute Illness and Nutrition Network, Nairobi, Kenya. Department of Global Health, University of Washington, Seattle. Department of Pediatrics, University of Washington, Seattle. Department of Medicine (Allergy and Infectious Diseases), University of Washington, Seattle. Kenya Medical Research Institute, Nairobi, Kenya. Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore. Department of Epidemiology, University of Washington, Seattle. Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore. Department of Medicine, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore. Centre pour le Développement des Vaccins, Bamako, Mali. Division of Advanced Primary Health Care Research and Clinical Trials, Centre pour le Développement des Vaccins, Bamako, Mali. Division of Clinical Microbiology and Molecular Biology, Centre pour le Développement des Vaccins, Bamako, Mali. International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Department of Pediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi. Malawi Liverpool Wellcome Trust Clinical Research Programme, Institute of Infection, Veterinary and Ecological Sciences, The University of Liverpool, Blantyre, Malawi. National Institutes of Health Research Health Protection Research Unit in Gastrointestinal Infections, University of Liverpool, Liverpool, United Kingdom. Malawi Liverpool Wellcome Trust Clinical Research Programme, Liverpool School of Tropical Medicine, Blantyre, Malawi. Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi. Department of Pediatrics and Child Heath, Aga Khan University, Karachi, Pakistan. Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan. Department of Pediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania. Department of Maternal, Child, and Adolescent Health and Aging, World Health Organization, Geneva, Switzerland.

JAMA network open. 2021;(12):e2136726
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Abstract

IMPORTANCE World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. OBJECTIVE To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. DESIGN, SETTING, AND PARTICIPANTS The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. INTERVENTIONS Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. MAIN OUTCOMES AND MEASURES Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. RESULTS A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. CONCLUSIONS AND RELEVANCE The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03130114.

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