A double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the Antibiotics for Children with Diarrhoea (ABCD) trial protocol

Abstract

Background Acute diarrhoea is a common cause of illness and death among children in low- to middle-income settings. World Health Organization guidelines for the clinical management of acute watery diarrhoea in children focus on oral rehydration, supplemental zinc and feeding advice. Routine use of antibiotics is not recommended except when diarrhoea is bloody or cholera is suspected. Young children who are undernourished or have a dehydrating diarrhoea are more susceptible to death at 90 days after onset of diarrhoea. Given the mortality risk associated with diarrhoea in children with malnutrition or dehydrating diarrhoea, expanding the use of antibiotics for this subset of children could be an important intervention to reduce diarrhoea-associated mortality and morbidity. We designed the Antibiotics for Childhood Diarrhoea (ABCD) trial to test this intervention. Methods ABCD is a double-blind, randomised trial recruiting 11,500 children aged 2–23 months presenting with acute non-bloody diarrhoea who are dehydrated and/or undernourished (i.e. have a high risk for mortality). Enrolled children in Bangladesh, India, Kenya, Malawi, Mali, Pakistan and Tanzania are randomised (1:1) to oral azithromycin 10 mg/kg or placebo once daily for 3 days and followed-up for 180 days. Primary efficacy endpoints are all-cause mortality during the 180 days post-enrolment and change in linear growth 90 days post-enrolment. Discussion Expanding the treatment of acute watery diarrhoea in high-risk children to include an antibiotic may offer an opportunity to reduce deaths. These benefits may result from direct antimicrobial effects on pathogens or other incompletely understood mechanisms including improved nutrition, alterations in immune responsiveness or improved enteric function. The expansion of indications for antibiotic use raises concerns about the emergence of antimicrobial resistance both within treated children and the communities in which they live. ABCD will monitor antimicrobial resistance. The ABCD trial has important policy implications. If the trial shows significant benefits of azithromycin use, this may provide evidence to support reconsideration of antibiotic indications in the present World Health Organization diarrhoea management guidelines. Conversely, if there is no evidence of benefit, these results will support the current avoidance of antibiotics except in dysentery or cholera, thereby avoiding inappropriate use of antibiotics and reaffirming the current guidelines. Trial registration Clinicaltrials.gov, NCT03130114. Registered on April 26 2017.

Etiology and Incidence of Moderate-to-Severe Diarrhea in Young Children in Niger

“…The combined high burden of diarrhea due to bacterial and protozoal pathogens in this study of predominantly watery diarrhea raises the question as to whether current guidelines which defer antimicrobial therapy in the absence of bloody diarrhea are sufficient in this setting [ 6 ] and suggests the potential value of clinical prediction tools or point-of-care diagnostics to better target antimicrobial therapy [ 21 ]. Evidence from a multisite clinical trial is forthcoming about the role of azithromycin in treating watery diarrhea [ 22 ] which may help further direct the value of point-of-care identification of bacterial enteropathogens in the absence of dysentery. Point-of-care diagnostics [ 23 ] and novel therapeutics [ 24 ] for Cryptosporidium are areas of active areas of investigation and on the basis of these findings should be prioritized.…”

Inhibitory Concentrations of Ciprofloxacin Induce an Adaptive Response Promoting the Intracellular Survival of Salmonella enterica Serovar Typhimurium

“…In a climate of mass drug administration (MDA) in parts of the world, it is particularly important to be aware of and actively study how bacteria respond to widespread antimicrobial exposure. In recent years, MDA studies have included single-dose administration of ciprofloxacin to combat Neisseria meningitidis in young children in the "meningitis belt" of Africa, prophylactic azithromycin in Niger, Malawi, and Tanzania to reduce childhood mortality, and azithromycin administration for children with nonbloody diarrhea in low-resource settings (53)(54)(55). While initial follow-up studies into resulting AMR have been performed, more genotypic and phenotypic surveillance is required (56).…”

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings

“…The ABCD trial was a multicountry, multicenter, double-blinded, randomized, parallel-group, placebo-controlled clinical trial implemented in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. The trial protocol has been published 15 ( Supplement 1 ). Ethics approval was obtained from the WHO Ethics Review Committee as well from the participating countries.…”

“…Children with acute watery diarrhea (Ն3 watery stools in the previous 24 hours), some or severe dehydration, and/or moderate wasting (defined as a weight-for-length z score >−3 and Յ−2 or a mid-upper arm circumference Ն115 mm and <125 mm) and/or severe stunting were eligible. 15 Children were excluded if they had dysentery, suspected cholera, severe acute malnutrition, signs of any other infection requiring antibiotic treatment, received antibiotics in the last 14 days, were already enrolled in another trial, or lived outside the study area. Detailed inclusion and exclusion criteria are provided in the trial protocol (Supplement 1).…”