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

Null Author_Id ,Jennifer Cornick,Mohamed Bakari,Anil Kumar Sharma,Jonathon Simon,Chifundo Ndamala,Rodrick Kisenge,Naor Bar-Zeev,Latif Ndeketa,Mohammod Jobayer Chisti,Queen Dube,Arup Dutta,Aneeta Hotwani,Doreen Rwigi,Dilruba Ahmed,Rozina Thobani,Mohammad Tahir Yousafzai,Christopher Duggan ,Rajiv Bahl,Upendo Kibwana,Usha Dhingra,Karen L Kotloff,Furqan Kabir,Jasnehta Permala-Booth,Tahmeed Ahmed,Mahbubur Rahman ,Pratibha Dhingra,Flanon Coulibaly,Shahida Qureshi,Henry Badji,Aishwarya Chouhan,Samba O Sow,Bridget Freyne,Nigel A Cunliffe ,Saikat Deb,Sunil Sazawal,Milagritos D Tapia,Benson Singa ,Dramane Malle,Desirée Witte ,Abraham Samma,Md Farhad Kabir ,Maurine Anyango,Fadima Cheick Haidara,Ayesha De Costa,Kevin Kariuki ,Churchil Nyabinda,Patricia B Pavlinac ,Sharon M Tennant,Vijay Jaiswal ,Stephanie N Tornberg-Belanger,Christine J Mcgrath,Judd L Walson,Tahmina Alam,Farah Naz Qamar,Sadia Shakoor,Ashka Mehta,Karim Manji,Jan Mohammed,Irin Parvin,E Deichsel ,Sarah Somji,Christopher R Sudfeld,Cecylia Msemwa,Per Ashorn

doi:10.1001/jamanetworkopen.2021.36726

Abstract

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. 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. 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. 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. Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. 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. 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. ClinicalTrials.gov Identifier: NCT03130114.

Highlights

Half a million children die annually as a result of acute diarrhea,[1] mostly in sub-Saharan Africa and south Asia
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
There was a small reduction in linear growth faltering in the azithromycin

Summary

Introduction

Half a million children die annually as a result of acute diarrhea,[1] mostly in sub-Saharan Africa and south Asia. Studies have shown that 1 or more pathogens can be identified in more than two-thirds of children with acute diarrhea in low- and middle-income settings.[5,6,7] After rotavirus, bacterial pathogens such as Shigella, heat-stable enterotoxin-producing Escherichia coli (ST-ETEC), Campylobacter, and typical enteropathogenic E coli are the leading causes of diarrhea. These bacterial pathogens are associated with subsequent death[8] and linear growth faltering.[9] With the implementation of rotavirus vaccine programs, the relative contributions of bacterial causes will likely increase but will remain undiagnosed in the absence of point-of-care diagnostics. Current treatment guidelines may be missing the opportunity to appropriately treat bacterial diarrhea in a select group of young children with dehydrating diarrhea or undernutrition who are at high risk of diarrhea-associated mortality.[1,10,11]

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Conclusion