Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics
Authors: Pavlinac Patricia B , Platts-Mills James A , Liu Jie , Atlas Hannah E , Gratz Jean , Operario Darwin , Rogawski McQuade Elizabeth T , Ahmed Dilruba , Ahmed Tahmeed , Alam Tahmina , Ashorn Per , Badji Henry , Bahl Rajiv , Bar-Zeev Naor , Chisti Mohammod Jobayer , Cornick Jen , Chauhan Aishwarya , De Costa Ayesha , Deb Saikat , Dhingra Usha , Dube Queen , Duggan Christopher P , Freyne Bridget , Gumbi Wilson , Hotwani Aneeta , Kabir Mamun , Islam Ohedul , Kabir Furqan , Kasumba Irene , Kibwana Upendo , Kotloff Karen L , Khan Shaila S , Maiden Victor , Manji Karim , Mehta Ashka , Ndeketa Latif , Praharaj Ira , Qamar Farah Naz , Sazawal Sunil , Simon Jonathon , Singa Benson O , Somji Sarah , Sow Samba O , Tapia Milagritos D , Tigoi Caroline , Toure Aliou , Walson Judd L , Yousafzai Mohammad Tahir , Houpt Eric R ,   for the AntiBiotics for Children with severe Diarrhea (ABCD) Study Group, Rahman Muhammad Waliur , Parvin Irin , Kabir Md. Farhad , Dhingra Pratibha , Dutta Arup , Sharma Anil Kumar , Jaiswal Vijay Kumar , Nyabinda Churchil , McGrath Christine , Deichsel Emily L , Anyango Maurine , Kariuki Kevin Mwangi , Rwigi Doreen , Tornberg-Belanger Stephanie N , Haidara Fadima Cheick , Coulibaly Flanon , Permala-Booth Jasnehta , Malle Dramane , Cunliffe Nigel , Ndeketa Latif , Witte Desiree , Ndamala Chifundo , Qureshi Shahida , Shakoor Sadia , Thobani Rozina , Mohammed Jan , Kisenge Rodrick , Sudfeld Christopher R , Bakari Mohamed , Msemwa Cecylia , Samma Abraham 
Published: July 2023

Abstract

Background
Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera.

Methods
AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2–23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies.

Results
Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, −11.6 [95% confidence interval {CI}, −15.6 to −7.6]) and possible bacterial etiology (RDpossible, −8.7 [95% CI, −13.0 to −4.4]) but not in other children (RDunlikely, −0.3% [95% CI, −2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, −3.1 [95% CI, −5.3 to −1.0]; RDpossible, −2.3 [95% CI, −4.5 to −.01]; RDunlikely, −0.6 [95% CI, −1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella.

Conclusions
Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment.

Clinical Trials Registration
NCT03130114.