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