Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics

• Published in: The Journal of infectious diseases 2024-04, Vol.229 (4), p.988-998
• Main 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
• Format: Article
• Language: English
• Subjects: Antibiotics; Azithromycin; Bacteria; Children; Clinical trials; Dehydration; Diarrhea; Dysentery; Etiology; Feces; Malnutrition; Morbidity; Pathogens; Pediatrics; Placebos; Rotavirus; Shigella; Thermal stability
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiad252

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. Improved clinical outcomes among children with acute watery diarrhea of bacterial etiology in this reanalysis of the ABCD trial suggest that a short course of azithromycin may be warranted if bacterial etiologies could be identified at the point of care.