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

Per Ashorn, Jean Gratz, James A Platts-Mills, Karim Manji, Mohammod Jobayer Chisti, Rajiv Bahl, Jonathon Simon, Karen L Kotloff, Judd L Walson, Sunil Sazawal, Christopher P Duggan, Jie Liu, Tahmeed Ahmed, Elizabeth T Rogawski McQuade, Eric R Houpt, Darwin Operario, Jen Cornick, Aishwarya Chauhan, Wilson Gumbi, Ohedul Islam, Irene Kasumba, Shaila S Khan, Victor Maiden, Caroline Tigoi, Aliou Toure, Sarah Somji, Dilruba Ahmed, Benson O Singa, Samba O Sow, Milagritos D Tapia, Ashka Mehta, Henry Badji, Naor Bar-Zeev, Bridget Freyne, Latif Ndeketa, Farah Naz Qamar, Upendo Kibwana, Tahmina Alam, Ayesha De Costa, Furqan Kabir, Aneeta Hotwani, Mohammad Tahir Yousafzai, Queen Dube, Patricia B Pavlinac, Hannah E Atlas, Ira Praharaj, Usha Dhingra, Saikat Deb, Mamun Kabir

Journal: The Journal of infectious diseases 2024;229(4):988-998

PMID: 37405406

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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.

Address: Department of Global Health.; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.; School of Public Health, Qingdao University, Qingdao, China.; Department of Global Health.; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.; Laboratory Sciences and Services Division.; Nutrition and Clinical Services Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh.; Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland.; Centre pour le Développement des Vaccines, Bamako, Mali.; Department of Maternal, Newborn, Child, and Adolescent Health and Aging, World Health Organization, Geneva, Switzerland.; International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.; Clinical Research Programme, Malawi Liverpool Wellcome Trust, Blantyre, Malawi.; Center for Public Health Kinetics, New Delhi, India.; Department of Pediatrics, Queen Elizabeth Central Hospital, Blantyre, Malawi.; Division of Gastroenterology, Hepatology and Nutrition, Department of Nutrition, Boston Children's Hospital, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.; Clinical Research Programme, Malawi Liverpool Wellcome Trust, Blantyre, Malawi.; Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.; Department of Women and Children's Health, School of Medicine, University College Dublin, Dublin, Ireland.; Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya.; Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics and Child Health, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Pediatrics, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, USA.; Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.; Center for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.; Department of Global Health.; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Infectious Diseases, Department of Pediatrics and Medicine, University of Washington, Seattle.

DOI: 10.1093/infdis/jiad252

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MeSH Terms: Humans, Infant, Anti-Bacterial Agents, Azithromycin, Bacteria, Bacterial Infections, Cryptosporidiosis, Cryptosporidium, Diarrhea, Dysentery, Pathology, Molecular, Shigella