Effects of a single oral dose of azithromycin in laboring women on antimicrobial resistance (AMR) and the microbiome: a protocol for the Antimicrobial Resistance Sub-Study of the A-PLUS trial

Abstract

Background The Azithromycin Prevention in Labor Use Study (A-PLUS), a large, multi-national randomized trial, was performed to evaluate the improvement of maternal and newborn outcomes following a single dose of azithromycin (AZ) given during labor. However, the immediate and long-term impact of this single dose on the microbiome and the development or prevalence of antimicrobial resistance are unknown. We designed a sub-study to assess AZ resistance of bacterial isolates from clinical infections and of three target bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli) from the serial surveillance of the nasopharynx and rectum. Additionally, the serially surveilled samples will be evaluated for changes to the microbiome and the resistome of the nasopharynx and rectum. Methods and Analysis As part of the large, randomized APLUS trial, maternal and neonatal clinical infections were monitored for up to 42 days postpartum, and samples collected for culture using site-specific routine methods. For this sub-study, cultured bacterial isolates will be assessed for AZ resistance using an antibiotic susceptibility method. Additionally, a random subset of maternal-neonatal dyads from the main trial will be selected for serial surveillance with aseptic swab collections of the nasopharynx and the rectum at baseline, and subsequently at 1-week, 6-weeks, 3-months, 6-months, and 12-months postpartum. The serial samples will undergo selective culturing of sentinel bacterial species and screened for AZ resistance. An additional set of serial samples will be stored for future microbiome and resistome analyses. Ethics and Dissemination The study protocol was reviewed, and ethics approval obtained from all the relevant ethical review boards at each research site. All participants will provide informed written consent prior to their enrollment. Results of the trial will be disseminated through peer- reviewed publications, presentations at relevant conferences, and at dissemination meetings with the ministries of health and local stakeholders at each research site. Trial Registration Approval Status 1 version 1 24 Sep 2024 view Muhammad Muddassir Ali , University of Veterinary and Animal Sciences, Lahore, Pakistan 1. Any reports and responses or comments on the article can be found at the end of the article. Gates Open Research Page 2 of 11 Gates Open Research 2024, 8:101 Last updated: 13 NOV 2024 Corresponding author: Jean H. Kim (jeankim@rti.org) Author roles: Kim JH: Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing; Babineau D: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing; Moore JL: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing; Subramaniam A: Methodology, Writing – Review & Editing; Tita A: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing; Chomba E: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Mwenchanya M: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Lokangaka A: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Tshefu A: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Patel A: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Das P: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Goudar SS: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Tikmani SS: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Ahmed I: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Saleem S: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Esamai F: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Mazariegos M: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Billah SM: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Haque R: Funding Acquisition, Investigation, Project Administration, Validation, Writing – Review & Editing; Goldenberg RL: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Bauserman M: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Bucher S: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Krebs NF: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Derman RJ: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Petri Jr WA: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing; Koso-Thomas M: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing; Hemingway-Foday JJ: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing; Aceituno A: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing; McClure EM: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing; Ward DV: Methodology, Writing – Review & Editing; Leal S: Methodology, Validation, Writing – Review & Editing; Carlo WA: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing; Hibberd PL: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing; Competing interests: No competing interests were disclosed. Grant information: This work was supported by the Bill and Melinda Gates Foundation [INV-008973]; the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040636, U10 HD076465, U10 HD078437, U10 HD076474, U10 HD076457, U10 HD078438, U10 HD078439, U10 HD076461]; and the Foundation for the National Institutes of Health [MCCL19APT]. Copyright: © 2024 Kim JH et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Kim JH, Babineau D, Moore JL et al. Effects of a single oral dose of azithromycin in laboring women on antimicrobial resistance (AMR) and the microbiome: a protocol for the Antimicrobial Resistance Sub-Study of the A-PLUS trial [version 1; peer review: 1 approved with reservations] Gates Open Research 2024, 8:101 https://doi.org/10.12688/gatesopenres.15992.1 First published: 24 Sep 2024, 8:101 https://doi.org/10.12688/gatesopenres.15992.1 NCT03871491.