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

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Kim" }, { "@type": "Person", "name": "Denise Babineau" }, { "@type": "Person", "name": "Janet L. Moore" }, { "@type": "Person", "name": "Akila Subramaniam" }, { "@type": "Person", "name": "Alan Tita" }, { "@type": "Person", "name": "Elwyn Chomba" }, { "@type": "Person", "name": "Musaku Mwenchanya" }, { "@type": "Person", "name": "Adrien Lokangaka" }, { "@type": "Person", "name": "Antoinette Tshefu" }, { "@type": "Person", "name": "Archana Patel" }, { "@type": "Person", "name": "Prabir Das" }, { "@type": "Person", "name": "Shivaprasad S. Goudar" }, { "@type": "Person", "name": "Shiyam Sunder Tikmani" }, { "@type": "Person", "name": "Imran Ahmed" }, { "@type": "Person", "name": "Sarah Saleem" }, { "@type": "Person", "name": "Fabian Esamai" }, { "@type": "Person", "name": "Manolo Mazariegos" }, { "@type": "Person", "name": "Sk Masum Billah" }, { "@type": "Person", "name": "Rashidul Haque" }, { "@type": "Person", "name": "Robert L. Goldenberg" }, { "@type": "Person", "name": "Melissa Bauserman" }, { "@type": "Person", "name": "Sherri Bucher" }, { "@type": "Person", "name": "Nancy F. Krebs" }, { "@type": "Person", "name": "Richard J. Derman" }, { "@type": "Person", "name": "William A. Petri Jr" }, { "@type": "Person", "name": "Marion Koso-Thomas" }, { "@type": "Person", "name": "Jennifer J. Hemingway-Foday" }, { "@type": "Person", "name": "Anna Aceituno" }, { "@type": "Person", "name": "Elizabeth M. McClure" }, { "@type": "Person", "name": "Doyle V. Ward" }, { "@type": "Person", "name": "Sixto Leal" }, { "@type": "Person", "name": "Waldemar A. Carlo" }, { "@type": "Person", "name": "Patricia L. Hibberd" }, { "@type": "Person", "name": "A-PLUS AMR Study Group" } ], "publisher": { "@type": "Organization", "name": "Gates Open Research", "logo": { "@type": "ImageObject", "url": "https://gatesopenresearch.org/img/AMP/Gates_image.png", "height": 600, "width": 47 } }, "image": { "@type": "ImageObject", "url": "https://gatesopenresearch.org/img/AMP/Gates_image.png", "height": 1200, "width": 94 }, "description": " 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 NCT03871491. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://gatesopenresearch.org/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://gatesopenresearch.org/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://gatesopenresearch.org/articles/8-101/v1", "name": "Effects of a single oral dose of azithromycin in laboring women on..." } } ] } Home Browse Effects of a single oral dose of azithromycin in laboring women on... ALL Metrics - Views Downloads Get PDF Get XML Cite 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 Res 2024, 8 :101 ( https://doi.org/10.12688/gatesopenres.15992.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol 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] Jean H. Kim https://orcid.org/0000-0002-2207-6263 1 , Denise Babineau https://orcid.org/0000-0002-9776-9080 1 , Janet L. Moore 1 , [...] Akila Subramaniam 2 , Alan Tita 2 , Elwyn Chomba 3 , Musaku Mwenchanya 3 , Adrien Lokangaka 4 , Antoinette Tshefu 4 , Archana Patel 5,6 , Prabir Das 5 , Shivaprasad S. Goudar https://orcid.org/0000-0002-8680-7053 7 , Shiyam Sunder Tikmani 8 , Imran Ahmed 8 , Sarah Saleem https://orcid.org/0000-0002-6797-8631 8 , Fabian Esamai 9 , Manolo Mazariegos 10 , Sk Masum Billah 11,12 , Rashidul Haque 11 , Robert L. Goldenberg 13 , Melissa Bauserman 14 , Sherri Bucher 15 , Nancy F. Krebs 16 , Richard J. Derman https://orcid.org/0000-0003-1148-1594 17 , William A. Petri Jr 12 , Marion Koso-Thomas 18 , Jennifer J. Hemingway-Foday 1 , Anna Aceituno 1 , Elizabeth M. McClure https://orcid.org/0000-0001-8659-5444 1 , Doyle V. Ward https://orcid.org/0000-0002-4952-824X 19 , Sixto Leal 2 , Waldemar A. Carlo https://orcid.org/0000-0003-0382-9976 2 , Patricia L. Hibberd https://orcid.org/0000-0002-7455-8117 20 , A-PLUS AMR Study Group Jean H. Kim https://orcid.org/0000-0002-2207-6263 1 , Denise Babineau https://orcid.org/0000-0002-9776-9080 1 , [...] Janet L. Moore 1 , Akila Subramaniam 2 , Alan Tita 2 , Elwyn Chomba 3 , Musaku Mwenchanya 3 , Adrien Lokangaka 4 , Antoinette Tshefu 4 , Archana Patel 5,6 , Prabir Das 5 , Shivaprasad S. Goudar https://orcid.org/0000-0002-8680-7053 7 , Shiyam Sunder Tikmani 8 , Imran Ahmed 8 , Sarah Saleem https://orcid.org/0000-0002-6797-8631 8 , Fabian Esamai 9 , Manolo Mazariegos 10 , Sk Masum Billah 11,12 , Rashidul Haque 11 , Robert L. Goldenberg 13 , Melissa Bauserman 14 , Sherri Bucher 15 , Nancy F. Krebs 16 , Richard J. Derman https://orcid.org/0000-0003-1148-1594 17 , William A. Petri Jr 12 , Marion Koso-Thomas 18 , Jennifer J. Hemingway-Foday 1 , Anna Aceituno 1 , Elizabeth M. McClure https://orcid.org/0000-0001-8659-5444 1 , Doyle V. Ward https://orcid.org/0000-0002-4952-824X 19 , Sixto Leal 2 , Waldemar A. Carlo https://orcid.org/0000-0003-0382-9976 2 , Patricia L. Hibberd https://orcid.org/0000-0002-7455-8117 20 , A-PLUS AMR Study Group PUBLISHED 24 Sep 2024 Author details Author details 1 RTI International, Research Triangle Park, North Carolina, USA 2 The University of Alabama at Birmingham, Birmingham, Alabama, USA 3 University Teaching Hospital, Lusaka, Zambia 4 Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo 5 Lata Medical Research Foundation, Nagpur, India 6 Datta Meghe Institute of Higher Education and Research, Maharashtra, India 7 KLE Academy Higher Education and Research, J N Medical College, Belagavi, Karnataka, India 8 The Aga Khan University, Karachi, Pakistan 9 Moi University School of Medicine, Eldoret, Kenya 10 Instituto de Nutrición de Centroamérica y Panamá, Guatemala City, Guatemala 11 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh 12 University of Virginia, Charlottesville, Virginia, USA 13 Columbia University School of Medicine, New York, New York, USA 14 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 15 Indiana School of Medicine, University of Indiana, Indianapolis, Indiana, USA 16 University of Colorado School of Medicine, Denver, Colorado, USA 17 Thomas Jefferson University, Philadelphia, Pennsylvania, USA 18 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA 19 University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA 20 Boston University School of Public Health, Boston, Massachusetts, USA Jean H. Kim Roles: Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Denise Babineau Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Janet L. Moore Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Akila Subramaniam Roles: Methodology, Writing – Review & Editing Alan Tita Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing Elwyn Chomba Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Musaku Mwenchanya Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Adrien Lokangaka Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Antoinette Tshefu Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Archana Patel Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Prabir Das Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Shivaprasad S. Goudar Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Shiyam Sunder Tikmani Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Imran Ahmed Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sarah Saleem Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Fabian Esamai Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Manolo Mazariegos Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sk Masum Billah Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Rashidul Haque Roles: Funding Acquisition, Investigation, Project Administration, Validation, Writing – Review & Editing Robert L. Goldenberg Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Melissa Bauserman Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sherri Bucher Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Nancy F. Krebs Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Richard J. Derman Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing William A. Petri Jr Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Marion Koso-Thomas Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing Jennifer J. Hemingway-Foday Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Anna Aceituno Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Elizabeth M. McClure Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Doyle V. Ward Roles: Methodology, Writing – Review & Editing Sixto Leal Roles: Methodology, Validation, Writing – Review & Editing Waldemar A. Carlo Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing Patricia L. Hibberd Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS 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 NCT03871491. READ ALL READ LESS Keywords low and middle-income countries, azithromycin, azithromycin resistance, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, microbiome, resistome Corresponding Author(s) Jean H. Kim ( [email protected] ) Close Corresponding author: Jean H. Kim Competing interests: No competing interests were disclosed. Grant information: This work was supported by the 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: 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 Res 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 ) Latest published: 24 Sep 2025, 8 :101 ( https://doi.org/10.12688/gatesopenres.15992.2 )  There is a newer version of this article available. Suppress this message for one day. Strengths and limitations of this study 1. This study evaluates the impact of routine use of a single prophylactic dose of AZ on the development or prevalence of antimicrobial resistance in clinically relevant bacteria causing infection in women and/or infants. 2. The study evaluates the changes over a period of time in the microbiome and the resistome following the single dose of AZ. 3. This study will seek to identify potentially novel resistant genes contributing to the AZ-resistant phenotypes observed by the target bacterial species. 4. To optimize generalizability, this study will be carried out in a racially, ethnically, and geographically diverse population in eight low-and-middle-income countries. 5. In some locations, azithromycin and other antibiotics are increasingly being used, especially with increasing use of cesarean section, and thus the impact of the outcome may be diminished. Introduction Background Azithromycin (AZ), a pregnancy class B macrolide, is a derivative of erythromycin exhibiting bacteriostatic activity by binding to the 50S ribosomal subunit and interfering with protein synthesis. AZ is a broad-spectrum antibiotic affecting aerobic and facultative Gram-negative and Gram-positive bacteria, genital Mycoplasma and Ureaplasma , and some anaerobes ( Peters et al. , 1992 ; Subramaniam et al. , 2019 ). Typically, the antibiotic is used to treat diseases such as respiratory infections, sexually transmitted infections (STIs), and enteric infections caused by a variety of bacterial species ( Heidary et al. , 2022 ). During pregnancy and parturition, macrolides together with penicillins and cephalosporins are frequently used to prevent or treat infections. AZ, compared to other macrolides (e.g., erythromycin), has additional benefits which may make it advantageous to use more widely for labor and delivery, particularly in low- and middle-income countries (LMIC). These benefits include better pharmacokinetics with a long elimination half-life (68 hours), a high tissue absorption resulting from minimal metabolism by human cytochrome P450 (CYP) enzymes, and additional immunomodulatory and anti-inflammatory properties ( Antonucci et al. , 2022 ; Fohner et al. , 2017 ; Tita et al. , 2016 ; Tita et al. , 2009 ). Since AZ is a broad-spectrum antibiotic, it possesses better coverage against bacteria that are commonly found in polymicrobial infections after labor. Additionally, AZ can rapidly transport across the placenta to provide effective concentrations in the cord blood and amniotic fluid and is found at sustainable levels in breast milk for 48 hours thus providing not only maternal protection but also neonatal protection against infection ( Sutton et al. , 2015 ). The use of prophylactic antibiotics including macrolides has been shown to reduce infections in preterm premature rupture of membranes (PPROM) and cesarean deliveries ( Keenan et al. , 2018 ; Roca et al. , 2016 ; Tita et al. , 2016 ; Tita et al. , 2023 ). Oral AZ was recognized to have great potential to prevent maternal and neonatal death/infections because of its ease of administration and spectrum activity. NICHD’s Global Network recently completed a trial of a single intrapartum oral dose of AZ versus placebo in eight LMICs (the Azithromycin Prevention in Labor Use study [A-PLUS]) showing a significant decrease in maternal and neonatal infection ( Tita et al. , 2023 ). Other previous randomized AZ trials in LMICs including the Gambia and the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trials have also shown successful reduction in infection of participants who received the drug ( Keenan et al. , 2018 ; Roca et al. , 2016 ). Although much has been done to show the beneficial effects of AZ, more research is needed to address the safety of the drug. One major concern which needs to be considered is antimicrobial resistance, especially resistance to AZ as its long half-life results in extended exposure. Globally, there is concern regarding the increasing use of AZ. One contributing factor is the availability of this antibiotic and others in community pharmacies without the use of a prescription ( Auta et al. , 2019 ). Additionally, during the COVID-19 pandemic, consumption of AZ increased when it was believed that the antibiotic effectively treated COVID-19 ( Kournoutou & Dinos, 2022 ). Unfortunately, these actions have resulted in a rise of AZ resistance among various bacterial species, with the greatest concern for species which can only be effectively treated by a macrolide (e.g., Campylobacter spp.). In South Asia, there are reports of AZ-resistant Salmonella typhi and other Salmonella spp. ( Heidary et al. , 2022 ; Hooda et al. , 2019 ). In other parts of the world including Europe, South America, Asia, and Africa, additional species have been reported with increasing rates of AZ-resistance. These include Streptococcus spp., Haemophilus influenzae , Chlamydia trachomatis , Campylobacter spp., Legionella pneumophila , Treponema pallidum , and Neisseria gonorrhoeae ( Derbie et al. , 2020 ; Heidary et al. , 2022 ). In the MORDOR and the Gambia trials, AZ resistance was also examined. The MORDOR study, which involved a mass drug administration of AZ for the reduction of childhood mortality, showed an increase in community-level AZ resistance in those who received the drug. However, the levels of resistance declined or returned to baseline when the mass distribution stopped ( Doan et al. , 2019 ; Haug et al. , 2010 ; O'Brien et al. , 2019 ). The Gambia study ( Roca et al. , 2016 ) demonstrated that a single oral dose of AZ during labor resulted in an initial higher prevalence of AZ-resistant Staphylococcus aureus among women and their babies four weeks after treatment but the increase subsequently waned by 12 months, and there was no induction of resistance towards other antibiotics by Streptococcus pneumoniae or S. aureus ( Bojang et al. , 2018 ; Roca et al. , 2016 ). Although this study suggests that a single prophylactic dose strategy is less likely to induce long-term antibiotic resistance, further evaluation is required including the effects of AZ on other organisms as well as the microbiome. Furthermore, these studies addressed community-level AZ resistance using surveillance methods but did not address resistant infections. Therefore, to describe the impact of a single large dose of prophylactic AZ in mothers and neonates on antimicrobial resistance, we planned a prospective sub-study to the A-PLUS trial. This sub-study will monitor antimicrobial resistance of maternal and neonatal infections up to 42 days postpartum and relevant commensal target species, Streptococcus pneumoniae and Staphylococcus aureus from the nasopharynx and Escherichia coli from the rectum, over time up to 12 months postpartum. Collectively, we will be able to assess whether immediate resistance to AZ is acquired by clinical isolates and by the commensal target species following the prophylactic dose and if resistance persists over time. Methods Study organization The A-PLUS AMR sub-study was conducted under the auspices of the A-PLUS trial, conducted by the Global Network for Women’s and Children’s Health Research (Global Network). The trial was overseen by the Global Network’s Steering Committee, comprised of 2 principal investigators (PIs) from each of the 8 participating sites and the PI at the data coordinating center. In addition, there was a A-PLUS Working Group and an AMR Sub-study Working Group, comprised of the lead PIs and DCC investigators, respectively, which developed the analytic plans and provided recommendations to the Steering Committee. Each study site had a lead investigator and study coordinator who oversaw conduct of the research at their site, with support from the DCC and Working Groups. An independent Data Safety and Monitoring Board comprised of technical experts in infectious disease, obstetrics, pediatrics and statistical methods, appointed by the National Institute for Child Health and Human Development (NICHD) reviewed the study enrollment, safety, and trial and sub-study progress. An interim analysis was planned to evaluate the efficacy at 70% of enrollment. Study design This A-PLUS prospective sub-study is designed to investigate two perspectives of AZ resistance: 1) the resistance phenotype of bacteria causing clinical infections and 2) the surveillance of target commensal bacteria over time and the resistome. In addition to AZ resistance, we are also assessing the microbiome as an indirect potential effect of altered microbial communities not necessarily related to antimicrobial resistance; the methods and results, however, will be described elsewhere. To achieve an understanding of all AZ resistance perspectives, the study will perform clinical monitoring and culturing of bacterial infections and obtain nasopharyngeal (NP) and rectal swab samples from the mother and the neonate over time, with participants from the AZ and placebo-assigned groups. The clinical monitoring and serial surveillance approaches will provide: i) Monitoring of AZ resistance of bacteria causing clinical infections. ii) Monitoring of AZ resistance patterns of commensal target bacteria including S. pneumoniae , S. aureus , and E. coli over time from maternal and newborn flora through culture and sensitivity testing; iii) Serial NP and rectal swab collection and storage for future assessment of the microbiome and resistome. Study population The target study population is the same as the primary trial ( Hemingway-Foday et al. , 2023 ; Tita et al. , 2023 ). Pregnant women >28 weeks gestion with a live fetus with a planned vaginal delivery at one of the pre-identified health facilities at eight Global Network sites will be screened by research staff. Women with evidence of chorioamnionitis or other infection requiring antibiotic therapy at the time of enrollment, active use of azithromycin or other macrolide, or any contraindication to macrolides will be excluded. Further details of the eligibility criteria are described elsewhere ( Hemingway-Foday et al. , 2023 ). Health facilities include hospitals and health centers where women routinely deliver. Following randomization, all women received standard clinical care, including antibiotic use, as per the local standards. In addition to routine care, research staff may contact women by phone or home visits to try to ensure high follow-up compliance with study visits. Microbiology laboratory capabilities and quality assurance All microbiology laboratories that support the health facilities including hospitals and health centers at each of the sites ( Table 1 ) have the basic clinical microbiology capabilities including culture, microorganism identification using biochemical and microscopic methods, and antimicrobial susceptibility testing. This study will build on these basic microbiology capabilities by incorporating microbial screening methods for the selection of specific commensal target species and presumptive AZ resistant isolates. Clinical capabilities will also be expanded for the appropriate collection of samples from infection sites, and the collection of NP and rectal swabs using aseptic techniques. To ensure successful execution of these expanded capabilities, all sites will be provided with detailed standard operating procedures (SOPs) and training sessions which will include on-site hands-on training, virtual training, and training videos. Additionally, quality assurances will be implemented to ensure that all procedures are performed proficiently and consistently at each of the sites providing high quality samples and results. These include the integration of quality controls in the SOPs for both clinical and laboratory tasks and the monitoring of procedures to verify the quality of performance by the sites. Additionally, bacterial isolates from all sites will be validated by the University of Alabama Birmingham to ensure correct identification and susceptibility assessment for AZ. Any inconsistent results or concerns and discrepancies observed will be addressed with additional training. Table 1. List of Study Sites and Their Affiliated Laboratories. Site Affiliated Laboratory Bangladesh International Centre for Diarrheal Disease Research, Bangladesh (icddr,b) Democratic Republic of Congo Gemena Provincial General Referral Hospital (South Ubangi Province) Guatemala Institute of Nutrition of Central America and Panama (INCAP) India (Belagavi) Jawaharlal Nehru Medical College, Women’s and Children’s Health Research Unit India (Nagpur) Lata Medical Research Foundation-affiliated laboratories at Government Medical College, Nagpur and at Mahatma Gandhi Institute of Medical Sciences, Sewagram Kenya Moi University College of Health Sciences Pakistan Clinical Microbiology Laboratory (Aga Khan University, Karachi) Zambia University Teaching Hospital (formerly Lusaka Hospital) Clinical monitoring of microbes and antimicrobial resistance profile of infections Sample set and collection The clinical monitoring for infection will use the same sample set and monitoring timeline as the primary trial ( Hemingway-Foday et al. , 2023 ). Participants infected by bacterial species will undergo a susceptibility test to determine the minimum inhibitory concentration (MIC) of AZ. The DCC will conduct quality and consistency checks to help ensure the accuracy of the data. Capacity building for improving sample collection techniques will be done to prevent exogenous contamination during the collection process. Criteria for the collection of clinical samples to prevent exogenous contamination will be followed, including the following: i) The use of aseptic technique where applicable including disinfection at the site of collection, disinfection of gloved hands, and the use of sterile collection equipment. ii) For wound/pus/abscess/boil samples, collection will only be from deep surfaces or closed spaces that require needle aspiration or incision/drainage or from circumscribed superficial collections of pus which can be freely expressed or drained. Culture method and susceptibility testing Site-specific routine clinical microbiological practices will be performed for the isolation and identification of dominant bacterial pathogens found in the various infection sites. These standard practices include culture using various selective and/or differential media (e.g., blood agar, Mannitol salt agar, or MacConkey agar). After 24 – 72 hours of incubation, the dominant organisms (up to three) on each culture plate will be selected for identification according to the routine method at each site, which may include observations of bacterial growth phenotypes (e.g., colony morphology, or variant growth on differential media), microscopic observations using various staining techniques (e.g., Gram stain, India ink, or Acid fast stain), performance of biochemical assay tests (e.g., catalase, indole, or cAMP), and antibody-based test methods (e.g., latex agglutination test). These dominant isolates will also be assessed for antibiotic susceptibility to AZ and other clinically relevant antibiotics, using standardized procedures and materials such as the disk diffusion method or a minimal inhibitory concentration (MIC) method (e.g., microdilution, agar dilution, Epsilometer test [Etest]). Each bacterial isolate will be interpreted as susceptible, intermediate, or resistant to the challenge antibiotic using the recommended breakpoints set by the Clinical and Laboratory Standard Institute ( CLSI, 2024 ). Analytic approach The identified pathogens will be summarized overall by treatment arm as well as separately by region (Asia, Africa, Central America), mother vs. infant, and by infection site. The susceptibility vs. resistance to AZ of relevant pathogens will also be summarized overall by treatment arm as well as by region, pathogen, infection site and by mother vs. infant. These analyses will be descriptive in nature but dependent on having sufficient data to run models, comparisons of treatment arms may be obtained including estimating relative risk estimates between treatment arms for pathogen presence and/or resistance. Full details of any such comparisons will be described in a data processing and statistical analysis plan. Data entry and management All clinical data will be entered into an electronic data capture system (REDCap 14.3.14; https://projectredcap.org/ ), developed by the DCC and hosted at each study site. Data consistency, quality and range checks will be performed at each site and centrally. Details of the data management plans are included in the methods paper ( Hemingway-Foday et al. , 2023 ). Serial monitoring of selected commensal organisms in Nasopharyngeal (NP) and rectal specimens for AZ susceptibility Subject selection A random subset of maternal-infant dyads at each site as selected by the DCC, enrolled prior to randomization, will have NP and rectal specimens obtained and monitored serially (at baseline [0–1 day], 1 week, 6 weeks, 3 months, 6 months, and 12 months) to assess the development of AZ resistance of target bacterial flora found in the NP and the rectum. The time points listed correspond to days postpartum which will also correlate to days when the prophylactic dose of AZ (two 500 mg film-coated tablets; Kern Pharma; Barcelona, Spain) is administered since administration will happen at the time of delivery in the site-specific health facilities. Baseline sampling will be taken at a time before or a day after the AZ is administered to the mother. Following the AZ administration, an early time point (i.e., 1 week), mid time points (i.e., 6 weeks and 3 months), and late time points (i.e., 6 months and 12 months) will be assessed to determine if AZ resistance is potentially acquired and how long the resistance persists. Specimen collection Bacterial collection will be performed following an SOP using sterile flocculated swabs. A mini-tip nasopharyngeal swab will be used to collect the nasopharyngeal flora in addition to the anterior nares and a standard swab will be used for the rectum. The swabs will be placed in a tube with 1 mL of Amies or Stuarts transport medium. The sampling scheme for this monitoring study is shown in Table 2 . A similar scheme will be used for collection and storage of specimens for microbiome (MB) analysis (see below). Table 2. Sample Scheme for Monitoring AZ Resistance ( S. pneumoniae and S. aureus [NP], and E. coli [Rectal]) and Effect on the Microbiome (MB) Studies in Subset. Timepoint Target Window Baseline * (0 – 1d) 1 Week (3 – 11d) 6 weeks (6 – <10wks) 3 months (3 – 4mos) 6 months (6 – 7mos) 12 months (12 – 13mos) Acceptable Window (0 – 1d) (3 d – <4wks) 4 – <10wks) (10wks – <6mos) (6 – <12mos) (12 – 18mos) MOTHER Rectal Swab MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture NP Swab MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture BABY Rectal Swab MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture NP Swab MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture MB/Culture * Ideally, maternal samples should be taken before drug administration; neonatal samples should be taken after delivery. d, day; wks, weeks; mos, months; NP, nasopharynx; MB, microbiome. Organism selection The target commensal bacteria selected include Streptococcus pneumoniae and Staphylococcus aureus from the nasopharynx and anterior nares, respectively, and Escherichia coli from the rectum. Both S. pneumoniae and S. aureus are clinically relevant species in which AZ is used to treat infections caused by these bacteria. Additionally, there is a worldwide increase in AZ resistance of these species, and it is important for us to monitor these bacteria to determine whether a prophylactic dose of AZ will contribute to their resistance. E. coli is a representative species abundantly found in the rectum and will be monitored for Gram-negative resistance even though AZ is not a primary drug for most E. coli infections. Sample size Assuming that the primary endpoint of interest is AZ resistance to at least one organism from any flora at each time point, samples from a total of 848 maternal-infant dyads will need to be monitored to estimate an overall prevalence of 10% +/- 2% with 95% confidence. Furthermore, this sample size will allow over 80% power to detect at least a 2-fold increase in AZ microbial resistance with AZ (RR=2) compared to 6–7% in placebo group. We will also be able to compare the number of organisms identified with resistance to AZ between randomized study groups. To account for an assumed rate of 15% for individuals declining consent to store samples for future testing, the final sample size goal will be 1000 maternal-infant dyads total. This corresponds to approximately 125 dyads per GN country for the duration of the study. Enrollment may vary across countries, but no individual country will enroll more than 25% of the planned sample size. Microbiological culture method and AZ susceptibility testing All sites, following the same SOP for the processing of the NP and rectal swabs, will initially plate an aliquot of each swab sample onto a selective and differential agar plate. The NP swabs will be plated onto gentamicin blood agar (5 µg/mL of gentamicin; 5% blood) for the isolation of S. pneumoniae and onto Mannitol salt agar (Fisher Scientific; Waltham, MA) for the isolation of S. aureus . The rectal swabs will be plated onto Brilliant E. coli and coliforms agar (Fisher Scientific; Waltham, MA) for the isolation of E. coli . From each agar plate, up to 50 presumptive isolates with the correct colony phenotypes will be picked and patched onto Mueller Hinton or blood agar plates with high concentrations of AZ to screen for resistant isolates. The concentration of AZ is determined based on the recommended MIC breakpoints for resistance found in the CLSI. Since the CLSI does not contain MIC breakpoints for E. coli , we will use the breakpoints specified for Enterobacteriaceae . Identification of the presumptive resistant isolates that grow will be confirmed using standardized biochemical assays and the AZ resistance will be validated using the Etest strips (Liofilchem™ MTS™ Azithromycin; Fisher Scientific; Waltham, MA). Serial monitoring of microbiome and resistance profile Sample size consideration and collection The same subset of dyads for AZ susceptibility monitoring described above will also provide an NP and rectal swab sample for microbiome (i.e., 16S V4 rRNA sequencing and metagenomics) and resistome analyses. This corresponds to a total of 1000 maternal-infant dyads who are randomly selected, consent to participate in the sub-study, and agree to have samples stored for future analysis. Sample collection will follow the same SOP that will be performed for the AZ susceptibility monitoring, and the swabs will be placed in 1 mL of Zymo DNA/RNA Shield buffer (Zymo Research; Irvine, CA). The samples will be stored at -80°C until ready for DNA extraction, sequencing, and analysis. The processing and sequencing methods will be described elsewhere. Conclusions The results of this sub-study will provide a better understanding of the impact of AZ when administered as a large prophylactic dose on the antimicrobial resistant phenotypes of bacterial isolates from clinical infections and the resistance profile of target commensal bacterial species as well as microbiome changes over time post drug administration. Since a serial surveillance approach is designed into the study, we will be able to assess both acute and long-term effects of AZ. An AZ trial in the US led to national changes in policy to use adjunctive AZ to prevent infections in women who undergo cesarean delivery after labor ( Tita et al. , 2016 ). In many LMICs most maternal and newborn infections occur in patients who deliver vaginally, and oral AZ provides a promising strategy to prevent maternal and newborn infection ( Roca et al. , 2016 ; Subramaniam et al. , 2019 ). A major concern for policy implications will be safety in terms of resistance and microbiome-mediated effects. Therefore, this proposed study will provide crucial information to inform policy decisions if AZ is found to prevent infection in LMICs. Ethics and dissemination Ethics approval and consent to participate The AMR sub-study protocol has been reviewed and approved on July 1, 2020 (approval number: IRD-300002323) by the University of Alabama Institutional Review Board and the University of Alabama Ethics Committee at the University of Alabama at Birmingham, which serves as the clinical lead site, and by other relevant ethics committees and regulatory authorities at each individual research site (Kinshasa School of Public Health, DRC; University Teaching Hospital, University of Zambia, Zambia; Moi University, Eldoret, Kenya; INCAP, Guatemala City, Guatemala; Lata Medical Research Foundation, Nagpur, India; KLE Academy for Research and Higher Education’s JN Medical College, Belagavi, India; The Aga Khan University, Karachi, Pakistan; icddr,b, Dhaka, Bangladesh) including the IRB at RTI International, which serves as the Data Coordinating Center. The DMC has reviewed the study protocol and will continue to review throughout the enrollment period. The study was registered (clinicaltrials.gov NCT03871491). All research staff responsible for obtaining informed consent were trained and certified in the protection of human subjects and the study-specific consent procedures. A model written informed consent form, developed according to the requirements of the OHRP, may be modified by each site to conform to local standards, but the OHRP required elements must be maintained. The research sites will also be responsible for translating the consent form into the appropriate language(s) for their local context. All women will provide informed written consent prior to participation. Data availability No data are associated with this article. Extended data Open Science Framework: Data collection form and SPIRIT checklist for 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. https://doi.org/10.17605/OSF.IO/BC4T2 ( Kim, 2024 ). This project contains the following extended data: Appendix 1_Susceptibility_Monitoring_and_Microbiome_Specimen_Collection_Form.pdf SPIRIT_checklist_complete.docx Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Contributors AT and WAC: Conceptualization, Protocol Development with input from EMC, DB, JH-F, MK-T, PLH, JHK, DW, SL, and AS, Investigation, Supervision, Writing – Review & Editing. DB and JLM: Statistical Analyses Plan. JHK: Writing – Initial Draft Preparations and Revisions with critical feedback from PLH, WAC, AT, EMC, DW, AK, AA, MK-T and DB. EC, M Mwenechanya, AL, ATshefu, AP, PD, SSG, SST, IA, SS, FE, MMazariegos, SMB, RH, RLG, MB, SB, NFK, RJD and WAP: Refinement and Finalization of Study Protocol and Trial Implementation, Writing – Review & Editing. Acknowledgments We are grateful to the the A-PLUS study laboratory managers at each of the study sites including the following: Gemena Provincial General Referral Hospital (South Ubangi Province), DRC: Miyalu Junior; International Centre for Diarrheal Disease Research, Bangladesh (icddr,b): Lolit Singh; Institute of Nutrition of Central America and Panama (INCAP): Lester Figueroa; Jawaharlal Nehru Medical College, Women’s and Children’s Health Research Unit, Belagavi, India: Sheetal Harakuni and Manjunath Somannavar; Government Medical College, Nagpur, India: Chaitali Gedam, Sunanda Shrikhande and Vaishali Kolhe; Mahatma Gandhi Institute of Medical Sciences, Sevagram, India: Vijayshri Deotale; Moi University College of Health Sciences, Kenya: Anderson Misati; Clinical Microbiology Laboratory (Aga Khan University, Karachi, Pakistan): Imran Ahmed and Najia Ghanchi; University Teaching Hospital (formerly Lusaka Hospital), Zambia: Ruth Nakazwe. 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PubMed Abstract | Publisher Full Text | Free Full Text Keenan JD, Bailey RL, West SK, et al. : Azithromycin to reduce childhood mortality in sub-Saharan Africa. N Engl J Med. 2018; 378 (17): 1583–1592. PubMed Abstract | Publisher Full Text | Free Full Text Kim J: 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. [Dataset]. 2024. http://www.doi.org/10.17605/OSF.IO/BC4T2 Kournoutou GG, Dinos G: Azithromycin through the lens of the COVID-19 treatment. Antibiotics (Basel). 2022; 11 (8): 1063–1074. PubMed Abstract | Publisher Full Text | Free Full Text O'Brien KS, Emerson P, Hooper PJ, et al. : Antimicrobial resistance following mass azithromycin distribution for trachoma: a systematic review. Lancet Infect Dis. 2019; 19 (1): e14–e25. PubMed Abstract | Publisher Full Text Peters DH, Friedel HA, McTavish D: Azithromycin. A review of its antimicrobial activity, pharmacokinetic properties and clinical efficacy. Drugs. 1992; 44 (5): 750–799. PubMed Abstract | Publisher Full Text Roca A, Oluwalana C, Bojang A, et al. : Oral azithromycin given during labour decreases bacterial carriage in the mothers and their offspring: a double-blind randomized trial. Clin Microbiol Infect. 2016; 22 (6): 565.e1–569. PubMed Abstract | Publisher Full Text | Free Full Text Subramaniam A, Waites KB, Jauk VC, et al. : Azithromycin-based extended-spectrum antibiotic prophylaxis for cesarean: role of placental colonization with genital ureaplasmas and mycoplasmas. Am J Perinatol. 2019; 36 (10): 1002–1008. PubMed Abstract | Publisher Full Text Sutton AL, Acosta EP, Larson KB, et al. : Perinatal pharmacokinetics of Azithromycin for cesarean prophylaxis. Am J Obstet Gynecol. 2015; 212 (6): 812.e811–816. PubMed Abstract | Publisher Full Text | Free Full Text Tita ATN, Carlo WA, McClure EM, et al. : Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med. 2023; 388 (13): 1161–1170. PubMed Abstract | Publisher Full Text | Free Full Text Tita ATN, Rouse DJ, Blackwell S, et al. : Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol. 2009; 113 (3): 675–682. PubMed Abstract | Publisher Full Text | Free Full Text Tita AT, Szychowski JM, Boggess K, et al. : Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med. 2016; 375 (13): 1231–1241. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 24 Sep 2024 ADD YOUR COMMENT Comment Author details Author details 1 RTI International, Research Triangle Park, North Carolina, USA 2 The University of Alabama at Birmingham, Birmingham, Alabama, USA 3 University Teaching Hospital, Lusaka, Zambia 4 Kinshasa School of Public Health, Kinshasa, Democratic Republic of the Congo 5 Lata Medical Research Foundation, Nagpur, India 6 Datta Meghe Institute of Higher Education and Research, Maharashtra, India 7 KLE Academy Higher Education and Research, J N Medical College, Belagavi, Karnataka, India 8 The Aga Khan University, Karachi, Pakistan 9 Moi University School of Medicine, Eldoret, Kenya 10 Instituto de Nutrición de Centroamérica y Panamá, Guatemala City, Guatemala 11 International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh 12 University of Virginia, Charlottesville, Virginia, USA 13 Columbia University School of Medicine, New York, New York, USA 14 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA 15 Indiana School of Medicine, University of Indiana, Indianapolis, Indiana, USA 16 University of Colorado School of Medicine, Denver, Colorado, USA 17 Thomas Jefferson University, Philadelphia, Pennsylvania, USA 18 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA 19 University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA 20 Boston University School of Public Health, Boston, Massachusetts, USA Jean H. Kim Roles: Investigation, Methodology, Project Administration, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Denise Babineau Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Janet L. Moore Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Akila Subramaniam Roles: Methodology, Writing – Review & Editing Alan Tita Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing Elwyn Chomba Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Musaku Mwenchanya Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Adrien Lokangaka Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Antoinette Tshefu Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Archana Patel Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Prabir Das Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Shivaprasad S. Goudar Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Shiyam Sunder Tikmani Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Imran Ahmed Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sarah Saleem Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Fabian Esamai Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Manolo Mazariegos Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sk Masum Billah Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Rashidul Haque Roles: Funding Acquisition, Investigation, Project Administration, Validation, Writing – Review & Editing Robert L. Goldenberg Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Melissa Bauserman Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Sherri Bucher Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Nancy F. Krebs Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Richard J. Derman Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing William A. Petri Jr Roles: Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Marion Koso-Thomas Roles: Conceptualization, Funding Acquisition, Supervision, Writing – Review & Editing Jennifer J. Hemingway-Foday Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Anna Aceituno Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Review & Editing Elizabeth M. McClure Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Doyle V. Ward Roles: Methodology, Writing – Review & Editing Sixto Leal Roles: Methodology, Validation, Writing – Review & Editing Waldemar A. Carlo Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Writing – Review & Editing Patricia L. Hibberd Roles: 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 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]. Article Versions (2) version 2 Revised Published: 24 Sep 2025, 8:101 https://doi.org/10.12688/gatesopenres.15992.2 version 1 Published: 24 Sep 2024, 8:101 https://doi.org/10.12688/gatesopenres.15992.1 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. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads Gates Open Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE 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 Res 2024, 8 :101 ( https://doi.org/10.12688/gatesopenres.15992.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 24 Sep 2024 Views 0 Cite How to cite this report: Ali MM. Reviewer Report For: 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 Res 2024, 8 :101 ( https://doi.org/10.21956/gatesopenres.17351.r38173 ) The direct URL for this report is: https://gatesopenresearch.org/articles/8-101/v1#referee-response-38173 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 25 Oct 2024 Muhammad Muddassir Ali , University of Veterinary and Animal Sciences, Lahore, Pakistan Approved with Reservations VIEWS 0 https://doi.org/10.21956/gatesopenres.17351.r38173 The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. ... Continue reading READ ALL The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1 Mati Ullah, et al 2023 Ref 2 Murtaza, et al 2023 Ref 3 Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Partly References 1. G A K Neamah, E A H Alalwany, F B Rabee, A M Jasim, et al.: Histopathological Detection of the Protective Role of Hydroxytyrosol Against the adverse Effect of Azithromycin in Rats. https://www.als-journal.com/11217-24 . 2024. 2. U Mati, R Fayyaz, K Noor, AShahzad, et al.: Antibiotic Resistance and its Gene Profile in Escherichia coli Isolated from Diseased Farm- Raised Carps in Punjab, Pakistan. 2023. Publisher Full Text 3. B N Murtaza, S tul Muntaha, M Siraj, M Ur Rehman, et al.: Embryotoxic effects of Ciprofloxacin in Chicken: A potential risk for antibiotic resistance. https://submission.als-journal.com/index.php/ALS/article/view/1103 . 2022. Competing Interests: No competing interests were disclosed. Reviewer Expertise: infectious diseases, I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ali MM. Reviewer Report For: 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 Res 2024, 8 :101 ( https://doi.org/10.21956/gatesopenres.17351.r38173 ) The direct URL for this report is: https://gatesopenresearch.org/articles/8-101/v1#referee-response-38173 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 24 Sep 2025 Jean Kim , RTI International, Research Triangle Park, USA 24 Sep 2025 Author Response COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap ... Continue reading COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. RESPONSE 1: We agree that more sampling may have been useful; however, we were limited by both funding as well as the practical considerations for having a mother and baby provide samples and as such selected the time points which aligned with prior research. COMMENT 2: Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. RESPONSE 2: We do collect history of antibiotics during pregnancy; however, as these are self-report data, the accuracy of the data is limited. As this was a placebo-controlled trial, we anticipate that the antibiotic use pre-randomization (i.e., during pregnancy) to be balanced. COMMENT 3: While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1, Mati Ullah, et al 2023 Ref 2, Murtaza, et al 2023 Ref 3. RESPONSE 3: Yes, we agree that assessing the microbiome does not address the functional changes related to the antibiotic resistance genes. We plan to assess the resistome using metagenomic approaches as you have indicated. This is addressed in the “Serial monitoring of microbiome and resistance profile” section. COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. RESPONSE 1: We agree that more sampling may have been useful; however, we were limited by both funding as well as the practical considerations for having a mother and baby provide samples and as such selected the time points which aligned with prior research. COMMENT 2: Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. RESPONSE 2: We do collect history of antibiotics during pregnancy; however, as these are self-report data, the accuracy of the data is limited. As this was a placebo-controlled trial, we anticipate that the antibiotic use pre-randomization (i.e., during pregnancy) to be balanced. COMMENT 3: While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1, Mati Ullah, et al 2023 Ref 2, Murtaza, et al 2023 Ref 3. RESPONSE 3: Yes, we agree that assessing the microbiome does not address the functional changes related to the antibiotic resistance genes. We plan to assess the resistome using metagenomic approaches as you have indicated. This is addressed in the “Serial monitoring of microbiome and resistance profile” section. Competing Interests: There are no competing interests to disclose. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 24 Sep 2025 Jean Kim , RTI International, Research Triangle Park, USA 24 Sep 2025 Author Response COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap ... Continue reading COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. RESPONSE 1: We agree that more sampling may have been useful; however, we were limited by both funding as well as the practical considerations for having a mother and baby provide samples and as such selected the time points which aligned with prior research. COMMENT 2: Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. RESPONSE 2: We do collect history of antibiotics during pregnancy; however, as these are self-report data, the accuracy of the data is limited. As this was a placebo-controlled trial, we anticipate that the antibiotic use pre-randomization (i.e., during pregnancy) to be balanced. COMMENT 3: While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1, Mati Ullah, et al 2023 Ref 2, Murtaza, et al 2023 Ref 3. RESPONSE 3: Yes, we agree that assessing the microbiome does not address the functional changes related to the antibiotic resistance genes. We plan to assess the resistome using metagenomic approaches as you have indicated. This is addressed in the “Serial monitoring of microbiome and resistance profile” section. COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. RESPONSE 1: We agree that more sampling may have been useful; however, we were limited by both funding as well as the practical considerations for having a mother and baby provide samples and as such selected the time points which aligned with prior research. COMMENT 2: Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. RESPONSE 2: We do collect history of antibiotics during pregnancy; however, as these are self-report data, the accuracy of the data is limited. As this was a placebo-controlled trial, we anticipate that the antibiotic use pre-randomization (i.e., during pregnancy) to be balanced. COMMENT 3: While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1, Mati Ullah, et al 2023 Ref 2, Murtaza, et al 2023 Ref 3. RESPONSE 3: Yes, we agree that assessing the microbiome does not address the functional changes related to the antibiotic resistance genes. We plan to assess the resistome using metagenomic approaches as you have indicated. This is addressed in the “Serial monitoring of microbiome and resistance profile” section. Competing Interests: There are no competing interests to disclose. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 24 Sep 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 2 (revision) 24 Sep 25 Version 1 24 Sep 24 read Muhammad Muddassir Ali , University of Veterinary and Animal Sciences, Lahore, Pakistan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Ali M. This is an open access peer review report 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. 25 Oct 2024 | for Version 1 Muhammad Muddassir Ali , University of Veterinary and Animal Sciences, Lahore, Pakistan 0 Views copyright © 2024 Ali M. This is an open access peer review report 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. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1 Mati Ullah, et al 2023 Ref 2 Murtaza, et al 2023 Ref 3 Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Partly Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Partly References 1. G A K Neamah, E A H Alalwany, F B Rabee, A M Jasim, et al.: Histopathological Detection of the Protective Role of Hydroxytyrosol Against the adverse Effect of Azithromycin in Rats. https://www.als-journal.com/11217-24 . 2024. 2. U Mati, R Fayyaz, K Noor, AShahzad, et al.: Antibiotic Resistance and its Gene Profile in Escherichia coli Isolated from Diseased Farm- Raised Carps in Punjab, Pakistan. 2023. Publisher Full Text 3. B N Murtaza, S tul Muntaha, M Siraj, M Ur Rehman, et al.: Embryotoxic effects of Ciprofloxacin in Chicken: A potential risk for antibiotic resistance. https://submission.als-journal.com/index.php/ALS/article/view/1103 . 2022. Competing Interests No competing interests were disclosed. Reviewer Expertise infectious diseases, I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 24 Sep 2025 Jean Kim, RTI International, Research Triangle Park, USA COMMENT 1: The surveillance schedule of 1 week, 6 weeks, 3 months, 6 months, and 12 months postpartum provides useful snapshots, but the intervals between time points, especially the gap between 6 weeks and 3 months, may miss key transitional microbial dynamics. Additional intermediate sampling points could reveal more detailed microbial and resistance evolution patterns, particularly in the critical early postpartum period. RESPONSE 1: We agree that more sampling may have been useful; however, we were limited by both funding as well as the practical considerations for having a mother and baby provide samples and as such selected the time points which aligned with prior research. COMMENT 2: Although the exclusion criteria include active use of azithromycin or other macrolides at the time of enrollment, the protocol does not address the potential impact of prior antibiotic exposure on the resistome or microbiome. Women may have been exposed to antibiotics earlier in their pregnancy, which could confound the results. The inclusion of a detailed antibiotic history would strengthen the analysis and ensure any pre-existing resistance is accounted for. RESPONSE 2: We do collect history of antibiotics during pregnancy; however, as these are self-report data, the accuracy of the data is limited. As this was a placebo-controlled trial, we anticipate that the antibiotic use pre-randomization (i.e., during pregnancy) to be balanced. COMMENT 3: While the microbiome analysis is a key strength of the study, the method used (16S rRNA sequencing) may have limitations in detecting functional changes, particularly those related to antibiotic resistance genes. Metagenomic approaches that focus on the functional resistome would provide a more accurate picture of resistance evolution post-azithromycin exposure. recent citations could be added to make more insights in this topic. it can be linked from transfer of issues from animal origin food to humans. e.g., Neamah, et al 2024 Ref 1, Mati Ullah, et al 2023 Ref 2, Murtaza, et al 2023 Ref 3. RESPONSE 3: Yes, we agree that assessing the microbiome does not address the functional changes related to the antibiotic resistance genes. We plan to assess the resistome using metagenomic approaches as you have indicated. This is addressed in the “Serial monitoring of microbiome and resistance profile” section. View more View less Competing Interests There are no competing interests to disclose. reply Respond Report a concern Ali MM. Peer Review Report For: 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 Res 2024, 8 :101 ( https://doi.org/10.21956/gatesopenres.17351.r38173) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://gatesopenresearch.org/articles/8-101/v1#referee-response-38173 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. 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