Antimicrobial resistance following azithromycin mass drug administration: potential surveillance strategies to assess public health impact Ines Mack1, Mike Sharland2, James A Berkley3,4, Nigel Klein5, Surbhi MalhotraKumar6, Julia Bielicki1,2 1 Paediatric Infectious Diseases, University Children’s Hospital Basel, Basel, Switzerland 2 Paediatric Infectious Disease Research Group, Institute for Infection and Immunity, St George's University of London, London, UK 3 Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK 4 KEMRI/Wellcome Trust Research Programme, Kilifi, Kenya 5 UCL Great Ormond Street Institute of Child Health, London, UK 6 Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, Universiteit Antwerpen, Antwerp, Belgium Key words: Macrolide; azithromycin; mass drug administration; antimicrobial resistance; surveillance; Running title: AMR surveillance after azithromycin MDA Article’s main points Azithromycin Mass Drug Administration results in a sustained increase in antimicrobial resistance when implemented at a population level. Targeted risk-based metagenomics approaches complementing traditional microbiological methods are recommended for surveillance of emerging short- and long-term antimicrobial resistance. 1 Corresponding author: Ines Mack | Spitalstr. 33 | 4056 Basel | Switzerland | | Phone 0041 61 704 22 37 | Fax 0041 61 704 12 53 Alternate corresponding author: Julia Bielicki | Spitalstr. 33 | CH-4056 Basel | Switzerland | | Phone 0041 61 704 28 58 | Fax 0041 61 704 12 53 2 ABSTRACT The reduction of childhood mortality noted in trials investigating azithromycin mass drug administration (MDA) for trachoma control has been confirmed by a recent large randomised controlled trial. Population-level implementation of azithromycin MDA may lead to selection of multi-resistant pathogens. Evidence suggests that repeated azithromycin MDA may result in a sustained increase in macrolide and other antibiotic resistance in gut and respiratory bacteria. Current evidence comes from standard microbiological techniques in studies focused on a time-limited intervention, while MDA implemented for mortality benefits would likely repeatedly expose the population over a prolonged period and may require a different surveillance approach. Targeted short-term and long-term surveillance of resistance emergence to key antibiotics, especially those from the WHO Access group, is needed throughout any implementation of azithromycin MDA, focusing on a genotypic approach to overcome the limitations of resistance surveillance in indicator bacteria. 3 DISCUSSION Intermittent childhood azithromycin mass drug administration in sub-Saharan Africa: current indications and supporting evidence The most frequent indication for azithromycin mass drug administration (AZM MDA) across Africa is endemic trachoma [1]. In 1997, the WHO established the Global Alliance for the Elimination of Blinding Trachoma by 2020 (GET 2020), and there is clear evidence that single-dose AZM MDA reduces the prevalence of active trachoma and ocular infection [2]. A reduction in childhood mortality was observed in studies of AZM MDA for trachoma in the sub-Saharan setting [3 ,[4]. The MORDOR I study (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance, # NCT02048007) [4] was specifically designed to investigate any potential mortality benefit. The study assigned communities in Malawi, Niger and Tanzania to four twice-yearly MDA rounds of either 20 mg/kg per dose oral AZM or placebo. This cluster randomized controlled trial demonstrated a reduction of allcause mortality in under-five year old children of 14% in the treatment group [4]. Mortality reduction (18%) was observed most clearly among infants in Niger and those who were less than 6 months of age with the highest mortality rate at baseline. Extension for two more rounds during MORDOR II did not show significant evidence of a waning effect of AZM MDA on childhood mortality [5]. In communities who received placebo originally, childhood mortality decreased after receipt of AZM [5]. Emergence of antibiotic resistance linked to antibiotic MDA could be a barrier to widespread implementation. There are concerns that AZM MDA will lead to selection of macrolide-resistant strains of Chlamydia trachomatis, and resistance to macrolides and other classes of antimicrobials in ot

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