Impact of azithromycin mass drug administration on the antibiotic-resistant gut microbiome in children: a randomized, controlled trial

Harry Pickering,Richard Stabler,Khumbo Kalua,Robin L Bailey,Ken Maleta,Martin J Holland,Sarah Burr,John D Hart

doi:10.1186/s13099-021-00478-6

Abstract

BackgroundMass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. Most recently, the MORDOR clinical trial demonstrated that MDA led to an overall reduction in all-cause childhood mortality in targeted communities. There is however concern about the potential of increased antimicrobial resistance in treated communities. This study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study, additionally profiling changes in the gut microbiome after treatment. For faecal metagenomics, 60 children were sampled prior to treatment and 122 children after four rounds of MDA, half receiving azithromycin and half placebo.ResultsThe proportion of bacteria carrying macrolide resistance increased after azithromycin treatment. Diversity and global community structure of the gut was minimally impacted by treatment, however abundance of several species was altered by treatment. Notably, the putative human enteropathogen Escherichia albertii was more abundant after treatment.ConclusionsMDA with azithromycin increased carriage of macrolide-resistant bacteria, but had limited impact on clinically relevant bacteria. However, increased abundance of enteropathogenic Escherichia species after treatment requires further, higher resolution investigation. Future studies should focus on the number of treatments and administration schedule to ensure clinical benefits continue to outweigh costs in antimicrobial resistance carriage.Trial registration ClinicalTrial.gov, NCT02047981. Registered January 29th 2014, https://clinicaltrials.gov/ct2/show/NCT02047981

Highlights

Mass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts
This study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study site, where the observed reduction in childhood mortality after azithromycin treatment was considerably less than in Niger
To determine the impact of treatment on known causes of diarrhoea, we further investigated differences in abundance of pathogenic bacteria identified by the Global Enteric Multicenter Study (GEMS) of diarrhoeal disease in infants and young children in developing countries [36]

Summary

Introduction

Mass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. This work has been expanded upon in studies across sub-Saharan Africa, demonstrating decreases in diarrhoea, malaria and all infectious mortality [5,6,7,8,9,10,11]. Alongside these benefits, there has been evidence of negative effects, primarily the emergence and increasing prevalence of antimicrobial resistance. A study of Aboriginal communities in Australia reported short-term reductions in the prevalence of nasopharyngeal Streptococcus pneumoniae carriage, but significant increases in macrolide-resistance in identified isolates [12]. Further studies have supported this increase in macrolide-resistant nasopharyngeal S. pneumoniae [3, 13, 14] as well as in faecal Escherichia coli [15,16,17], with evidence of macrolide and non-macrolide antimicrobial resistance in the latter

Methods

Results

Discussion

Conclusion