The impact of different antimicrobial exposures on the gut microbiome in the ARMORD observational study

Background: Better metrics to compare the impact of different antimicrobials on the gut microbiome would aid efforts to control antimicrobial resistance (AMR). Methods: The Antibiotic Resistance in the Microbiome - Oxford (ARMORD) study recruited inpatients, outpatients and healthy volunteers in Oxfordshire, UK, who provided stool samples for metagenomic sequencing. Data on previous antimicrobial use and potential confounders were recorded. Exposures to each antimicrobial were considered as factors in a multivariable linear regression, also adjusted for demographics, with separate analyses for those contributing samples cross-sectionally or longitudinally. Outcomes were Shannon diversity and relative abundance of specific bacterial taxa (Enterobacteriaceae, Enterococcus, and major anaerobic groups) and antimicrobial resistance genes (targeting beta-lactams, tetracyclines, aminoglycosides, macrolides, and glycopeptides). Results: 225 adults were included in the cross-sectional analysis, and a subset of 79 patients undergoing haematopoietic stem cell transplant provided serial samples for longitudinal analysis. Results were largely consistent between the two sampling frames. Recent use of piperacillin-tazobactam, meropenem, intravenous co-amoxiclav and clindamycin were associated with large reductions in microbiome diversity and reduced abundance of anaerobes. Exposure to piperacillin-tazobactam and meropenem were associated with a decreased abundance of Enterobacteriaceae, and an increased abundance of Enterococcus and major AMR genes, but there was no evidence that these antibiotics had a greater impact on microbiome diversity than iv co-amoxiclav or oral clindamycin. In contrast, co-trimoxazole, doxycycline, antifungals and antivirals had less impact on microbiome diversity and selection of AMR genes. Conclusion: Simultaneous estimation of the impact of over 20 antimicrobials on the gut microbiome and AMR gene abundance highlighted important differences between individual drugs. Some drugs in the WHO Access group (co-amoxiclav, clindamycin) had similar magnitude impact on microbiome diversity to those in the Watch group (meropenem, piperacillin-tazobactam) with potential implications for acquisition of resistant organisms. Metagenomic sequencing can be used to compare the impact of different antimicrobial agents and treatment strategies on the commensal flora. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with the UK Health Security Agency (NIHR200915), and the NIHR Biomedical Research Centre, Oxford ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the East Midlands-Leicester Central Research Ethics Committee, UK (15/EM/0270) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors