Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

Abstract

AbstractThe global dissemination of a ciprofloxacin-resistant (cipR)S. sonneiclone outlines the mobility of this important agent of diarrheal disease, and threatens the utility of ciprofloxacin as a first-line antimicrobial for shigellosis. Here, we aimed to track the emergence of cipRS. sonneiin Vietnam to understand how novel antimicrobial resistant (AMR)Shigellaclones become established in new locations. From 2014 to 2016, we isolated and genome sequenced 79S. sonneifrom children hospitalized with dysenteric diarrhea in southern Vietnam. The novel cipRS. sonneiclone displaced the resident ciprofloxacin-susceptible lineage while acquiring resistance against third-generation cephalosporins, macrolides, and aminoglycosides. This process was not the result of a single clonal expansion, as we identified at least thirteen independent acquisitions of ESBL-encoding plasmids. The frequency and diversity of the variable AMR repertoire in an expanding clonal background ofS. sonneiis unprecedented and we speculated that it was facilitated by horizontal gene transfer from commensal organisms in the human gut. Consequently, we characterized non-ShigellaEnterobacteriaceae fromShigella-infected and healthy children by shotgun metagenomics. We identified a wide array of AMR genes and plasmids in the commensal Enterobacteriaceae, including anE. coliisolated from aShigella-infected child with an identical ESBL plasmid to that characterized in the infectingS. sonnei. We confirmed that these AMR plasmids could be exchanged between commensalE. coliandS. sonneiand found that supplementation of ciprofloxacin into the conjugation media significantly increased the conjugation frequency of IncI/blaCTX-M-15, IncB/O/blaCTX-M-27and IncF/blaCTX-M-27plasmids. In a setting with high antimicrobial use and a high prevalence of AMR commensals, cipRS. sonneimay be propelled towards pan-resistance by adherence to outdated international treatment guidelines. Our work highlights the role of the gut microbiota in transferring resistance plasmids into enteric pathogens and provides essential data to restrict the use of ciprofloxacin globally.