Ceftriaxone administration disrupts intestinal homeostasis, mediating non-inflammatory proliferation and dissemination of commensal enterococci.

Enterococci are Gram-positive commensals of the mammalian intestinal tract and harbor intrinsic resistance to broad-spectrum cephalosporins. Disruption of colonization resistance in humans by antibiotics allow enterococci to proliferate in the gut and cause disseminated infections. In this study, we used Enterococcus faecalis (EF) colonized mice to study the dynamics of enterococci, commensal microbiota and host in response to systemic ceftriaxone administration. We found that the mouse model recapitulates intestinal proliferation and dissemination of enterococci seen in humans. Employing a ceftriaxone-sensitive strain of enterococci (EFJL308 ), we showed that increased intestinal abundance is critical for the systemic dissemination of enterococci. Investigation of the impact of ceftriaxone on the mucosal barrier defenses and integrity suggested that translocation of enterococci across the intestinal mucosa was not associated with intestinal pathology or increased permeability. Ceftriaxone-induced alteration of intestinal microbial composition was associated with transient increase in the abundance of multiple bacterial Operational Taxonomic Units (OTUs) in addition to enterococci, for example, lactobacilli, which also disseminated to the extra-intestinal organs. Collectively, these results emphasize that ceftriaxone-induced disruption of colonization resistance and alteration of mucosal homeostasis, facilitate increased intestinal abundance of a limited number of commensals along with enterococci, allowing their translocation and systemic dissemination in a healthy host.