Editors' ChoiceInfectious Disease

The resistance potential of a quintessential commensal

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Science Translational Medicine  15 Aug 2018:
Vol. 10, Issue 454, eaau7387
DOI: 10.1126/scitranslmed.aau7387

Abstract

Whole-genome sequencing and microbiome analysis illuminate the emergence of invasive, linezolid-resistant Staphylococcus epidermidis.

Rising rates of antibiotic resistance confound the treatment of previously manageable infections and may lead to 10 million deaths annually by 2050 in the absence of new interventions. Linezolid is a last-line drug reserved for complicated infections caused by Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), yet even resistance to this strategic agent has arisen in the past decade. Despite the critical nature of this situation, the factors driving emergence and dissemination of linezolid resistance are incompletely understood. Li and colleagues used whole-genome sequencing to understand the emergence of linezolid resistance in Staphylococcus epidermidis, a commensal that is contextually pathogenic in susceptible hosts, including those undergoing intensive antimicrobial treatment.

The authors first examined institutional linezolid prescription and prevalence of resistance in patients with S. epidermidis bacteremia and found that patients who received linezolid within 90 days were more likely to have a resistant isolate. Next, they deployed whole-genome sequencing to interrogate the genomic landscape of linezolid-resistant S. epidermidis. They found that clonal expansion and dissemination of a single multidrug-resistant strain was responsible for 79% of resistant cases, largely in leukemic patients. Further characterization of this strain identified cfr, a ribosomal methyltransferase gene, on a plasmid surrounded by a region with 100% identity to a cfr-containing plasmid first recognized in livestock from China and eventually in regional patient populations.

Driven by a hypothesis that linezolid exposure could increase the risk of invasive infection by inducing proliferation of resistant staphylococci present at low abundance within the gut microbiome, they performed serial 16S rRNA sequencing of stool samples to longitudinally assess community composition. They found that prior linezolid exposure was associated with staphylococcal dominance in a subset of patients, the majority of whom also had a concomitant increase in cfr abundance within their gut antimicrobial resistome.

Together, these findings indicate that antimicrobial use might drive emergence of invasive, resistant strains of typically commensal species, and emphasize the value of both antimicrobial stewardship and rigorous infection control practices to prevent and mitigate resistance emergence in high-risk populations. Furthermore, the authors’ genomic and microbiome-based analyses provide a framework for investigating emergence and dissemination of other potentially pathogenic symbionts. Future work can examine the capacity of horizontal transfer of linezolid resistance to other commensals and to key pathogens such as S. aureus. In addition, it will be of interest to determine whether proactive surveillance of the gut microbiome for pathogen dominance or resistance gene emergence is a useful approach for identifying patients at high risk for invasive drug-resistant infections.

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