The Clinical and Molecular Epidemiology of Noncarbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae: A Case-Case-Control Matched Analysis

Abstract

Background: Risk factors and outcomes associated with carbapenem-resistant Enterobacteriaceae (CRE) acquisitions are derived primarily from cohorts consisting of carbapenemase-producing (CP) strains. Worldwide epidemiology of non-CP-CRE is evolving, but controlled epidemiological analyses are lacking.

Methods: A matched case-case-control investigation was conducted at Shamir (Assaf Harofeh) Medical Center, Israel, on November 2014-December 2016. Noncarbapenemase-producing CRE (as defined by the US Clinical and Laboratory Standards Institute Standards) carriers were matched to patients with non-CRE Enterobacterales and to uninfected controls (1:1:1 ratio). Matched and nonmatched multivariable regression models were constructed to analyze predictors for acquisition and the independent impact of carriage on multiple outcomes, respectively. Representative isolates were whole genome sequenced and analyzed for resistome and phylogeny.

Results: Noncarbapenemase-producing CRE carriers (n = 109) were matched to the 2 comparative groups (overall n = 327). Recent exposure to antibiotics (but not specifically to carbapenems), prior intensive care unit admission, and chronic skin ulcers were all independent predictors for non-CP-CRE acquisition. Acquisitions were almost exclusively associated with asymptomatic carriage (n = 104), and despite strong associations per univariable analyses, none were independently associated with worse outcomes. Genomic analyses of 13 representative isolates revealed polyclonality, confirmed the absence of carbapenemases, but confirmed the coexistence of multiple other genes contributing to carbapenem-resistance phenotype (multiple beta-lactamases and efflux pumps).

Conclusions: Noncarbapenemase-producing CRE acquisitions are primarily associated with asymptomatic carriage, specifically among prone populations with extensive recent exposures to antibiotics. The prevalent mode of acquisition is "emergence of resistance" (not "patient-to-patient transmission"), and therefore the role of stewardship interventions in reducing the spread of these therapeutically challenging pathogens should be further explored.

Keywords: CRE; antimicrobial resistance; case-case control; multidrug resistance; nosocomial infection.

Figure 1.

Phylogenetic analysis of representative study isolates. A minimum spanning tree was constructed based on an ad hoc core genome multilocus sequence typed schema of 3635 loci. Each node represents a Klebsiella pneumoniae isolate (n = 13), and the numerical labels over connecting lines indicate the number of different loci between the sequenced isolates.