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, 11/2014-12/2016. Non-CP-CRE (as defined by CLSI) carriers, were matched to patients with non-CRE Enterobacterales and to uninfected controls (1:1:1 ratio). Matched and non-matched multivariable regression models were constructed in order 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 Non-CP-CRE carriers (n=109) were matched to the two comparative groups (overall n=327). Recent exposure to antibiotics (but not specifically to carbapenems), prior ICU 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 the co-existence of multiple other genes contributing to carbapenem-resistance phenotype (multiple beta-lactamases and efflux pumps). Conclusions Non-CP-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.

Comparative Genomics Revealed Fluoroquinolone Resistance Determinants and OmpF Deletion in Carbapenem-Resistant Escherichia coli

“…The mode of acquisition of non-CP-CREc was through an endogenous pathway, which involves selective pressure of antibiotics on the intestinal microbiota and is primarily associated with recent exposure to antibiotics. While for CP-CREc, the mode of acquisition was primarily exogenous through “patient-to-patient” horizontal spread (Goodman et al, 2016 ; van Duin and Doi, 2017 ; Bouganim et al, 2020 ). By investigating the molecular mechanisms of CREc, we can better predict the risk factors among patients who are at risk of being infected with CREc and prevent CREc.…”

Systematic Analysis of Mobile Genetic Elements Mediating β-lactamase Gene Amplification in Non-Carbapenemase-Producing Carbapenem Resistant Enterobacterales Bloodstream Infections

“…Carbapenem resistant Enterobacterales (CRE) infections are major public health challenges, particularly within vulnerable patient populations (1–6). There is a strong correlation between carbapenem and multi-drug resistance (MDR), in part because carbapenem resistant infections commonly occur in patients who have previously received multiple courses of antimicrobials (7, 8). A primary factor responsible for the dissemination of MDR phenotypes are mobile genetic elements (MGEs).…”

Molecular epidemiology of carbapenem-resistant Enterobacterales in Thailand, 2016–2018

“…Evidence suggests distinct differences in the epidemiology of CRE with and without carbapenemase production. Carbapenemase producing CRE (CP-CRE) are more virulent and are associated with higher levels of antimicrobial resistance, worse outcomes, and more rapid spread, while noncarbapenemase-producing CRE (non-CP-CRE) have been associated with asymptomatic carriage and perhaps less person-to-person transmission [12][13][14]. For this reason, CP-CRE have been identified as an important target for prevention sometimes warranting enhanced infection control interventions [15].…”