Clinical and molecular characteristics and risk factors for patients acquiring carbapenemase-producing and non-carbapenemase-producing carbapenem-nonsusceptible-Enterobacterales bacteremia.

Carbapenem-nonsusceptible Enterobacterales (CNSE) are a growing global threat. Carbapenemases are often produced by plasmids, which allow rapid transmission. This study aimed to investigate (1) the bacterial type (2) resistant genes (3) antimicrobial susceptibility and (4) risk factors for acquisition of carbapenemase-producing carbapenem-nonsusceptible Enterobacterales (CP-CNSE) and non-carbapenemase-producing carbapenem-nonsusceptible Enterobacterales (non-CP-CNSE) bacteremia. There were a total of 113 isolates of Enterobacterales from 2013 to 2018. After excluding nonblood isolates and including only one sample from each patient, 99 isolates were analyzed and the medical charts of these patients were reviewed. Carbapenemase genes, β-lactamase genes and antimicrobial susceptibility of the isolates were determined. Multilocus sequence typing (MLST) was performed on CP-CNSE isolates. CP-CNSE carried more blaSHV (P = 0.004) and were more resistant to imipenem than non-CP-CNSE (P < 0.001). In the univariate analyses, we found that CP-CNSE bloodstream infection was associated with patient <65 years of age (odds ratio, 3.90; 95% confidence interval [CI], 1.16 to 13.10; P = 0.027), mechanical ventilation at the time of bloodstream infection (BSI) (odds ratio, 3.85; 95% CI, 1.16-12.78; P = 0.028) and exposure to piperacillin/tazobactam (odds ratio, 3.96; 95% CI, 1.09-14.38; P = 0.037). However, on multivariate analyses, no independent predictor for CP-CNSE was identified in this study. CP-CNSE carried more blaSHV and were more resistant to imipenem when compared to non-CP-CNSE. No independent predictor for CP-CNSE was identified after multivariate analysis. This is the first study conducted in Taiwan comparing risk factors between CP-CNSE and non-CP-CNSE from both clinical and molecular aspects.

Wu AY ，Chang H ，Wang NY ，Sun FJ ，Liu CP ... -  《-》

Systematic Analysis of Mobile Genetic Elements Mediating β-Lactamase Gene Amplification in Noncarbapenemase-Producing Carbapenem-Resistant Enterobacterales Bloodstream Infections.

Noncarbapenemase-producing carbapenem-resistant (non-CP-CRE) are increasingly recognized as important contributors to prevalent carbapenem-resistant (CRE) infections. However, there is limited understanding of mechanisms underlying non-CP-CRE causing invasive disease. Long- and short-read whole-genome sequencing was used to elucidate carbapenem nonsusceptibility determinants in bloodstream isolates at MD Anderson Cancer Center in Houston, Texas. We investigated carbapenem nonsusceptible (CNSE) mechanisms (i.e., isolates with carbapenem intermediate resistance phenotypes or greater) through a combination of phylogenetic analysis, antimicrobial resistance gene detection/copy number quantification, porin assessment, and mobile genetic element (MGE) characterization. Most CNSE isolates sequenced were non-CP-CRE (41/79; 51.9%), whereas 25.3% (20/79) were with intermediate susceptibility to carbapenems (CIE), and 22.8% (18/79) were carbapenemase-producing (CPE). Statistically significant copy number variants (CNVs) of extended-spectrum β-lactamase (ESBL) genes (Wilcoxon Test; -value < 0.001) were present in both non-CP-CR E. coli (median CNV = 2.6×; = 17) and K. pneumoniae (median CNV = 3.2×,  = 17). All non-CP-CR E. coli and K. pneumoniae had predicted reduced expression of at least one outer membrane porin gene (i.e., or ). Completely resolved CNSE genomes revealed that IS and IS structures harboring variants along with other antimicrobial resistance elements were associated with gene amplification, occurring in mostly IncFIB/IncFII plasmid contexts. MGE-mediated β-lactamase gene amplifications resulted in either tandem arrays, primarily mediated by IS translocatable units, or segmental duplication, typically due to IS transposition units. Non-CP-CRE strains were the most common cause of CRE bacteremia with carbapenem nonsusceptibility driven by concurrent porin loss and MGE-mediated amplification of genes. Carbapenem-resistant (CRE) are considered urgent antimicrobial resistance (AMR) threats. The vast majority of CRE research has focused on carbapenemase-producing (CPE) even though noncarbapenemase-producing CRE (non-CP-CRE) comprise 50% or more of isolates in some surveillance studies. Thus, carbapenem resistance mechanisms in non-CP-CRE remain poorly characterized. To address this problem, we applied a combination of short- and long-read sequencing technologies to a cohort of CRE bacteremia isolates and used these data to unravel complex mobile genetic element structures mediating β-lactamase gene amplification. By generating complete genomes of 65 carbapenem nonsusceptible (CNSE) covering a genetically diverse array of isolates, our findings both generate novel insights into how non-CP-CRE overcome carbapenem treatments and provide researchers scaffolds for characterization of their own non-CP-CRE isolates. Improved recognition of mechanisms driving development of non-CP-CRE could assist with design and implementation of future strategies to mitigate the impact of these increasingly recognized AMR pathogens.

Shropshire WC ，Konovalova A ，McDaneld P ，Gohel M ，Strope B ，Sahasrabhojane P ，Tran CN ，Greenberg D ，Kim J ，Zhan X ，Aitken S ，Bhatti M ，Savidge TC ，Treangen TJ ，Hanson BM ，Arias CA ，Shelburne SA ... -  《mSystems》

The influence of hospital antimicrobial use on carbapenem-non-susceptible Enterobacterales incidence rates according to their mechanism of resistance: a time-series analysis.

Carbapenem non-susceptible Enterobacterales (CNSE) can be broadly divided into those that produce carbapenemases (carbapenemase-producing Enterobacterales (CPE)), and those that harbour other mechanisms of resistance (non-carbapenemase-producing CNSE (NCP-CNSE)). To determine the predictors of CNSE nosocomial incidence rates according to their mechanism of resistance. A time-series analysis was conducted (July 2013 to December 2018) to evaluate the relationship in time between hospital antibiotic use and the percentage of adherence to hand hygiene with the CNSE rates. In all, 20,641 non-duplicated Enterobacterales isolates were identified; 2.2% were CNSE. Of these, 48.1% and 51.9% were CPE and NCP-CNSE, respectively. Of the CPE, 78.3% possessed a blaOXA-232 gene. A transfer function model was identified for CNSE, CPE, and OXA-232 CPE that explained 20.8%, 19.3%, and 24.2% of their variation, respectively. According to the CNSE and CPE models, an increase in piperacillin-tazobactam (TZP) use of 1 defined daily dose (DDD) per 100 hospital patient-days (HPD) would lead to an increase of 0.69 and 0.49 CNSE and CPE cases per 10,000 HPD, respectively. The OXA-232 CPE model estimates that an increase of 1 DDD per 100 HPD of TZP use would lead to an increase of 0.43 OXA-232 CPE cases per 10,000 HPD. A transfer function model was not identified for NCP-CNSE, nor was there an association between the adherence to handhygiene and the CNSE rates. The use of TZP is related in time with the CPE nosocomial rates, mostly explained by its effect on OXA-232 CPE.

Ortiz-Brizuela E ，Caro-Vega Y ，Bobadilla-Del-Valle M ，Leal-Vega F ，Criollo-Mora E ，López Luis BA ，Esteban-Kenel V ，Torres-Veintimilla E ，Galindo-Fraga A ，Olivas-Martínez A ，Tovar-Calderón E ，Torres-González P ，Sifuentes-Osornio J ，Ponce-de-León A ... -  《-》

Comparing mortality in patients with carbapenemase-producing carbapenem resistant Enterobacterales and non-carbapenemase-producing carbapenem resistant Enterobacterales bacteremia.

Carbapenem-resistant Enterobacterales (CRE) are classified as either carbapenemase-producing CRE (CP-CRE) or non-carbapenemase-producing CRE (non-CP-CRE) based on their mechanism of carbapenem resistance. Few studies have compared outcomes associated with each type of infection. We attempted to determine if either CRE subset is associated with increased mortality. We performed a retrospective observational study to collect demographic, clinical and outcomes data to compare patients with CP-CRE and non-CP-CRE bacteremia. Of 146 cases analyzed, 88/146 (60%) were CP-CRE and 58/146 (40%) were non-CP-CRE. Patients with CP-CRE bacteremia were less likely to receive active empiric or targeted antibiotic therapy. Non-CP-CRE bacteremia was associated with a 2.4 times higher hazard of death at 30 days after bacteremia onset compared to CP-CRE (HR, 2.4; 95% CI, 1.2, 4.6). Patients with non-CP-CRE bacteremia had a higher hazard of death at 30 days after bacteremia onset compared to those with CP-CRE bacteremia.

Hovan MR ，Narayanan N ，Cedarbaum V ，Bhowmick T ，Kirn TJ ... -  《-》

Risk factors for acquisition of carbapenemase-producing versus non-carbapenemase-producing enterobacterales: a case-control study.

We aimed to assess the association between carbapenem-resistant Enterobacterales (CRE) colonization pressure and carbapenem exposure and acquisition of carbapenemase-producing Enterobacterales (CPE) and non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE). We conducted a parallel 1:2 matched case-control study at Rambam Health Care Campus, Israel, from January 2014 to June 2017. The cases included all adults who acquired CPE or non-CP-CRE in hospital. The controls were hospitalized patients who were negative for CRE on screening and matched by age, hospitalization division and the number of hospitalization days 90 days prior to CRE screening. The exposures of interest were high CRE colonization pressure, defined as a higher-than-median proportion of CRE carriers in the concurrent patient's department before acquisition, and carbapenem exposure, assessed as days of treatment. Conditional logistic regression was used for analyses of CPE and non-CP-CRE. In total, 1058 patients were included: 278 CPE and 75 non-CP-CRE cases, matched to 556 and 149 controls, respectively. High CRE colonization pressure was associated with CPE acquisition (adjusted odds ratio [aOR], 2.6; 95% CI, 1.69-4.02); however, the duration of carbapenem treatment was not (aOR, 1.004; 95% CI, 0.98-1.03; 1-day increment). The duration of carbapenem treatment was significantly associated with non-CP-CRE acquisition (aOR per day, 1.07; 95% CI, 1.03-1.11). A source patient was identified significantly more frequently in epidemiological acquisition investigations of CPE than in those of non-CP-CRE (107/240, 44.6% vs. 18/64, 28.1%, respectively; p 0.017). CPE acquisition was associated with horizontal transmission, whereas non-CP-CRE was associated with carbapenem exposure. Differences in the drivers of acquisition mandate tailored infection prevention efforts.

Hassoun-Kheir N ，Hussein K ，Karram M ，Saffuri M ，Badaan S ，Peleg S ，de Kraker MEA ，Aboelhega W ，Warman S ，Alon T ，Eluk O ，Geffen Y ，Paul M ... -  《-》