Antecedent Carbapenem Exposure as a Risk Factor for Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae and Carbapenemase-Producing Enterobacteriaceae

Abstract

Carbapenem-resistant <i>Enterobacteriaceae</i> (CRE) can be mechanistically classified into carbapenemase-producing <i>Enterobacteriaceae</i> (CPE) and non-carbapenemase-producing carbapenem nonsusceptible <i>Enterobacteriaceae</i> (NCPCRE). We sought to investigate the effect of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CRE colonization and infection, we conducted a case-control study comparing patients with NCPCRE (cases) and patients with CPE (controls). The presence of carbapenemases was investigated with phenotypic tests followed by PCR for predominant carbapenemase genes. We included 843 unique patients with first-episode CRE, including 387 (45.9%) NCPCRE and 456 (54.1%) CPE. The resistance genes detected in CPEs were <i>bla</i>_NDM (42.8%), <i>bla</i>_KPC (38.4%), and <i>bla</i>_OXA-48-like (12.1%). After adjusting for confounders and clustering at the institutional level, the odds of prior 30-day carbapenem exposure was three times higher among NCPCRE than CPE patients (adjusted odds ratio [aOR], 3.48; 95% confidence interval [CI], 2.39 to 5.09; <i>P</i> < 0.001). The odds of prior carbapenem exposure and NCPCRE detection persisted in stratified analyses by <i>Enterobacteriaceae</i> species (<i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i>) and carbapenemase gene (<i>bla</i>_NDM and <i>bla</i>_KPC). CPE was associated with male gender (aOR, 1.45; 95% CI, 1.07 to 1.97; <i>P</i> = 0.02), intensive care unit stay (aOR, 1.84; 95% CI, 1.24 to 2.74; <i>P</i> = 0.003), and hospitalization in the preceding 1 year (aOR, 1.42; 95% CI, 1.01 to 2.02; <i>P</i> = 0.05). In a large nationwide study, antecedent carbapenem exposure was a significant risk factor for NCPCRE versus CPE, suggesting a differential effect of antibiotic selection pressure.