Cumulative cefepime exposure in cancer patients is associated with an increased risk of ertapenem non-susceptible, meropenem susceptible Enterobacterales bacteremia

Carbapenem resistance in non-carbapenemase producing Enterobacterales can display susceptibility discordance (e.g., ertapenem-non-susceptible, meropenem-susceptible), often in patients with prior antimicrobial use. We aim to characterize risk factors for carbapenem susceptibility discordant Enterobacterales (CSD-E) bloodstream infections in immunocompromised patients. We performed a retrospective, single-center study comparing adults with Enterobacterales BSI who developed subsequent carbapenem susceptibility concordant (CSC; meropenem and ertapenem susceptible) or CSD-E BSI with the same organism within 1 year. Patients who developed subsequent CSD-E BSI were matched to those with repeat CSC-E BSI based on organism. Logistic regression models evaluated CSD-E risk factors. Time-varying covariate Cox proportional hazards models evaluated time-dependent changes in antibiotic exposure when estimating the association between antibiotic use and CSD-E. Comparative genomics of available paired whole-genome sequencing (WGS) data was performed to assess genetic relatedness and antimicrobial resistance (AMR) gene content. Beta-lactam survival mechanisms (BLSM) were assessed via Tolerance Disk Test (TDTest) and Population Analysis Profiling (PAP). We evaluated 829 patients with Enterobacterales BSI. Repeat BSI was CSC-E in 81 patients (9.8%) and CSD-E in 14 patients (1.7%). Matching provided 43 CSC-E controls and 14 CSD-E cases. Univariate analysis revealed any ceftazidime-avibactam (CZA) exposure was associated with developing CSD-E BSI (odds ratio [OR], 7.41; P = 0.01). Time-varying covariate Cox regression identified each additional day of cefepime is associated with CSD-E BSI development (hazard ratio [HR], 1.055; P = 0.016). Genomic data suggest beta-lactamase amplification and outer membrane porin mutations may be potential CSD-E development mechanisms. CSD-E BSI risk factors in immunocompromised patients may include any CZA exposure and cumulative cefepime exposure. Further studies are warranted to validate CSD-E risk factors. IMPORTANCE Non-carbapenemase-producing (non-CP) carbapenem-resistant Enterobacterales (CRE) are an important classification of CRE. Increasing rates of non-CP CRE that display carbapenem susceptibility discordance (CSD-E; ertapenem-resistant, meropenem susceptible) have been observed globally and at our institution. Our article aims to characterize risk factors, including cumulative antibiotic exposure, leading to carbapenem susceptibility discordant Enterobacterales (CSD-E) bloodstream infection (BSI) in immunocompromised patients with a history of Enterobacterales BSI. In addition, we analyzed paired whole-genome sequencing data to assess antimicrobial gene content for mechanistic rationales supporting our clinical findings. The risk factors for CSD-E development identified in this study require further validation in multicenter cohorts.