BACKGROUND The IDSA guidance suggests treating Enterobacterales resistant to ertapenem but susceptible to imipenem or meropenem with a susceptible carbapenem in the absence of carbapenemase production; however, clinical outcomes data are limited. METHODS We conducted a multicenter prospective cohort study of hospitalized patients with invasive ceftriaxone-resistant Enterobacterales infections, comparing 30-day mortality between ertapenem-susceptible (ETP-S) and ertapenem-resistant (ETP-R) isolates. ETP-S isolates with an ESBL/AmpC phenotype served as the comparator because carbapenems are reliably active against these organisms. Carbapenem susceptibility was confirmed by broth microdilution. Inclusion criteria included: (1) susceptibility to imipenem or meropenem, (2) absence of carbapenemase genes, and (3) >72 hours of definitive therapy with imipenem or meropenem. Inverse probability weighting (IPW) adjusted for baseline differences, and logistic regression estimated odds ratios with 95% confidence intervals. RESULTS Among 374 patients, 238 (64%) were infected with ETP-S and 136 (36%) ETP-R isolates. Baseline characteristics were balanced after IPW. ETP-R infection was associated with higher 30-day mortality (OR 2.24, 95% CI 1.26-3.98, p=0.006). Similarly, 14-day and in-hospital mortality were significantly higher among patients with ETP-R infections. The highest mortality was observed among patients with isolates resistant to two carbapenems (e.g., ertapenem and meropenem). Genomic analyses demonstrated enrichment of porin alterations and more non-carbapenemase β-lactamase genes (e.g., blaCTX-M, blaOXA-10) in ETP-R isolates. CONCLUSION Among patients with Enterobacterales bacteremia treated with imipenem or meropenem, ETP-R isolates were associated with higher mortality than ETP-S isolates, challenging current guidance. This likely reflects combined porin loss and increased β-lactamase activity, potentially resulting in partial hydrolysis of higher-order carbapenems despite in vitro susceptibility.
