Recurrent infections caused by ESBL-producing enterobacterales with or without subsequent development of distinct carbapenem-resistant phenotypes: differential driving factors and impact on outcome

Abstract Objectives The aim of this study was to identify factors contributing to distinct carbapenem-resistant phenotypes and associated healthcare utilization and outcomes in patients with ESBL-producing Escherichia coli (EC) or Klebsiella pneumoniae (KP) with or without evolved carbapenem-heteroresistance (cHR) or -resistance (CR). Methods A retrospective longitudinal evaluation of patients with repeated isolation of clonally related EC or KP during separate encounters. Patients were grouped by carbapenem susceptibility trajectory: (1) ESBL-ESBL; (2) ESBL-cHR; and (3) ESBL-CR. Groups were compared for host and microbial characteristics, antimicrobial exposure, and outcomes. Results 30 patients (14 ESBL-ESBL, 9 ESBL-cHR, and 7 ESBL-CR) contributed 111 encounters involving 55 EC and 56 KP. Carbapenem-resistant groups demonstrated significantly greater need for feeding tubes and central venous catheters, particularly after resistance evolved from ESBL. The ESBL-CR group was primarily involved by KP from wound and respiratory sites, whereas the ESBL-ESBL and ESBL-cHR groups were predominantly EC from urine and blood. Compared to the ESBL-ESBL group, the ESBL-CR group had the most healthcare visits, whereas the ESBL-cHR group had the longest intervals between visits. Following resistance evolution, hospitalization duration increased by 3 and 1 day, respectively, for ESBL-CR and ESBL-cHR groups (P = 0.01), while the ESBL-cHR group experienced more ICU admissions and septic shock. The ESBL-CR group had the highest overall antimicrobial and carbapenem exposure, while the ESBL-cHR group had the lowest. Conclusions Evolution from ESBL to carbapenem-resistant phenotypes appeared organism-specific, as EC showed patterns consistent with cHR emergence over longer intervals and lower carbapenem exposure, whereas KP more often progressed to CR from non-urinary sources with greater healthcare utilization. If confirmed in a larger cohort, these observations may inform organism-specific stewardship strategies, enhanced diagnostics for ESBL-cHR, and further investigation into non-antibiotic mechanisms driving heteroresistance.