Pharmacokinetic/pharmacodynamic optimization of temocillin treatment against CTX-M-15-producing <i>Klebsiella pneumoniae</i> isolates in a hollow-fiber infection model

Temocillin, a β-lactam antibiotic, has been proposed as an alternative to carbapenems for the treatment of ESBL-producing Enterobacteriaceae. The present EUCAST breakpoints for temocillin are established based on exposure levels derived from a dosing regimen of 2 g every 8 h via intermittent infusion (II). However, the evidence supporting the efficacy of continuous infusion (CI) against ESBL-producing <i>Klebsiella pneumoniae</i> remains limited. The objective of the present study was to evaluate whether CI improves temocillin activity compared with II in a hollow-fiber infection model (HFIM) against CTX-M-15-producing <i>K. pneumoniae</i>. Four clinical isolates were characterized by whole-genome sequencing and tested for temocillin susceptibility. Mutant frequencies were estimated, and temocillin activity was assessed via time-kill assays and HFIM simulating human pharmacokinetics of temocillin 6 g/day via II and CI. Bacterial counts were performed to detect total and resistant subpopulations. Isolates showing regrowth were sequenced to identify resistance-associated mutations. The results showed that both regimens reduced bacterial burden within 8 h. However, three isolates regrew under II, while only one did under CI. CI achieved more sustained bacterial suppression and delayed or prevented the emergence of resistant subpopulations. Mutations in the <i>cpxA</i> gene were associated with increased temocillin MICs in regrown isolates. While both regimens demonstrated initial bactericidal activity, CI was more effective in sustaining bacterial suppression and limiting resistance emergence. These findings support the potential clinical benefit of CI for treating infections caused by CTX-M-15-producing <i>K. pneumoniae</i> and warrant further clinical validation.