Evaluation of temocillin efficacy against KPC-2 producing K. pneumoniae isolates in a hollow- fiber infection model.

Temocillin is an old antimicrobial that is resistant to hydrolysis by extended-spectrum beta- lactamases but has uncertain activity against carbapenemase-producing Enterobacteriaceae. The current EUCAST susceptibility breakpoints for Enterobacterales are set at =16 mg/L (susceptible with increased exposure) based on a dose of 2g/Q8h, but there is limited information on the efficacy of this dose against temocillin-susceptible carbapenemase- producing K. pneumoniae isolates. The aim of the present study was to evaluate the efficacy of this dose using a hollow fibre infection model (HFIM) against six KPC-2-producing clinical isolates of K. pneumoniae. The isolates were characterised by WGS and temocillin susceptibility was determined using standard and high inoculum, temocillin mutant frequencies were estimated and temocillin activity was tested in time-kill assays and in the HFIM. The hollow fibre infection model was performed over three days to mimic human-like pharmacokinetics of 2g/Q8h. Bacterial counts were performed by plating in MHA and MHA containing 64 mg/L temocillin to detect resistant subpopulations. Three of the isolates were classified as susceptible (MIC= 16 mg/L) and three as resistant (>16 mg/L). All isolates showed a decrease in bacterial population of at least 3 log CFU/mL within the first 8 hours of treatment. Subsequently, the three resistant isolates and one susceptible isolate recovered due to the emergence of highly temocillin-resistant mutants. These data suggest that an optimised pharmacokinetic regimen or the addition of a second antimicrobial agent may be of clinical interest for the treatment of KPC-2-producing K. pneumoniae susceptible to temocillin.