Pharmacodynamic evaluation of intermittent versus prolonged infusion dosing regimens of piperacillin/tazobactam in a hollow-fiber infection model against two susceptible Klebsiella pneumoniae clinical isolates

Abstract

Background - This study aims to compare the bacterial killing and suppression of resistance emergence of intermittent and prolonged infusions of piperacillin/tazobactam (PTZ) against clinical K. pneumoniae isolates. Methods - Two clinical isolates, CTX-M-14 producing #69 (MIC 1 mg/L), and DHA-1, SHV-106 producing #68 (MIC 8 mg/L), were studied in a dynamic hollow-fiber infection model over 7 days (initial inoculum 107 CFU/mL). Three piperacillin doses (4/0.5g over 0.5h, and 4h infusion 8 hourly; 12/1.5g continuous infusion 24h) against #69, and six dosages of piperacillin (4/0.5g over 0.5h, and 4h infusion 8 hourly, and 12/1.5g continuous infusion 24h; 4/0.5g over 0.5h, and 3h infusion 6 hourly, and 16/2g continuous infusion 24h) against #68 were tested. The total and less-susceptible bacterial populations were determined. Results - For all PTZ dosing regimens against #69, there were ∼4 logs of bacterial killing over 8h. The amplification of less-susceptible subpopulation were associated with intermittent infusion (T>MIC 90%, Cmin/MIC = 0.4) after 24h, and with extended infusion (T>MIC 100%, Cmin/MIC = 2.76) after 72h. However, continuous infusion (Cmin/MIC = 35) prevented drug resistance amplification and sterilized the model system. For #68, there was a similar initial bacterial killing profile; however, all regimens were associated with the emergence of a resistant subpopulation after 8h. The MIC of resistant subpopulations exceeded 256 mg/L. Conclusions – To maximize bacterial killing and suppress the emergence of resistance of multiple-beta-lactamases producing K. pneumoniae isolates with higher MIC alternative therapeutic strategies are required.