Urinary piperacillin/tazobactam pharmacokinetics in-vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriacae

Abstract Background Urinary tract infections caused by multi-drug resistant Enterobacteriaceae are a growing burden worldwide. Recent studies of urinary pharmacokinetics described high piperacillin/tazobactam concentrations in urine, but it is unknown whether this results in treatment efficacy. Objectives This study investigated the pharmacodynamics of piperacillin/tazobactam in a static in-vitro model for Enterobacteriaceae to determine the concentration-effect relationship and ultimately the required time above the Minimum Inhibitory Concentration (MIC) (fT>MIC) required for bacterial killing. Methods The static simulation model investigated piperacillin/tazobactam fT>MIC between 0% and 100%. Resistant E.coli and K.pneumoniae isolates with MICs of 4096/512 mg/L, 1024/128 mg/L, and 128/16 mg/L piperacillin/tazobactam were investigated. Two of three organisms were carbapenenase resistant. Clinical efficacy was determined as a three-log-reduction over the dosing interval by comparing interval growth with controls. Results Piperacillin/tazobactam was observed to exhibit time-dependence for all organisms. The fT>MIC was determined to be 37.5%, 37.5%, and 50% for MICs of 4096/512 mg/L, 1024/128 mg/L and 128/16 mg/L respectively. Linear regression identified the overall target to be 49.85±16.9% fT>MIC. Conclusions Bactericidal activity against piperacillin/tazobactam resistant Enterobacteriacea e occurred at 49.85±16.9% fT>MIC. This suggests that highly resistant urinary organisms, including carbapenemase producers, with MICs up to 4096/512 mg/L could be treated with piperacillin/tazobactam. Further investigations are required to elucidate urinary breakpoints and explore the impact of different resistance mechanisms.