Optimal Piperacillin-Tazobactam Dosing Strategies against Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae

Piperacillin/tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae. However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin/tazobactam to efficacy using a modified pharmacokinetic/pharmacodynamic index. Using a clinical Klebsiella pneumoniae isolate expressing CTX-M-15, piperacillin MICs were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory E max model. A hollow fiber infection model (HFIM) was used to evaluate the efficacy of escalating tazobactam dosing with a fixed piperacillin exposure. Simulated drug concentrations from the HFIM were incorporated in the E max model to determine the percentage of free-time above instantaneous MIC (% f T>MICi) associated with each experimental exposure. The target % f T>MICi associated with growth suppression was prospectively validated using a SHV-12-producing isolate of Escherichia coli and 2 other CTX-M-15-producing K. pneumoniae isolates. Based on our reference isolate, piperacillin/tazobactam exposures of % f T>MICi ≥55.1% were associated with growth suppression. Despite underlying differences, these findings were consistent with prospective observations in 3 other clinical isolates. Our modeling approach can be applied relatively easily in the clinical setting and appeared to be robust in predicting the effectiveness of various piperacillin/tazobactam exposures. This modified pharmacokinetic/pharmacodynamic index could be used to characterize response to other β-lactam/β-lactamase inhibitor combinations.