Population Pharmacokinetics of Piperacillin and Tazobactam in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation: an ASAP ECMO Study

Vesa Cheng, Mohd H. Abdul-Aziz https://orcid.org/0000-0002-8889-5579 mohd.abdulaziz1@uq.net.au, Fay Burrows, Hergen Buscher, Young-Jae Cho, Amanda Corley, Arne Diehl, , Eileen Gilder, Stephan M. Jakob, Hyung-Sook Kim, Bianca J. Levkovich, Sung Yoon Lim, Shay McGuinness, Rachael Parke, Vincent Pellegrino, Yok-Ai Que, Claire Reynolds, Sam Rudham, Steven C. Wallis, Susan A. Welch, David Zacharias, John F. Fraser, Kiran Shekar, Jason A. Roberts https://orcid.org/0000-0001-6218-435X

Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%fT>MIC) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.