Population pharmacokinetics of continuous infusion of piperacillin/tazobactam in very elderly hospitalized patients and considerations for target attainment against Enterobacterales and Pseudomonas aeruginosa

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa . Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with < 10% probability of Css > 157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration ( f Css)/minimum inhibitory concentration (MIC) >1 and >4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CL CR ) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CL CR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m 2 , respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for f Css/MIC >1 in patients with CL CR 20-79 mL/min/1.73 m 2 . Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis . Permissible dosages and CL CR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients. (c) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.