LAUSR

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. The aims is 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 P. aeruginosa. A 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 18g daily by CI). Permissible doses were defined as those associated with <10% probability of Css>157.2 mg/L. PTAs at the pharmacodynamic targets of fCss/MIC≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients, whose median age was 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 (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05L/h for clearance (CL) and 3.09mg/h for Michaelis-Menten saturative constant (Km). Permissible doses were up to 4.5, 9, 11.25 and 13.5g daily by CI for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses achieved optimal PTA only for fCss/MIC≥1 in patients with CLCR 20-79mL/min/1.73m2. Optimal CFRs with the permissible doses were attained only against E. coli and P. mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.