Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis.

Abstract

This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0.5, 0.5-2, 2-4 and 4-6 or 8h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment model best described the data. Piperacillin clearance (CL) was 5.37 L/h, central volume of distribution (V1) was 9.35 L, and peripheral volume of distribution was 7.77 L. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. Subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. The usual dosage regimen, 4g of piperacillin infused over 0.5h every 6h, could not achieve the target for susceptible organisms with MIC 16mg/L in patients with CLCr ≥ 60mL/min. Our proposed regimen for the patients with CLCr 60-120mL/min was an extended 2h infusion of 4g of piperacillin every 6h. Most regimens provided CFR ≥ 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection.