Population Pharmacokinetics and Pharmacodynamics of Piperacillin/Tazobactam in Patients with Nosocomial Infections

Abstract

Objective

The study was to establish a population pharmacokinetic (PPK) model of piperacillin (PIP) and tazobactam (TAZ) that explain pharmacokinetic variability and to propose optimized dosage regimens in patients with nosocomial infections.

Methods

In total, 310 PIP and 280 TAZ concentration–time points were collected at steady state over multiple dosing intervals from 50 patients who received PIP/TAZ infused within 30 min or over 3 h. Drug analysis was performed by high-performance liquid chromatography (HPLC). Nonlinear mixed effects modeling was employed to develop PPK model and 1000 Monte Carlo simulation was used to predict the probability of target attainment (PTA) with a target time of non-protein-bound concentration above MIC > 50 % of the dosing interval.

Results

A model with one-compartment model had the best predictive performance for the PPK model. The population estimates of PIP were 13.8 L/h (31.1 %) for clearance (CL) and 21.7 L (38 %) for volume of distribution (V). The population estimates of TAZ were 9.3 L/h (29.1 %) for CL and 16 L (35.3 %) for V. Influence of creatinine clearance (CLcr) and body weight were identified as important covariates for PIP/TAZ CL and V, respectively. A 30-min infusion of 4 g every 6 h achieved robust (≥90 %) PTAs for MIC ≤ 16 mg/L. As an alternative mode of administration, a 3-h infusion of 4 g every 6 h achieved robust PTAs for Pseudomonas aeruginosa and Klebsiella pneumoniae.

Conclusions

Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 16 and 40 mg/L.