An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients

Abstract

Background and objectives: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.

Methods: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.

Results: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.

Conclusions: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.

Gov identifier: NCT03738683.

Conflict of interest statement

All authors declared no competing interests related to this work.

© 2022. The Author(s).

Figures

Fig. 1

Observed piperacillin concentrations versus observed tazobactam concentrations

Fig. 2

Schematic depiction of the pharmacokinetic model. The elimination rate constants describing the model are as follows: k12 = Qpiperacillin/V1,piperacillin,k21 = Qpiperacillin/V2,piperacillin, k10 = CLnonrenal,piperacillin/V1,piperacillin, k15 = CLrenal,piperacillin/V1,piperacillin, k34 = Qtazobactam/V1,tazobactam, k43 = Qtazobactam/V2,tazobactam, k30 = CLnonrenal,tazobactam/V1,tazobactam, k36 = CLrenal,tazobactam/V1,tazobactam

Fig. 3

Simulated piperacillin concentrations for different dosing regimens versus creatinine clearance. The blue horizontal lines represent a target of 100% fT>1×MIC (22.9 mg/L) and 100% fT>5×MIC (114 mg/L), assuming an MIC of 16 mg/L. The red horizontal line represents the upper limit of toxicity (157 mg/L). Simulations were performed in 20 groups of creatinine clearance between 10 and 200 mL/min, with 10 mL/min increments. In this figure, pairs of two groups have been combined. MIC minimum inhibitory concentration

Fig. 4

Simulated tazobactam concentrations for different dosing regimens versus creatinine clearance. The blue horizontal line represents a target of 2.86 mg/L. Simulations were performed in 20 groups of creatinine clearance between 10 and 200 mL/min, with 10 mL/min increments. In this figure, pairs of two groups have been combined

Fig. 5

Piperacillin (left) and tazobactam (right) concentrations in urine