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. ClinicalTrials.gov identifier NCT03738683. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-022-01113-6.

Predictive Factors of Piperacillin Exposure and the Impact on Target Attainment after Continuous Infusion Administration to Critically Ill Patients

“…Patients were treated with P/T, but only piperacillin concentrations were measured. There is enough evidence supporting the existence of a high correlation between piperacillin and tazobactam concentrations [ 28 , 46 , 47 ]. In fact, a recent PK study showed that tazobactam concentrations were above the threshold in 92% of cases in which the piperacillin PK/PD target was achieved [ 47 ].…”

“…In previous PPK studies carried out in patients undergoing RRT [ 16 , 19 ], simulated tazobactam concentrations were found to be above threshold at all times. In a more recent study in which P/T was administered by II, tazobactam concentrations were predicted in critically ill patients with creatinine clearance up to 200 mL/min [ 28 ]. The tazobactam target was reached in 94% and 99% of the patients when doses of 1.5 g/24 h and ≥2 g/24 h were administered, thus P/T efficacy was considered to be uniquely related to piperacillin concentration.…”

“…While several piperacillin PPK models have been previously published in critically ill adult patients, most of them were the target population undergoing renal replacement therapy (RRT) and are, therefore, not applicable to other population groups [ 16 , 17 , 18 , 19 , 20 ]. Furthermore, in models developed in patients without RRT, CL CR was frequently identified as the strongest covariate with a significant linear relationship to piperacillin clearance [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. However, in the vast majority, P/T administered as II was used to predict PK behavior in CI [ 22 , 25 , 26 , 27 , 28 ].…”

“…Furthermore, in models developed in patients without RRT, CL CR was frequently identified as the strongest covariate with a significant linear relationship to piperacillin clearance [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. However, in the vast majority, P/T administered as II was used to predict PK behavior in CI [ 22 , 25 , 26 , 27 , 28 ]. Caution should be taken when making dose estimates in CI based on models developed in II, as non-linear PKs have been postulated with the latter form of administration due to saturation of piperacillin elimination [ 29 , 30 ].…”

Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant)

“…In a report of CAP cases from 2016 to 2020 at Central Department of Anesthesiology and Intensive Care (Uzsoki Teaching Hospital, Budapest, Hungary) 122 patients with CAP were registered (30 patients per year). Wallenburg et al conducted a clinical study with similar objectives in which work 39 patients were enrolled [ 39 ]. Based on the prevalence of CAP patients at Central Department of Anesthesiology and Intensive Care, as well as a study design of recent clinical researches our aim is to recruit 40 patients.…”