Population pharmacokinetics of piperacillin/tazobactam in critically ill Korean patients and the effects of extracorporeal membrane oxygenation

Abstract

Objectives: To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients.

Methods: Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24 h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation.

Results: A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16 g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170 mL/min/1.73 m2.

Conclusions: ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8 mg/L or when patients have an eGFR of 130-170 mL/min/1.73 m2.

Figure 1.

Goodness-of-fit plots for piperacillin (top) and tazobactam (bottom): (a) and (e) conditional weighted residuals versus time, (b) and (f) conditional weighted residuals versus population predicted concentration, (c) and (g) observed concentration versus population predicted concentration, and (d) and (h) observed concentration versus individual predicted concentration.

Figure 2.

Probabilities of target attainment of empirical therapy by recommended dosing regimen for patients with creatinine clearance of 0–130 mL/min/1.73 m². Bars indicate the MIC distribution for Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Figure 3.

Probabilities of target attainment (50% fT_>MIC). Simulation results in critically ill and patients with three doses (2, 3, or 4 g) and two dosing intervals (6 or 8 h), three infusion times (0.5, 2, or 4 h), various renal functions, and various MICs.

Figure 4.

Probabilities of target attainment (100% fT_>MIC). Simulation results in critically ill patients with three infusion methods (standard 30 min, prolonged 4 h, or continuous), various renal functions, and various MICs. The dosing interval was fixed to 6 h for intermittent infusion.

Figure 5.

Probabilities of target attainment (100% fT_>4×MIC). Simulation results in critically ill patients with three infusion methods (standard 30 min, prolonged 4 h, or continuous), various renal functions, and various MICs. The dosing interval was fixed to 6 h for intermittent infusion.