Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

Abstract

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.).

Keywords: augmented renal clearance; dosage optimization; piperacillin; population pharmacokinetics; sepsis.

Copyright © 2018 American Society for Microbiology.

Figures

FIG 1

Visual predictive check based on the final model. Red circles, the observed concentrations in the current study; red solid line, the median of the observations; red dashed lines, 95th and 5th outer percentiles of the observations. The shaded area is derived from simulations from the final model, with the central dark gray area representing a 95% confidence interval for the median and the light gray areas representing the 95% confidence intervals for the 95th and 5th outer percentiles of the simulations.

FIG 2

Predictions from the model for nine dosing regimens with a total administration of 16 g (A), 12 g (B), or 8 g (C) over 24 h for the median (left) and highest (right) creatinine clearances. Horizontal dashed lines, an MIC of 16 mg/liter. Continuous infusion was initiated with a loading dose of 4 g. IA, intermittent administration; EI, extended infusion; CI, continuous infusion.

FIG 3

Probability of target attainment (PTA) for each of the nine regimens using the final model and a distribution of creatinine clearance values. The graphs indicate the total administration of 16 g (A), 12 g (B), or 8 g (C) as intermittent administration (IA), extended infusion (EI), or continuous infusion (CI). Dashed lines, 90% of the simulated patients reached the specified target; fTMIC, the percentage of the dosing interval that the free drug concentration is maintained above the MIC.

FIG 4

Probability of target attainment (PTA) for intermittent administration (IA) at 4 g q8h using the final model and a distribution of creatinine clearance values split into three empirical categories. Dashed lines, PTA of 90%; fTMIC, the percentage of the dosing interval that the free drug concentration is maintained above the MIC.