Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations?

Abstract

Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50% fT>4×MIC and 100% fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.).

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Figures

FIG 1

Visual predictive check (VPC) of final PK model based on 1,000 simulations. Open circles, observations; solid black line, median interpolated observations; gray dashed lines, 10th and 90th percentiles of observations. Shaded areas are the 90% model prediction interval of the median (dark) and the 10th and 90th percentiles (light).

FIG 2

Illustrations of 24-h piperacillin pharmacokinetic profiles following intermittent bolus administration (IA), extended infusion (EI), and continuous infusion (CI) at 16 g/day, 12 g/day, and 8 g/day. Each profile is predicted from the PK model presented in Fig. 1. (A) Predictions for an average patient in the population; (B) prediction for a patient with PK parameters equivalent to the patient with the lowest PK profile in the population. The dotted line represents a MIC of 16 mg/liter.

FIG 3

Probability of target attainment (PTA) versus MIC for different dosing regimens and modes of administration, for the first day of piperacillin treatment. Calculations were done based on 1,000 simulations of PK in the population using the final model. IA, intermittent bolus administration; EI, extended infusion; CI, continuous infusion. The dotted black lines represent a PTA of 90%.

FIG 4

Probability of target attainment (PTA) versus MIC for different estimates of p-creatinine level, each derived from 1,000 simulations of data (the third consecutive dose of intermittent bolus dosing of 4 g q8h). The black lines demonstrate PTA when patient p-creatinine level is unknown but within the range observed in this population (53 to 446 μmol/liter). The gray lines demonstrate PTA in three scenarios where patient p-creatinine level is known (80, 150, and 250 μmol/liter). The dotted black lines represent a PTA of 90%.