A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients

Abstract

The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 μg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level β-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 μg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against β-lactamase-producing Gram-negative bacteria.

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

“…Considerably less is known about the pharmacokinetics of tazobactam in critically ill patients. The typical total clearance for tazobactam was estimated to be higher (10.3 L/h, 95% CI 9.1–11.7 L/h) than reported in a small study in critically ill patients (5.3 L/h, 95% CI 2.2–9.1 L/h), but similar to reported in patients undergoing colorectal surgery (11.3 L/h, 95% CI 5.1–17.4 L/h) [ 14 , 28 ].…”

Population Pharmacokinetics and Dosing Optimization of Piperacillin-Tazobactam in Critically Ill Patients on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy

“…Because tazobactam has only bacteriostatic activity, the proportion of dosing interval above the minimum effective concentration (MEC) was calculated. The PTA for 63% f T > 2 mg/L of free tazobactam was evaluated, and the acceptable PTA level was set at ≥50% ( 30 , 31 ).…”

Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative Bacterial Infections: A PK/PD Approach

“…For strains expressing higher levels of beta-lactamase, TA was defined as concentrations above 2 mg/L free tazobactam for 85% of the dosing interval. A model was created using data from 18 critically ill patients, and demonstrated that a TZP 16/2 g CI/day would result in >75% TA for tazobactam [27]. Further, 16/2 g CI/day would also result in adequate alveolar concentrations of piperacillin and tazobactam [28].…”