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

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    Author
    Kalaria, Shamir N
    Gopalakrishnan, Mathangi
    Heil, Emily L
    Date
    2020-02-21
    Journal
    Antimicrobial Agents and Chemotherapy
    Publisher
    American Society for Microbiology
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1128/AAC.02093-19
    https://doi.org/10.1128/AAC.00137-21
    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.
    Description
    ERRATUM- Volume 64, no. 3, e02093-19, 2020, https://doi.org/10.1128/AAC.02093-19. In the legend to Fig. 3, “The dashed lines represent 50% target attainment” should read “The dashed lines represent 80% target attainment,” and in the legend to Fig. 4, “The dashed line represents 50% target attainment” should read “The dashed line represents 80% target attainment.”
    Rights/Terms
    Copyright © 2020 American Society for Microbiology.
    Keyword
    critical care
    pharmacodynamics
    pharmacokinetics
    tazobactam
    β-lactamase inhibitor
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/15086
    ae974a485f413a2113503eed53cd6c53
    10.1128/AAC.02093-19
    Scopus Count
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    UMB Open Access Articles 2020

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