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Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations.

ABSTRACT: BACKGROUND:Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. OBJECTIVES:To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. METHODS:First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. RESULTS:A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33?mL/min and 1?g q6h, 87% for patients with eGFR of 96?mL/min and 2?g q4h and 71% for patients with eGFR of 153?mL/min and 2?g q4h. CONCLUSIONS:For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

SUBMITTER: Jager NGL

PROVIDER: S-EPMC7443729 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations.

Jager Nynke G L NGL van Hest Reinier M RM Xie Jiao J Wong Gloria G Ulldemolins Marta M Brüggemann Roger J M RJM Lipman Jeffrey J Roberts Jason A JA

The Journal of antimicrobial chemotherapy 20200901 9

<h4>Background</h4>Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets.<h4>Objectives</h4>To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients.<h4>Methods</h4>First, we developed a population PK model, estimated between-patient variability ( ...[more]

PMID: 32443147

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Dataset Information

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations.

Publications

Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations.

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