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

Author:

Jager Nynke G L12ORCID,van Hest Reinier M3,Xie Jiao4,Wong Gloria1,Ulldemolins Marta5ORCID,Brüggemann Roger J M2,Lipman Jeffrey167,Roberts Jason A1678ORCID

Affiliation:

1. University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, Australia

2. Department of Pharmacy, Radboud University Medical Center and Radboud Institute for Health Sciences, Nijmegen, The Netherlands

3. Department of Hospital Pharmacy - Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

4. Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Shaanxi, China

5. Internal Medicine - Infectious Diseases Departments, Hospital Universitari de Bellvitge, l’Hospitalet de Llobregat, Spain

6. Departments of Pharmacy (J.A.R.) and Intensive Care (J.L.), Royal Brisbane and Women’s Hospital, Brisbane, Australia

7. Nîmes University Hospital, University of Montpellier, Nîmes, France

8. Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia

Abstract

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.

Funder

Australian National Health and Medical Research Council for Centre of Research Excellence

Practitioner Fellowship

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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