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

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 p...

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Autores principales: Jager, Nynke G L, van Hest, Reinier M, Xie, Jiao, Wong, Gloria, Ulldemolins, Marta, Brüggemann, Roger J M, Lipman, Jeffrey, Roberts, Jason A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443729/
https://www.ncbi.nlm.nih.gov/pubmed/32443147
http://dx.doi.org/10.1093/jac/dkaa187
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author Jager, Nynke G L
van Hest, Reinier M
Xie, Jiao
Wong, Gloria
Ulldemolins, Marta
Brüggemann, Roger J M
Lipman, Jeffrey
Roberts, Jason A
author_facet Jager, Nynke G L
van Hest, Reinier M
Xie, Jiao
Wong, Gloria
Ulldemolins, Marta
Brüggemann, Roger J M
Lipman, Jeffrey
Roberts, Jason A
author_sort Jager, Nynke G L
collection PubMed
description 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.
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spelling pubmed-74437292020-08-26 Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations Jager, Nynke G L van Hest, Reinier M Xie, Jiao Wong, Gloria Ulldemolins, Marta Brüggemann, Roger J M Lipman, Jeffrey Roberts, Jason A J Antimicrob Chemother Original Research 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. Oxford University Press 2020-09 2020-05-22 /pmc/articles/PMC7443729/ /pubmed/32443147 http://dx.doi.org/10.1093/jac/dkaa187 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Research
Jager, Nynke G L
van Hest, Reinier M
Xie, Jiao
Wong, Gloria
Ulldemolins, Marta
Brüggemann, Roger J M
Lipman, Jeffrey
Roberts, Jason A
Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title_full Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title_fullStr Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title_full_unstemmed Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title_short Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
title_sort optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443729/
https://www.ncbi.nlm.nih.gov/pubmed/32443147
http://dx.doi.org/10.1093/jac/dkaa187
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