Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients

J M Boonstra; A G Märtson; I Sandaradura; J G W Kosterink; T S van der Werf; D J E Marriott; J G Zijlstra; D J Touw; J W C Alffenaar

doi:10.1128/AAC.01554-20

Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients

Antimicrob Agents Chemother. 2021 Feb 17;65(3):e01554-20. doi: 10.1128/AAC.01554-20. Print 2021 Feb 17.

Authors

J M Boonstra^#¹, A G Märtson^#¹, I Sandaradura^{2

3}, J G W Kosterink^{1

4}, T S van der Werf^{5

6}, D J E Marriott^{7

8}, J G Zijlstra⁹, D J Touw¹, J W C Alffenaar^{10

3

11}

Affiliations

¹ University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
² The University of Sydney, Faculty of Medicine and Health, School of Pharmacy, Sydney, Australia.
³ Westmead Hospital, Sydney, Australia.
⁴ University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands.
⁵ University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, the Netherlands.
⁶ University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, the Netherlands.
⁷ St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia.
⁸ Department of Clinical Microbiology and Infectious Diseases, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
⁹ University of Groningen, University Medical Center Groningen, Department of Critical Care, Groningen, the Netherlands.
¹⁰ The University of Sydney, Faculty of Medicine and Health, School of Pharmacy, Sydney, Australia johannes.alffenaar@sydney.edu.au.
¹¹ Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia.

^# Contributed equally.

Abstract

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (C_min). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole C_min therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02491151.).

Keywords: critically ill; fluconazole; invasive candidiasis; pharmacokinetics.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Anti-Bacterial Agents
Candidiasis, Invasive* / drug therapy
Candidiasis, Invasive* / prevention & control
Critical Illness
Fluconazole* / therapeutic use
Humans
Microbial Sensitivity Tests
Renal Dialysis

Substances

Anti-Bacterial Agents
Fluconazole

Associated data

ClinicalTrials.gov/NCT02491151