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Open Access 03-02-2025 | Pharmacokinetics | Original

Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units—the SAFE-ICU study

Authors: Jason A. Roberts, Fekade B. Sime, Jeffrey Lipman, María Patricia Hernández-Mitre, João Pedro Baptista, Roger J. Brüggemann, Jai Darvall, Jan J. De Waele, George Dimopoulos, Jean-Yves Lefrant, Mohd Basri Mat Nor, Jordi Rello, Leonardo Seoane, Monica A. Slavin, Miia Valkonen, Mario Venditti, Giancarlo Ceccarelli, Wai Tat Wong, Markus Zeitlinger, Claire Roger

Published in: Intensive Care Medicine

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Abstract

Purpose

Appropriate antifungal therapy is a major determinant of survival in critically ill patients with invasive fungal disease. We sought to describe whether contemporary dosing of antifungals achieves therapeutic exposures in critically ill patients.

Methods

In a prospective, open-label, multicenter pharmacokinetic study, intensive care unit (ICU) patients prescribed azoles, echinocandins, or polyene antifungals for treatment or prophylaxis of invasive fungal disease were enrolled. Blood samples were collected on two occasions, with three samples taken during a single dosing interval on each occasion. Total concentrations were centrally measured using validated chromatographic methods. Pharmacokinetic parameters were estimated using noncompartmental methods. Antifungal dosing adequacy was assessed using predefined PK/PD targets.

Results

We included 339 patients from 30 ICUs across 12 countries. Median age 62 (interquartile range [IQR], 51–70) years, median APACHE II score 22 (IQR, 17–28), and 61% males. Antifungal therapy was primarily prescribed for treatment (80.8%). Fluconazole was the most frequently prescribed antifungal (40.7%). The most common indication for treatment was intra-abdominal infection (30.7%). Fungi were identified in 45% of patients, of which only 26% had a minimum inhibitory concentration available. Target attainment was higher for patients receiving prophylaxis (> 80% for most drugs). For patients receiving treatment, low target attainment was noted for voriconazole (57.1%), posaconazole (63.2%), micafungin (64.1%) and amphotericin B (41.7%).

Conclusion

This study highlights the varying degrees of target attainment across antifungal agents in critically ill patients. While a significant proportion of patients achieved the predefined PK/PD targets, wide variability and subtherapeutic exposures persist.

Trial registration

ClinicalTrials.gov Identifier: NCT03136926, 2017-04-21.
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Metadata
Title
Are contemporary antifungal doses sufficient for critically ill patients? Outcomes from an international, multicenter pharmacokinetics study for Screening Antifungal Exposure in Intensive Care Units—the SAFE-ICU study
Authors
Jason A. Roberts
Fekade B. Sime
Jeffrey Lipman
María Patricia Hernández-Mitre
João Pedro Baptista
Roger J. Brüggemann
Jai Darvall
Jan J. De Waele
George Dimopoulos
Jean-Yves Lefrant
Mohd Basri Mat Nor
Jordi Rello
Leonardo Seoane
Monica A. Slavin
Miia Valkonen
Mario Venditti
Giancarlo Ceccarelli
Wai Tat Wong
Markus Zeitlinger
Claire Roger
Publication date
03-02-2025
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-025-07793-5