• Intensive care medicine · Feb 2025

    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.

    • 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, and Claire Roger.
    • University of Queensland Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Building 71/918 Royal Brisbane and Women's Hospital Campus, Herston, Brisbane, Australia. j.roberts@uq.edu.au.
    • Intensive Care Med. 2025 Feb 3.

    PurposeAppropriate 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.MethodsIn 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.ResultsWe 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%).ConclusionThis 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 RegistrationClinicalTrials.gov Identifier: NCT03136926, 2017-04-21.© 2025. The Author(s).

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