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

Roberts, JA; Sime, FB; Lipman, J; Hern&#225;ndez-Mitre, MP; Baptista, JP; Br&#252;ggemann, RJ; Darvall, J; De Waele, JJ; Dimopoulos, G; Lefrant, JY; Mat Nor, MB; Rello, J; Seoane, L; Slavin, MA; Valkonen, M; Venditti, M; Ceccarelli, G; Wong, WT; Zeitlinger, M; Roger, C

Author(s): Roberts, JA; Sime, FB; Lipman, J; Hernández-Mitre, MP; Baptista, JP; Brüggemann, RJ; Darvall, J; De Waele, JJ; Dimopoulos, G; Lefrant, JY; Mat Nor, MB; Rello, J; Seoane, L; Slavin, MA; Valkonen, M; Venditti, M; Ceccarelli, G; Wong, WT; Zeitlinger, M; Roger, C;
Details: Publication Year 2025-02,Volume 51,Issue #2,Page 302-317
Journal Title: Intensive Care Medicine
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Humans; *Antifungal Agents/pharmacokinetics/administration & dosage/therapeutic use; Male; Middle Aged; Female; *Critical Illness; Aged; Prospective Studies; *Intensive Care Units/statistics & numerical data; *Invasive Fungal Infections/drug therapy; Echinocandins/pharmacokinetics/administration & dosage/therapeutic use; Fluconazole/pharmacokinetics/administration & dosage/therapeutic use; Antifungals; Critically ill; Intensive care unit; Invasive fungal disease; Pharmacokinetics
Department(s): Infectious Diseases
Publisher's Version: https://doi.org/10.1007/s00134-025-07793-5
Open Access at Publisher's Site: https://doi.org/10.1007/s00134-025-07793-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-04-08 07:34:59

Last Modified: 2025-04-08 07:35:28