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 1 , Sime FB 2 , Lipman J 2 , Hernández-Mitre MP 2 , Baptista JP 3 , Brüggemann RJ 4 Show all authors , Darvall J 5 , De Waele JJ 6 , Dimopoulos G 7 , Lefrant JY 8 , Mat Nor MB 9 , Rello J 8 , Seoane L 10 , Slavin MA 11 , Valkonen M 12 , Venditti M 13 , Ceccarelli G 14 , Wong WT 15 , Zeitlinger M 16 , Roger C 8

Affiliations 

  • 1 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
  • 2 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
  • 3 Department of Intensive Care, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal
  • 4 Department of Pharmacy and Radboudumc Institute for Medical Innovation, And Radboudumc/CWZ Center of Expertise in Mycology, Radboud University Medical Center, Nijmegen, The Netherlands
  • 5 Department of Critical Care, The University of Melbourne, Melbourne, Australia
  • 6 Department of Intensive Care Medicine, Ghent University Hospital, Ghent, Belgium
  • 7 Head of 3rd Department of Critical Care, EVGENIDIO Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  • 8 UR-UM103 IMAGINE, Univ Montpellier, Division of Anesthesia Critical Care, Pain and Emergency Medicine, Nîmes University Hospital, Montpellier, France
  • 9 Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan Campus, Kuantan, Pahang, Malaysia
  • 10 Faculty of Medicine, The University of Queensland, New Orleans, USA
  • 11 National Centre for Infections in Cancer and Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 12 Intensive Care Medicine, Department of Perioperative, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  • 13 Department of Public Health and Infectious Diseases, University "Sapienza" of Rome, Rome, Italy
  • 14 Department of Public Health and Infectious Diseases, University of Rome "Sapienza" and University Hospital Umberto I, Rome, Italy
  • 15 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China
  • 16 Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Intensive Care Med, 2025 Feb 03.
PMID: 39899034 DOI: 10.1007/s00134-025-07793-5

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Similar publications