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

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.

Keywords: Antifungals; Critically ill; Intensive care unit; Invasive fungal disease; Pharmacokinetics.

Fig. 1

PK/PD target-related exposures per occasion of the study antifungals prescribed for treatment. The shaded area represents the PK/PD target used in this study. For fluconazole, 15 data points are outside the y-axis limits (max AUC_0-24/MIC value was 3250.3); ICU intensive care unit; AUC_0-24 area under the plasma concentration-time curve from zero to 24 h; fAUC_0-24 free AUC_0-24; MIC minimum inhibitory concentration; Cmin minimum observed plasma concentration; Cmax maximum observed plasma concentration