Variability and target attainment of fluconazole in critically ill patients

Background: Fluconazole is an antifungal drug frequently used in the intensive care unit (ICU) but few data are available regarding its exposure in this population. A subanalysis of the DALI-study raised some concerns considering variability in exposure and inadequate target attainment in critically ill patients. We aimed to determine fluconazole variability and target attainment at the ICU.
Materials/methods: All adult, critically ill patients treated with intravenous fluconazole between May and September 2019 were included, provided that the DNR code was <2 and written informed consent was obtained. The administered dose was left at the discretion of the treating clinician. Trough samples were collected during a maximum period of 15 days. Samples were analysed using an UPLC-DAD analytic method. The intra-and intersubject variability of fluconazole trough concentrations was calculated by dividing the standard deviation by the mean*100. Moreover, the difference between the maximum and minimum fluconazole concentration within each patients was determined. For target attainment, the fAUC/MIC from clinical data amounts to 100 corresponding with trough levels >10-15 mg/L, as recommended by EUCAST and ECIL-6. The limit for toxicity was set on 50 mg/L.
Results: Seventeen patients were included, resulting in 95 fluconazole trough levels. Patients had a median APACHE-II score of 18 [16-23] and administered dose of 5.1 [4.1-7.5] mg/kg/day. The median fluconazole trough level was 26.6 [19.7-35.3] mg/L. In Figure 1, fluconazole trough concentrations are depicted in function of the dose. The mean intra-and intersubject variability (CV%) were 18,4% and 34,5%, respectively. The median difference between the maximum and minimum concentration for the 14 patients with >1 measured fluconazole level, was 14,8 [6,6-18,9] mg/L. In two patients, this difference was more than 2-fold. All trough levels were >10mg/L and 85/95 (89%) samples were >15mg/L. None of the levels exceeded the upper limit of 50 mg/L.
Conclusions: As shown in the DALI-study, a considerable intra-and intersubject variability in fluconazole levels was observed at the ICU. Despite this variability, all fluconazole trough levels were above the lower limit of 10 mg/L and most of them >15 mg/L. No toxic concentrations were observed.