Changes in fl uconazole pharmacokinetics can impact on antifungal effectiveness in critically ill burn patients: a PharmacokineticPharmacodynamic (PK/PD) approach

Objectives: The Fluconazole pharmacokinetic-pharmacodynamic relationship was investigated in a few clinical settings and only limited studies regarding burned patients are available. Thus, the authors aimed to investigate fluconazole pharmacokinetics changes and its impact on antifungal therapy coverage against dose-dependent Candida spp. applying the PK/PD approach in critically ill severely burned patients. Methods: Fluconazole was administered as a one-hour intravenous infusion of 200 mg q12h. Doses were increased according to the coverage based on the PK/PD approach. Blood samples were collected at the end of the infusion (1(st) hour), two hours after (3(rd) hour), and before the next dose (12(th) or 24(th) hour). Serum concentrations were obtained by HPLC-UV. Pharmacokinetic parameters were estimated by noncompartmental analysis and compared with data described in healthy subjects. The effectiveness predictive index was based on the AUC(0-24h)(ss)/MIC ratio, with a target above 25. Results: Every pharmacokinetic parameter was reduced throughout all three sets of the study. Compared to healthy subjects, the volume of distribution was decreased about 3-7 times, biological half-life was 2-3 times shorter and total body clearance was slightly altered but statistically significant. Both half-life and total body clearance were correlated to the volume of distribution. Consequently, an increase in fluconazole daily dose was necessary to improve empiric coverage. Conclusions: Fluconazole pharmacokinetics is altered in critically ill severely burned patients, mainly related to the volume of distribution. Doses higher than usual may be necessary to reach the PK/PD target and guarantee antifungal coverage against dose-dependent Candida spp. up to MIC 32 mg/L.