A Pharmacokinetic Analysis of Intravenous Fluconazole in Adult Patients Undergoing Mechanical Circulatory Support...

There is limited information on the pharmacokinetics and optimal dosing of fluconazole in patients undergoing mechanical circulatory support (MCS) device implantation.

The aim of this study was to describe fluconazole pharmacokinetics and identify dosing regimens that achieve pharmacokinetic/pharmacodynamic targets in this patient cohort.

In this prospective, single-centre study, adults undergoing MCS device implantation received intravenous fluconazole 200 mg or 400 mg, continued once daily for 5 days. Fluconazole concentrations were measured at four peri-operative time points, on return to the intensive care unit, and on days 3 and 5 following implantation. The area under the concentration-time curve from time zero to 24 h (AUC_0-24) was estimated, with target exposures defined as AUC_0-24/minimum inhibitory concentration (MIC) ≥ 50 for prophylaxis and AUC_0-24/MIC ≥ 100 for therapy. Population pharmacokinetic modelling was performed using non-linear mixed-effects methods and for Monte Carlo dosing simulations.

Sixty-five fluconazole concentrations from 10 male patients (median age 51.5 years; IQR 50.0-57.0) were included. A two-compartment model including an additional renal replacement therapy (RRT)-dependent clearance pathway best described the data. Parameter estimates from the final model included a central volume of distribution of 5.75 L, non-RRT clearance of 0.45 L/h, and RRT clearance of 2.22 L/h. Simulations showed that doses of 800 mg or 12 mg/kg would be required for the highest probability of target attainment for Candida fluconazole MICs up to 4 mg/L (AUC_0-24/MIC ≥ 50) and 2 mg/L (AUC_0-24/MIC ≥ 100).

In patients undergoing MCS device implantation, intravenous fluconazole 200 mg administered pre-operatively and continued daily for 5 days is insufficient for Candida spp. with MICs > 1 mg/L (prophylaxis, AUC_0-24/MIC ≥ 50) and > 0.5 mg/L (treatment, AUC_0-24/MIC ≥ 100).