Kelly A. Cairns, Maria Patricia Hernandez-Mitre, Trisha N. Peel, Iain J. Abbott, David M. Kaye, Silvana Marasco, David Daly, Victoria Warner, Anna Coldham, Jeffrey D. Pope, Hans G Schneider, Michael J. Dooley, Xin Liu, Jason A. Roberts & Andrew A. Udy (2025)
Abstract
Background and objective: There is limited information on the pharmacokinetics and optimal dosing of fluconazole in patients undergoing mechanical circulatory support (MCS) device implantation.
Aim: The aim of this study was to describe fluconazole pharmacokinetics and identify dosing regimens that achieve pharmacokinetic/pharmacodynamic targets in this patient cohort.
Methods: 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 (AUC0-24) was estimated, with target exposures defined as AUC0-24/minimum inhibitory concentration (MIC) ≥ 50 for prophylaxis and AUC0-24/MIC ≥ 100 for therapy. Population pharmacokinetic modelling was performed using non-linear mixed-effects methods and for Monte Carlo dosing simulations.
Results: 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 (AUC0-24/MIC ≥ 50) and 2 mg/L (AUC0-24/MIC ≥ 100).
Conclusion: 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, AUC0-24/MIC ≥ 50) and > 0.5 mg/L (treatment, AUC0-24/MIC ≥ 100).
