Development of fluconazole dosage guidelines in critically ill patients receiving continuous venovenous hemodiafiltration

Objectives: To investigate the pharmacokinetics of fluconazole in critically ill anuric patients receiving continuous venovenous hemodiafiltration (CVVHDF), and to determine a dosing regimen that achieves appropriate pharmacodynamic endpoints in this population.

Design: An open-labeled study performed over a 28 month period. Setting: Intensive care unit at the Royal Brisbane and Womens’ Hospital in Australia. Patients: Ten critically ill patients requiring CVVHDF for acute kidney injury (AKI), and fluconazole to treat a known or suspected infection.

Methods: Pharmacokinetic profiles of initial and steady-state doses of 200mg twice daily intravenous fluconazole were obtained from plasma and CVVHDF effluent. Nonlinear mixed-effects modeling (NONMEM version 6.1) was used to describe the disposition of fluconazole, and to perform Monte Carlo dosing simulations. For each dosing regimen, the area under the concentration-time curve (AUC)-to-minimum inhibitory concentration (MIC) was calculated. The percentage of patients achieving an AUC/MIC ratio greater than 25 was then compared for a range of MIC values.

Results: A 2-compartment model with first order elimination best described the disposition of fluconazole. The estimate for total fluconazole clearance was 2.67 L/h, and was 2.3 times faster than that previously reported in healthy volunteers. Of this, fluconazole clearance by the CVVHDF route (CLCVVHDF) represented 62% of its total systemic clearance. When the effect of filter age was included as a covariate, the between-subject variability (BSV) on CLCVVHDF was reduced from 34.4% to 19.8%. In addition, the predicted efficiency of CLCVVHDF decreased to 36.8%, when filters aged > 48 h were in use. Monte Carlo dosing simulations demonstrated that a dose of 400mg twice daily maximizes empiric treatment against fungal organisms with MIC values up to 16 mg/L.

Conclusions: This is the first study we are aware of that uses Monte Carlo simulations in this patient population to inform dosing requirements of fluconazole. We found that a doubling of the standard 200mg twice daily dose (to 400mg twice daily) is required to achieve optimal empiric antifungal activity in anuric patients receiving CVVHDF and fluconazole treatment.