Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis

Abstract

Scedosporium apiospermum is a medically important fungal pathogen that causes a wide range of infections in humans. There are relatively few antifungal agents that are active against Scedosporium spp. Little is known about the pharmacodynamics of voriconazole against Scedosporium. Both static and dynamic in vitro models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by Scedosporium apiospermum were used to describe the pharmacodynamics of voriconazole. Mathematical pharmacokinetic-pharmacodynamic models were fitted to the data to estimate the drug exposure required to suppress the release of fungal antigen. The experimental results were bridged to humans using Monte Carlo simulation. All 3 strains of S. apiospermum tested invaded through the cellular bilayer of the in vitro models and liberated antigen. There was a concentration-dependent decline in antigen with near maximal antifungal activity in all 3 strains with 10 mg/L. Similarly, there was a drug exposure dependent decline in circulating antigen in the dynamic model and complete suppression of antigen with an AUC of approximately 80 mg.h/L. A regression of the AUC:MIC versus area under the antigen time curve showed that near maximal effect was obtained with AUC:MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/L enable pharmacodynamic targets to be acheived with a standard regimen of voriconazole. Isolates with higher MICs may need higher drug exposure targets than are currently recommended for other fungi.