Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis

Box, Helen, Negri, Clara, Livermore, Joanne, Whalley, Sarah, Johnson, Adam ORCID: 0000-0002-6684-3321, McEntee, Laura, Alastruey-Izquierdo, Ana, Meis, Jacques F, Thornton, Christopher and Hope, William ORCID: 0000-0001-6187-878X
(2018) Pharmacodynamics of Voriconazole for Invasive Pulmonary Scedosporiosis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 62 (5). e02516-e02517.

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<i>Scedosporium apiospermum</i> 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 <i>Scedosporium</i> spp. Little is known about the pharmacodynamics of voriconazole against <i>Scedosporium</i> Both static and dynamic <i>in vitro</i> models of invasive scedosporiosis were developed. Monoclonal antibodies that target a soluble cell wall antigen secreted by <i>Scedosporium apiospermum</i> 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 <i>S. apiospermum</i> tested invaded through the cellular bilayer of the <i>in vitro</i> models and liberated antigen. There was a concentration-dependent decline in the amount of antigen, with near maximal antifungal activity against all 3 strains being achieved with voriconazole at 10 mg/liter. Similarly, there was a drug exposure-dependent decline in the amount of circulating antigen in the dynamic model and complete suppression of antigen, with an area under the concentration-time curve (AUC) of approximately 80 mg · h/liter. A regression of the AUC/MIC versus the area under the antigen-time curve showed that a near maximal effect was obtained with an AUC/MIC of approximately 100. Monte Carlo simulation suggested that only isolates with an MIC of 0.5 mg/liter enabled pharmacodynamic targets to be achieved with a standard regimen of voriconazole. Isolates with higher MICs may need drug exposure targets higher than those currently recommended for other fungi.

Item Type: Article
Uncontrolled Keywords: Scedosporium apiospermum, antifungal therapy, pharmacodynamics, pharmacokinetics, pneumonia, voriconazole
Depositing User: Symplectic Admin
Date Deposited: 11 Apr 2018 08:02
Last Modified: 13 Feb 2024 09:24
DOI: 10.1128/AAC.02516-17
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