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Pharmacodynamics of Isavuconazole in a Dynamic In Vitro Model of Invasive Pulmonary Aspergillosis

2015; American Society for Microbiology; Volume: 60; Issue: 1 Linguagem: Inglês

10.1128/aac.01364-15

1098-6596

Helen Box, Joanne Livermore, Adam Johnson, Laura McEntee, Timothy Felton, Sarah Whalley, Joanne Goodwin, William Hope,

Helminth infection and control

Isavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamic in vitro model of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates of Aspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.