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Pharmacodynamics of Isavuconazole in an Aspergillus fumigatus Mouse Infection Model

2015; American Society for Microbiology; Volume: 59; Issue: 5 Linguagem: Inglês

10.1128/aac.04907-14

1098-6596

Seyedmojtaba Seyedmousavi, Roger J. M. Brüggemann, Jacques F. Meis, Willem J. G. Melchers, Paul E. Verweij, Johan W. Mouton,

Fungal Biology and Applications

ABSTRACT Azole resistance is an emerging problem in Aspergillus fumigatus which translates into treatment failure. Alternative treatments with new azoles may improve therapeutic outcome in invasive aspergillosis (IA) even for strains with decreased susceptibility to current azoles. The in vivo efficacy of 0.25, 1, 4, 16, 64, 128, 256, and 512 mg/kg of body weight/day prodrug isavuconazonium sulfate (BAL8557) (isavuconazole [ISA]-equivalent doses of 0.12, 0.48, 1.92, 7.68, 30.7, 61.4, 122.9, and 245.8 mg/kg/day, respectively) administered by oral gavage was assessed in an immunocompetent murine model of IA against four clinical A. fumigatus isolates: a wild-type isolate (ISA MIC EUCAST , 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in the cyp51A gene: G54W (ISA MIC EUCAST , 0.5 mg/liter), M220I (ISA MIC EUCAST , 4 mg/liter), and TR 34 /L98H (ISA MIC EUCAST , 8 mg/liter). The maximum effect (100% survival) was reached at a prodrug isavuconazonium sulfate dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W mutant, and 256 mg/kg two times per day (q12) for the M220I mutant. A maximum response was not achieved with the TR 34 /L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC 0–24 /MIC EUCAST ratio for ISA total drug was 24.73 (95% confidence interval, 22.50 to 27.18). The efficacy of isavuconazole depended on both the drug exposure and the isavuconazole MIC of the isolates. The quantitative relationship between exposure and effect (AUC 0–24 /MIC) can be used to optimize the treatment of human infections by A. fumigatus , including strains with decreased susceptibility.