Pharmacodynamics of isavuconazole in an Aspergillus fumigatus mouse infection model

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

61 Citaten (Scopus)


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 MICEUCAST, 0.5 mg/liter) and three azole-resistant isolates harboring substitutions in the cyp51A gene: G54W (ISA MICEUCAST, 0.5 mg/liter), M220I (ISA MICEUCAST, 4 mg/liter), and TR34/L98H (ISA MICEUCAST, 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 TR34/L98H isolates with the highest dose of prodrug isavuconazonium sulfate (256 mg/kg q12). For a survival rate of 50%, the effective AUC0-24/MICEUCAST 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 (AUC0-24/MIC) can be used to optimize the treatment of human infections by A. fumigatus, including strains with decreased susceptibility.

Originele taal-2Engels
Pagina's (van-tot)2855-2866
Aantal pagina's12
TijdschriftAntimicrobial Agents and Chemotherapy
Nummer van het tijdschrift5
StatusGepubliceerd - 1 mei 2015
Extern gepubliceerdJa


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