Objectives 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. We determined the efficacy of Isavuconazole in an immunocompent A. fumigatus murine model.
Methods The in vivo efficacy of 0.25, 1, 4, 16, 64, 128 and 256 mg/kg/day prodrug isavuconazonium sulfate (BAL8557) administered orally was assessed in an immunocompetent murine model of IA against four clinical A. fumigatus isolates: a wild-type isolate (AZN 8196, ISA MIC, 0.5 mg/l) and three azole-resistant isolates harboring substitutions in the cyp51A-gene: G54W (V 59-73, ISA MIC, 0.5 mg/l), M220I (V28-37, ISA MIC, 4 mg/l) and TR34/L98H (V 52-35, ISA MIC, 8 mg/l). MICs were determined using EUCAST methods. In addition, ISA concentrations in blood were assayed in a separate pharmacokinetic (PK) study at 10 predefined time points post challenge by a validated UPLC method.
Results In PK studies, the dose normalized AUC0–24 (area under the plasma concentration-time curve from time zero to 24 h post infusion) ratios ranged from 0.24 to 0.84. The AUC correlated with the dose in a linear fashion over the entire dosing range with the exception of dose groups 0.25 mg/kg and 128 mg/kg. In efficacy studies, the maximum effect (100% survival) was reached at a dose of 64 mg/kg for the wild-type isolate, 128 mg/kg for the G54W and 256 mg/kg for M220I mutant. A maximal response was not achieved with the TR34/L98H isolates with the highest dose of Isavuconazole (256 mg/kg). The AUC correlated with the dose in a linear fashion over the entire dosing range with the exception of dose groups 0.25 mg/kg and 128 mg/kg. The Hill equation with a variable slope fitted the data well with a significant relationship between 24-h AUC/MIC ratio and 14-days survival (R2= 0.96) (P <0.05). For a survival of 50%, the effective AUC0-24/MIC ratio for Isavuconazole total drug was 24.73 (95% confidence interval, 22.50 to 27.18).
Conclusions Efficacy of ISA in an A. fumigatus murine model of infection was dependent both on the drug exposure and on the ISA MIC of the isolate. 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.
Keywords Isavuconazole, Aspergillus fumigatus, Azole-resistance, Pharmacodynamics
- ECCMID 24th (2014)