Pharmacodynamics of voriconazole against wild-type and azole-resistant Aspergillus flavus isolates in a non-neutropenic murine model of disseminated aspergillosis [PublishAheadOfPrint]

Invasive aspergillosis (IA) due to Aspergillus flavus is associated with a high mortality. Though voriconazole (VRC) is widely recommended as first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a non-neutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C-gene) and two wild-type isolates without mutations.

All isolates exhibited a dose–response relationship and voriconazole treatment improved the mouse survival in a dose-dependent manner. At 40 mg/kg, 100% efficacy was observed for 1-susceptible and 1-resistant (with mutation) isolate whereas for another susceptible and resistant isolate (without mutation) survival was 81% and 72% respectively. The Hill equation with a variable slope fitted the relationship between the AUC/MIC ratio and 14-day survival well for each strain. An F-test showed the 50% effective dose to be significantly different from each other (p=0.0023). However, contrary to expectation, there was a significant difference in exposure response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective PK/PD index (EI₅₀) required being negatively and log-linearly related to MIC (p=0.04). We conclude that efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.

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