| Summary: | <i>Aspergillus fumigatus</i> is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in <i>A. fumigatus</i> has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a <i>Galleria mellonella</i> model of invasive infection due to azole-susceptible or azole-resistant <i>A. fumigatus</i> isolates. We also sought to describe the pharmacokinetics of VRZ in the <i>G. mellonella</i> model. <i>G. mellonella</i> larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of <i>A. fumigatus</i>. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible <i>A. fumigatus</i> isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a C<sub>min</sub> (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, <i>G. mellonella</i> is a suitable model for testing the efficacy of antifungal agents against <i>A. fumigatus</i>.
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