Pharmacodynamics of Anidulafungin against Clinical Aspergillus fumigatus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

Abstract

Azole resistance is an emerging increasing problem in Aspergillus fumigatus that results in treatment failure. Alternative treatments may improve the therapeutic outcome in patients with azole-resistant invasive aspergillosis (IA). Little is known about the in vivo efficacy of the echinocandin anidulafungin (AFG) in IA. The in vivo efficacy of 2.5, 5, 10, and 20 mg/kg of body weight AFG was assessed against two clinical Aspergillus fumigatus isolates with identical AFG minimum effective concentrations (MECs; 0.03 mg/liter) in a murine model of IA: a wild-type voriconazole (VCZ)-susceptible (VCZ(s)) A. fumigatus isolate (AZN 8196) and a VCZ-resistant (VCZ(r)) A. fumigatus isolate (V52-35) harboring the TR(34)/L98H resistance mechanism (substitution at codon L98 in combination with a 34-bp tandem repeat in the promoter region of the CYP51A gene). The pharmacokinetics of AFG were also assessed for each dose. Increasing doses increased survival for both isolates in a manner dependent on the AFG dose level (R(2) = 0.99 and 0.95, respectively) up to a maximum of 72.7% and 45.45% for the VCZ(s) and VCZ(r) isolates, respectively. The area under the concentration-time curve (AUC) correlated significantly with the dose in a linear fashion over the entire dosing range (R(2) = 0.86). The Hill equation with a variable slope fitted the relationship between the 24-h AUC/MEC ratio and 14-day survival well (R(2) = 0.87; P < 0.05). The 50% effective AUC/MEC for total AFG was 126.5 (95% confidence interval, 79.09 to 202.03). AFG treatment improved the survival of mice in a dose-dependent manner; however, a maximal response was not achieved with either isolate even in those treated with the highest AFG dose.