title: 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.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Seyedmojtaba
authors.initials: S
authors.lastname: Seyedmousavi
authors.forename: Roger J M
authors.initials: RJ
authors.lastname: Brüggemann
authors.forename: Willem J G
authors.initials: WJ
authors.lastname: Melchers
authors.forename: Paul E
authors.initials: PE
authors.lastname: Verweij
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D054714:Echinocandins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D009504:Neutrophils / Q000166:cytology; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D016019:Survival Analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D000077612:Anidulafungin; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole