title: Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin.
abstract: Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafungin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P</=.001), residual fungal burden (P</=.05), and serum galactomannan antigenemia (P</=.01), compared with either agent alone. Combination therapy also resulted in reduction (P</=.05) of organism-mediated pulmonary injury and of pulmonary infiltrates detected by thoracic computed tomography (P</=.001). No toxicity was observed with the echinocandin-triazole combination. An MTT hyphal damage assay demonstrated significant in vitro synergistic interaction between the antifungal triazole and the echinocandin. The combination of an antifungal triazole and echinocandin may represent a new strategy for treatment of invasive pulmonary aspergillosis.
authors.affiliation: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.forename: Alia A
authors.initials: AA
authors.lastname: Sarafandi
authors.forename: Amy M
authors.initials: AM
authors.lastname: Kelaher
authors.forename: Caron A
authors.initials: CA
authors.lastname: Lyman
authors.forename: Heather E
authors.initials: HE
authors.lastname: Casler
authors.forename: Tin
authors.initials: T
authors.lastname: Sein
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: John
authors.initials: J
authors.lastname: Bacher
authors.forename: Nilo A
authors.initials: NA
authors.lastname: Avila
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D054714:Echinocandins; D005260:Female; D055666:Lipopeptides; D008074:Lipoproteins / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000188:drug therapy*; D000077551:Micafungin; D009929:Organ Size; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*; D011817:Rabbits; D013844:Thiazoles / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use*
chemical_list: D054714:Echinocandins; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D013844:Thiazoles; D014230:Triazoles; C104066:ER 30346; D000077551:Micafungin