title: Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.
abstract: The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ying-Lien
authors.initials: YL
authors.lastname: Chen
authors.forename: Virginia N
authors.initials: VN
authors.lastname: Lehman
authors.forename: Anna F
authors.initials: AF
authors.lastname: Averette
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage*; D001483:Base Sequence; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy; D000077336:Caspofungin; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D054714:Echinocandins / Q000008:administration & dosage* / Q000494:pharmacology; D004875:Ergosterol / Q000378:metabolism; D055666:Lipopeptides; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D012689:Sequence Homology, Nucleic Acid; D016559:Tacrolimus / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D014230:Triazoles; C101425:posaconazole; D000077336:Caspofungin; D016559:Tacrolimus; D004875:Ergosterol