title: In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus.
abstract: The optimal treatment for invasive aspergillosis remains elusive, despite the increased efficacy of newer agents. The immunosuppressants cyclosporine (CY), tacrolimus (FK506), and sirolimus (formerly called rapamycin) exhibit in vitro and in vivo activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae, including fungicidal synergy with azole antifungals. We report here that both FK506 and CY exhibit a clear in vitro positive interaction with caspofungin against Aspergillus fumigatus by disk diffusion, microdilution checkerboard, and gross and microscopic morphological analyses. Microscopic morphological analyses indicate that the calcineurin inhibitors delay filamentation, and in combination with caspofungin there is a positive interaction. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and existing antifungal agents to augment activity against A. fumigatus.
authors.affiliation: Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. stein022@mc.duke.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Steinbach
authors.forename: Wiley A
authors.initials: WA
authors.lastname: Schell
authors.forename: Jill R
authors.initials: JR
authors.lastname: Blankenship
authors.forename: Chiatogu
authors.initials: C
authors.lastname: Onyewu
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D000077336:Caspofungin; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D054714:Echinocandins; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic; D011743:Pyrimidines / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D065095:Calcineurin Inhibitors; D054714:Echinocandins; D055666:Lipopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D011743:Pyrimidines; D014230:Triazoles; D016572:Cyclosporine; D019703:Calcineurin; D000077336:Caspofungin; D065819:Voriconazole; D016559:Tacrolimus