title: In vitro combination therapy with isavuconazole against Candida spp.
abstract: Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Katragkou
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: McCarthy
authors.affiliation: Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Kaiser
authors.initials: K
authors.lastname: Hussain
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Patriss W
authors.initials: PW
authors.lastname: Moradi
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Gittel E
authors.initials: GE
authors.lastname: Strauss
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Kyaw L
authors.initials: KL
authors.lastname: Myint
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Myo H
authors.initials: MH
authors.lastname: Zaw
authors.affiliation: Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kovanda
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Ruta
authors.initials: R
authors.lastname: Petraitiene
authors.affiliation: Infectious Disease Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roilides
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.|Department of Pediatrics, Weill Cornell Medicine of Cornell University, New York, New York, USA.|Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.affiliation: Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
authors.forename: Vidmantas
authors.initials: V
authors.lastname: Petraitis
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects*; D058365:Candidiasis, Invasive / Q000188:drug therapy; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D066298:In Vitro Techniques; D055666:Lipopeptides / Q000494:pharmacology*; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole; D000666:Amphotericin B; D000077551:Micafungin
keywords: Candida; amphotericin B; isavuconazole; micafungin; yeasts