title: Efficacy of isavuconazole, voriconazole and fluconazole in temporarily neutropenic murine models of disseminated Candida tropicalis and Candida krusei.
abstract: OBJECTIVE
  The aim of this study was to assess the dose-response of isavuconazole, voriconazole and fluconazole in disseminated Candida tropicalis and Candida krusei infections.
  
  
  METHODS
  Mice were immunosuppressed using either one dose [temporarily neutropenic (TN)] or two doses [persistently neutropenic (PN)] of cyclophosphamide. Treatment was started 5 h after infection with oral isavuconazole (6, 15, 30, 60, 90, 120 or 150 mg/kg equivalent active compound), intravenous voriconazole (5, 20 or 40 mg/kg plus grapefruit gavage twice daily) or oral fluconazole (15, 50 or 150 mg/kg) all administered twice daily. Kidney burden was assessed for C. tropicalis, and kidney and brain burden for C. krusei.
  
  
  RESULTS
  Vehicle controls developed a non-lethal infection with high burdens in both models. In the TN models, isavuconazole, voriconazole and fluconazole (>50 mg/kg) reduced kidney burden compared with controls; >60 mg/kg isavuconazole and 50 mg/kg fluconazole were superior to alternative treatments (other than voriconazole 40 mg/kg). Isavuconazole (all doses) reduced brain burden (P<0.05) in the C. krusei model; fluconazole (all doses) and voriconazole (5 and 20 mg/kg) did not. In the C. krusei kidney burden model, isavuconazole 120 and 150 mg/kg and voriconazole 40 mg/kg were superior to controls and fluconazole. In the C. tropicalis model, PN isavuconazole (all doses), voriconazole (>5 mg/kg) and fluconazole (all doses) reduced kidney burden (P<0.05). Only isavuconazole (all doses) and 40 mg/kg voriconazole were effective against C. krusei in the brain, isavuconazole and voriconazole reduced tissue burden (P<0.05). Fluconazole had no significant effect on brain burden even at 150 mg/kg.
  
  
  CONCLUSIONS
  Isavuconazole significantly reduced kidney burden in mice infected with C. tropicalis and both kidney and brain burdens in mice infected with C. krusei. Isavuconazole was as effective as voriconazole and much more effective than fluconazole at reducing brain burden.
authors.affiliation: School of Medicine, University of Manchester, 1.800 Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: J
authors.initials: J
authors.lastname: Majithiya
authors.forename: A
authors.initials: A
authors.lastname: Sharp
authors.forename: A
authors.initials: A
authors.lastname: Parmar
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
authors.forename: P A
authors.initials: PA
authors.lastname: Warn
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000382:microbiology; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D015725:Fluconazole / Q000008:administration & dosage / Q000627:therapeutic use*; D007668:Kidney / Q000382:microbiology; D008297:Male; D051379:Mice; D009503:Neutropenia; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D011743:Pyrimidines; D014230:Triazoles; C508735:isavuconazole; D015725:Fluconazole; D065819:Voriconazole