title: In vivo activity of amphotericin B lipid complex in immunocompromised mice against fluconazole-resistant or fluconazole-susceptible Candida tropicalis.
abstract: We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 microg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Hope Hospital, University of Manchester, United Kingdom.
authors.forename: P A
authors.initials: PA
authors.lastname: Warn
authors.forename: J
authors.initials: J
authors.lastname: Morrissey
authors.forename: C B
authors.initials: CB
authors.lastname: Moore
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D002175:Candida / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D015169:Colony Count, Microbial; D004338:Drug Combinations; D004352:Drug Resistance, Microbial; D015725:Fluconazole / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D016867:Immunocompromised Host / Q000276:immunology*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000627:therapeutic use*; D010715:Phosphatidylglycerols / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D004338:Drug Combinations; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; C068538:liposomal amphotericin B; D000666:Amphotericin B; D015725:Fluconazole