title: Activity of micafungin (FK463) against an itraconazole-resistant strain of Aspergillus fumigatus and a strain of Aspergillus terreus demonstrating in vivo resistance to amphotericin B.
abstract: We compared the activity of four doses of micafungin (FK463) with that of amphotericin B, liposomal amphotericin B and itraconazole in a murine model of disseminated aspergillosis. Temporarily neutropenic mice were infected with a lethal dose of either an itraconazole-resistant Aspergillus fumigatus isolate or Aspergillus terreus, a species that is less susceptible to amphotericin B. Treatment was started 24 h after infection and lasted for 7 days. Mice were treated with either amphotericin B (0.5 or 5 mg/kg), liposomal amphotericin (5 or 25 mg/kg), itraconazole (25 or 75 mg/kg) or FK463 (either 1, 2, 5 or 10 mg/kg). Treatment of the A. fumigatus model with either amphotericin B, liposomal amphotericin or FK463 prolonged survival. Doses of FK463 5 and 10 mg/kg had a 100% survival. Treatment of A. terreus infection with either itraconazole or FK463, but not amphotericin B, also prolonged survival. Doses of liposomal amphotericin of 5 and 25 mg/kg were ineffective against A. terreus infection. No treatment regime was able to totally clear the liver or kidneys in either model. The data indicate that FK463 may have a clinical role in the treatment of life-threatening invasive aspergillosis.
authors.affiliation: School of Medicine, University of Manchester, Manchester, UK. pwarn@fs1.ho.man.ac.uk
authors.forename: P A
authors.initials: PA
authors.lastname: Warn
authors.forename: G
authors.initials: G
authors.lastname: Morrissey
authors.forename: J
authors.initials: J
authors.lastname: Morrissey
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000666:Amphotericin B / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D015169:Colony Count, Microbial; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017964:Itraconazole / Q000097:blood / Q000494:pharmacology*; D055666:Lipopeptides; D008074:Lipoproteins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D000077551:Micafungin; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000382:microbiology; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D007166:Immunosuppressive Agents; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D017964:Itraconazole; D000666:Amphotericin B; D000077551:Micafungin