title: Efficacy of LY303366 against amphotericin B-susceptible and -resistant Aspergillus fumigatus in a murine model of invasive aspergillosis.
abstract: LY303366 is a novel antifungal echinocandin with excellent in vitro activity against Aspergillus spp. We compared four doses (1, 2.5, 10, and 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 mg/kg) in a temporarily neutropenic murine model of invasive aspergillosis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo response. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and lasted for 10 days. LY303366 was given once daily intravenously for 10 days, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily intraperitoneally for 10 days, or only on days 1, 2, 4, and 7 (at 5 mg/kg). Kidneys and lungs from survivors were cultured on day 11. Control mice in both experiments had 90 to 100% mortality. Amphotericin B at 0.5 mg/kg and LY303366 at 1 mg/kg yielded 10 to 20% survival rates for mice infected with either AF210 or AF65. Amphotericin B at 2 and 5 (both regimens) mg/kg yielded a 70 to 100% survival rate for mice infected with AF210 but a 10 to 30% survival rate for mice infected with AF65 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY303366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, which was as effective as amphotericin B for AF210, but superior to amphotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 and 25 mg/kg/day was superior to amphotericin B at 2 and 5 mg/kg/day in reducing tissue colony counts (P = 0.01 to 0.003), and for AF210, amphotericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effective than all four regimens of LY303366 in reducing renal culture counts (P = 0.01 to 0.0001). The present study shows, for the first time, that in vivo resistance of A. fumigatus to amphotericin B exists, although this could not be detected by in vitro susceptibility assays. Furthermore, LY303366 appears to be effective against amphotericin B-susceptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.
authors.affiliation: Department of Medical Microbiology, University Hospital Nijmegen, The Netherlands. p.verweij@mmb.azn.nl
authors.forename: P E
authors.initials: PE
authors.lastname: Verweij
authors.forename: K L
authors.initials: KL
authors.lastname: Oakley
authors.forename: J
authors.initials: J
authors.lastname: Morrissey
authors.forename: G
authors.initials: G
authors.lastname: Morrissey
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects*; D015169:Colony Count, Microbial; D003520:Cyclophosphamide / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D054714:Echinocandins; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000382:microbiology; D010456:Peptides, Cyclic / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D000666:Amphotericin B; D003520:Cyclophosphamide; D000077612:Anidulafungin