EFFICACY OF LY303366 AGAINST AMPHOTERICIN-B-SUSCEPTIBLE AND AMPHOTERICIN-B-RESISTANT ASPERGILLUS-FUMIGATUS IN A MURINE MODEL OF INVASIVE ASPERGILLOSIS

LY303366 is a novel antifungal echinocandin with excellent in vitro ac tivity against Aspergillus spp. We compared four doses (1, 2.5, 10, an d 25 mg/kg of body weight) of LY303366 with amphotericin B (0.5 to 5 m g/kg) in a temporarily neutropenic murine model of invasive aspergillo sis against an amphotericin B-susceptible (AF210) and an amphotericin B-resistant (AF65) Aspergillus fumigatus isolate based on in vivo resp onse. Mice were immunosuppressed with cyclophosphamide (200 mg/kg) and infected 3 days later. Treatment started 18 h after infection and las ted for 10 days. LY303366 was given once daily intravenously for 10 da ys, and amphotericin B (at 0.5, 2, and 5 mg/kg) was given once daily i ntraperitoneally 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 (b oth regimens) mg/kg yielded a 70 to 100% survival rate for mice infect ed with AF210 but a 10 to 30% survival rate for mice infected with AF6 5 (P = 0.01 to 0.04 compared with AF210). Against AF210 and AF65, LY30 3366 at 2.5, 10, and 25 mg/kg produced a survival rate of 70 to 80%, w hich was as effective as amphotericin B for AF210, but superior to amp hotericin B for AF65 (P < 0.03 to 0.0006). For AF65, LY303366 at 10 an d 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, amph otericin B at 5 mg/kg/day and at 5 mg/kg in four doses was more effect ive than all four regimens of LY303366 in reducing renal culture count s (P = 0.01 to 0.0001). The present study shows, for the first time, t hat in vivo resistance of A. fumigatus to amphotericin B exists, altho ugh this could not be detected by in vitro susceptibility assays. Furt hermore, LY303366 appears to be effective against amphotericin B-susce ptible and -resistant A. fumigatus infection in this model and should be further evaluated clinically.