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.