IN-VITRO AND IN-VIVO ANTIFUNGAL ACTIVITIES OF DU-6859A, A FLUOROQUINOLONE, IN COMBINATION WITH AMPHOTERICIN-B AND FLUCONAZOLE AGAINST PATHOGENIC FUNGI

DU-6859a is an investigational fluoroquinolone agent with potent bacte ricidal activity, but by itself it has no antifungal activity. When co mbined with amphotericin B (AmB), however, DU-6859a clearly enhanced t he in vitro antifungal activity of AmB against Candida albicans, Candi da tropicalis, Candida krusei, Candida glabrata, and Cryptococcus neof ormans in microdilution checkerboard studies. Positive interactions of DU-6859a with AmB against Aspergillus fumigatus were dependent on the medium used; yeast nitrogen base supplemented with amino acids, ammon ium sulfate, and 1% glucose was better for demonstrating synergism, wh ile in RPMI 1640 medium, unexpected antagonism between the drugs occur red against three of the strains tested. In combination with fluconazo le (Flu), DU-6859a increased the activity of Flu against C. albicans b oth in synthetic amino acid medium fungal and in supplemented yeast ni trogen base. An in vitro time-kill study revealed that DU-6859a combin ed with AmB significantly suppressed the regrowth of C. albicans compa red with the suppression brought about by AmB used alone in a concentr ation-dependent fashion. Furthermore, in a model of C. albicans infect ion in mice, the fungal load in infected kidneys was significantly les s in mice given the combination treatment of DU-6859a plus either AmB or Flu, and thus, the combination treatment resulted in prolonged surv ival of infected mice compared with treatment with either antifungal a lone. The prolonged survival in mice given the combined treatment was also observed in mice with A. fumigatus infection, indicating that DU- 6859a potentiated the actions of the antifungal agents in vivo as well as in vitro.