PNEUMOCANDIN L-743,872 ENHANCES THE ACTIVITIES OF AMPHOTERICIN-B AND FLUCONAZOLE AGAINST CRYPTOCOCCUS-NEOFORMANS IN-VITRO

Cryptococcus neoformans infections in patients with AIDS are often inc urable, despite aggressive antifungal therapy, Combination regimens wi th additive or synergistic drugs could provide additional options for treating cryptococcal meningitis, We evaluated the efficacy of combina tion therapies using L-743,872, a pneumocandin antifungal drug, and am photericin B or fluconazole against 18 strains of C. neoformans, inclu ding 11 C. neoformans var. neoformans, 3 C. neoformans var. gattii, an d 4 fluconazole-resistant isolates. The combination of subinhibitory c oncentrations of L-743,872 with amphotericin B significantly enhanced amphotericin B activity against C. neoformans as measured by turbidity (antifungal susceptibility studies using the National Committee of Cl inical and Laboratory Standards method), quantitative CFU, and tetrazo lium salt reduction assays, Similarly, the addition of subinhibitory c oncentrations of L-743,872 to fluconazole enhanced fluconazole activit y, but the effect was less dramatic than for the pneumocandin-amphoter icin B combination, A marked synergism was observed in all combination s of amphotericin B and L-743,872 (fractional inhibitory concentration index [FLC] of less than or equal to 0.5). Fluconazole-resistant stra ins showed a susceptibility to amphotericin B and L-743,872 which was comparable to that of susceptible isolates, Combinations of pneumocand in with fluconazole revealed different activities for the various stra ins, including synergism (FIC < 1.0), additivity (FIC = 1.0), and auto nomy (FIC between 1.0 and 2.0), Combination studies with fluconazole a nd L-743,872 showed additive and autonomous activities against flucona zole-resistant isolates, No antagonistic interactions (FIC > 2.0) were observed for any combination of L-743,872 with either amphotericin B or fluconazole. The results of this study suggest that L-743,872 can e nhance the efficacy of fluconazole or amphotericin B in vitro and indi cate a potential role for L-743,872 in combination therapy against C. neoformans.