INTERACTION BETWEEN KETOCONAZOLE, AMPHOTERICIN B AND TERBINAFIN AND THREE DIAZENUMDIOLATES IN CONCOMITANT USES AGAINST SOME FUGAL SPECIES

A checkerboard broth microdilution method was performed to investigate the in vitro antifungal activitiesof three diazeniumdiolates derivatives (DETA/NO, DPTA/NO, DEA/NO) alone and in combination withketoconazole, amphotricin B or terbinafine against five Candida species, Cryptococcus neoformance andfour dermatophyte strains. MICs and MLCs were recorded, and synergy was calculated by usingfractional inhibitory and fractional lethal concentration index. DETA/NO with a half-life of 57h at 25°Cshowed antifungal activity against all tested dermatophyte species (MIC 0.150 to 2.5mg/ml), DPTA/NOwith a half life of 3h at 37°C showed antifungal activity against five species of Candida andCryptococcus neoformans, and DEA/NO with a half life of 2 min at 37°C and 16 min at 25°C did notshow antifungal activity against tested strains. Combinations of DPTA-NO with either ketoconazole oramphotericin B were either synergistic or indifferent for all tested strain of Candida and Cryptococcusneoformance. DETA/NO was unable to enhance the antifungal activity of terbinafine againstdermatophyte strains. Even where no synergistic activity was achieved, there was still a decrease in theMIC of one or both drugs which were used in combination. Antagonism was observed betweenterbinafine and DETA-NO against Trichophyton rubrum. Our result suggests that DETA/NO andDPTA/NO may be useful for development of new therapeutic strategies for treatment of dermatophyteand Candida infections. Clinical studies are warranted to elucidate the potential utility of thesecombination therapies.