Combination therapy of experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis in mice.
Combination pairs of 5-fluorocytosine (5-FC) + itraconazole (Itra), 5-FC + fluconazole (Fluc), and amphotericin B (Amph B) + Itra were administered to mice with experimental candidiasis, cryptococcosis, aspergillosis and wangiellosis with a variety of combination ratios. The life-prolonging effect of the combinations was compared with the effect of each partner administered alone and with a double dosage. Using the U test of Mann and Whitney, the effects of the concentration were classified as synergistic, additive, indifferent or antagonistic; the degree of the interaction was compared with the known effect of Amph B and 5-FC combinations. The combination 5-FC + Itra was definitely synergistic or additive in candidiasis and aspergillosis. The most pronounced synergism occurred in the infection with a 5-FC-resistant strain of Candida albicans. The degree of synergism was the same as with 5-FC + Amph B. In cryptococcosis this combination was indifferent. The combination of 5-FC + Itra merits clinical investigation, especially in candidiasis and aspergillosis. Amph B + Itra was mostly indifferent and weakly antagonistic; the degree of antagonism was significantly weaker than the one observed with Amph B + ketoconazole (Keto). In candidiasis, 5-FC + Fluc was synergistic, but indifferent in cryptococcosis and aspergillosis.
Polak
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Department of Pharmaceutical Research, F. Hoffmann-La Roche, Basel, Switzerland.
D000666:Amphotericin B / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D002177:Candidiasis / Q000188:drug therapy*; D003453:Cryptococcosis / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005093:Exophiala / Q000187:drug effects; D015725:Fluconazole; D005437:Flucytosine / Q000627:therapeutic use; D017964:Itraconazole; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D009181:Mycoses / Q000188:drug therapy*; D014230:Triazoles / Q000627:therapeutic use
D000935:Antifungal Agents; D014230:Triazoles; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; D005437:Flucytosine; D007654:Ketoconazole