Synergistic interaction of terbinafine with triazoles or amphotericin B against Aspergillus species.
The in vitro activity of terbinafine alone and in combination with other antifungal agents was tested against isolates of Aspergillus fumigatus, A. flavus and A. niger. Testing was performed in a modified National Committee for Clinical Laboratory Standards (NCCLS) macrodilution broth assay, and interactions were examined using a checkerboard design. Terbinafine was highly active against Aspergillus isolates (minimum inhibitory concentration [MIC] 0.01 to 2 microg ml(-1)) with a primary fungicidal action (minimum fungicidal concentration [MFC] 0.02 to 4 microg ml(-1)). Amphotericin B was also highly active and cidal as expected (MIC 1 microg ml(-1), MFC 1 to 4 microg ml(-1)). The triazoles itraconazole and voriconazole were highly active but showed a variable degree of cidal activity against the different strains, voriconazole having the more potent cidal activity. Fluconazole had no significant activity (MIC > 128 microg ml(-1)). Drug combinations were tested in the A. fumigatus and A. niger strains. Terbinafine and amphotericin showed an additive to synergistic interaction depending on the isolate. Combinations of terbinafine with itraconazole or voriconazole displayed a potent synergistic interaction and fungicidal activity against all isolates. Surprisingly, fluconazole also potentiated the activity of terbinafine in an additive to synergistic fashion, despite its lack of activity alone. The results suggest potential clinical application of terbinafine in aspergillosis, either alone or in combination with amphotericin or triazoles.
Novartis Research Institute, Vienna, Austria. neil.ryder@pharma.novartis.com
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D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects; D001232:Aspergillus fumigatus / Q000187:drug effects*; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000077291:Terbinafine; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole
D000935:Antifungal Agents; D009281:Naphthalenes; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D000666:Amphotericin B; D015725:Fluconazole; D000077291:Terbinafine; D065819:Voriconazole