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VOL.42 NO.3 R= H: Itraconazole R=OH: Hydroxy-itraconazole (R 63373) Fig. 1. Structures of itraconazole and hydroxyitraconazole. Candida albicans, Candida glabrata, Candida guilliermondii, Candida tropicalis, Candida parapsilosis, Candida krusei, Cryptococcus neoformans, Epidermophyton flocossum, Microsporum canis, Microsporum gypseum, Trichosporon cutaneum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichop-

CHEMOTHERAPY MAR. 1994

VOL.42 NO.3

CHEMOTHERAPY MAR. 1994

VOL.42 NO.3 2) Fromtling R A: Overview of medically important antifungal azole derivatives. Clin. Microbiol. Rev. 1: 187-217, 1988 3) Dismukes W E: Azole antifungal drugs, old and new. Ann. Intern. Med. 109, 177-179, 1988 7) Odds F C, Webster C E, Abbott A B: Antifungal relative inhibition factors: BAY 1-9139, bifonazole, butoconazole, isoconazole, itraconazole (R 51211), oxiconazole, Ro 14-4767/002, sulconazole, terconazole and vibunazole (BAY n-7133) compared in vitro with nine established antifungal agents. J. Antimicrob. Chemother. 14: 105 ` 114, 1984 9) Cutsem J V, Gerven F V, Van De Ven M, Borgers M, Janssen P A J: Itraconazole, a new triazole that is orally active in aspergillosis. Antimicrob. Agents Chemother.. 26: 527-534, 1984 10) Cutsem J V, Gerven F V, Janssen P J: Activity of orally, topically, and parenterally administered itraconazole in the treatment of superficial and deep mycoses; animal models. Rev. Infect. Dis 9: S15 `S32, 1987 11) Cutsem J Van: The in-vitro antifungal spectrum of itraconazole. Mycoses 32: 7-13, 1989 12) Cutsem J V: Oral, topical and parenteral antifungal treatment with itraconazole in normal and in immunocompromised animals. Mycoses 32: 14 ` 34, 1989 14) Heykants J A Van Peer A, Van de Velde V, Van Rooy P, Meuldermans W, Lavrijsen K, Woestenborghs R, Van Cutsem J, Cauwenbergh G: The clinical pharmacokinetics of itraconazole: An overview. Mycoses 32: 67-87, 1989 15) Pfaller M A, Dupont B, Kobayashi G, Muller J, Rinaldi M G, Espinel-Ingroff A, Shadomy S, Troke P F, Walsh J, Warenock D W: Standardized susceptibility testing of fluconazole: an international collaborative study. Antimicrob.

CHEMOTHERAPY MAR. 1994 Agents Chemother. 36: 1805 `1809, 1989 16) Rogers T E, Galgiani J N: Activity of fluconazole (UK 49, 858) and ketoconazole against Candida albicans in vitro and in vivo. Antimicrob. Agents Chemother. 30: 418 `422, 1986 17) Mikami Y, Scalarone G M, Kurita N, Yazawa K, Uno J, Miyaji M: Synergistic postantifungal effect of flucytosine and fluconazole on Candida albicans. J. Med. Vet. Mycol. 30: 197 `206, 1992 18) Mikami Y, Takahashi K, Yazawa K, Terao K, Ueno Y: Synergistic interaction of miconazole and fluconazole at sub-mic level on Candida albicans. Mycoses 35: 321 `327, 1992 19) Scalarone G M, Mikami Y, Kurita K, Yazawa K, Miyaji M: Comparative studies on the postantifung. al effect produced by the synergistic interaction of flucytosine and amphotericin B on Candida albicans. Mycopathol. 120: 133 `138, 1992 20) Mikami Y, Sakamoto T, Yazawa K, Gonoi T, Ueno Y, Hasegawa S: Comparison of in vitro antifungal activity of itraconazole and hydroxyitraconazole by colorimetric MTT assay. Mycoses, in press. 21) Buttke T M, McCubrey J A, Owen T C: Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of Imphokinedependent cell lines. J. Immunol. Methods 157: 233 `240, 1993 In vitro antifungal activities of hydroxy-itraconazole, an active metabolite of itraconazole Yuzuru Mikami, Katsukiyo Yazawa and Kazuko Nishimura Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260, Japan The in vitro antifungal activity of hydroxy-itraconazole (ITZ-OH), an active metabolite of itraconazole (ITZ) was determined by a liquid microdilution assay method using four different media: Sabouraud dextrose broth (SAB), synthetic amino acid medium-fungal (SAAMF), yeast nitrogen base with 1% glucose (YNBG) and brain heart infusion broth (BHI). ITZ-OH showed almost the same antifungal activity as ITZ against all tested filamentous and yeast-like fungi. When the activities of ITZ-OH and ITZ were compared with those of 8 reference antifungals, i. e., amphotericin B, bifonazole, clotrimazole, fluconazole, flucytosine, griseofulvin, ketoconazole and miconazole, both drugs were found to have much higher activities against Aspergillus fumigatus and Candida albicans. However, the MIC values of ITZ-OH and ITZ against dermatophytes, including Trichophyton mentagrophytes and Trichophyton rubrum were similar to those of reference antifungals. The MIC values of ITZ-OH and ITZ fluctuated depending on the medium used. The lowest MIC value was observed with A. fumigatus in BHI medium. However, the MIC end point of ITZ-OH and ITZ against C. albicans was difficult to determine in the medium. SAAMF medium was considered a good choice for MIC determination in C. albicans.

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