In Vitro Activities of Voriconazole (UK-109,496) and Four Other Antifungal Agents against 394 Clinical Isolates of Candida spp.

Voriconazole (formerly UK-109,496) is a new monotriazole antifungal agent which has potent activity against Candida, Cryptococcus, and Aspergillus species. We investigated the in vitro activity of voriconazole compared to those of fluconazole, itraconazole, amphotericin B, and flucytosine (5FC) against 394 bloodstream isolates of Candida (five species) obtained from more than 30 different medical centers. MICs of all antifungal drugs were determined by the method recommended by the National Committee for Clinical Laboratory Standards using RPMI 1640 test medium. Overall, voriconazole was quite active against all the yeast isolates (MIC at which 90% of the isolates are inhibited [MIC90], <0.5 mg/ml). Candida albicans was the most susceptible species (MIC90, 0.06 mg/ml) and Candida glabrata and Candida krusei were the least (MIC90 ,1 mg/ml). Voriconazole was more active than amphotericin B and 5FC against all species except C. glabrata and was also more active than itraconazole and fluconazole. For isolates of Candida spp. with decreased susceptibility to fluconazole and itraconazole MICs of voriconazole were also higher. Based on these results, voriconazole has promising antifungal activity and further in vitro and in vivo investigations are warranted. Newer azoles such as fluconazole and itraconazole are frequently used in the treatment of fungal infections due to Candida spp. They offer potential advantages over amphotericin B, including reduced toxicity and versatility of oral or intravenous (fluconazole only) administration. However, acquired or intrinsic resistance to these compounds is well known, and failure of azole therapy has been reported (11, 12). There is, therefore, a clear need for new drugs to improve the treatment of fungal infections. Voriconazole (UK-109,496) is a new monotriazole antifungal agent obtained by modification of the structure of fluconazole (14). It exhibits dose-dependent pharmacokinetics and is usually well tolerated after oral or intravenous administration (10). Early clinical studies have suggested that voriconazole may be effective in the treatment of oropharyngeal candidiasis and of acute or chronic pulmonary aspergillosis (3, 4, 17). The efficacy of voriconazole in experimental models of invasive aspergillosis and in the treatment of Aspergillus fumigatus endocarditis has also been documented (5, 7, 8). Previous in vitro investigations have shown activity against several fungal pathogens, including Candida spp., Cryptococcus neoformans, and Aspergillus spp. (1, 6, 16). Barry and Brown (2) found that voriconazole had better in vitro activity than fluconazole against six Candida species. Ruhnke et al. (15) also reported good activity of voriconazole against Candida albicans strains isolated from patients with human immunodeficiency virus infection. However, the number of clinical isolates of Candida spp. included in these studies is limited, and there is a lack of comparative data for other antifungal agents. In this study, we evaluated the in vitro activities of voriconazole and four other antifungal agents against 394 clinical isolates of Candida spp. The comparison agents tested were fluconazole, itraconazole, amphotericin B, and flucytosine (5FC). The in vitro susceptibility testing method employed was a microdilution adaptation of the guidelines set forth by the National Committee for Clinical Laboratory Standards (NCCLS) (9).