Candida tropicalis is less commonly isolated from clinical specimens than Candida albicans. Unlike C. albicans, which can be occasionally found as a commensal, C. tropicalis is almost always associated with the development of fungal infections. In addition, C. tropicalis has been reported to be resistant to fluconazole (FLC). To analyze the development of FLC resistance in C. tropicalis, an FLC-susceptible strain (ATCC 750) (MIC ‫؍‬ 1.0 g/ml) was cultured in liquid medium containing increasing FLC concentrations from 8.0 to 128 g/ml. The strain developed variable degrees of FLC resistance which paralleled the concentrations of FLC used in the medium. The highest MICs of FLC were 16, 256, and 512 g/ml for strains grown in medium with 8.0, 32, and 128 g of FLC per ml, respectively. Development of resistance was rapid and could be observed already after a single subculture in azole-containing medium. The resistant strains were cross-resistant to itraconazole (MIC > 1.0 g/ml) and terbinafine (MIC > 512 g/ml) but not to amphotericin B. Isolates grown in FLC at concentrations of 8.0 and 32 g/ml reverted to low MICs (1.0 g/ml) after 12 and 11 passages in FLC-free medium, respectively. The MIC for one isolate grown in FLC (128 g/ml) (128 R) reverted to 16 g/ml but remained stable over 60 passages in FLC-free medium. Azole-resistant isolates revealed upregulation of two different multidrug efflux transporter genes: the major facilitators gene MDR1 and the ATP-binding cassette transporter CDR1. The development of FLC resistance in vitro correlated well with the results obtained in an experimental model of disseminated candidiasis. While FLC given at 10 mg/kg of body weight/ day was effective in reducing the fungal burden of mice infected with the parent strain, the same dosing regimen was ineffective in mice infected with strain 128 R. Finally, the acquisition of in vitro FLC resistance in strain 128 R was related to a loss of virulence. The results of our study elucidate important characteristics and potential mechanisms of FLC resistance in C. tropicalis.

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A broth microdilution method performed in accordance with the National Committee for Clinical Laboratory Standards guidelines was used to compare the in vitro activity of the new antifungal triazole SCH 56592 (SCH) to that of fluconazole (FLC), itraconazole (ITC), and ketoconazole (KETO) against 257 clinical yeast isolates. They included 220 isolates belonging to 12 different species of Candida, 15 isolates each of Cryptococcus neoformans and Saccharomyces cerevisiae, and seven isolates of Rhodotorula rubra. The MICs of SCH at which 50% (MIC 50 ) and 90% (MIC 90 ) of the isolates were inhibited were 0.06 and 2.0 g/ml, respectively. In general, SCH was considerably more active than FLC (MIC 50 and MIC 90 of 1.0 and 64 g/ml, respectively) and slightly more active than either ITC (MIC 50 and MIC 90 of 0.25 and 2.0 g/ml, respectively) and KETO (MIC 50 and MIC 90 of 0.125 and 4.0 g/ml, respectively). Our in vitro data suggest that SCH has significant potential for clinical development.

A chequerboard titration broth microdilution method, performed according to the recommendations of the National Committee for Clinical Laboratory Standards, was applied to study the in-vitro interaction of terbinafine with amphotericin B, fluconazole and itraconazole against 30 strains of Candida albicans isolated from the oral cavities of AIDS patients. MICs were determined spectrophotometrically at 490 nm and read at either 24 h or 48 h. The end-point was defined as the drug concentration resulting in > or = 90% inhibition of growth relative to control growth. Synergy, defined as a fractional inhibitory concentration (FIC) index of < or = 0.50, was observed in 93% (28 of 30) of terbinafine-amphotericin B interactions, in 47% (14 of 30) of terbinafine-fluconazole interactions and in 43% (13 of 30) of terbinafine-itraconazole interactions; antagonism (FIC > 2.0) was not observed. Where synergy was not achieved, there was still a decrease, although not as dramatic, in the MIC of one or both drugs when used in combination. Reading the MICs on day 2 did not significantly affect the mode of interaction of terbinafine-triazoles, while for terbinafine-amphotericin B the proportion of synergic interactions dropped from 93% (28 of 30) to 30% (nine of 30; P = 0.0001). Antagonism was not observed for any drug combination even at 48 h. Minimum fungicidal concentrations (MFCs) of all drugs alone and in combination were determined against five isolates. Neither terbinafine nor the two triazoles showed fungicidal activity when tested alone or in combination. The fungicidal activity of amphotericin B was slightly enhanced when combined with terbinafine, there being a decrease of two-fold dilutions in the amphotericin B MFCs against all five isolates tested. Thus terbinafine enhances the activities of amphotericin B and triazoles against C. albicans in vitro. Clearly, clinical studies are warranted to elucidate further the potential utility of these combination therapies.

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