In Vitro Activities of 5-Fluorocytosine against 8,803 Clinical Isolates of Candida spp.: Global Assessment of Primary Resistance Using National Committee for Clinical Laboratory Standards Susceptibility Testing Methods

We determined the in vitro activity of flucytosine (5-fluorocytosine [5FC]) against 8,803 clinical isolates of Candida spp. (18 species) obtained from more than 200 medical centers worldwide between 1992 and 2001. The MICs were determined by broth microdilution tests performed according to NCCLS guidelines by using RPMI 1640 as the test medium and the following interpretive breakpoints: susceptible (S), ≤4 μg/ml; intermediate (I), 8 to 16 μg/ml; resistant (R), ≥32 μg/ml. 5FC was very active against the 8,803 Candida isolates (MIC(90), 1 μg/ml), 95% S. A total of 99 to 100% of C. glabrata (MIC(90), 0.12 μg/ml), C. parapsilosis (MIC(90), 0.25 μg/ml), C. dubliniensis (MIC(90), 0.12 μg/ml), C. guilliermondii (MIC(90), 0.5 μg/ml), and C. kefyr (MIC(90), 1 μg/ml) were susceptible to 5FC at the NCCLS breakpoint. C. albicans (MIC(90), 1 μg/ml; 97% S) and C. tropicalis (MIC(90), 1 μg/ml; 92% S) were only slightly less susceptible. In contrast, C. krusei was the least susceptible species: 5% S; MIC(90), 32 μg/ml. Primary resistance to 5FC is very uncommon among Candida spp. (95% S, 2% I, and 3% R), with the exception of C. krusei (5% S, 67% I, and 28% R). The in vitro activity of 5FC, combined with previous data demonstrating a prolonged post-antifungal effect (2.5 to 4 h) and concentration-independent activity (optimized at 4× MIC), suggest that 5FC could be used in lower doses to reduce host toxicity while maintaining antifungal efficacy.