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ABSTRACTSince epidemiological cutoff values (ECVs) using CLSI MICs from multiple laboratories are not available for Candidaspp. and the echinocandins, we established ECVs for anidulafungin and micafungin on the basis of wild-type (WT) MIC distributions (for organisms in a species-drug combination with no detectable acquired resistance mechanisms) for 8,210 Candida albicans, 3,102 C. glabrata, 3,976 C. parapsilosis, 2,042 C. tropicalis, 617 C. krusei, 258 C. lusitaniae, 234 C. guilliermondii, and 131 C. dubliniensisisolates. CLSI broth microdilution MIC data gathered from 15 different laboratories in Canada, Europe, Mexico, Peru, and the United States were aggregated to statistically define ECVs. ECVs encompassing 97.5% of the statistically modeled population for anidulafungin and micafungin were, respectively, 0.12 and 0.03 μg/ml for C. albicans, 0.12 and 0.03 μg/ml for C. glabrata, 8 and 4 μg/ml for C. parapsilosis, 0.12 and 0.06 μg/ml for C. tropicalis, 0.25 and 0.25 μg/ml for C. krusei, 1 and 0.5 μg/ml for C. lusitaniae, 8 and 2 μg/ml for C. guilliermondii, and 0.12 and 0.12 μg/ml for C. dubliniensis. Previously reported single and multicenter ECVs defined in the present study were quite similar or within 1 2-fold dilution of each other. For a collection of 230 WT isolates (no fksmutations) and 51 isolates with fksmutations, the species-specific ECVs for anidulafungin and micafungin correctly classified 47 (92.2%) and 51 (100%) of the fksmutants, respectively, as non-WT strains. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin and micafungin due to fksmutations.

ABSTRACTPrevious pharmacodynamic studies using in vivocandidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicansand were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosisstrains with various MICs (anidulafungin, 0.015 to 4.0 μg/ml; caspofungin, 0.03 to 4.0 μg/ml; and micafungin, 0.008 to 1.0 μg/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosisrequired more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis(mean, 7) and C. glabrata(mean, 7) were significantly lower than those for C. albicans(mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.

ABSTRACTPrevious studies using in vivo candidiasis models have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum/MIC and 24-h area under the curve (AUC)/MIC, are associated with echinocandin treatment efficacy. The current investigations used a neutropenic murine model of disseminated Candida albicansand C. glabratainfection to identify the 24-h AUC/MIC index target associated with a stasis and killing endpoint for the echinocandin, micafungin. The kinetics after intraperitoneal micafungin dosing were determined in neutropenic infected mice. Peak levels and AUC values were linear over the 16-fold dose range studied. The serum drug elimination half-life ranged from 7.5 to 16 h. Treatment studies were conducted with 4 C. albicansand 10 C. glabrataisolates with micafungin MICs varying from 0.008 to 0.25 μg/ml to determine whether similar 24-h AUC/MIC ratios were associated with efficacy. The free drug AUC/MICs associated with stasis and killing (1-log) endpoints were near 10 and 20, respectively. The micafungin exposures associated with efficacy were similar for the two Candidaspecies. Furthermore, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those recently reported for another echinocandin, anidulafungin, against the identical Candidaisolates in this model.

ABSTRACTCaspofungin is an echinocandin antifungal agent with broad-spectrum activity against Candidaand Aspergillusspp. The in vitro activities of caspofungin against 3,959 isolates of Candidaspp. obtained from over 95 different medical centers worldwide were compared with those of fluconazole and itraconazole. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the NCCLS method using RPMI 1640 as the test medium. Caspofungin was very active against Candidaspp. (MIC at which 90% of the isolates were inhibited [MIC90], 1 μg/ml; 96% of MICs were ≤2 μg/ml). Candida albicans, C. dubliniensis, C. tropicalis, and C. glabratawere the most susceptible species of Candida(MIC90, 0.25 to 0.5 μg/ml), and C. guilliermondiiwas the least susceptible (MIC90, >8 μg/ml). Caspofungin was very active against Candidaspp., exhibiting high-level resistance to fluconazole and itraconazole (99% of MICs were ≤1 μg/ml). These results provide further evidence for the spectrum and potency of caspofungin activity against a large and geographically diverse collection of clinically important isolates of Candidaspp.

ABSTRACTWe determined the in vitro activity of flucytosine (5-fluorocytosine [5FC]) against 8,803 clinical isolates of Candidaspp. (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 Candidaisolates (MIC90, 1 μg/ml), 95% S. A total of 99 to 100% of C. glabrata(MIC90, 0.12 μg/ml), C. parapsilosis(MIC90, 0.25 μg/ml), C. dubliniensis(MIC90, 0.12 μg/ml), C. guilliermondii(MIC90, 0.5 μg/ml), and C. kefyr(MIC90, 1 μg/ml) were susceptible to 5FC at the NCCLS breakpoint. C. albicans(MIC90, 1 μg/ml; 97% S) and C. tropicalis(MIC90, 1 μg/ml; 92% S) were only slightly less susceptible. In contrast, C. kruseiwas the least susceptible species: 5% S; MIC90, 32 μg/ml. Primary resistance to 5FC is very uncommon among Candidaspp. (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.

ABSTRACTWe compared the in vitro activity of BMS-207147, an investigational triazole, with those of itraconazole and fluconazole against 613 clinical bloodstream isolates of Candidaspp. collected from SENTRY participating hospitals during 1997 and 1998. Overall, BMS-207147 was the most active azole against all Candidaspp. While both BMS-207147 and itraconazole displayed a stepwise decrease in activity against isolates for which the fluconazole MICs were elevated, BMS-207147 had two- to fourfold greater activity than itraconazole both against Candidaspp. that were dose-dependently fluconazole susceptible and against those that were fluconazole resistant.

ABSTRACTIn a phase 2 open-label, dose-ranging study in patients with candidemia, anidulafungin was effective in eradicating Candida albicansand other species of Candida. The anidulafungin MIC distribution showed that Candida albicansand C. glabratawere the most susceptible species and C. parapsilosiswas the least susceptible species.