Correlation of MIC with outcome for Candida species tested against caspofungin, anidulafungin, and micafungin: analysis and proposal for interpretive MIC breakpoints

Abstract

The CLSI Antifungal Subcommittee followed the M23-A2 "blueprint" to develop interpretive MIC breakpoints for anidulafungin, caspofungin, and micafungin against Candida species. MICs of < or = 2 microg/ml for all three echinocandins encompass 98.8 to 100% of all clinical isolates of Candida spp. without bisecting any species group and represent a concentration that is easily maintained throughout the dosing period. Data from phase III clinical trials demonstrate that the standard dosing regimens for each of these agents may be used to treat infections due to Candida spp. for which MICs are as high as 2 microg/ml. An MIC predictive of resistance to these agents cannot be defined based on the data from clinical trials due to the paucity of isolates for which MICs exceed 2 microg/ml. The clinical data set included only three isolates from patients treated with an echinocandin (caspofungin) for which the MICs were > 2 microg/ml (two C. parapsilosis isolates at 4 microg/ml and one C. rugosa isolate at 8 microg/ml). Based on these data, the CLSI subcommittee has decided to recommend a "susceptible only" breakpoint MIC of < or = 2 microg/ml due to the lack of echinocandin resistance in the population of Candida isolates thus far. Isolates for which MICs exceed 2 microg/ml should be designated "nonsusceptible" (NS). For strains yielding results suggestive of an NS category, the organism identification and antimicrobial-susceptibility test results should be confirmed. Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method.

FIG. 1.

Scatterplots of anidulafungin (a) and micafungin (b) versus caspofungin MICs and of anidulafungin versus micafungin (c) MICs for 5,346 isolates of Candida spp. Excellent correlations were observed for all three comparisons (r = 0.85, 0.84, and 0.89, respectively). MICs were determined for each drug using RPMI 1640 medium, a 24-h incubation, and a partial-inhibition (≥50%) endpoint.

FIG. 1.

Scatterplots of anidulafungin (a) and micafungin (b) versus caspofungin MICs and of anidulafungin versus micafungin (c) MICs for 5,346 isolates of Candida spp. Excellent correlations were observed for all three comparisons (r = 0.85, 0.84, and 0.89, respectively). MICs were determined for each drug using RPMI 1640 medium, a 24-h incubation, and a partial-inhibition (≥50%) endpoint.