Characterization of In Vitro Resistance Development to the Novel Echinocandin CD101 in Candida Species

Abstract

CD101 is a novel echinocandin with a long half-life undergoing clinical development for treatment of candidemia/invasive candidiasis and vulvovaginal candidiasis. The potential for and mechanisms underlying the development of resistance to CD101 in Candida species were investigated by using spontaneous resistance and serial passage selection methodologies. Four Candida spp. (C. albicans, C. glabrata, C. parapsilosis, and C. krusei) were chosen for resistance characterization with CD101, anidulafungin, and caspofungin. The frequency of spontaneous, single-step mutations conferring reduced susceptibility to CD101 at 1× the agar growth inhibition concentration was low across all species, with median frequencies ranging from 1.35 × 10(-8) to 3.86 × 10(-9), similar to ranges generated for anidulafungin and caspofungin. Serial passage of Candida spp. on agar plates containing drug gradients demonstrated a low potential for resistance development, with passage 20 CD101-selected strains possessing increases in MICs equivalent to or lower than those for the majority of strains generated under selection with anidulafungin and caspofungin. A total of 12 fks "hot spot" mutations were identified, typically in strains with the highest MIC shifts. Cross-resistance was broadly observed among the 3 echinocandins evaluated, with no CD101-selected mutants (with or without fks hot spot mutations) exhibiting reduced susceptibility to CD101 but not also to anidulafungin and/or caspofungin. Consistent with currently approved echinocandins, CD101 demonstrates a low potential for resistance development, which could be further enhanced in vivo by the high maximum concentration of drug in serum (Cmax)/area under the concentration-time curve (AUC) plasma drug exposure achieved with once-weekly dosing of CD101.

FIG 1

Gradient-plate serial passage MIC plots. MIC values for the selecting drugs CD101, anidulafungin (ANF), and caspofungin (CSF) were performed every fifth passage on total cell populations.