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.

Activity of a Long-Acting Echinocandin, Rezafungin, and Comparator Antifungal Agents Tested against Contemporary Invasive Fungal Isolates (SENTRY Program, 2016 to 2018)

“…In addition, the same study showed that the mutant prevention concentration, the concentration of drug that would inhibit emerging resistant mutants, for both rezafungin and micafungin was 16 g/ml (27). Given that the high plasma drug exposure of rezafungin easily exceeds the mutant prevention concentration for Candida, a possible advantage of rezafungin may be to prevent the development of resistance to the echinocandin class of antifungal agents (20,22,24,27).…”

“…Rezafungin (Cidara Therapeutics, Inc.) is a novel echinocandin that exhibits a prolonged half-life and that displays chemical stability in plasma, in aqueous solution, and at an elevated temperature (15,(21)(22)(23)(24)(25)(26)(27). The in vitro activity of rezafungin against Candida spp.…”

Repurposing of Ribavirin as an Adjunct Therapy against Invasive Candida Strains in an In Vitro Study

“…The mutation frequencies of C. albicans Q181103513 on RPMI agar plates with 3.04, 6.08, and 12.16 g/ml of ribavirin were 1.6 ϫ 10 Ϫ4 , 1.1 ϫ 10 Ϫ4 , and 9.8 ϫ 10 Ϫ4 , respectively. Thus, the overall mutation frequency was in the range of 10 Ϫ3 to 10 Ϫ4 per strain, relatively higher than that reported for classical antifungals (17). This result indicates that it is preferable to use ribavirin for a short time or in association with other antimicrobial drugs.…”

“…Mutation frequency. The frequencies of spontaneous mutations were determined on C. albicans ATCC 90028 and the multidrug-resistant (MDR) C. albicans strain Q181103513 by plating 100 l of the growing yeast at an appropriate dilution (10 3 CFU) on ribavirin-free plates and without dilution (10 5 CFU) on ribavirin-containing plates (17). RPMI 1640 agar plates with different ribavirin concentrations (1ϫ MIC, 2ϫ MIC, 4ϫ MIC) were prepared as described previously (23).…”

Opciones terapéuticas frente a especies de Candida resistentes a las equinocandinas

“…La equinocandina CD101 es un nuevo antifúngico de larga vida media (66). Su mecanismo de acción es similar al de las equinocandinas actualmente aprobadas, el cual es la inhibición de la glucano-sintasa (67) y adicionalmente presenta una modificación en su estructura (figura 1) que le confiere mejores propiedades farmacocinéticas y potencialmente mejor perfil de seguridad en comparación con otros medicamentos de la misma clase (68,69).…”