In Vitro Antifungal Activity of Manogepix and Other Antifungal Agents against South African Candida auris Isolates from Bloodstream Infections

Abstract

We determined the susceptibility of South African Candida auris bloodstream surveillance isolates to manogepix, a novel antifungal, and several registered antifungal agents. C. auris isolates were submitted to a reference laboratory between 2016 and 2017. Species identification was confirmed by phenotypic methods. We determined MICs for amphotericin B, anidulafungin, caspofungin, micafungin, itraconazole, posaconazole, voriconazole, fluconazole, and flucytosine using Sensititre YeastOne and manogepix using a modified Clinical and Laboratory Standards Institute broth microdilution method. Clade distribution was determined for a subset of isolates using whole-genome sequencing. Of 394 tested isolates, 357 were resistant to at least 1 antifungal class. The manogepix MIC range was 0.002 to 0.06 μg/mL for 335 isolates with fluconazole monoresistance. Nineteen isolates were resistant to both fluconazole and amphotericin B yet still had low manogepix MICs (range, 0.004 to 0.03 μg/mL). Two isolates from the same patient were panresistant but had manogepix MICs of 0.004 μg/mL and 0.008 μg/mL. Comparing MIC₅₀ values, manogepix was >3-fold more potent than azoles, 4-fold more potent than echinocandins, and 9-fold more potent than amphotericin B. Of 84 sequenced isolates, the manogepix MIC range for 70 clade III isolates was 0.002 to 0.031 μg/mL, for 13 clade I isolates was 0.008 to 0.031 μg/mL, and for one clade IV isolate, 0.016 μg/mL. Manogepix exhibited potent activity against all isolates, including those resistant to more than one antifungal agent and in three different clades. These data support manogepix as a promising candidate for treatment of C. auris infections. IMPORTANCE Since C. auris was first detected in South Africa in 2012, health care-associated transmission events and large outbreaks have led to this pathogen accounting for more than 1 in 10 cases of candidemia. A large proportion of South African C. auris isolates are highly resistant to fluconazole but variably resistant to amphotericin B and echinocandins. There is also an emergence of pandrug-resistant C. auris isolates, limiting treatment options. Therefore, the development of new antifungal agents such as fosmanogepix or the use of new combinations of antifungal agents is imperative to the continued effective treatment of C. auris infections. Manogepix, the active moiety of fosmanogepix, has shown excellent activity against C. auris isolates. With the emergence of C. auris isolates that are pandrug-resistant in South Africa, our in vitro susceptibility data support manogepix as a promising new drug candidate for treatment of C. auris and difficult-to-treat C. auris infections.

Keywords: Candida auris; antifungal susceptibility; candidemia; fosmanogepix; manogepix; multidrug-resistant; panfungal-resistant.

FIG 1

Manogepix MICs distribution for mono-, multi-, and pandrug-resistant C. auris isolates (n = 357), South Africa, 2016 to 2017. Fluconazole MIC ≥ 32 μg/mL, micafungin MIC ≥ 4 μg/mL, amphotericin B MIC ≥ 2 μg/mL.

FIG 2

Whole-genome sequencing single nucleotide polymorphism analysis of 84 South African bloodstream C. auris isolates collected between 2016 to 2017 during national laboratory-based candidemia surveillance. The phylogenetic tree shows the relationship of isolates by clade and their susceptibility to fluconazole (FLC), micafungin (MICA), amphotericin B (AMB), and manogepix (MGX) with corresponding point mutations in the ERG11 gene (Y132F, VF125AL) associated with azole resistance, and the FKS1 gene hot spot 1 (S639P) associated with echinocandin resistance. Blue, clade III isolates; orange, clade I isolates; purple, clade IV isolate; turguoise, clade V reference isolate; red, clade II reference isolate; red, resistant isolates (FLC: ≥32 μg/mL, MICA: ≥4 μg/mL, AMB: ≥2 μg/mL); green, susceptible isolates (FLC: ≤32 μg/mL, MICA: ≤4 μg/mL, AMB: ≤2 μg/mL, MGX: ≤0.016 μg/mL); gray, mutation absent; black, mutation present.

FIG 3

Manogepix MICs distribution across different clades of C. auris isolates (n = 84), 2016 to 2017. Seventy isolates belonged to clade III, 13 to clade I, and 1 to clade IV.