Dataset Information

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

ABSTRACT: Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e., Candida (except Candida krusei), Aspergillus, and hard-to-treat molds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 (1.8%) Cryptococcus neoformans var. grubii isolates, 14.7% were Aspergillus spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC₅₀, 0.008??g/ml; MIC₉₀, 0.06??g/ml) was the most active agent tested against Candida sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC₉₀ values were 16- to 64-fold higher. Similarly, APX001A (MIC₅₀, 0.25??g/ml; MIC₉₀, 0.5??g/ml) was ?8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (50% minimal effective concentration [MEC₅₀], 0.015??g/ml; MEC₉₀, 0.03??g/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare molds, including 11 isolates of Scedosporium spp. (MEC values, 0.015 to 0.06??g/ml). APX001A demonstrated potent in vitro activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.

SUBMITTER: Pfaller MA

PROVIDER: S-EPMC6658749 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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<i>In Vitro</i> Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

Pfaller M A MA Huband M D MD Flamm R K RK Bien P A PA Castanheira M M

Antimicrobial agents and chemotherapy 20190725 8

Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major ...[more]

PMID: 31182527

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Project description:We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n?=?1,904 isolates; 6 species), Cryptococcus neoformans (n?=?73), Aspergillus fumigatus (n?=?183), and Aspergillus flavus (n?=?45) isolates were tested for their susceptibility (S) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates (MIC50/90, 0.03/0.06??g/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.12??g/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06??g/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06??g/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12??g/ml) at ?0.12??g/ml. All (329/329 [100.0%]) Candida parapsilosis isolates (MIC50/90,1/2??g/ml) were inhibited by rezafungin at ?4??g/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C. parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other echinocandins. Detection of the HS mutation was performed by sequencing echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other echinocandins against A. fumigatus and A. flavus These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.

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Dataset Information

In Vitro Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

Publications

<i>In Vitro</i> Activity of APX001A (Manogepix) and Comparator Agents against 1,706 Fungal Isolates Collected during an International Surveillance Program in 2017.

Similar Datasets

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