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

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

Antimicrob Agents Chemother. 2019 Jun 10;:

Authors: Pfaller MA, Huband MD, Flamm RK, Bien PA, Castanheira M

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 moulds that 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: Candida (except C. krusei), Aspergillus, and hard-to-treat moulds, including Fusarium and Scedosporium In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected worldwide during 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), Asia-Pacific (12.7%), and Latin America (6.6%). Among the isolates tested, 78.5% were Candida spp., 3.9% were non-Candida yeasts, including 30 Cryptococcus neoformans var. grubii (1.8%), 14.7% were Aspergillus spp., and 2.9% were other moulds. All isolates were tested by CLSI reference broth microdilution.APX001A (MIC50/90, 0.008/0.06 μg/ml) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, APX001A (MIC50/90, 0.25/0.5 μg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var. grubii Against Aspergillus spp., AXP001A (MEC50/90, 0.015/0.03 μg/ml) was comparable in activity to anidulafungin and micafungin. Aspergillus isolates (>98%) exhibited a wild-type phenotype for the mould active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of Candida, non-Candida yeasts, and rare moulds, including 11 isolates of Scedosporium spp. (MEC values, 0.015-0.06 μg/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, yet 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.

PMID: 31182527 [PubMed – as supplied by publisher]

Source: Industry