Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019)
Michael A. Pfaller, Michael D. Huband, Robert K. Flamm, Paul Bien, Mariana Castanheira
Abstract
ABSTRACT Objectives : Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei ), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018–2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non- Candida yeasts including 49 Cryptococcus neoformans var. grubii , 21.7% were Aspergillus spp. and 4.1% were other moulds. Methods Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. Results Manogepix (MIC 50/90 , 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC 90 values were 16- to 64-fold higher. Similarly, manogepix (MIC 50/90 , 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii . Against Aspergillus spp., manogepix (MEC 50/90 , 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida , non- Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora ( Scedosporium ) prolificans. Conclusion Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections.