Activities of E1210 and Comparator Agents Tested by CLSI and EUCAST Broth Microdilution Methods against Fusarium and Scedosporium Species Identified Using Molecular Methods

Abstract

Fusarium (n ‫؍‬ 67) and Scedosporium (n ‫؍‬ 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC 90 values (g/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 g/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC 90 was 0.12 g/ml for S. apiospermum, but 1 to >8 g/ml for other tested agents. Against S. aurantiacum, the MEC 50 for E1210 was 0.06 g/ml versus 0.5 to >8 g/ml for the comparators. Against S. prolificans, the MEC 90 for E1210 was only 0.12 g/ml, compared to >4 g/ml for amphotericin B and >8 g/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ؎2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole-and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

The Investigational Agent E1210 Is Effective in Treatment of Experimental Invasive Candidiasis Caused by Resistant Candida albicans

“…Aspergillus, and Fusarium species (6)(7)(8)(9)(10)(11)(12). Interestingly, the in vivo activity of E1210 was similar to that of fluconazole in our animal model despite the in vitro resistance of this isolate against fluconazole.…”

“…E1210 is a broadspectrum investigational antifungal agent that inhibits inositol acyltransferase, thereby preventing GPI-anchored protein maturation (6). This agent has potent in vitro activity against different pathogenic fungi, including Candida, Aspergillus, Fusarium, and Scedosporium species (6)(7)(8)(9)(10), and inhibition of inositol acyltransferase by E1210 appears to be fungus specific (11). Animal models have also demonstrated in vivo efficacy of this agent against invasive candidiasis, invasive aspergillosis, and fusariosis (12).…”

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

“…E1210 is a broad spectrum antifungal agent against different pathogenic fungi, including Candida , Aspergillus , Fusarium , and Scedosporium species (190)(191)(192)(193). Importantly, the compound seems to be fungal specifi c and does not inhibit mammalian GPI inositol acylase PIG-W activity ( 194 ).…”

International Evaluation of MIC Distributions and Epidemiological Cutoff Value (ECV) Definitions for Fusarium Species Identified by Molecular Methods for the CLSI Broth Microdilution Method

“…ECVs can identify non-wild-type (non-WT [often harboring molecular mechanisms of resistance]) isolates or isolates that are less susceptible to the antifungal agent being evaluated. Although amphotericin B and triazole MIC data have been reported for a variety of Fusarium spp., most available data were obtained for isolates identified only to the genus level or by nonmolecular methods, or the number of isolates evaluated was small (2,4,(28)(29)(30)(31). Therefore, there was a need to pool data from multiple laboratories in order to define ECVs for Fusarium spp.…”