title: 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 (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC(90) was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC(50) for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC(90) for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/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.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA. mariana-castanheira@jmilabs.com
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.forename: Frederick P
authors.initials: FP
authors.lastname: Duncanson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Diekema
authors.forename: Josep
authors.initials: J
authors.lastname: Guarro
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pfaller
mesh_terms: D000215:Acylation / Q000187:drug effects; D000631:Aminopyridines / Q000494:pharmacology*; D000666:Amphotericin B / Q000494:pharmacology; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000494:pharmacology*; D000077336:Caspofungin; D054714:Echinocandins / Q000494:pharmacology; D005670:Fusarium / Q000187:drug effects* / Q000254:growth & development; D017261:Glycosylphosphatidylinositols / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007294:Inositol / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology; D021681:Scedosporium / Q000187:drug effects* / Q000254:growth & development; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: C570438:APX001A; D000631:Aminopyridines; D000935:Antifungal Agents; D054714:Echinocandins; D017261:Glycosylphosphatidylinositols; D007555:Isoxazoles; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D007294:Inositol; C101425:posaconazole; D000666:Amphotericin B; D000077612:Anidulafungin; D000077336:Caspofungin; D065819:Voriconazole
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