title: In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Aspergillus spp. determined by CLSI and EUCAST broth microdilution methods.
abstract: E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates of Aspergillus were tested including 20 isolates of Aspergillus flavus species complex (SC), 22 of A. fumigatus SC, 13 of A. niger SC, and 23 of A. terreus SC. The collection included 15 AMB-R (MIC, ≥ 2 μg/ml) isolates of A. terreus SC and 10 itraconazole-R (MIC, ≥ 4 μg/ml) isolates of A. fumigatus SC (7 isolates), A. niger SC (2 isolates), and A. terreus SC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ± 2 log(2) dilution steps) was 100% for all comparisons with the exception of posaconazole versus A. terreus SC (EA = 91.3%). The minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: for A. flavus SC, 0.03, ≤ 0.008, 0.12, 1, 1, and 1; for A. fumigatus SC, 0.06, 0.015, 0.12, >8, 1, and 4; for A. niger SC, 0.015, 0.03, 0.12, 4, 1, and 2; and for A. terreus SC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains of A. terreus SC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 μg/ml), A. niger SC (MEC, 0.008 μg/ml), and A. terreus SC (MEC, 0.015 μg/ml). In conclusion, E1210 was a very potent and broad-spectrum antifungal agent regardless of in vitro method applied, with excellent activity against AMB-R and itraconazole-R strains of Aspergillus spp.
authors.affiliation: JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pfaller
authors.forename: Frederick
authors.initials: F
authors.lastname: Duncanson
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Messer
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Moet
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects*; D001231:Aspergillus flavus / Q000187:drug effects; D001232:Aspergillus fumigatus / Q000187:drug effects; D000077336:Caspofungin; D054714:Echinocandins / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D055666:Lipopeptides; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: C570438:APX001A; D000631:Aminopyridines; D000935:Antifungal Agents; D054714:Echinocandins; D007555:Isoxazoles; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D017964:Itraconazole; D000077612:Anidulafungin; D000077336:Caspofungin; D065819:Voriconazole