In Vitro Activity of Ibrexafungerp against a Collection of Clinical Isolates of Aspergillus, Including Cryptic Species and Cyp51A Mutants, Using EUCAST and CLSI Methodologies.

Olga Rivero-Menendez,Juan Carlos Soto-Debran,Manuel Cuenca-Estrella,Ana Alastruey-Izquierdo

doi:10.3390/jof7030232

Abstract

Ibrexafungerp is a new orally-available 1,3-β-D-glucan synthesis inhibitor in clinical development. Its in vitro activity and that of amphotericin B, voriconazole, and micafungin were evaluated against a collection of 168 clinical isolates of Aspergillus spp., including azole–susceptible and azole–resistant (Cyp51A mutants) Aspergillus fumigatus sensu stricto (s.s.) and cryptic species of Aspergillus belonging to six species complexes showing different patterns of antifungal resistance, using EUCAST and CLSI antifungal susceptibility testing reference methods. Ibrexafungerp displayed low geometric means of minimal effective concentrations (MECs) against A. fumigatus s.s. strains, both azole susceptible (0.040 mg/L by EUCAST and CLSI versus 1.231 mg/L and 0.660 mg/L for voriconazole, respectively) and azole resistant (0.092 mg/L and 0.056 mg/L, EUCAST and CLSI, while those for voriconazole were 2.144 mg/L and 2.000 mg/L). Ibrexafungerp was active against most of the cryptic species of Aspergillus tested, yielding MEC values only comparable to those of micafungin. Nevertheless, this new compound exhibited a moderate activity against A. ustus complex species, MECs ≥ 0.5 mg/L against Aspergillus insuetus and Aspergillus keveii strains, and was inactive against the Aspergillus alliaceus isolates tested (MEC90s ≥ 16 mg/L). All in all, ibrexafungerp shows encouraging in vitro results against cryptic species of Aspergillus and azole–susceptible and azole resistant strains of A. fumigatus, some of which are difficult to treat using the available therapeutic options.

Highlights

Aspergillus species are ubiquitous filamentous fungi that can cause a wide range of infections that are increasing their incidence and threatening the survival of their hosts, especially immunocompromised patients [1]
While Aspergillus fumigatus is responsible for most of the fatal cases of invasive fungal disease, the availability of molecular identification tools has led to the description of cryptic species that had previously been misidentified by classical methods [2]
Its in vitro activity has been successfully assessed against Candida spp., including echinocandin resistant and multidrug–resistant Candida glabrata and Candida auris [11,12,13], and several Aspergillus species, among which azole or echinocandin resistant A. fumigatus isolates stand out, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus, and a scarce number of Aspergillus glaucus, Aspergillus nidulans, and Aspergillus westerdijkiae strains have been tested leading to promising results [14,15,16,17]

Summary

Introduction

Aspergillus species are ubiquitous filamentous fungi that can cause a wide range of infections that are increasing their incidence and threatening the survival of their hosts, especially immunocompromised patients [1]. Related cryptic species are gathered in species complexes Their importance in the clinical setting, in which they have been reported to have a prevalence of up to 19% in several studies [3,4,5], and up to 29% in a recent one [6], is determined by the low susceptibility they generally show against antifungals [3]. Ibrexafungerp, formerly SCY–078, is the most representative compound within the triterpenes, a new class of antifungals This semisynthetic derivative of enfumafungin inhibits the fungal β-(1,3)-D-glucan synthase as echinocandins do, it is structurally different from those [9] and has an overlapping but independent binding site to the enzyme that generates an alternative drug–enzyme interaction [10]. Ibrexafungerp has been reported to display a moderate activity against Scedosporium spp. and Scopulariopsis spp., it has been proved to be ineffective against Purpureocillium lilacinum, Fusarium spp

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