APX001A In Vitro Activity against Contemporary Blood Isolates and Candida auris Determined by the EUCAST Reference Method

Abstract

APX001A is the active moiety of the first-in-class drug candidate APX001. So far, most susceptibility testing studies have examined ≤30 isolates/species, and only one used the EUCAST method. Here, we investigated the activity of APX001A and five comparators against 540 candidemia and 122 isolates. Isolates (17 and 3 yeast species) were identified using CHROMagar, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) and, when needed, internal transcribed space (ITS) sequencing. EUCAST E.Def 7.3.1 susceptibility testing included APX001A, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Wild-type upper limits (WT-UL) were established following the EUCAST principles for epidemiological cutoff value setting for APX001A, allowing classification as wild type (WT) or non-WT. APX001A MIC values (mg/liter) were as follows: ,, and , 0.004 to 0.008; and , 0.016;, 0.06; and ,>0.5. APX001A MICs against the rare species varied from ≤0.0005 () to >0.5 (). APX001A was equally or more active than the comparators against all species except and Four isolates were APX001A non-WT; all were fluconazole resistant. A correlation was observed between APX001A and fluconazole MICs across all species except and , and when comparing high and low fluconazole MIC isolates of, ,, , and APX001A showed promising activity against most and other yeast species, including , compared to five comparators. WT-UL were suggested for the common species, and a new and unexplained correlation to fluconazole susceptibility was observed.

The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates In Vitro and In Vivo Activity against Candida auris

“…Several investigational agents that may alleviate the need for daily intravenous administration have shown promising in vitro activity against C. auris and in vivo efficacy in animal models of invasive infections caused by this species. These include the echinocandin rezafungin (formerly CD101) (16)(17)(18), and APX001, the prodrug of APX001A, which inhibits inositol acyltransferase, thereby preventing glycosylphosphatidylinositol-anchored protein maturation (19)(20)(21)(22). In addition, the glucan synthase inhibitor ibrexafungerp (formerly SCY-078) has demonstrated promising in vitro activity against planktonic cells and biofilms of C. auris (23,24).…”

Fungal Cell Wall: Emerging Antifungals and Drug Resistance

“…Rezafungin has potent in vitro activity against common Candida and Aspergillus species (Wiederhold et al, 2018; Arendrup et al, 2018a,b). Furthermore, this antifungal has strong in vitro antifungal activity against the potential multidrug-resistant species C. auris (Berkow and Lockhart, 2018).…”

Antifungal Resistance: Specific Focus on Multidrug Resistance in Candida auris and Secondary Azole Resistance in Aspergillus fumigatus

“…The combination of antifungals such as voriconazole and echinocandins has been shown to be promising in vitro against resistant C. auris [79]. Although some studies show variable susceptibility of C. auris to the echinocandin class [80], the good news is that there are new drugs in development with excellent activity against C. auris [71,72,73,81,82,83,84,85]. SCY-078, a novel orally bioavailable 1,3-β- d -glucan synthesis inhibitor, has been shown to exhibit both in vitro and in vivo activity against C. auris , including some echinocandin-resistant isolates.…”