Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris

Abstract

has simultaneously emerged on five continents as a fungal pathogen causing nosocomial outbreaks. The challenges in the treatment of infections are the variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, the susceptibility to echinocandin antifungal drugs was determined and sequencing was performed on 106 clinical isolates. Four isolates were identified to be resistant to all tested echinocandins (MIC ≥ 4 mg/liter) and harbored an S639F mutation in hot spot region 1. All remaining isolates were wild type (WT) and echinocandin susceptible, with micafungin being the most potent echinocandin (MIC = 0.125 mg/liter). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all WT isolates exhibited an Eagle effect (also known as the paradoxical growth effect), which occurred at various intensities. To assess whether the Eagle effect resulted in pharmacodynamic resistance, 8 representative isolates were evaluated for their drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in are echinocandin resistant and that routine testing of isolates for susceptibility to caspofungin by the broth microdilution method should be viewed cautiously or avoided.

Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen

“…Notably, C. auris strains were able to grow when exposed to caspofungin concentrations above their MIC, a phenomenon known as “Paradoxal effect” or “Eagle effect” (34). This effect was previously reported for Aspergillus and Candida species (34), and was very recently described for C. auris (35). C. auris MMC2 was susceptible to fluconazole, presenting a MIC at 8 μg/mL.…”

Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses

“…Numerous mechanisms of antifungal resistance have been described for C. auris . Echinocandin resistance has been linked to a single mutation at S639P/F in FKS1 , the gene that encodes the echinocandin target 1,3-beta-D-glucan synthase (23). Most isolates display a mutation linked to fluconazole resistance in C. albicans ; three mutations, Y132F, K143R, and F126L, have been identified in ERG11 , the gene that encodes the azole target lanosterol 14-α-demethylase.…”

Glucuronoxylomannan in theCryptococcusspecies capsule as a target for CAR+T-cell therapy

“…The treatments of cryptococcosis and other invasive fungal infections should display rapid fungicidal activity and completely eliminate the fungus from the host system. The rising number of antibiotic resistance strains of fungi, such as C. gattii [32] and Candida auris [33] also poses a significant threat to health. From 2004-2007 there were 83 cases of C. gattii infection in Washington and Oregon, with a mortality rate of 33%.…”