The multidrug-resistant Candida auris, Candida haemulonii complex and phylogenetic related species: Insights into antifungal resistance mechanisms

Abstract

The rise of multidrug-resistant (MDR) fungal pathogens poses a serious global threat to human health. Of particular concern are Candida auris, the Candida haemulonii complex (which includes C. haemulonii sensu stricto, C. duobushaemulonii and C. haemulonii var. vulnera), and phylogenetically related species, including C. pseudohaemulonii and C. vulturna. These emerging, widespread, and opportunistic pathogens have drawn significant attention due to their reduced susceptibility to commonly used antifungal agents, particularly azoles and polyenes, and, in some cases, therapy-induced resistance to echinocandins. Notably, C. auris is classified in the critical priority group on the World Health Organization's fungal priority pathogens list, which highlights fungal species capable of causing systemic infections with significant mortality and morbidity risks as well as the challenges posed by their MDR profiles, limited treatment and management options. The mechanisms underlying antifungal resistance within these emerging fungal species is still being explored, but some advances have been achieved in the past few years. In this review, we compile current literature on the distribution of susceptible and resistant clinical strains of C. auris, C. haemulonii complex, C. pseudohaemulonii and C. vulturna across various antifungal classes, including azoles (fluconazole, voriconazole, itraconazole), polyenes (amphotericin B), echinocandins (caspofungin, micafungin, anidulafungin), and pyrimidine analogues (flucytosine). We also outline the main antifungal resistance mechanisms identified in planktonic cells of these yeast species. Finally, we explore the impact of biofilm formation, a classical virulence attribute of fungi, on antifungal resistance, highlighting the resistance mechanisms associated with this complex microbial structure that have been uncovered to date.

Keywords: Antifungal resistance; Biofilm; Candida auris; Candida haemulonii complex; Candida pseudohaemulonii; Candida vulturna.

Graphical abstract

Fig. 1

Candida auris and Candida haemulonii species complex macromorphology in CHROMagar™ Candida Plus after 48 h at 37 °C (A) and micromorphology evaluated by light microscopy (B) and by scanning electron microscopy (C), in which can be observed homogeneous populations of yeasts with oval shape, composed both by single and aggregated cells. Ca, means C. auris; Ch, C. haemulonii; Cd, C. duobushaemulonii and Chv, C. haemulonii var. vulnera.

Fig. 2

Distribution of susceptible (S) and resistant (R) strains of Candida auris and the Candida haemulonii species complex against fluconazole (FLC), voriconazole (VRC), itraconazole (ITC), amphotericin B (AMB), caspofungin (CSF), micafungin (MFG), anidulafungin (ANF) and flucytosine (5-FC) based on the literature review. The search was conducted in PubMed database (https://pubmed.ncbi.nlm.nih.gov) using the terms “Candida auris antifungal resistance”; “Candida haemulonii antifungal resistance”; “Candida haemulonii var. vulnera antifungal resistance”; “Candida duobushaemulonii antifungal resistance”; “Candida pseudohaemulonii antifungal resistance” and “Candida vulturna antifungal resistance” in the category “title/abstract”. Papers available in English published from 2014 to 2024, that used molecular approaches for the identification of the clinical isolates were analyzed.

Fig. 3

Scanning electron microscopy (SEM) images of the biofilms formed by clinical isolates of the C. haemulonii species complex on polystyrene surface. Yeasts (200 μL containing 10⁶ cells) were placed to interact with polystyrene coverslips at 37 °C for 48 h, and were then processed and visualized using SEM. The images reveal a dense network of yeast cells, forming three-dimensional structures by the three members of the C. haemulonii complex: C. haemulonii (A), C. duobushaemulonii (B) and C. haemulonii var. vulnera (C). The presence of an extracellular matrix (D) surrounding and holding the cells together can also be observed (white arrows).

Fig. 4

Antifungal resistance mechanisms of fungal biofilms. The image includes the main antifungal resistance mechanisms described in Candida species biofilms (the red text refers to the resistance mechanisms associated with biofilms described in C. auris until now).