Candida (Candidozyma) auris is an emerging multidrug-resistant fungal pathogen capable of establishing persistent skin colonization, contaminating the environment, and causing nosocomial outbreaks associated with high mortality rates. Conventional monotherapy frequently proves inadequate against biofilm-associated infections, underscoring the urgent need for novel therapeutic strategies. Therefore, we investigated the physiological and molecular responses of South Asian clade C. auris biofilms to treatment with a caspofungin-posaconazole combination. This regimen markedly reduced the median minimum inhibitory concentrations (4- to 32-fold for caspofungin; 8- to 64-fold for posaconazole) compared with monotherapies. Synergistic interactions were observed in all isolates, with fractional inhibitory concentration indices ranging from 0.078 to 0.31, and were further confirmed in vivo. Transcriptomic profiling revealed activation of multiple stress-response pathways, driving adaptive changes such as enhanced extracellular matrix production and biofilm-forming capacity, maintenance of intracellular cation homeostasis, osmotic stress response, and extensive cell wall and membrane remodeling affecting the mannan-glucan complex, chitin, sphingolipids, phosphatidylinositol-(4,5)-bisphosphate, and ergosterol content. Additional responses included activation of RCT1 (fluconazole-inducible protein) and MDR1 (drug efflux pump), collectively promoting survival under combined antifungal pressure. These findings demonstrate the potent synergistic activity of caspofungin and posaconazole against C. auris biofilms, thereby supporting the development of effective combination therapies for this high-risk pathogen.IMPORTANCECandida auris is a rapidly emerging fungal pathogen that presents substantial challenges for infection control owing to its multidrug resistance, persistence in healthcare environments, and capacity to cause large-scale outbreaks. Biofilm formation on indwelling medical devices plays a pivotal role in C. auris outbreaks within healthcare settings and is implicated in nearly 90% of C. auris candidemia cases. These biofilms also exhibit pronounced tolerance to antifungal agents, thereby restricting available treatment options. Our study demonstrates that the combination of caspofungin and posaconazole exerts a strong synergistic effect against C. auris biofilms, both in vitro and in vivo. By elucidating the molecular mechanisms behind this synergy-including stress-response activation, cell wall and membrane remodeling, calcium signaling, and regulation of drug efflux pumps-this work provides important insights into antifungal therapeutic responses in C. auris and underscores combination therapy as a promising strategy to overcome biofilm-associated antifungal resistance in this high-risk pathogen.
Kovács et al. (Thu,) studied this question.