Optimizing antifungal therapies for Candida infections: evidence, resistance, and emerging approaches

Invasive Candida infections are among the most common fungal diseases worldwide, with significant morbidity and mortality in immunocompromised individuals. The increasing prevalence of antifungal resistance in Candida species, particularly non-albicans Candida, complicates clinical management and necessitates novel treatment approaches. The emergence of resistance mechanisms has reduced the efficacy of available antifungal therapies, prompting the need for alternative strategies.

This manuscript aims to review the primary mechanisms underlying antifungal resistance in Candida species and explore emerging therapeutic strategies, including combination therapies and novel antifungal agents.

Peer-reviewed literature, clinical guidelines, and recent studies were reviewed to provide a comprehensive overview of antifungal resistance mechanisms, as well as current evidence on novel antifungal agents and combination therapy strategies for the treatment of Candida infections.

Antifungal resistance in Candida species arises through multiple mechanisms including the overexpression of efflux pumps, reducing intracellular drug concentrations; target site mutations, altering drug binding and efficacy; biofilm formation, providing a physical barrier against antifungals; phenotypic switching and adaptive stress responses; and genomic plasticity, promoting heteroresistance. Emerging therapies include novel antifungals such as rezafungin, ibrexafungerp, and fosmanogepix, as well as combination therapies targeting resistance pathways.

The increasing burden of antifungal resistance highlights the need for optimized therapeutic strategies and improved diagnostic tools. Combination therapies and novel antifungals offer promising alternatives, but further research is essential to evaluate their clinical efficacy. Strengthening antifungal stewardship programmes and enhancing surveillance for resistance patterns are critical to managing Candida infections effectively and mitigating the public health threat posed by resistant strains.