Antifungal resistance has emerged as a critical global health challenge, threatening the management of invasive fungal diseases (IFDs) among immunocompromised individuals. Limited therapeutic options, delayed diagnosis, and rising drug resistance converge to create a perfect storm for poor outcomes. Although only five main antifungal classes— allylamines (e.g., terbinafine), echinocandins (e.g. anidulafungin, caspofungin, micafungin, and rezafungin), polyenes (e.g. amphotericin B), pyrimidine analogues (e.g. flucytosine), and triazoles (e.g. fluconazole, isavuconazole, itraconazole, posaconazole, and voriconazole) —are currently available, resistance now affects each of them, including multidrug-resistant and intrinsically resistant fungi such as Candida auris/Candidozyma auris and Candida glabrata/Nakaseomyces glabrata. The intersection of clinical misuse, environmental selection, and inadequate diagnostics underscores the urgency of developing coordinated, evidence-based antifungal strategies.
Four major antifungal strategies—prophylaxis, empiric, pre-emptive, and targeted therapy—define current clinical practice, each with distinct benefits and pitfalls. Prophylaxis, essential in high-risk hematologic and transplant populations, prevents infection but drives selective pressure that favours resistant Candida and Aspergillus species. Empiric therapy, often initiated during persistent febrile neutropenia, may improve survival but risks unnecessary exposure and resistance selection. Pre-emptive and targeted therapies rely on timely diagnostics to balance early intervention with antifungal stewardship (AFS), yet limited access to mycology services and rapid biomarker testing hampers their implementation—especially outside high-income regions.
Rapid molecular and antigen-based assays (e.g., galactomannan, β-D-glucan) have revolutionized early detection, but diagnostic gaps persist in sensitivity, turnaround time, and resistance detection. Therapeutic drug monitoring (TDM) plays a pivotal role in ensuring adequate exposure for variable pharmacokinetics of azoles and other agents, preventing subtherapeutic levels that foster adaptation. Personalized dosing, particularly in critically ill or transplant patients, remains central to resistance prevention and improved outcomes.
New antifungals—such as rezafungin, olorofim, and fosmanogepix—bring hope by introducing novel mechanisms or extended half-lives that enhance efficacy and adherence while reducing selection pressure. Long-acting echinocandins (e.g., once-weekly rezafungin) mitigate suboptimal dosing in outpatient settings, while oral amphotericin B and lipid formulations improve safety and accessibility. Combination regimens, nanotechnology-based delivery systems, and emerging immunotherapies, including CAR T cells and monoclonal antibodies targeting fungal antigens, exemplify a new frontier in resistance management.
AFS integrates diagnostics, pharmacology, and surveillance to preserve efficacy. Inappropriate empiric use, incomplete step-down therapy, and unmonitored prophylaxis remain key drivers of resistance. Global surveillance initiatives and “One Health” frameworks are essential to address the environmental and agricultural reservoirs of azole resistance, bridging human, animal, and environmental health.
Progress will depend on closing diagnostic gaps, refining prophylactic protocols, and expanding access to TDM and novel agents worldwide. Genomic epidemiology will clarify transmission dynamics of resistant strains, while precision medicine approaches may guide tailored antifungal regimens. The convergence of stewardship, diagnostic innovation, and drug development offers a path forward—transforming antifungal resistance from an escalating threat into a manageable challenge.
Reference
Van Rhijn, N., & White, P.L. Antifungal treatment strategies and their impact on resistance development in clinical settings. J Antimicrob Chemother (2025). https://doi.org/10.1093/jac/dkaf382
