Emerging Challenges and Mechanisms of Antifungal Drug Resistance: Implications for Treatment and Future Therapeutic Strategies
Vishnu Priya, Sushma Verma, Navneet KhuranaIntroduction:
Antifungal resistance has become a rapidly growing worldwide issue that severely impairs our ability to effectively treat patients with all forms of systemic (invasive) fungal infections, particularly those who are immunocompromised. For example, growing rates of resistance among Candida auris, azole-resistant Aspergillus fumigatus, and multidrugresistant Candida species are complicating our ability to provide effective therapy to these patients.
Methods:
We conducted a comprehensive review of major fungal pathogens, resistance mechanisms, clinical patterns/trends in the literature during the past(1) 5 years, and novel therapeutic options for management of antifungal resistance based on evidence from clinical, microbiological, and translational studies involving antifungal resistance, surveillance, and innovative ways to prevent/reduce it.
Results:
Six major mechanisms of resistance to antifungals have been identified: alterations at the target site, active efflux of the antifungal agent, decreased absorption of the antifungal agent, protection via biofilms, inactivation of antifungal agents via metabolism, and activation of stress-response pathways. Contributing factors to these mechanisms of resistance include inappropriate use of antifungal agents, exposure to azoles through agricultural practices, spread of antifungals in hospitals, biofilms associated with medical devices, and adaptation of fungi through epigenetic modification. The result of these resistance mechanisms is treatment failure, lasting infections, and increased mortality.
Discussion:
Traditional antifungal agents continue to play an important role in medicine, but they are hampered by either fungi developing resistance over time or their toxicity. This study's findings support the need for more rigorous surveillance, therapeutic drug monitoring, antifungal stewardship, and more stringent regulation on the use of fungicides in agriculture. Potential new approaches to treating fungal infections include immunotherapy directed at the host, new antifungal agents (e.g., ibrexafungerp, olorofim, rezafungin, fosmanogepix), combination therapy with pre-existing and new antifungal agents, utilization of nanotechnology delivery systems, and genomics-guided treatment strategies.
Conclusion:
Antifungal resistance requires a coordinated, multidimensional response. One Health framework integrating human, animal, agricultural, and environmental sectors is critical to slow resistance and support sustainable antifungal therapy.