Alternating antifungal therapy reduces echinocandins resistance in Nakaseomyces glabratus candidemia

The study was mainly led by researchers from China, together with international collaborators, to investigate whether an actively alternating antifungal treatment strategy could limit the adaptive evolution of echinocandin resistance in Nakaseomyces glabratus, an important cause of candidemia.

Echinocandins are currently considered frontline therapies for candidemia. However, the increasing emergence of echinocandin resistant fungal pathogens has become a major challenge in clinical treatment. Current clinical recommended antifungal treatment strategy that continuous exposure to a single antifungal drug such as echinocandin may create an evolutionary environment that favors the selection of resistant populations.

Previous studies have shown that resistance may not arise directly during treatment, but can develop from small populations of fungal cells that survive antifungal exposure through a state known as echinocandin tolerance. N. glabratus is particularly suitable for studying echinocandin resistance evolution because tolerant fungal cells can persist under echinocandin pressure and subsequently acquire resistance associated changes.

To address this challenge, researchers evaluated an alternating treatment strategy in which infected host would first receive the echinocandin drug caspofungin, proactively followed by a switch to liposomal amphotericin B. Using candidemia mouse models with different immune conditions and N. glabratus isolates with different levels of echinocandin tolerance, the team systematically compared this strategy with continuous caspofungin treatment.

The results showed that alternating caspofungin with liposomal amphotericin B accelerated fungal clearance across tested organs and reduced the emergence of echinocandin resistant populations. Regardless of whether the host is immunocompetent or immunosuppressed, and regardless of the characteristics of N. glabratus, the alternating antifungal treatment strategy showed significant advantages, suggesting its potential for clinical translation.

Further analyses demonstrated that the benefit of the alternating strategy was not primarily caused by drug synergy. Instead, the sequential use of antifungals with different mechanisms of action reduced the duration of echinocandin exposure and allowed liposomal amphotericin B to eliminate remaining echinocandin tolerant fungal cells that could otherwise serve as a reservoir for resistance evolution.

The researchers also investigated resistance associated genetic changes and found that continuous echinocandin treatment more readily promoted the emergence of resistant fungal populations, whereas alternating therapy minimized this evolutionary pathway. Safety evaluations indicated that although liposomal amphotericin B exposure was associated with measurable changes in some liver and kidney biomarkers, histological analyses showed comparable tissue damage between treatment groups.

The study provides a comprehensive way to evaluate antifungal treatment strategies, and highlights the importance of considering fungal adaptation and evolutionary dynamics when improving antifungal therapies. Rather than relying on prolonged exposure to a single drug, actively alternating antifungal agents with different mechanisms may provide an effective new strategy to improve infection clearance while reducing the likelihood of resistance development.

In summary, the new active alternating strategy proposed in this study breaks away from classic antifungal treatment strategies and holds promise for alleviating the clinical dilemma of echinocandin resistance. It provides clinically translatable new insights for echinocandin resistant or refractory fungal infections, especially candidemia, and offers solid evidence for further clinical research.

Cite this article:

Cai L, Xue X, Salehi M, et al. Alternation of Echinocandins with Liposomal Amphotericin B for Treatment of Nakaseomyces glabratus Candidemia: An Effective Strategy to Reduce Echinocandin Tolerant Pool and to Minimize Echinocandin Resistance. iFungi, 2026, 1(1): 9670002. https://doi.org/10.26599/iFungi.2026.9670002

Founders

This work was supported in part by the National Natural Science  Foundation  of  China  (82472304,  82302546, U25A2088,  82272355,  82202543),  Project  of  the  Ministry  of  Science  and  Technology  (2022YFC2504803, 2025ZD01900112),  Shanghai  Science  and  Technology

Committee (20DZ2272000), Key Clinical Specialty (JDLCZDZK-PWH),  and  the  Research  Project  of  Shanghai Changning  District  Health  Commission  (20234Y039).

About the Authors

Wenjie Fang, PhD, has an H-index of 26. His research focuses on medical mycology, invasive fungal infections, antifungal resistance, and the development of novel diagnostic and therapeutic strategies for fungal diseases. He has published nearly 100 papers, including articles in Signal Transduction and Targeted Therapy, Journal of the American Academy of Dermatology, Journal of Biomedical Science, etc. He is a corresponding author of the study.

Amir Arastehfar, PhD, has an H-index of 38. His research focuses on fungal drug resistance and tolerance, host pathogen interactions, and the development of novel antifungal therapeutic strategies for invasive fungal diseases. He has published more than 100 papers, including articles in The Lancet Infectious Diseases, Nature Communications, Clinical Microbiology Reviews, Studies in Mycology, and Antimicrobial Agents and Chemotherapy, etc. He is a corresponding author of the study.

Weihua Pan, PhD, has an H-index of 36. Her research focuses on medical mycology, fungal infections, antifungal resistance, and the development of innovative diagnostic and therapeutic strategies for invasive fungal diseases. She has published more than 200 papers, including articles in iMeta, Clinical Microbiology Reviews, American Journal of Respiratory and Critical Care Medicine, etc. She is a corresponding author of the study.

Liuyang Cai, MD, conducts research on medical mycology, antifungal drug resistance, fungal adaptive evolution, and innovative therapeutic strategies for invasive fungal diseases. She has published papers in Frontiers in Immunology, Frontiers in Microbiology, and BMC Microbiology, etc. She is the first-listed co-first author of the study.

Xiaochun Xue, PhD, has an H-index of 11. Her research focuses on medical mycology, antifungal resistance, fungal adaptive evolution, and the development of innovative therapeutic strategies for invasive fungal diseases. She has published more than 70 papers, including articles in Medical mycology, BMC Infectious Diseases, Mycopathologia, etc. She is a co-first author of the study.