Unlocking New Defenses: The Changing Landscape of Candida auris Management

Candida (Candidozyma) auris is a rapidly emerging global nosocomial pathogen with limited therapeutic options. Its persistence on skin and surfaces leads to transmission and outbreaks, making infection prevention vital. Nearly all US isolates are resistant to fluconazole and 15% are resistant to polyenes.¹

Echinocandin resistance is uncommon (<1%), but pan-resistant isolates have been reported in the United States.^2-4 These resistance estimates are based on preliminary Centers for Disease Control and Prevention (CDC) breakpoints, as standardized Clinical Laboratory Standards Institute (CLSI) breakpoints are unavailable.⁵ Although CLSI breakpoints are lacking, the European Committee for Antimicrobial Susceptibility Testing (EUCAST) recently published breakpoints for certain antifungals.⁶ Echinocandins remain the first-line treatment for invasive infections, yet emerging resistance highlights the need for new and combination strategies partnered with antifungal and diagnostic stewardship.

Next-Generation Antifungals

Rezafungin, approved in 2023 for candidemia and invasive candidiasis, is a second-generation echinocandin with a prolonged half-life and once-weekly dosing. Its potent in vitro activity extends across the 6 C auris clades and its high initial drug exposure and favorable tissue distribution show promise for effective treatment with possibly lower risk of resistance. However, FKS-mediated echinocandin resistance remains a concern.⁷

Fosmanogepix, the prodrug of manogepix, represents a new antifungal class that inhibits the fungal Gwt1 enzyme, ultimately compromising the cell wall. It has excellent in vitro activity against pan-resistant C auris isolates.^8-11 Early clinical evidence is promising. In a small phase 2 clinical trial of nine patients with Cauris candidemia, survival at 30 days was 89% with no treatment-related adverse events.¹² 

Ibrexafungerp, an oral triterpenoid FDA-approved for vulvovaginal candidiasis, targets 1,3 β-d-glucan synthase at a different binding site from echinocandins and may have limited cross-resistance. MICs against C auris typically range from 0.25 to 2 μg/mL, suggesting good in vitro activity.^13,14 A small ongoing study shows promise; among eight cases of Cauris candidemia treated with ibrexafungerp, seven patients survived.¹⁵

Evolving Combination Strategies

For infections with echinocandin-resistant C auris or those showing clinical failure, combination therapy with echinocandin and liposomal amphotericin B can be considered. This is based on consistent in vitro synergy, reported in 80% of isolates with micafungin and all isolates tested with anidulafungin or caspofungin.^16-18 Echinocandin-triazole combinations also show promise.

Micafungin combined with isavuconazole or voriconazole demonstrated synergy, while anidulafungin demonstrated mostly synergistic or additive effects with these triazoles.^19-21 Caspofungin showed synergistic and additive effects with isavuconazole, whereas 50% and 0% synergy was observed with posaconazole and voriconazole, respectively.^{19, 21-23} Flucytosine combinations resulted in additive effects with some antagonism.^24,25 Among combinations tested, isavuconazole consistently demonstrated the strongest synergy with echinocandins, offering an alternative when amphotericin is contraindicated. Despite this encouraging data, clinical correlation remains limited and combination use should be guided by susceptibilities, infection site, and patient tolerance.

New antifungals may expand future options to treat C auris infections. Currently, managing these infections requires vigilant stewardship, early detection of resistance, and evidence-based combination therapy while awaiting larger efficacy trials.

Disclaimer: The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control (CDC). The use of any product names or trade names is for identification purposes only, and does not imply endorsement or government sanction by the US Department of Health and Human Services.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

References:

1. Centers for Disease Control and Prevention. Antifungal susceptibility testing for C. auris. CDC. 2025. https://www.cdc.gov/candida-auris/hcp/laboratories/antifungal-susceptibility-testing.html. Accessed November 17, 2025.

2. Centers for Disease Control and Prevention. Tracking C. auris. CDC. 2025. https://www.cdc.gov/candida-auris/tracking-c-auris/index.html. Accessed November 17, 2025.​

3. Ostrowsky B, Greenko J, Adams E, et al. Candida auris Isolates Resistant to Three Classes of Antifungal Medications — New York, 2019. MMWR Morb Mortal Wkly Rep 2020;69:6–9. DOI: http://dx.doi.org/10.15585/mmwr.mm6901a2.

4. Lyman M, Forsberg K, Reuben J, et al. Notes from the Field: Transmission of Pan-Resistant and Echinocandin-Resistant Candida auris in Health Care Facilities ― Texas and the District of Columbia, January–April 2021. MMWR Morb Mortal Wkly Rep 2021;70:1022–1023. DOI: http://dx.doi.org/10.15585/mmwr.mm7029a2.

5. Centers for Disease Control and Prevention. Clinical Treatment of C. auris infections. https://www.cdc.gov/candida-auris/hcp/clinical-care/index.html. Accessed November 17, 2025.

6. Arendrup MC, Guinea J, Arikan-Akdagli S, et al; Subcommittee on Antifungal Susceptibility Testing of the ESCMID European Committee for Antimicrobial Susceptibility Testing. How to interpret MICs of amphotericin B, echinocandins and flucytosine against Candida auris (Candidozyma auris) according to the newly established European Committee for Antimicrobial Susceptibility Testing (EUCAST) breakpoints. Clin Microbiol Infect. 2025 Jul 11:S1198-743X(25)00340-4. doi: 10.1016/j.cmi.2025.07.002.

7. Locke JB, Andes D, Flanagan S, Redell M, Ong V, Aram JA, Pappas PG, Castanheira M, Thompson GR 3rd. Activity of rezafungin against Candida auris. J Antimicrob Chemother. 2025 Jun 3;80(6):1482-1493. doi: 10.1093/jac/dkaf124.

8. Berkow EL, Lockhart SR. Activity of novel antifungal compound APX001A against a large collection of Candida auris. J Antimicrob Chemother. 2018 Nov 1;73(11):3060-3062. doi: 10.1093/jac/dky302.

9. Maphanga TG, Naicker SD, Kwenda S, Muñoz JF, van Schalkwyk E, Wadula J, Nana T, Ismail A, Coetzee J, Govind C, Mtshali PS, Mpembe RS, Govender NP; for GERMS-SA. In Vitro Antifungal Resistance of Candida auris Isolates from Bloodstream Infections, South Africa. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0051721. doi: 10.1128/AAC.00517-21.

10. Zhu Y, Kilburn S, Kapoor M, Chaturvedi S, Shaw KJ, Chaturvedi V. In Vitro Activity of Manogepix against Multidrug-Resistant and Panresistant Candida auris from the New York Outbreak. Antimicrob Agents Chemother. 2020 Oct 20;64(11):e01124-20. doi: 10.1128/AAC.01124-20.

11. Arendrup MC, Chowdhary A, Jørgensen KM, Meletiadis J. Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e00656-20. doi: 10.1128/AAC.00656-20.

12. Vazquez JA, Pappas PG, Boffard K, Paruk F, Bien PA, Tawadrous M, Ople E, Wedel P, Oborska I, Hodges MR. Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial. Antimicrob Agents Chemother. 2023 May 17;67(5):e0141922. doi: 10.1128/aac.01419-22.

13. Wiederhold NP, Najvar LK, Olivo M, Morris KN, Patterson HP, Catano G, Patterson TF. Ibrexafungerp Demonstrates In Vitro Activity against Fluconazole-Resistant Candida auris and In Vivo Efficacy with Delayed Initiation of Therapy in an Experimental Model of Invasive Candidiasis. Antimicrob Agents Chemother. 2021 May 18;65(6):e02694-20. doi: 10.1128/AAC.02694-20.

14. Winkler M, Rhomberg P, Klauer A, Edeker S, Min S, Castanheira M. Activity of ibrexafungerp and comparator antifungals tested against Candida and Aspergillus isolates collected from invasive infections in a global surveillance program in 2023. Open Forum Infect Dis. 2025;12(Suppl 1):ofae631.1284. doi:10.1093/ofid/ofae631.1284.

15. Azie NE, King TR, Chen T, Angulo DA. Outcomes of oral ibrexafungerp in the treatment of 18 patients with Candida auris infections, from the CARES Study. SCYNEXIS, Inc. Published 2022. https://www.scynexis.com/wp-content/uploads/2022/12/2022-09-MSGERC-Outcomes-of-Oral-Ibrexafungerp-in-the-Treatment.pdf. Accessed November 17, 2025.

16. Jaggavarapu S, Burd EM, Weiss DS. Micafungin and amphotericin B synergy against Candida auris. Lancet Microbe. 2020 Dec;1(8):e314-e315. doi: 10.1016/S2666-5247(20)30194-4.

17. Hernando-Ortiz A, Eraso E, Jauregizar N, de Groot PW, Quindós G, Mateo E. Efficacy of the combination of amphotericin B and echinocandins against Candida auris in vitro and in the Caenorhabditis elegans host model. Microbiol Spectr. 2024 Jan 11;12(1):e0208623. doi: 10.1128/spectrum.02086-23.

18. Caballero U, Eraso E, Quindós G, Jauregizar N. In vitro interaction and killing-kinetics of amphotericin B combined with anidulafungin or caspofungin against Candida auris. Pharmaceutics. 2021;13(9):1333. doi:10.3390/pharmaceutics13091333.

19. Fakhim H, Chowdhary A, Prakash A, Vaezi A, Dannaoui E, Meis JF, Badali H. In Vitro Interactions of Echinocandins with Triazoles against Multidrug-Resistant Candida auris. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01056-17. doi: 10.1128/AAC.01056-17.

20. Pfaller MA, Messer SA, Deshpande LM, Rhomberg PR, Utt EA, Castanheira M. Evaluation of Synergistic Activity of Isavuconazole or Voriconazole plus Anidulafungin and the Occurrence and Genetic Characterization of Candida auris Detected in a Surveillance Program. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02031-20. doi: 10.1128/AAC.02031-20.

21. Caballero U, Eraso E, Quindós G, Vozmediano V, Schmidt S, Jauregizar N. PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris. CPT Pharmacometrics Syst Pharmacol. 2023 Jun;12(6):770-782. doi: 10.1002/psp4.12949.

22. Nagy F, Tóth Z, Nyikos F, Forgács L, Jakab Á, Borman AM, Majoros L, Kovács R. In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms. Med Mycol. 2021 Oct 4;59(10):1015-1023. doi: 10.1093/mmy/myab032.

23. Balla N, Kovács F, Balázs B, Borman AM, Bozó A, Jakab Á, Tóth Z, Kobaissi O, Majoros L, Kovács R. Synergistic Interaction of Caspofungin Combined with Posaconazole against FKS Wild-Type and Mutant Candida auris Planktonic Cells and Biofilms. Antibiotics (Basel). 2022 Nov 11;11(11):1601. doi: 10.3390/antibiotics11111601.

24. John LLH, Thomson DD, Bicanic T, Hoenigl M, Brown AJP, Harrison TS, Bignell EM. Heightened Efficacy of Anidulafungin When Used in Combination with Manogepix or 5-Flucytosine against Candida auris In Vitro. Antimicrob Agents Chemother. 2023 Jun 15;67(6):e0164522. doi: 10.1128/aac.01645-22.

25. Bidaud AL, Botterel F, Chowdhary A, Dannaoui E. In vitro antifungal combination of flucytosine with amphotericin B, voriconazole, or micafungin against Candida auris shows no antagonism. Antimicrob Agents Chemother. 2019 Sep 9;63(12):e01393-19. doi: 10.1128/AAC.01393-19.