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May 1, 2025

Rezafungin, a New Second-Generation Echinocandin

Written by: Amir Seyedmousavi

CLSI AST News Update | Volume 10, Issue 1, April 2025

 

Rezafungin is a novel systemic antifungal agent of the echinocandin class, which was approved by the US Food and Drug Administration (FDA) in March 2023 for the treatment of candidemia and invasive candidiasis in adults with limited treatment options. The echinocandins are members of a class of systemic antifungal agents that directly target the fungal cell wall.1,2 They are semi-synthetic lipopeptides developed from fermentation products of certain fungi such as Aspergillus nidulans.3 Currently, four echinocandins have been developed for clinical use: first-generation echinocandins caspofungin, micafungin, and anidulafungin, and, most recently, the second-generation rezafungin. All four inhibit β-1,3-D-glucan synthase that catalyzes the biosynthesis of β-1,3- D-glucan, a key component of the cell wall of most fungi.4 Since mammalian cells do not contain this enzyme, direct human cell toxicity is minimal.5 Although the echinocandins exhibit similar activity against a wide spectrum of fungal pathogens, differences in pharmacokinetics and pharmacodynamics should be considered when treating patients with serious fungal infections. Each of the echinocandins differs in its kinetics of hepatic metabolism, tissue distribution, half-life and drug-drug interaction profiles that leads to different dosing strategies. Of note, the echinocandins that are currently approved for humans have limited oral bioavailability and therefore, must be administered by intravenous infusion.

CLSI AST News Update | Volume 10, Issue 1, April 2025

 

Rezafungin is a novel systemic antifungal agent of the echinocandin class, which was approved by the US Food and Drug Administration (FDA) in March 2023 for the treatment of candidemia and invasive candidiasis in adults with limited treatment options. The echinocandins are members of a class of systemic antifungal agents that directly target the fungal cell wall.1,2 They are semi-synthetic lipopeptides developed from fermentation products of certain fungi such as Aspergillus nidulans.3 Currently, four echinocandins have been developed for clinical use: first-generation echinocandins caspofungin, micafungin, and anidulafungin, and, most recently, the second-generation rezafungin. All four inhibit β-1,3-D-glucan synthase that catalyzes the biosynthesis of β-1,3- D-glucan, a key component of the cell wall of most fungi.4 Since mammalian cells do not contain this enzyme, direct human cell toxicity is minimal.5 Although the echinocandins exhibit similar activity against a wide spectrum of fungal pathogens, differences in pharmacokinetics and pharmacodynamics should be considered when treating patients with serious fungal infections. Each of the echinocandins differs in its kinetics of hepatic metabolism, tissue distribution, half-life and drug-drug interaction profiles that leads to different dosing strategies. Of note, the echinocandins that are currently approved for humans have limited oral bioavailability and therefore, must be administered by intravenous infusion.

Echinocandins are highly active (i.e., fungicidal) against a range of Candida species including isolates that are resistant to triazoles (e.g., fluconazole, voriconazole) and those that form biofilms.6,7 They have modest activity (i.e., fungistatic) against Aspergillus spp., thermally dimorphic fungi, and melanized fungi.8-10 Their activity is weak against Mucorales, Fusarium spp., Scedosporium spp., Cryptococcus spp., and Trichosporon spp. due to lack of β-1,3-D-glucan in the cell wall of these organisms.5

Rezafungin

Rezafungin (formerly known as biafungin, CD101, and SP3025) possesses chemical and biological properties that are improved over those of the first-generation echinocandins. It is more stable both in vitro and in vivo than the other echinocandins, with higher solubility in aqueous solutions. It has a long half-life of ~80 hours following first dose (~3-fold longer than other echinocandins) and slower clearance (~7-fold slower) after intravenous injection, which enables once-weekly dosing as opposed to the first-generation echinocandins that require dosing once-daily. Tissue penetration is high, and the safety profile of rezafungin is good.

Rezafungin shows potent in vitro and in vivo activity against Candida spp. including Candida auris and other Candida species resistant to first-generation echinocandins.11 Most C. auris isolates demonstrate susceptibility to rezafungin. Studies also show that rezafungin may be used to treat infections due to Candida isolates with FKS mutations (i.e., resistant to first-generation echinocandins) when administered in higher than usual doses.12

Despite not being FDA-approved for mold infections, it has been used experimentally for Aspergillus spp., including A. fumigatus isolates harboring CYP51A mutations that lead to azole resistance.13

Susceptibility Testing and Breakpoints for Rezafungin

CLSI standard methods can be used for disk diffusion and minimal inhibitory concentration (MIC) testing of rezafungin for yeasts.14 Currently, rezafungin disks (5 μg, FDA-approved) are commercially available from Hardy Diagnostics and Oxoid Limited (Part of Thermo Fisher Scientific). The YeastOne AST plates from ThermoFisher Scientific (YO4IVD: FDA-cleared panel and YO11: Research Use Only) can be also used for rezafungin susceptibility testing (in the dilution range of 0.008-8μg/mL) using the Sensititre platform. Verification/ validation should be performed before rezafungin testing has been clinically implemented, ideally with a set of isolates that have been tested by reference broth microdilution. Currently, FDA publishes rezafungin breakpoints (MIC and disk diffusion) for four Candida species: C. albicans, C. glabrata, C. parapsilosis and C. tropicalis (Table 1). However, in 2022, CLSI published rezafungin MIC breakpoints for seven Candida species: C. auris, C. dubliniensis, and C. krusei, in addition to the 4 species listed above.15 The FDA and CLSI breakpoints for rezafungin are shown in Table 1. CLSI has not yet approved disk diffusion breakpoints for rezafungin. The only species for which the FDA and CLSI MIC breakpoints are the same is C. parapsilosis. Since nonsusceptible isolates have only been rarely recovered at this point, only a susceptible breakpoint exists. If a C. auris tests nonsusceptible to rezafungin, the laboratory should confirm identification of the isolate, repeat the MIC test using reference broth microdilution, if possible (or perform an MIC test if disk diffusion testing was initially performed), and, if your results reproduce, consider sending to a public health laboratory for confirmation.

In summary, rezafungin is an intravenous echinocandin antifungal agent approved by the FDA for once-weekly treatment of candidemia and invasive candidiasis in adults who have limited or no alternative treatment options. Rezafungin is the only antifungal agent for which a clinical breakpoint has been set by CLSI for C. auris and also offers a promising treatment option for several Candida spp. when other echinocandins test resistant.

 

References

  1. Denning DW. Echinocandins: a new class of antifungal. J Antimicrob Chemother. 2002;49(6):889-891.
  2. Mukherjee PK, Sheehan D, Puzniak L, Schlamm H, Ghannoum MA. Echinocandins: Are they all the same? J Chemother. 2011;23(6):319-325.
  3. Nyfeler R, Keller-Schierlein W. [Metabolites of microorganisms. 143. Echinocandin B, a novel polypeptide-antibiotic from Aspergillus nidulans var. echinulatus: Isolation and structural components]. [Article in German]. Helv Chimica Acta. 1974;57(8):2459-2477.
  4. Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J Med Vet Mycol. 1997;35(2):79-86.
  5. Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag. 2007;3(1):71-97.
  6. Bachmann SP, Patterson TF, Lopez-Ribot JL. In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol. 2002;40(6):2228-2230.
  7. Bachmann SP, VandeWalle K, Ramage G, et al. In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother. 2002;46(11):3591-3596.
  8. Bowman JC, Abruzzo GK, Flattery AM, et al. Efficacy of caspofungin against Aspergillus flavus, Aspergillus terreus, and Aspergillus nidulans. Antimicrob Agents Chemother. 2006;50(12):4202-4205.
  9. Kohler S, Wheat LJ, Connolly P, et al. Comparison of the echinocandin caspofungin with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model. Antimicrob Agents Chemother. 2000;44(7):1850-1854.
  10. Seyedmousavi S, Samerpitak K, Rijs AJ, et al. Antifungal susceptibility patterns of opportunistic fungi in the genera Verruconis and Ochroconis. Antimicrob Agents Chemother. 2014;58(6):3285-3292.
  11. Pfaller MA, Carvalhaes C, Messer SA, Rhomberg PR, Castanheira M. Activity of a long-acting echinocandin, rezafungin, and comparator antifungal agents tested against contemporary invasive fungal isolates (SENTRY program, 2016 to 2018). Antimicrob Agents Chemother. 2020;64(4):e00099-20. doi: 10.1128/AAC.00099-20.
  12. Bader JC, Lakota EA, Flanagan S, et al. Overcoming the resistance hurdle: Pharmacokinetic-pharmacodynamic target attainment analyses for rezafungin (CD101) against Candida albicans and Candida glabrata. Antimicrob Agents Chemother. 2018;62(6): e02614-17. doi: 10.1128/AAC.02614-17.
  13. Wiederhold NP, Locke JB, Daruwala P, Bartizal K. Rezafungin (CD101) demonstrates potent in vitro activity against Aspergillus, including azole-resistant Aspergillus fumigatus isolates and cryptic species. J Antimicrob Chemother. 2018;73(11):3063-3067.
  14. CLSI. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. 4th ed. CLSI standard M27. Wayne, PA: Clinical and Laboratory Standards Institute; 2017.
  15. CLSI. Performance Standards for Antifungal Susceptibility Testing of Yeasts. 3rd ed. CLSI supplement M27M44S. Wayne, PA: Clinical and Laboratory Standards Institute; 2022.

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