Investigational Rezafungin Shows In Vitro Activity Against Azole-Resistant Aspergillus

Rezafungin, an investigational antifungal therapy with an approximate half-life in humans of 130 hours, has demonstrated in vitro activity against Aspergillus spp, according to the results of a recent study published in the Journal of Antimicrobial Chemotherapy.^1,2 Activity was noticeable against azole-resistant A fumigatus isolates and cryptic species with increased posaconazole and voriconazole minimum inhibitory concentration (MICs).

Clinical Aspergillus isolates obtained from the University of Texas Health Science Center at San Antonio were used for analysis. Isolates were comprised of wild type (n = 15), azole-resistant A fumigatus (n = 31), A lentulus (n = 11), A thermomutatus (n = 5), A udagawae (n = 5), and A calidoustus (n = 11).

The investigators obtained rezafungin powder prepared stock solutions of caspofungin, rezafungin, caspofungin, micafungin, posaconazole, and voriconazole in dimethyl sulfoxide (DMSO). Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth microdilution methods were used to perform in vitro susceptibility testing. For caspofungin, rezafungin, and micafungin, the minimum effective concentrations (MECs) were recorded “as the lowest concentration that resulted in morphological changes (ie, short, stubby, abnormally branched hyphae) after 24 hours of incubation at 35°C.” Additionally, the MICs of both posaconazole and voriconazole were recorded “as the lowest concentration that resulted in 100% growth inhibition after 48 hours of incubation.”

In regard to A fumigatus, geometric mean MECs of rezafungin were .024 and .043 mg/L for wild type and azole-resistant isolates, respectively. The investigators observed activity of rezafungin against cryptic species of Aspergillus, including A calidoustus (.044 mg/L), A lentulus (.016 mg/L), A thermomutatus (MEC range ≤.015—.25 mg/L), and A udagawae (≤.015—.03 mg/L).

Activity of the investigational therapeutic was similar for caspofungin and micafungin except for A calidoustus. Rezafungin demonstrated significantly greater potency against the A calidoustus species compared with caspofungin (GM MEC .044 vs .468 mg/L, respectively; P<.0001).

Findings from this study support previously published research which has demonstrated the in vitro activity of rezafungin against isolates of A fumigatus, A flavus, A niger, and A terreus. According to these studies, MEC ranges of ≤.008-.06 mg/L of rezafungin for Aspergillus spp were observed, and mode values between .008-.015 mg/L were also found for the drug.^2,3 In 1 of these studies, the researchers found that rezafungin also showed activity against a total of 12 itraconazole non-WT isolates of A fumigatus.³

A limitation of the study was the in vitro nature of the analysis, which reduces the ability to extrapolate findings to patients. “Since our findings are from an in vitro study, it is difficult to say how these may ultimately impact clinical care,” lead study author Nathan Wiederhold, PharmD, of the University of Texas Health Science Center at San Antonio, told Contagion®.

“They do point to another potential option in patients with invasive aspergillosis. But, further studies are needed to determine if these in vitro findings are clinically relevant.” According to Dr. Wiederhold, these studies may include “animal models of invasive aspergillosis and ultimately data from clinical studies in which rezafungin is used in patients with this opportunistic fungal infection.”

Reference:

1. Krishnan BR, James KD, Polowy K, et al. CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. J Antibiot (Tokyo). 2017;70:130-135.
2. 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 [published online July 18, 2018]. J Antimicrob Chemother. doi: 10.1093/jac/dky280.
3. Pfaller MA, Messer SA, Rhomberg PR, et al.CD101,along-acting echinocandin, and comparator antifungal agents tested against a global collection of invasive fungal isolates in the SENTRY 2015 Antifungal Surveillance Program. Int J Antimicrob Agents. 2017;50:352-358.
4. Pfaller MA, Messer SA, Rhomberg PR, et al. Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp, including echinocandin- and azole-resistant isolates. J Antimicrob Chemother. 2016;71:2868-2873.