1947. Activity of Rezafungin against Echinocandin–Non-wild type C. glabrata Clinical Isolates from the Rezafungin Surveillance Program (2014–2021)
Authors: Carvalhaes Cecilia G , Rhomberg Paul , Klauer Abby , Deshpande Lalitagauri M , Castanheira Mariana 
Published: November 2023

Abstract

Background
Fluconazole (FLC) resistance (R) is common in C. glabrata (CGLA). Echinocandins (ECHs) are often used as first-line therapy. R to ECHs has been associated with FKS1 and FKS2 gene alterations. Rezafungin (RZF), a new ECH approved by the US FDA to treat candidemia and invasive candidiasis, was evaluated against a collection of ECH–non-wild type (NWT) CGLA isolates.

Methods
A total of 1045 CGLA collected (1/patient) in 2014–2021 from 58 medical centers located in North America (NA; n=459; 20 centers), Europe (EU; n=396; 23 centers), Asia-Pacific (AP; n=130; 10 centers), and Latin America (LA, n=60; 5 centers) were identified by MALDI-TOF and/or sequencing and tested by CLSI broth microdilution. CLSI breakpoints (BP) and epidemiological cut-off values were applied. ECH NWT isolates were submitted to FKS analysis by whole genome sequencing.

Results
RZF showed similar activity to other ECHs against CGLA (Table), inhibiting 98.5% at ≤0.5 mg/L. Anidulafungin (ANF), caspofungin (CSF), and micafungin (MCF) susceptibility (S) rates were 96.2%, 97.5%, and 97.3%, respectively. ECH-NWT CGLA were detected in 42 isolates (4.0% overall): NA showed the highest rate of ECH NWT isolates (29; 6.3%), followed by EU (10; 2.5%), AP (2; 1.5%), and LA (1; 1.7%). The RZF S rate was 61.9% of ECH-NWT CGLA, while the S rate to ANF, CSF, and MCF was 21.4%, 40.5%, and 33.3%, respectively. Alteration in FKS genes were observed in 31 CGLA (73.8% of ECH NWT; 3.0% overall). RZF was active against &gt;50% of these isolates. RFZ was also active against &gt;90% of ECH-NWT CGLA carrying wildtype FKS genes. Equivalent activity was noted to other ECHs against ECH-NWT isolates. However, ECHs were 4 to 8-fold more active against ECH-NWT CGLA that did not display alterations in FKS genes than those with FKS alterations. FKS2 hot spot(HS)-1 alterations were observed in 22 isolates (12 displayed S663F), while FKS1-HS1 alterations were noted in 9 isolates (7 displayed S629P). FLC-R was observed in 6.9% of CGLA overall and 16.7% of the ECH-NWT isolates.

Conclusion
RZF demonstrated potent in vitro activity against CGLA and remained active against most isolates of CGLA displaying an ECH-NWT phenotype with or without FKS alterations.

Disclosures
Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Paul Rhomberg, BS, MT(ASCP), bioMerieux: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Abby Klauer, BS, Melinta: Grant/Research Support Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Paratek: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support