1947. Activity of Rezafungin against Echinocandin–Non-wild type C. glabrata Clinical Isolates from the Rezafungin Surveillance Program (2014–2021)

Abstract

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 >50% of these isolates. RFZ was also active against >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