682. Novel rpoB mutations and trends in clinical Clostridioides difficile isolates with reduced fidaxomicin susceptibility

BACKGROUND: Fidaxomicin use is increasing to treat Clostridioides difficile infection (CDI) following clinical treatment guideline updates placing it as first-line therapy. This puts a selection pressure on the development of fidaxomicin resistance, which has been associated with in vitro fitness costs compared to wildtype isolates. Here we aimed to assess the epidemiology of reduced susceptibility (RS) to fidaxomicin and prevalence of rpoB mutations in a clinical cohort. METHODS: Stool samples from patients with CDI were collected from two different healthcare systems in Houston, TX between 2016-21. Fidaxomicin minimum inhibitory concentrations (MIC) were determined via agar dilution susceptibility testing following CLSI standards. RS was defined as MIC > 0.5 mg/L based on the EUCAST [T]ECOFF. A subgroup of 40 isolates with RS underwent Sanger sequencing to detect rpoB single nucleotide polymorphisms (SNPs). RESULTS: Of 535 patients included, 114 (21.3%) had infecting strains with fidaxomicin RS (MIC50 = 0.5 mg/L, MIC90 = 1.0 mg/L). Fidaxomicin RS was more common in RT 027 (49.4%, 41/83) compared to non-027 strains (16%, 68/425; P < 0.001). There were no differences in the proportions demonstrating RS across collection years (P=0.18) or based on location in or out of the Texas Medical Center (P=0.29). Mean MICs were similar between isolates collected before and after the IDSA/SHEA guideline update in 2018 (P =0.1). rpoB SNP mutations were detected in 12.5% (5/40) of isolates at 7 novel base positions; no SNPs were detected at previously reported position 3428. CONCLUSION: RS to fidaxomicin occurred in one fifth of clinical isolates with no changes in incidence between 2016-21. Several new rpoB SNPs were observed in isolates with RS. Studies are needed to determine potential association(s) between fidaxomicin exposure and MIC changes. DISCLOSURES: Anne J. Gonzales-Luna, PharmD, BCIDP, Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Personal Fees|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin Garey, PharmD, MS, BCIDP, Acurx Pharmaceuticals: Grant/Research Support|Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Vedanta Therapeutics: Grant/Research Support