Use of vancomycin to treat Clostridioides difficile infection (CDI) has increased following recent IDSA/SHEA treatment guideline updates, applying a selection pressure for resistance development. We previously demonstrated acquired mutations in VanSR two-component system led to constitutive vanG expression and improved in vitro C. difficile survival in physiologic vancomycin concentrations. We aim to describe the molecular epidemiology of reduced vancomycin susceptibility in clinical isolates during a period of high vancomycin use.
A cohort study was performed including adult patients hospitalized with CDI in two health systems (14 hospitals) in the Houston Area between 2017-2021. (Stool transport) C. difficile were ribotyped by fluorescent PCR and susceptibility tested by agar dilution in accordance with CLSI standards. Reduced vancomycin susceptibility was defined by minimum inhibitory concentrations (MICs) <2 mg/L. Sanger sequencing was conducted on a subgroup of isolates to identify VanSR mutations. Analysis using Chi square was performed using IBM SPSS Statistics (v 126.96.36.199).
A total of 36% (165/465) of isolates exhibited reduced vancomycin susceptibility (MIC50 = 2 mg/L, MIC90 = 4 mg/L, range 0.5-16 mg/L), of which 348 were ribotyped. A significantly higher proportion of ribotype (RT) 027 isolates demonstrated reduced vancomycin susceptibility (83%) compared to other common ribotypes (30%); p> 0.001). No differences based on collection year (p=0.3) or healthcare system (p=0.08) were observed. Overall, 11% (7/56) of isolates exhibiting mutations in VanS (n=1), VanR (n=5), or both (n=1). VanSR mutations were present in 47% (7/15) of those with MICs <2mg/L vs 0% (0/41) of those with MICs 2 mg/L (p> 0.001).
A high proportion of clinical C. difficile isolates exhibited elevated MICs to vancomycin, which was most common in RT027 isolates. Mutations in the vanG regulator, VanSR, correlated with elevated MICs in a subgroup of isolates. Future research is needed to expand upon molecular mechanisms and clinical implications of reduced vancomycin susceptibility.
Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support.