Serial Fecal Microbiota Transplant Plus Fidaxomicin in the Treatment of Severe or Fulminant Clostridioides Difficile Infection

Abstract

BACKGROUND Severe and fulminant Clostridioides Difficile infection (CDI) is associated with high rates of mortality and morbidity. Current practice guidelines recommend high dose vancomycin with metronidazole for treatment. Emerging evidence suggests efficacy of sequential fecal microbiota transplantation (FMT) by colonoscopy combined with vancomycin in patients failing maximal medical therapy. Fidaxomicin is non-inferior to vancomycin in treating CDI; however, it has not been studied in severe/fulminant cases. This single-center, prospective, open-label study aimed to determine the efficacy and safety of combined serial FMT by enema plus fidaxomicin to treat patients who have severe or fulminant CDI not responding to maximal medical therapy. This study also explored changes in host serum metabolites, immune profiles, and stool metabolites before and after treatment. METHODS Consecutive patients with severe or fulminant CDI who fulfilled study inclusion and exclusion criteria were recruited. Sequential cycles of FMT, administered by enema daily over three days (720cc followed by 360cc and 180cc), plus fidaxomicin 200mg orally twice daily were given. Clinical symptoms and inflammatory markers were monitored during the study. Serum and stool samples were taken at regular intervals to determine changes in bile acids, short chain fatty acids and C difficile antibody production in these patients. The primary outcome was resolution of diarrhea 2 weeks following final FMT. Secondary outcomes were 1) resolution of diarrhea 8 weeks following final FMT; 2) safety of proposed treatment; and 3) colectomy rate. Exploratory outcomes included changes in host and microbiome metabolomics with serum and stool short-chain fatty acids and serum bile acids in addition to host immune response through antibody production after treatment. Study samples were compared to a historical control who received FMT and vancomycin. RESULTS A total of three patients were enrolled in this study between Jan 22, 2019, to Aug 8, 2019; two of them reached both primary and secondary outcomes. There were no adverse events reported during this study. Of note the patient that failed the primary outcome had four prior episodes of CDI in which he failed multiple FMTs with vancomycin and metronidazole. Changes in both bile acids and short-chain fatty acids before and after treatment in a responding patient found trends similar to prior literature for recurrent CDI patients. CONCLUSIONS This pilot study is the first to demonstrate efficacy and safety of combined FMT by enema and fidaxomicin in treating severe or fulminant CDI patients. Exploratory analysis sheds light on the intricacies of the host-microbiome interaction with CDI. Further studies are needed to develop more refined therapeutic options for CDI.