Systems biology evaluation of refractory Clostridioides difficile infection including multiple failures of fecal microbiota transplantation

•This patient level investigation used microbiologic and genomic techniques to investigate FMT failure.•A single C difficile strain was noted for the majority of the entire study period.•One single nucleotide polymorphism (SNP) variant was identified in the RNA polymerase (RNAP) β-subunit RpoB.•This SNV was associated with metabolic shifts but phenotypic differences in fidaxomicin MIC were not observed.•Microbiome differences were observed over time during antibiotic therapy and after failed FMTs.