Clostridioides difficile infection (CDI) is a major concern in hospital settings. Antimicrobial resistance is a key contributing factor in CDI outbreaks. This study analysed the antimicrobial susceptibility and PCR ribotypes (RTs) of 745 C. difficile isolates collected at a single institution over 5 years. Seventeen known RTs were identified in 643 isolates (86.3%), of which RTs 018, 017, 015, 001 and 002 were the most prevalent. Reduced susceptibility to metronidazole (MTZ) and vancomycin (VAN) was rare (2.0% and 0.7%, respectively). Resistance to rifaximin (RFX), moxifloxacin (MXF) and clindamycin (CLI) was high in multiple RTs (29.3%, 67.0% and 69.4% of total isolates, respectively). Antimicrobial susceptibility varied among RTs. Whilst non-susceptibility to VAN, RFX, MXF, CLI and piperacillin/tazobactam (TZP) mostly occurred in commonly identified RTs, MTZ resistance was observed in diverse RTs. Correlation analysis between the MICs of the six antimicrobials for annual isolates and antimicrobial consumption in the hospital by year showed variable degrees of correlation; significant positive correlation for TZP (P = 0.037), significant negative correlation for VAN (P < 0.001) and no significant correlation for the other antimicrobials. MIC creep of TZP occurred during the study period with the appearance of 19 isolates with TZP intermediate-resistance mostly in 2013 (89.5%; 17/19), and three RTs containing TZP-intermediate-resistant isolates, including RT015 (n = 4), RT002 (n = 12) and RT112 (n = 1), increased over time (P = 0.010). These findings suggest an association of antibiotic consumption and resistant C. difficile strains and question TZP use for limiting CDI in hospitals.