Abstract Background Revised clinical practice guidelines for Clostridium difficile infection (CDI) were published in February 2018. Our objective was to determine if oral vancomycin, fidaxomicin and oral metronidazole use in the United States (US) changed after publication of the revised guidelines. Methods We obtained US antibiotic prescription data (IQVIA, Durham, NC) from 2006-August 2019, and used vancomycin, fidaxomicin and metronidazole dosing regimens recommended against CDI to estimate monthly numbers of 10-day treatment courses of each drug. Interrupted time-series analyses were performed, adjusted by month for possible seasonality. We compared linear trends for monthly numbers of treatment courses in different time periods.