Dr. John Toney, Professor of Medicine at the USF Morsani College of Medicine, looks at the current landscape of Clostridioides difficile infection in the post-COVID environment. A great deal has changed in the years COVID-19 was a major health treat…including taxonomy, epidemiology, and disease prevalence and distribution, as well as treatment practices. Dr. Toney looks at the role of bile acids in C. difficile, as well as virulence mechanisms. Next, he describes the growing recognition for the need for two step testing to screen for true c. diff associated diarrhea. He then describes antimicrobial management, divided into first episode and subsequent recurrences. Also discussed are emerging biotherapeutic options for treatment and whether a C. difficile vaccine will ever be possible.