Vancomycin vs. FidaxomicinVancomycin Taper to Prevent Recurrent Clostridioides Difficile

Inclusion Criteria

1. Inpatient or outpatient adults (≥18 years old) treated at the participating institutions.
2. First episode or first recurrence of CDI (i.e., second episode within 120 days) defined by a positive C. difficile assay (including PCR toxin gene detection, toxin enzyme immunoassay, and/or cell cytotoxicity neutralization assay) and the presence of either ≥3 unformed stools in <24 hours with a duration >24 hours, endoscopic/histologic evidence of pseudomembranous colitis, or ileus. For eligibility, CDI will be considered a first recurrence if the patient experiences 2 episodes within a 120-day timeframe; those with a first ever episode, or 2 episodes separated by more than 120 days, will be categorized as a first-episode.

Clinical Exclusion Criteria

1. Treatment with CDI-active antibiotics that will be continued throughout the trial (i.e., rifaximin for hepatic encephalopathy).
2. Planned or current treatment of the present episode of CDI with FMT, intravenous immunoglobulins, or other microbiome therapies (i.e., VOWST or REBYOTA).
3. Inability to take medications orally.
4. Ileostomy, colostomy, or total colectomy with ileorectal anastomosis.
5. Severe intolerance or allergy to oral vancomycin or fidaxomicin.
6. The patient is being admitted to a palliative care ward or is anticipated to die within 3 months of enrollment from another illness.
7. Fulminant CDI, defined according to the IDSA definition of CDI with the presence of hypotension, shock, ileus, and/or toxic megacolon.
8. Receipt of more than 72 hours of off-study fidaxomicin or vancomycin CDI therapy for the current episode of CDI.
9. Pregnancy or planning to become pregnant during the study period because minimal data on fidaxomicin in pregnancy are available.
10. Active breastfeeding because minimal data on fidaxomicin in breastfeeding are available.
11. Patients who have had ≥3 episodes of CDI in the last 1 year.
12. Treating team declined participation.
13. Prior enrolment in TAPER-V2.

Administrative Exclusion Criteria

1. Prior enrollment in this trial.
2. Inability to consent without a healthcare proxy.
3. Lack of health insurance.
4. Anticipated transfer to a site not involved in this trial, or to a palliative care ward
5. Patient-declared anticipated inability to participate in study follow-up or lack of means for contact in the outpatient setting.