Re-exposure to systemic antibiotics (i.e., antibiotics absorbed into the bloodstream) is common after a Clostridioides difficile infection (CDI) and is the strongest risk factor for a recurrent episode. Oral vancomycin to prevent a recurrence during antibiotic re-exposure may reduce this risk but the data supporting this practice are limited. The aim of this trial is:
1\) Does oral vancomycin prophylaxis prevent CDI recurrences in patients with recent CDI (within 120 days) and who are re-exposed to systemic antibiotics?
The trial will compare oral vancomycin to placebo.
Participants will:
* Take the study drug (either vancomycin or placebo) twice daily for the duration of systemic antibiotics plus once daily for 7 days after completion of systemic antibiotics. * Attend an in-person or over the phone follow-up at day 56 * Respond to weekly electronic questionnaires
Inpatient or outpatient adults (≥18 years old) treated at the participating institutions.
An episode of CDI within the preceding 120 days, diagnosed by both 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.
Treatment of the qualifying CDI episode with vancomycin or fidaxomicin for ≥10 days, and achievement of clinical cure (≤3 unformed stool per 24 hours in ≥2 days10).
Receipt of ≤3 days of at least one oral or intravenous systemic antibiotic, for which therapy is planned for at least one additional consecutive day in duration.
≥72 hours of off-study vancomycin prophylaxis for the current episode of antibiotic re-exposure.
≤1 day elapsed since discontinuation of CDI treatment
Treatment of the qualifying episode of CDI with metronidazole monotherapy or intravenous immunoglobulins.
Planned treatment with or treatment of the qualifying episode of CDI with fecal microbiota transplantation (FMT), bezlotoxumab, VOWST, REBYOTA, or another microbiome agent.
Parallel
Oral Vancomycin Prophylaxis
Drug125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days
Placebo
Drug2 capsules PO BID for the duration of antibiotic re-exposure + 1 capsule PO QD x 7 days
CDI Recurrence
Patients reporting diarrhea will be brought in for an in-person appointment that is standard of care for patients with potential rCDI and investigated as appropriate clinically without unblinding. Additionally, patients and/or their proxy will be instructed to contact the study team if they believe they are having a recurrence between contacts. Patients will be able to come be assessed for potential recurrence by infectious diseases physicians at each site (who may or may not be a part of the study) or could see their usual doctors. Recurrence will be assessed by clinical record review (chart, laboratory, pharmacy records) and any direct patient interview. CDI recurrence will be defined by 1) three or more unformed stools in a 24-hour period, 2) a positive PCR for toxin gene or and/or detection of toxin by enzyme immunoassay or cell cytotoxicity neutralization assay, and 3) administration of CDI treatment. This is similar to the definition used in the NEJM fidaxomicin trial.
Late CDI Recurrence
As per the primary outcome.
All-Cause Mortality
Patients present for their day 56 in-person follow-up are considered alive. Those responding to weekly/bi-weekly surveys (text/email/phone) are considered alive at the response time. If a patient misses the day 56 follow-up, the investigators will review their hospital file for death. If unclear, the investigators will contact the patient or proxy by phone. If unreachable and unresponsive to surveys, the investigators will check obituaries. After day 56, survey responses confirm vital status. If there is no response to the day 120 survey by day 125, the investigators will review the hospital file, check obituaries, and then attempt phone contact with the patient or proxy. If unsuccessful, the investigators will send a registered letter. Without a response, the patient will be recorded as lost to follow-up.
Discontinuation of the Study Drug Due to Adverse Event
During the in-person visit on Day 56 the investigators will inquire about adherence to the study drug and completion of the prescribed course. If the course was not completed, the investigators will inquire as to the reason why. Patients reporting cessation of the study drug due to an adverse event will be recorded as such.
Emergency Room Visits or Hospital Admissions
Within 120 days the investigators will look in the chart and the patient email/text surveys for the first episode of each of emergency room visit and/or hospital admission and record the date. Patient charts will also be flagged for immediate review should they visit the emergency room or be admitted to study centres. With explicit written patient consent, medical records from outside hospitals will be also requested for review if they report presenting elsewhere.
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