Description

Clostridioides difficile is a gram-positive spore-forming anaerobic bacteria that can cause severe diarrhea through colitis. While the incidence of CDI is decreasing in Canada it remains a major cause of nosocomial infections. The annual incidence of CDI in Canada is 16,000 cases with 1,300 (8.1%) associated deaths. Estimates suggest that CDI is associated with annual economic losses of ~$150 million in Canada and that 23% of these losses are attributable to recurrent cases.

Despite appropriate treatment, approximately 20% of CDI cases experience a recurrence. Recurrent CDI (rCDI) is associated with a higher risk of death than index episodes. Although treatments such as fidaxomicin reduce the recurrence rate of CDI by approximately ~10%, cost and availability prohibit their widespread use and a substantial risk of recurrence remains (10-15%). Thus, rCDI is associated with significant morbidity, mortality, and economic cost, and consequently prevention is a substantially unmet clinical need.

Antibiotic re-exposure following completion of CDI treatment is common and is one of the strongest risk factors for CDI recurrence. In a study of 18,246 index cases of CDI, 7,730 were re-exposed to antibiotics within 8 weeks of completion of CDI treatment. Antibiotic re-exposure was the strongest predictor of rCDI with an adjusted odds ratio of 3.2 (95% Confidence Interval [95%CI]=2.9-3.4). Although avoidance of antibiotics after an index episode of CDI would be an ideal prevention strategy, it is frequently unavoidable. Therefore, strategies to reduce the recurrence rate of CDI arising from antibiotic re-exposure are of significant clinical interest.

The pathogenesis of rCDI is thought to involve persistent C. difficile colonization in a patient with an already vulnerable microbiome that is further disrupted by re-exposure to antibiotics. Vancomycin prophylaxis has been proposed as a potential strategy to reduce the risk of rCDI by inhibiting the proliferation of C. difficile during antibiotic re-exposure.

Observational evidence suggests that vancomycin prophylaxis may reduce the recurrence rate of CDI. In a Canadian study of 551 episodes of CDI with antibiotic re-exposure, patients who received vancomycin prophylaxis (n=227, 41.2%) experienced significantly less rCDI after adjusting for age (adjusted hazard ratio=0.59, 95% CI=0.43-0.80). This benefit was only identified following recurrent episodes of CDI. However, the evidence base is inconsistent, as another study found a benefit only in patients with a first episode of CDI and another suggested no benefit at all. These inconsistencies could be attributable to varying degrees of confounding by indication, ascertainment bias, immortal time bias, and a competing risk of mortality, which preclude firm conclusions from observational studies.

A single randomized controlled trial (RCT) of primary oral vancomycin prophylaxis in patients at high risk of CDI and who continued to receive systemic antibiotics demonstrated benefit in the prevention of healthcare-onset CDI (placebo 6/50 [12.0%] versus prophylaxis 0/50 [0%], P=0.03). Results of this trial are limited by its open-label design which may have led to ascertainment bias and an extremely high loss to follow-up (>50%) for the overall rCDI outcome. No RCTs of vancomycin prophylaxis for the prevention of rCDI during antibiotic re-exposure have been published to date. There is one small RCT of vancomycin prophylaxis versus placebo, randomized in a 2:1 ratio, underway with a target enrollment of 108 participants. This RCT uses a 10-day fixed duration of oral vancomycin; however, observational evidence suggests that vancomycin prophylaxis is more effective when given for ≥50% of the duration of systemic antibiotics. Thus, if the trial is negative, dosing based on the duration of antibiotic re-exposure might prove effective. Further, while this trial is appreciated, it is underpowered and unlikely to provide definitive evidence regardless of the result.

Guidelines are heterogeneous in their recommendations for vancomycin prophylaxis following antibiotic re-exposure. Whereas the American College of Gastroenterology and AMMI Canada recommend consideration of prophylaxis, the Infectious Disease Society of America refrain from making a recommendation, and the European Society of Clinical Microbiology and Infectious Diseases discourage prophylaxis. Heterogeneous conclusions from observational studies and conflicting international guideline recommendations implies clinical equipoise. Therefore, to definitively determine whether vancomycin prophylaxis is an efficacious strategy to prevent rCDI during antibiotic re-exposure, the investigators propose a randomized double-blind trial comparing vancomycin prophylaxis to placebo for patients with CDI in the past 120 days who are re-exposed to antibiotics. The proposed trial will directly inform clinical practice on the use of vancomycin for CDI prophylaxis during antibiotic re-exposure. The results are expected to be of international importance given the high incidence and economic burden of rCDI and because oral vancomycin is inexpensive, safe, and widely accessible.