Secondary Prevention of Clostridioides Difficile Using Vancomycin

Официальное название

Secondary Prophylaxis of Recurrent Clostridioides Difficile Infections During Systemic Antibiotics With Vancomycin: A Randomized Controlled Trial

Обзор

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

Подробное описание

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.

Вмешательства

• Препарат Oral Vancomycin Prophylaxis
  125mg PO BID for the duration of antibiotic re-exposure + 125mg PO QD for 7 days
• Препарат Placebo
  2 capsules PO BID for the duration of antibiotic re-exposure + 1 capsule PO QD x 7 days

Первичные конечные точки

• CDI Recurrence [Срок оценки: 56 Days]

Вторичные конечные точки (5)

• Late CDI Recurrence [Срок оценки: 120 Days]
• All-Cause Mortality [Срок оценки: At 56 and 120 days]
• Discontinuation of the Study Drug Due to Adverse Event [Срок оценки: 56 Days]
• Emergency Room Visits or Hospital Admissions [Срок оценки: At 56 and 120 days]
• Adverse Events [Срок оценки: 56 days]

Критерии участия

Критерии включения

• 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.

Clinical Exclusion Criteria

• ≥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.
• Inability to take medications orally.
• Ileostomy, colostomy, or total colectomy with ileorectal anastomosis.
• Severe intolerance or allergy to oral vancomycin.
• Lack of achievement of clinical cure during the treatment of the qualifying CDI episode
• The qualifying antibiotic is solely for prophylaxis (e.g., once daily trimethoprim sulfamethoxazole) or the patient is anticipated to require systemic antibiotics for >4 weeks (e.g., lifelong suppressive therapy or for the treatment of left-sided endocarditis or a deep-seated abscess).
• Patients on ongoing systemic antibiotics since the completion of treatment for the qualifying episode of CDI that have not been interrupted by at least one day.
• Patients admitted to a palliative care ward or who are anticipated to die within 8 weeks of enrollment from another illness.
• The qualifying antibiotic is non-systemic (i.e., topical) or is not considered a significant risk factor for CDI including: single-dose antibiotics, as well as macrolides, nitrofurantoin, intravenous vancomycin, metronidazole, tetracyclines, and oral fosfomycin. If two or more systemic antibiotics are given (i.e., ceftriaxone and azithromycin), as long as at least one of the systemic antibiotics does not meet exclusion criteria, then the patient will still be eligible.
• Concomitant receipt of rifaximin (e.g., for hepatic encephalopathy).
• Receipt of ≥2 courses of vancomycin prophylaxis since the qualifying episode of CDI or <2 weeks since the last course of vancomycin prophylaxis.
• Treating team declined participation.

Administrative Exclusion Criteria

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

Канада · 1 центр

• McGill University Health Centre — Montreal

Публикации

• van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, Krutova M, Noren T, Allerberger F, Coia JE, Goorhuis A, van Rossen TM, Ooijevaar RE, Burns K, Scharvik Olesen BR, Tschudin-Sutter S, Wilcox MH, Vehreschild MJGT, Fitzpatrick F, Kuijper EJ; Guideline Committee of the European Study Group on Clostridioides difficile. European Society of Clinical Microbiology and Infectious Diseases: PMID 34678515
• Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021 Sep 7;73(5):e1029-e1044. doi: 10.1093/cid/ciab549. PMID 34164674
• McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar PMID 29562266
• Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, Stollman NH. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021 Jun 1;116(6):1124-1147. doi: 10.14309/ajg.0000000000001278. PMID 34003176
• San-Juan R, Origuen J, Campion K, Fernandez-Ruiz M, Diaz-Pollan B, Callejas-Diaz A, Candela G, Orellana MA, Lora D, Llorente Munoz I, Garcia MT, Martinez-Una M, Ferrari JM, Aguado JM. Evaluation of the effectiveness and safety of oral vancomycin versus placebo in the prevention of recurrence of Clostridioides difficile infection in patients under systemic antibiotic therapy: a phase III, randomise PMID 37709311
• Maraolo AE, Mazzitelli M, Zappulo E, Scotto R, Granata G, Andini R, Durante-Mangoni E, Petrosillo N, Gentile I. Oral Vancomycin Prophylaxis for Primary and Secondary Prevention of Clostridioides difficile Infection in Patients Treated with Systemic Antibiotic Therapy: A Systematic Review, Meta-Analysis and Trial Sequential Analysis. Antibiotics (Basel). 2022 Jan 30;11(2):183. doi: 10.3390/antibiot PMID 35203786
• Johnson SW, Brown SV, Priest DH. Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure. Clin Infect Dis. 2020 Aug 22;71(5):1133-1139. doi: 10.1093/cid/ciz966. PMID 31560051
• McDonald EG, Prosty C, Hanula R, Bortolussi-Courval E, Albuquerque AM, Tong SYC, Hamilton F, Lee TC. Observational versus randomized controlled trials to inform antibiotic treatment durations: a narrative review. Clin Microbiol Infect. 2023 Feb;29(2):165-170. doi: 10.1016/j.cmi.2022.09.002. Epub 2022 Sep 13. PMID 36108947

Идентификаторы

NCT: NCT06979609 · 2025-11089

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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