Fecal Bacteriotherapy for Relapsing Clostridium difficile Infection

描述(申请人提供)：艰难梭菌是一种常见的医院病原体。艰难梭菌感染(CDI)是迄今为止北美住院患者感染性腹泻的最常见原因，自2000年以来，其发病率出现了惊人的上升。伴随着这一上升的是，导致结肠切除和/或死亡的严重疾病的比率不断上升。同样令人关切的是，社区相关CDI的发病率有所增加，据报告，这是在以前被认为是低风险的人群中发生的。CDI的一个常见管理问题是复发，在最初的感染治疗后，高达20%的患者会复发。经历1次复发的患者有40%的风险进一步复发，而有2次或更多发作的患者面临60%的风险。虽然第一次复发通常用第二个疗程的甲硝唑或万古霉素治疗，但目前的指南建议在第二次复发后逐渐减少口服万古霉素的疗程，通常在4-8周内给予，费用为3500美元。不幸的是，对于那些进一步复发的患者，治疗选择有限。许多患者变得“万古霉素依赖”，每当停止使用这种抗生素时，就会出现CDI复发。抗菌剂被认为可以改变胃肠道的正常细菌菌群，从而允许定植和/或增殖和 艰难梭菌精制毒素。用于治疗CDI的特定抗菌药也可能通过维持受干扰的肠道菌群而使患者容易进一步复发，并可能导致新出现的耐药性问题。粪便微生物区系移植(FMT)包括将健康个体的粪便注入复发的CDI患者体内，以促进正常肠道菌群缺失的再繁殖。文献仅限于个别病例和病例系列，但这些报道的近300例病例的经验表明，平均89%的接受治疗的患者中，FMT治愈了复发性CDI。FMT似乎是安全的，没有副作用或并发症，耐用且价格低廉。到目前为止，还没有发表过FMT治疗CDI的前瞻性临床试验。有必要进行研究，记录疗效以及患者的安全性和耐受性。还需要制定标准的治疗方案。我们建议进行一项随机对照临床试验，在结肠镜检查时给予FMT治疗复发的CDI，目的是建立有效性和安全性数据。这项研究包括与一名研究人员的合作，他将分析从我们的受试者(FMT前后)及其捐赠者收集的粪便中复杂的细菌群落。鉴于CDI的发病率和严重性日益增加，相当多的患者存在复发疾病的问题，以及长期口服万古霉素带来的经济负担和耐药感染，确定FMT对复发性CDI是否有效至关重要。 公共卫生相关性：在过去十年中，艰难梭菌感染(CDI)在北美的发病率和严重程度出现了令人震惊的增长。在接受CDI治疗的患者中，复发感染是一个常见的问题，通常需要长时间和昂贵的口服万古霉素疗程，而替代治疗选择有限。这项研究将确定粪便微生物区系移植是否是一种有效和安全的治疗方法。粪便微生物区系移植涉及将健康粪便捐赠者的粪便菌群应用于复发的CDI患者。

DESCRIPTION (provided by applicant): Clostridium difficile is a common nosocomial pathogen. By far the most common cause of infectious diarrhea in hospitalized patients in North America, there has been an alarming rise in incidence of C. difficile infection (CDI) since 2000. This rise has been accompanied by increasing rates of severe disease resulting in colectomy and/or death. Equally as concerning has been the increased incidence of community-associated CDI which has been reported in populations previously believed to be low risk. A common management problem in CDI is relapse, which occurs in up to 20% of patients after treatment of the initial infection. Patients who experience 1 recurrence have a 40% risk of further relapse and those with 2 or more episodes face a 60% risk. While the first relapse is generally treated with a second course of metronidazole or vancomycin, current guidelines recommend a tapering course of oral vancomycin, which is typically given over 4-8 weeks at a cost of $3500, after a second recurrence. Unfortunately, treatment options are limited for those patients who develop further recurrences. A number of patients become "vancomycin dependent," developing CDI relapse whenever this antibiotic is stopped. Antimicrobial agents are thought to alter the normal bacterial flora of the gastrointestinal tract so as to permit colonization and/or proliferation and toxin elaboration by C. difficile. The specific antimicrobials used to treat CDI also may predispose patients to further relapses through the maintenance of perturbed intestinal flora and may contribute to the emerging problems of drug resistance. Fecal microbiota transplantation (FMT) involves administration of feces from a healthy individual into a patient with relapsing CDI to promote recolonization with missing components of normal intestinal flora. The literature is limited to individual cases and case series, but these reported experiences with nearly 300 cases shows that FMT has cured relapsing CDI in a mean of 89% of patients treated. FMT appears to be safe, with no adverse effects or complications yet described, durable and inexpensive. To date there has not been a published prospective clinical trial of FMT for CDI. There is a need for research documenting efficacy as well as patient safety and tolerability. Standard treatment protocols also need to be developed. We propose to conduct a randomized, controlled clinical trial of FMT delivered at colonoscopy for treatment of relapsing CDI with the goal of establishing efficacy and safety data. This study includes collaboration with an investigator who will analyze the complex bacterial communities in stool collected from our subjects (before and after FMT) and their donors. Given the increasing incidence and severity of CDI, the problem of recurrent disease in a significant number of patients and the economic burden and drug-resistant infections associated with long- term use of oral vancomycin, it is important to determine whether FMT is effective for treatment of relapsing CDI. PUBLIC HEALTH RELEVANCE: There has been an alarming increase in the incidence and severity of Clostridium difficile infection (CDI) in North America over the past decade. Relapsing infection is a common problem in patients treated for CDI, often requiring prolonged and expensive courses of oral vancomycin with limited alternative treatment options. This study will determine if fecal microbiota transplantation, which involves administering fecal flora from a healthy stool donor to a patient with relapsing CDI, is an effective and safe treatment.