Evaluation of C. difficile Severity in Epidemiologic Studies & in Animal Models

描述（由申请人提供）：艰难梭菌相关性腹泻（CDAD）是院内腹泻的主要原因。甲硝唑或万古霉素治疗进一步抑制正常菌群，导致15-25%的复发率和延长机体脱落。CDAD的流行和社区感染表明CDAD的性质正在发生变化。III型毒素，NAP1/027/BI菌株（BI），虽然自1984年以来就存在，但现在具有喹诺酮类药物耐药性，并且与疾病严重程度增加有关。此外，一种自然产生的菌株8864毒素a -/B+，带有变异毒素B，已被证明分别在小鼠和仓鼠模型中导致死亡率和腹泻增加。对于这些特征、获得风险因素或这些新出现菌株与传统菌株患者的详细临床病程之间的关系的性质尚未达成共识。该项目将利用在开创性肠道发病机理实验室的经验、公共卫生科学专业知识、UVA数据库以及与TechLab的合作，对新出现的菌株开展关键研究，以评估风险因素和影响，为创新的预防和控制方法做准备。这项研究使研究者与大学/行业合作，特别是推进她的职业目标进行临床试验。具体目的是：(1)进行回顾性病例对照分析，以确定成人发生BI引起的非传染性CDAD的危险因素；(2)前瞻性病例对照分析，评价非传染性BI CDAD成年患者的临床病程；(3)确定临床分离的BI菌株对叙利亚仓鼠模型疾病和死亡率的影响，以及纯化的BI相关毒素对家兔回肠袢模型分泌和组织学变化的影响。该项目还将研究菌株8864在这2种动物模型中的作用，为测试疾病控制的新方法做准备。这些问题的答案将提供对新出现的CDAD的更好理解，从而使用新开发的方法改进这种令人担忧的不断发展的疾病的治疗策略，无论是通过结合毒素（Louie， Peppe等人，2006）还是通过药物阻断或逆转其作用，正如我们小组所做的那样（Cavalcante， Castro等人，2006）。

DESCRIPTION (provided by applicant): C. difficile associated diarrhea (CDAD) is the leading cause of nosocomial diarrhea. Treatment with metronidazole or vancomycin further suppresses normal flora and contributes to the 15-25% relapse rate and prolonged shedding of the organism. CDAD epidemics and community acquisition suggest that the nature of CDAD is changing. Toxinotype III, NAP1/027/BI strains (BI), although present since 1984, now have quinolone resistance, and they have been associated with increased disease severity. Additionally, a naturally occurring strain, 8864, toxin A-/B+, with variant toxin B, has been shown to cause increased mortality and diarrhea in mouse and hamster models, respectively. There is not a consensus as to the nature of the relationship of these characteristics, risk factors for acquisition, or detailed clinical course of patients with these emerging strains versus traditional strains. Building upon experience in a pioneering enteric pathogenesis laboratory, expertise in public health sciences, the UVA data repository, and collaborations with TechLab, this project will launch critical studies with the emerging strains to evaluate risk factors and impact, in preparation for innovative approaches to prevention and control. This study engages the investigator with university/industry collaborations that specifically advance her career goals of conducting clinical trials. The specific aims are to (1) conduct a retrospective case-control analysis to identify risk factors for adults developing non-epidemic CDAD caused by BI; (2) perform a prospective case-control analysis to evaluate the clinical course of adult patients with non-epidemic BI CDAD; and (3) determine the effects of clinically isolated BI strains on disease and mortality in the Syrian hamster model and the effects of purified toxins associated with BI on secretion and histological changes in the rabbit ileal loop model. The project will also examine the effects of strain 8864 in these 2 animal models in preparation for testing novel approaches to disease control. The answers to these questions will offer an improved understanding of the emerging CDAD, so as to lead to improved treatment strategies for this worrisome evolving disease using newly developing approaches, whether by binding toxin(s) (Louie, Peppe et al. 2006) or by pharmacologically blocking or reversing their effects, as done by our group (Cavalcante, Castro et al. 2006).