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

描述(申请人提供)：艰难梭菌相关性腹泻(CDAD)是医院内腹泻的主要原因。用甲硝唑或万古霉素治疗会进一步抑制正常菌群，导致15%-25%的复发率和机体长时间脱落。CDAD的流行和社区获取表明CDAD的性质正在发生变化。Toxinotype III，NAP1/027/BI菌株(BI)虽然自1984年就存在，但现在对喹诺酮类药物具有耐药性，并且它们与疾病严重程度的增加有关。此外，一种自然产生的菌株8864毒素A-/B+，带有变异毒素B，已被证明分别导致小鼠和仓鼠模型死亡率和腹泻的增加。对于这些新出现的菌株与传统菌株患者的这些特征、获得的风险因素或详细的临床病程之间的关系的性质，还没有达成共识。基于开创性的肠道发病机制实验室的经验、公共卫生科学的专业知识、UVA数据库以及与TechLab的合作，该项目将启动对新兴菌株的关键研究，以评估风险因素和影响，为创新的预防和控制方法做准备。这项研究让研究人员与大学/行业合作，特别是促进了她进行临床试验的职业目标。具体目的是(1)进行回顾性病例对照分析，以确定由BI引起的成人非流行性CDAD的危险因素；(2)进行前瞻性病例对照分析，以评估非流行性BI CDAD成人患者的临床病程；(3)在叙利亚仓鼠模型中确定临床分离的BI毒株对疾病和死亡率的影响，以及与BI相关的纯化毒素对兔回肠回肠模型分泌和组织学变化的影响。该项目还将检查8864菌株在这两个动物模型中的影响，为测试疾病控制的新方法做准备。对这些问题的回答将提供对新出现的CDAD的更好的理解，从而导致使用新开发的方法，无论是通过结合毒素(S)(路易，佩佩等人)来改进对这一令人担忧的进行性疾病的治疗策略。或通过药物阻断或逆转它们的作用，如我们小组所做的(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).