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

描述（由申请人提供）：C。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进一步抑制正常植物群，并导致15-25%的复发率和延长的有机体脱落。CDAD的流行和社区获得表明CDAD的性质正在发生变化。毒素型III，NAP 1/027/BI菌株（BI），虽然自1984年以来就存在，但现在具有喹诺酮耐药性，并且它们与疾病严重程度增加有关。此外，天然存在的菌株8864，毒素A-/B+，以及变体毒素B，已显示分别在小鼠和仓鼠模型中引起死亡率增加和腹泻。关于这些特征之间的关系性质、获得的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，尚未达成共识。基于开拓性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，为预防和控制的创新方法做准备。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BI引起的成人非流行性CDAD的风险因素;（2）进行前瞻性病例对照分析，以评价非流行性BI CDAD成人患者的临床病程;以及（3）确定临床分离的BI菌株对叙利亚仓鼠模型中疾病和死亡率的影响，以及与BI对兔回肠袢模型中的分泌和组织学变化的影响。该项目还将在这两种动物模型中检查菌株8864的影响，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的更好的理解，从而使用新开发的方法，无论是通过结合毒素（Louie，Peppe et al. 2006）还是通过阻断或逆转其作用（如我们小组所做的那样）（Cavalcante，Castro et al. 2006），改进这种令人担忧的不断发展的疾病的治疗策略。

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).