New Treatment for C. difficile-Associated Diarrhea

描述(由申请人提供)：艰难梭菌，一种产毒的革兰氏阳性厌氧细菌，是医院内腹泻的最常见原因。在过去的15年里，艰难梭菌相关性腹泻(CDAD)的发病率一直在稳步上升，这种疾病目前在北美和欧洲的部分地区流行。随着美国和加拿大出现耐抗生素、超强毒力的菌株，CDAD的严重发病率和死亡率急剧上升。CDAD的主要风险因素是使用广谱抗生素，这会扰乱肠道菌群，允许艰难梭菌过度生长。目前治疗的最大缺点是停药后复发率高(~20%)。OPT-80是一种新型大环抗生素，也被称为PAR-101，正在开发用于治疗这种疾病。该化合物具有选择性，对艰难梭菌有较强的抑制作用。这种化合物的选择性分布应该允许患者在治疗过程中用正常菌群重新填充结肠，并减少复发的可能性。这项拟议工作的目标是通过进行毒理学和微生物学研究进一步证明该化合物及其主要代谢物(OP-1118)的安全性和有效性，其中一些研究将作为即将进行的针对CDAD患者的关键试验的辅助研究。这些研究将包括(I)OP-1118的微生物学特征，(Ii)OPT-80/PAR-101在Beagle狗身上的体内毒理学研究，(Iii)艰难梭菌对OPT-80/PAR-101的可能耐药机制的检查，包括对OPT-80/PAR-101的摄取减少和靶向修饰，(Iv)对参加PAR-101阶段2B/3关键试验的受试者分离的艰难梭菌进行分子分型(REA和Rep-PCR)，以证明对所有克隆性菌株的疗效，并证实接受OPT-80/PAR-101治疗的患者的低复发率。(V)在OPT-80/PAR-101治疗后对肠道菌群进行生态检查(采用传统培养方法以及DGGE和FISH分析)，以确定窄谱活性的最佳剂量，并将治疗过程中的耐药性发展降至最低，最后(Vi)对北美各地的艰难梭菌分离株进行监测研究，以监测这些分离株与OPT-80/PAR-101的抗菌谱变化，以及针对当前和其他潜在有效的CDAD治疗方法。 艰难梭菌是医院和长期护理机构中抗生素相关性腹泻(CDAD)的重要原因，并已导致CDAD在北美和欧洲的重大爆发。CDAD的增加与医疗成本的显著上升和住院时间过长有关。本申请中提出的微生物学和毒理学研究将为开发针对艰难梭菌的新型和更具选择性的抗生素(OPT-80/PAR-101)提供进一步的支持。

DESCRIPTION (provided by applicant): Clostridium difficile, a toxigenic, gram-positive anaerobic bacterium, is the most common cause of nosocomial diarrhea. Over the past 15 years there has been a steady increase in the incidence of Clostridium difficile- associated diarrhea (CDAD), a disease that is now epidemic in parts of North America and Europe. Serious morbidity and mortality due to CDAD has increased sharply with the emergence of antibiotifc-resistant, hypervirulent strains in the US and Canada. The primary risk factor for CDAD is the use of broad-spectrum antibiotics, which disrupt the gut flora and allow overgrowth of toxigenic C. difficile. The most significant disadvantage of current treatments is the high recurrence rate (~20%) following the withdrawal of therapy. OPT-80, a novel macrocyclic antibiotic also known as PAR-101, is being developed for the treatment of this disease. This compound is selective, with potent activity against C. difficle. The selectivity profile of this compound should allow the patient to repopulate the colon with normal flora during the course of treatment and reduce the probability of recurrence. The goal of this proposed work is to further demonstrate the safety and effectiveness of this compound and its major metabolite (OP-1118) by performing toxicology and microbiological studies, some of which will be ancillary studies to the upcoming pivotal trials in CDAD patients. These studies will include (i) microbiological characterization of OP-1118, (ii) in vivo toxicological studies of OPT-80/PAR-101 in Beagle dogs, (iii) examination of possible resistance mechanisms, including reduced uptake and target modifications, in C. difficile to OPT-80/PAR-101, (iv) molecular typing (REA and Rep-PCR) of C. difficile isolates from subjects enrolled in the PAR-101 Phase 2B/3 pivotal trial to demonstrate efficacy on all clonal strains and confirm the low recurrence rate in OPT-80/PAR-101 treated patients, (v) ecological examination (with both traditional culture methods and DGGE and fish analysis) of gut flora following treatment with OPT-80/PAR-101 to establish optimal dosing for narrow spectrum activity and minimize development of drug resistance during treatment, and finally (vi) perform a surveillance study of C. difficile isolates across North America to monitor antibiogram shift of those isolates vs. OPT-80/PAR-101 as well as against current and other potentially effective future CDAD treatments. Clostridium difficile is an important cause of antibiotic-associated diarrhea (CDAD) in hospitals and long-term care facilities and has been responsible for major outbreaks of CDAD in North America and Europe. The increase in CDAD has been associated with a significant rise in healthcare costs and excess hospital stays. The microbiological and toxicological studies proposed in this application will provide further support for development of a novel and more selective antibiotic (OPT-80/PAR-101) against C. difficile.