New Treatment for C. difficile-Associated Diarrhea

描述（由申请人提供）：艰难梭菌是一种产毒素的革兰氏阳性厌氧菌，是院内腹泻的最常见原因。在过去的15年中，艰难梭菌相关性腹泻（CDAD）的发病率稳步上升，这种疾病目前在北美和欧洲部分地区流行。在美国和加拿大，由于抗生素耐药、高毒性菌株的出现，CDAD的严重发病率和死亡率急剧增加。CDAD的主要危险因素是使用广谱抗生素，这会破坏肠道菌群，使产毒艰难梭菌过度生长。目前治疗的最大缺点是停药后复发率高（约20%）。OPT-80是一种新型的大环抗生素，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，对艰难梭菌具有有效的活性。这种化合物的选择性应该允许患者在治疗过程中以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在CDAD患者中进行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） Beagle犬OPT-80/PAR-101的体内毒理学研究，（iii）艰难梭菌对OPT-80/PAR-101的可能耐药机制的研究，包括减少摄取和靶标修饰。（iv）来自PAR-101 2B/3期关键试验受试者的艰难梭菌分离物的分子分型（REA和Rep-PCR），以证明对所有克隆菌株的有效性，并证实在OPT-80/PAR-101治疗的患者中复发率低；(v)在使用OPT-80/PAR-101治疗后对肠道菌群进行生态学检查（包括传统培养方法和DGGE和鱼类分析），以确定窄谱活性的最佳剂量，并尽量减少治疗期间耐药性的产生；最后（vi）对整个北美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的抗生素谱变化，以及对当前和其他潜在有效的未来CDAD治疗的变化。

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.