New Treatment for C. difficile-Associated Diarrhea

描述（由申请方提供）：艰难梭菌是一种产芽孢革兰氏阳性厌氧菌，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。由于CDAD的严重发病率和死亡率急剧增加，在美国和加拿大出现了抗药性，高毒力菌株。CDAD的主要危险因素是使用广谱抗生素，这会破坏肠道植物群并使致炎性C菌过度生长。很难目前治疗的最大缺点是停药后复发率高（约20%）。OPT-80是一种新的大环抗生素，也称为PAR-101，正在开发用于治疗这种疾病。该化合物具有选择性，对C.很难该化合物的选择性特征应允许患者在治疗过程中用正常植物群重新填充结肠，并降低复发的可能性。这项拟定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产物（OP-1118）的安全性和有效性，其中一些研究将是即将在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的微生物学表征，（ii）比格犬中OPT-80/PAR-101的体内毒理学研究，（iii）在C中检查可能的耐药机制，包括摄取减少和靶向修饰。（iv）用REA和Rep-PCR对C. difficile进行分子分型。PAR-101 2B/3期关键性试验入组受试者的艰难梭菌分离株，以证明对所有克隆菌株的疗效，并证实OPT-80/PAR-101治疗患者的复发率较低，（五）生态考察用OPT-80/PAR处理后肠道植物群的变化（传统培养方法和DGGE和鱼类分析）101，以建立窄谱活性的最佳剂量，并最大限度地减少治疗期间耐药性的发展，最后（vi）进行C.对北美的艰难梭菌分离株进行分析，以监测这些分离株相对于OPT-80/PAR-101以及相对于当前和其他潜在有效的未来CDAD治疗的细菌色谱图变化。 艰难梭菌是医院和长期护理机构中腹泻相关性腹泻（CDAD）的重要原因，并且是北美和欧洲CDAD重大爆发的原因。CDAD的增加与医疗保健成本显着增加和住院时间过长有关。本申请中提出的微生物和毒理学研究将为开发一种新的、更具选择性的抗C.很难

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.