Cranberry and Prevention of UTI A Comprehensive Approach

描述(由申请人提供)：尿路感染是年轻健康女性中非常常见的门诊问题，导致相当大的发病率和医疗费用。抗生素耐药性的增加，特别是在社区获得性尿路感染中，使这些感染的治疗变得更加困难。因此，迫切需要新颖、安全和有效的非抗菌素预防策略。公众、卫生保健提供者和科学界一直感兴趣的一种方法是摄取用于预防和/或治疗尿路感染的小红莓产品。然而，尽管小红莓很受欢迎，但还没有研究将它的体外效应与临床效应联系起来，这使得从机械上解释临床试验中观察到的结果变得困难。因此，需要研究利用具有良好特性的小红莓产品，评估剂量范围效应，并将体外活性测量与临床结果测量联系起来，作为证明小红莓在预防UTI方面具有生物活性和有效性的原则。进行这些研究是本提案主要目标的基础。具体目标1涉及一项评估尿液抗粘连活性的阶段1研究，这些尿液来自摄入递增剂量的蔓越莓汁的妇女。随后将进行第二阶段的“概念验证”、安慰剂对照、随机临床试验，用于预防有反复尿路感染病史的妇女的尿路感染。这项临床研究将评估低剂量和高剂量蔓越莓汁的疗效，并提供临床结果与我们的体外活性测量之间的相关性，即抑制大肠杆菌与膀胱上皮细胞的黏附和抗甘露糖血凝。对引起红莓和安慰剂治疗妇女尿路感染的大肠杆菌在阴道内的定植和毒力特征进行评估，将进一步增强我们对蔓越莓汁在解剖部位以及细菌种类和微生物毒力特征方面的广泛活性的理解。鉴于引起尿路感染的大肠埃希氏菌的抗药性日益普遍，而且除抗菌剂外，缺乏任何有效的预防手段，因此，证明使用蔓越莓汁的可行性和有效性，将是预防健康育龄妇女复发尿路感染的非抗菌素干预措施的重大突破。

DESCRIPTION (provided by applicant): UTI is an exceedingly common outpatient problem among young healthy women, resulting in considerable morbidity and health care costs. Increasing antibiotic resistance, particularly among community-acquired UTIs, is making treatment of these infections even more problematic. Thus, novel, safe and effective non-antimicrobial prevention strategies are urgently needed. One approach that has been of interest to the public, health care providers, and the scientific community is ingestion of cranberry products for prevention and/or therapy of UTI. However, despite it's popularity, there have been no studies correlating in vitro effects of cranberry to clinical effects, making it difficult to explain mechanistically the outcomes observed in clinical trials. Thus, studies utilizing well-characterized cranberry products, assessing dose-range effects, and relating in vitro measures of activity to clinical outcome measures are needed as proof-of-principle that cranberry has biological activity and efficacy in the prevention of UTI. Performing these studies comprises the basis for the main aims of this proposal. Specific Aim 1 involves a Phase 1 study assessing urinary anti-adherence activity of urine collected from women pre and post ingestion of escalating doses of cranberry juice. This will be followed by a Phase II "proof-of-concept", placebo-controlled, randomized clinical trial of prevention of UTI in women with a history of recurrent UTI. The clinical study will assess the efficacy of low and high doses of cranberry juice and provide a correlation between the clinical outcomes and our in vitro measures of activity, namely inhibition of E. coli adherence to bladder epithelial cells and mannose-resistant hemagglutination. Assessment of vaginal E. coli colonization and virulence characteristics of E. coil strains causing UTI in the cranberry versus placebo treated women will further enhance our understanding of the breadth of activity of cranberry juice in terms of anatomic sites as well as bacterial species and microbial virulence characteristics. Given the increasing prevalence of antimicrobial resistance in E. coli strains causing UTI, and the absence of any effective means of prevention other than antimicrobials, demonstration of the feasibility and effectiveness of using cranberry juice would represent a major breakthrough in non-antimicrobial interventions for prevention of recurrent UTI in healthy reproductive-age women.