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非常常见的门诊问题，导致相当高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、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入蔓越莓产品来预防和/或治疗尿路感染。然而，尽管它很受欢迎，但还没有研究将蔓越莓的体外效果与临床效果联系起来，因此很难从机制上解释临床试验中观察到的结果。因此，需要利用表征良好的蔓越莓产品进行研究，评估剂量范围效应，并将体外活性测量与临床结果测量相关联，以证明蔓越莓在预防尿路感染方面具有生物活性和有效性。进行这些研究是本建议主要目标的基础。具体目标1涉及一项1期研究，评估从摄入不断增加剂量的蔓越莓汁前后收集的女性尿液的尿液抗粘附活性。随后将进行II期“概念验证”、安慰剂对照、随机临床试验，以预防有复发性尿路感染史的妇女的尿路感染。临床研究将评估低剂量和高剂量蔓越莓汁的功效，并提供临床结果与体外活性指标之间的相关性，即抑制大肠杆菌粘附膀胱上皮细胞和甘露糖抗性血凝。评估阴道大肠杆菌定植和引起蔓越莓与安慰剂治疗女性尿路感染的大肠杆菌菌株的毒力特征，将进一步增强我们对蔓越莓汁在解剖部位、细菌种类和微生物毒力特征方面的活性广度的理解。鉴于引起尿路感染的大肠杆菌菌株对抗菌素的耐药性日益普遍，而且除了抗菌素之外没有任何有效的预防手段，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性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.