Cranberry and Prevention of UTI A Comprehensive Approach

描述（由申请人提供）：UTI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保健费用。越来越多的抗生素耐药性，特别是在社区获得性UTI中，使这些感染的治疗更加困难。因此，迫切需要新的、安全有效的非抗菌预防策略。公众、医疗保健提供者和科学界感兴趣的一种方法是摄入蔓越莓产品以预防和/或治疗UTI。然而，尽管它很受欢迎，但还没有研究将蔓越莓的体外作用与临床作用相关联，因此很难从机械上解释临床试验中观察到的结果。因此，需要利用充分表征的蔓越莓产品，评估剂量范围效应，并将体外活性测量与临床结果测量相关联的研究作为蔓越莓在预防UTI中具有生物活性和功效的原理证明。开展这些研究是本提案主要目标的基础。具体目标1涉及一项I期研究，评估从摄入剂量递增的蔓越莓汁前后的女性中收集的尿液的尿抗粘附活性。随后将进行一项II期“概念验证”、安慰剂对照、随机临床试验，以预防有复发性UTI病史的女性的UTI。临床研究将评估低剂量和高剂量的蔓越莓汁的功效，并提供临床结果与我们的体外活性测量（即抑制E.大肠杆菌粘附于膀胱上皮细胞和甘露糖耐药血凝反应。阴道E.大肠杆菌定殖和毒力特性。在蔓越莓与安慰剂治疗的妇女中引起UTI的大肠杆菌菌株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活性广度的理解。鉴于大肠杆菌耐药性的日益普遍，大肠杆菌菌株引起尿路感染，以及没有任何有效的预防手段以外的抗菌药物，证明使用蔓越莓汁的可行性和有效性将代表一个重大突破，在非抗菌干预措施，预防复发性尿路感染的健康育龄妇女。

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.