Bacterial Interference to Prevent Catheter-Associated Urinary Tract Infection

描述(由申请人提供)：这项建议针对长期使用导尿管的个人的导尿管相关性尿路感染(CAUTI)这一慢性且昂贵的问题。这些人长期患有细菌症，并因尿路病原体侵袭组织而反复发病。我们对CAUTI的预防方法是使用细菌干扰，因为我们故意将良性菌群接种到插管者的膀胱中，以防止病原体的症状感染。这种以益生菌为基础的新方法避免了使用抗菌剂，因此不会对人类宿主的菌群产生耐药性。这项提案的总体目标是对涂有良性导尿管的导尿管进行试点试验 大肠杆菌(HU2117)菌株，作为一种接种长期导尿管的老年人膀胱的方法。E.ColiHU2117是野生型无症状菌尿菌株E.Coli83972的衍生物，其中P菌毛基因已被缺失，阻止了这一可能的毒力因子的表达。我们之前已经使用大肠杆菌HU2117故意接种了114名患有继发于脊髓损伤的神经源性膀胱的人类受试者的膀胱。目前的建议有两个具体目的：(1)检验涂层良性大肠杆菌HU2117导尿管将是长期留置导尿管的老年人膀胱定植的安全有效手段的假设；(2)检验涂层大肠杆菌HU2117导尿管插入前后膀胱和导尿管菌群变化将预测膀胱定植和预防重叠感染成败的假设。这项研究设计是一项前瞻性的临床试验，所有20名受试者都将接受一种预涂有大肠杆菌HU2117的研究导管。受试者年龄为50岁，依赖长期留置导尿管进行膀胱引流，并有基线菌尿。研究中的导管将在膀胱中放置28天，然后被取出进行微生物分析。受试者将接受连续的尿液培养，直到大肠杆菌HU2117从他们的尿液中消失，并在12个月内出现严重的不良反应。我们的目标1的主要结果是安全性、CAUTI率、殖民成功率。安全性的定义是没有受试者经历有症状的CAUTI或肯定与E.ColiHU2117有关的严重不良事件。在大肠杆菌HU2117定植之前、期间和之后，将记录有症状的CAUTI的发生率。定植成功的定义是在研究导管插入后28天尿液中出现大肠杆菌HU2117。对于目标2，将通过连续、定量的尿液培养收集数据，这些数据来自研究对象在定居之前、期间和之后，以及从被拆除的研究导管的培养和显微镜研究中收集的数据。目标2的目标是制定殖民成功和预防双重感染的预测规则。如果这项试点试验成功，结果将被用于设计一项随机的、安慰剂对照的试验，以这些大肠杆菌涂层导管作为预防CAUTI的一种手段。该试验方案已获得食品和药物管理局的批准(IND#14007)。 公共卫生相关性：导尿管相关性尿路感染(CAUTI)对于许多需要长期留置导尿管进行膀胱引流的老年人来说是一个反复出现的问题。这一问题严重干扰了个人的生活质量，而且在治疗费用和CAUTI治疗过程中产生的耐药生物体方面都对社会造成了影响。我们建议使用涂有良性(益生菌)细菌的导尿管作为预防CAUTI的一种方法，而不需要使用抗生素。

DESCRIPTION (provided by applicant): This proposal addresses the chronic and costly problem of catheter-associated urinary tract infection (CAUTI) in individuals with long-term urinary catheters. Such persons are chronically bacteriuric and suffer recurrent morbidities from tissue invasion by uropathogens. Our preventive approach to CAUTI uses bacterial interference, as we deliberately inoculate catheterized persons' bladders with benign flora in order to prevent symptomatic infection by pathogens. This novel probiotic-based approach avoids use of antimicrobial agents and thus does not select for resistance in the human host's flora. The overall goal of this proposal is to conduct a pilot trial of urinary catheters coated with a benign strain of E. coli (HU2117) as a means to inoculate the bladders of older persons with long-term urinary catheters. E. coli HU2117 is a derivative of wild-type asymptomatic bacteriuria strain E. coli 83972 in which the gene for P pili has been deleted, preventing expression of this possible virulence factor. We have previously used E. coli HU2117 to deliberately inoculate the bladders of 114 human subjects with neurogenic bladders secondary to spinal cord injury. The current proposal has two specific aims: (1) to test the hypothesis that urinary catheters coated with a biofilm of benign E. coli HU2117 will be a safe and effective means to colonize the bladders of older persons wearing long-term indwelling urinary catheters, and (2) to test the hypothesis that microbiological changes in the bladder and catheter flora before and after insertion of catheters coated with E. coli HU2117 will predict success or failure of bladder colonization and prevention of superinfection. The research design is a prospective clinical trial in which all 20 subjects wil receive a study catheter that has been pre-coated with E. coli HU2117. Subjects will be > 50 years of age, dependent upon long-term catheters for bladder drainage, and will have baseline bacteriuria. The study catheters will be left in the bladder for 28 days and then will be removed for microbiological analysis. Subjects will be followed with serial urine cultures until disappearance of E. coli HU2117 from their urine and for serious adverse events over 12 months. Our primary outcomes for Aim 1 are safety, rates of CAUTI, colonization success. Safety is defined as no subject experiencing symptomatic CAUTI or a serious adverse event definitely related to E. coli HU2117. The rates of symptomatic CAUTI will be recorded before, during, and after colonization with E. coli HU2117. Colonization success is defined as the presence of E. coli HU2117 in the urine at 28 days after study catheter insertion. For Aim 2, data will be collected through serial, quantitative urine cultures from subjects before, during, an after colonization as well as from culture and microscopy studies of the removed study catheters. The goal of Aim 2 is to develop prediction rules for colonization success and prevention of superinfection. If this pilot trial is successful, the results will be used to designa randomized, placebo-controlled trial of these E. coli-coated catheters as a means to prevent CAUTI. The trial protocol has been approved by the FDA (IND #14007). PUBLIC HEALTH RELEVANCE: Catheter-associated urinary tract infection (CAUTI) is a recurrent problem for the many older individuals who require long-term urinary catheters for bladder drainage. This problem interferes significantly with individual quality of life and is costy to society, both in terms of the expense of treatment and in terms of the resistant organisms that arise through the treatment of CAUTI. We propose to use urinary catheters coated with benign (probiotic) bacteria as a means to prevent CAUTI without requiring the use of antibiotics.