Bacterial Interference to Prevent Catheter-Associated Urinary Tract Infection

描述（由申请人提供）：该提案解决了长期使用导尿管的患者的慢性和昂贵的导尿管相关尿路感染（CITTI）问题。这些人是慢性菌尿性的，并且由于尿路病原体的组织侵入而患有复发性疾病。我们对膀胱炎的预防方法是使用细菌干扰，因为我们故意用良性植物群覆盖导尿病人的膀胱，以防止病原体引起的症状性感染。这种新型的基于益生菌的方法避免了使用抗微生物剂，因此不会在人类宿主的植物群中选择抗性。这项提案的总体目标是进行一项试验性的导尿管涂层与良性 大肠杆菌菌株大肠杆菌（HU 2117）作为一种手段，以膀胱的老年人与长期导尿管。E. coliHU 2117是野生型无症状菌尿E.大肠杆菌83972，其中P皮利基因已被删除，阻止了这种可能的毒力因子的表达。我们以前用E。coli HU 2117对114例脊髓损伤后神经源性膀胱患者的膀胱进行了体外培养。目前的建议有两个具体的目标：（1）测试的假设，导尿管涂有良性大肠杆菌的生物膜。大肠杆菌HU 2117是一种安全有效的方法，可以定植在长期留置导尿管的老年人膀胱中;（2）检验插入大肠杆菌涂层导尿管前后膀胱和导尿管植物群的微生物变化。大肠杆菌HU 2117对膀胱定植成功与否及预防重复感染有预测作用。研究设计是一项前瞻性临床试验，其中所有20名受试者都将接受预涂有E的研究导管。coli HU2117。受试者将> 50岁，依赖于用于膀胱引流的长期导管，并且将具有基线菌尿。研究导管将留在膀胱中28天，然后取出进行微生物分析。将对受试者进行连续的尿培养，直至大肠杆菌消失。大肠杆菌HU 2117，并在12个月内发生严重不良事件。我们的目标1的主要结果是安全性、抗真菌感染率、定植成功率。安全性定义为没有受试者发生症状性ESTTI或与E明确相关的严重不良事件。coli HU2117。在大肠杆菌定植前、定植期间和定植后记录症状性肠易激综合征的发生率。coli HU2117。定殖成功定义为E.研究导管插入后28天尿液中的大肠杆菌HU 2117。对于目标2，将通过受试者定植前、定植期间和定植后的连续定量尿培养以及取出的研究导管的培养和显微镜研究收集数据。目标2的目标是开发定植成功和预防重复感染的预测规则。如果这个初步试验成功，结果将被用于设计一个随机的，安慰剂对照的试验。大肠杆菌涂层导管作为一种手段，以防止急性呼吸道感染。该试验方案已获得FDA批准（IND #14007）。

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).