权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Bacteriophage to treat multidrug‐resistant UTI in Persons with Spinal Cord Injury

噬菌体治疗脊髓损伤患者的多重耐药性尿路感染

基本信息

批准号：
10908259
负责人：
BARBARA Wells TRAUTNER
金额：
--
依托单位：
MICHAEL E DEBAKEY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10908259
关键词：
Activities of Daily Living Aftercare Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Bacteremia Bacteria Bacterial Antibiotic Resistance Bacteriophages Behavioral Biological Bladder Bladder Control Blood Circulation Catheter Management Catheters Cause of Death Charge Clinical Clinical Management Clostridium difficile Collection Dangerousness Directed Molecular Evolution Dose Drainage procedure Environment Epidemiology Escherichia coli Escherichia coli drug resistance Evolution Health Healthcare Hospitals Human Image Impairment In Vitro Indwelling Catheter Infection Infective cystitis Laboratories Length of Stay Libraries Life Lytic Measures Medical Device Metagenomics Methods Microbial Biofilms Microbiology Modeling Morbidity - disease rate Multi-Drug Resistance Multiple Bacterial Drug Resistance Mus Nature Neurogenic Bladder Organism Outcome Patients Personal Satisfaction Persons Phenotype Population Procedures Property Quality of life Recommendation Recurrence Reporting Research Resistance Resources Risk Role Sepsis Severity of illness Site Source Spinal cord injury Spinal cord injury patients Sterilization Structure Surface Testing Time Tissues United Nations United States National Institutes of Health Urinary tract Urinary tract infection Urine Veterans Virus Work bacterial resistance catheter associated UTI clinical outcome measures combat current pandemic efficacy evaluation efficacy testing experience experimental study gut microbiome health assessment improved in vivo in vivo evaluation indexing infection risk microbiome military veteran mortality mouse model novel novel therapeutics pandemic disease pathogen prevent prospective resistant strain self-renewal therapy resistant urinary urologic virology

项目摘要

Our overall purpose is to take aim at two urgent clinical problems for persons with spinal cord injury (SCI). The first problem is ongoing morbidity from urinary tract infections (UTI) and mortality from bacteremia and sepsis arising from pathogens in the urinary tract. Urinary tract infections and associated complications are a common threat to the wellbeing and even survival of persons with spinal cord injury (SCI). The second clinical dilemma is the disproportionate harm persons with SCI are experiencing from multidrug -resistant bacteria, particularly Escherichia coli, the most common urinary pathogen. We plan to develop bacteriophage, viruses that kill specific strains of bacteria, as a treatment for multidrug-resistant E. coli UTI and sepsis in SCI. Phage have numerous properties that suggest they will be effective in this role, including lack of cross resistance with antibiotics, ability to attack biofilms, evolvability in vitro, and being a self-renewing agent at the site of infection. Phage therapy for resistant urinary organisms has potential applications in the SCI population beyond UTI treatment and also for the Veteran population in general, such as for bladder sterilization prior to urologic procedures. Phage therapy aligns with VHA antibiotic stewardship efforts and may alleviate the burden of Clostridium difficile experienced by Veterans. The work we propose here with the most common urinary pathogen in SCI, E. coli, would subsequently be applied to the other SCI urinary pathogens to create broadly effective phage cocktails. Project Objectives: We will develop E. coli-specific phages that are efficacious against a broad range of SCI-specific E. coli isolates from our VA hospital in a mouse model of catheter-associated urinary tract infection (CAUTI) and/or sepsis. Aim 1 is to determine the efficacy of phage in killing antibiotic-resistant E. coli in murine infection models of CAUTI (1A), bacteremia (1B), and in combination with antibiotics to which the infecting E. coli pathogen is resistant (1C). Aim 2 is to develop and test a bank of phages effective against contemporary E. coli isolates from Veterans with SCI. In Aim 2A, we will actively collect E. coli clinical isolates from Veterans with SCI, creating an SCI-specific bacterial strain bank. In Aim 2B, we will collect and experimentally generate phages with broad host range against E. coli, creating a bank of sequenced phage that cover over 80% of the SCI E. coli strains. In Aim 2C we will create phage cocktails from our phage bank, and test the efficacy of the cocktails in the mouse model of CAUTI induced by SCI E. coli. Aim 3 is to examine the emergence of phage-resistant E. coli during treatment of CAUTI and determine how to overcome phage resistance. Aim 3A: Determine if E. coli persistence after phage treatment results from bacterial resistance to phage. Aim 3Bb: Determine if a “recharge” dose of phage several days into therapy prevents recurrence of E. coli. Methods: We propose to study bacteriophage in vitro and in vivo using our established models of mouse CAUTI and bacteremia for all three aims. In these experiments we will track microbiological outcomes and clinical outcomes. The microbiological outcomes include quantitative counts of bacteria and phage, [microbiome diversity before and after treatment with phage and/or antibiotics, and images of urinary catheter-associated biofilms.] Our clinical outcomes are intended to recapitulate the human experience, particularly the ability to perform activities of daily living. We have two measures of clinical outcomes: the disease severity index (assesses health) and the behavioral score (assesses whether animals still perform routine activities). The experiments in Aim 1 will use bacteria (E. coli JJ2528) and phage (HP3) from our existing collections, so that the work can begin immediately. At the end of this proposal, we will have a bacterial strain bank specific to SCI, and we also will have developed, characterized, and tested in vivo a library of phage that are effective at lysing over 80% of these SCI isolates. Our team brings together complementary expertise in clinical infections, epidemiology, SCI clinical management, SCI research, microbiology, virology, [metagenomics, biofilm imaging,] and animal studies to accomplish the work proposed.

我们的总体目的是针对两个迫切的临床问题的人与脊髓损伤（SCI）。的第一个问题是尿路感染（UTI）的持续发病率和菌血症和脓毒症的死亡率由泌尿道中的病原体引起。尿路感染和相关并发症是常见的对脊髓损伤（SCI）患者的健康甚至生存构成威胁。第二个临床困境是SCI患者遭受多重耐药细菌的不成比例的伤害，大肠杆菌，最常见的泌尿道病原体。我们计划开发噬菌体，菌株的细菌，作为多药耐药E.大肠埃希菌UTI和SCI中的脓毒症。噬菌体有许多这些特性表明它们在这一作用中是有效的，包括缺乏与抗生素的交叉耐药性，攻击生物膜，体外进化能力，以及在感染部位作为自我更新剂。噬菌体治疗耐药泌尿微生物在SCI人群中具有潜在的应用，超出UTI治疗，一般退伍军人人群，如泌尿外科手术前的膀胱绝育。噬菌体疗法与VHA抗生素管理工作一致，可能减轻艰难梭菌的负担退伍军人。我们在这里提出的工作与SCI中最常见的泌尿系病原体，E。大肠杆菌，随后应用于其他SCI泌尿病原体以产生广泛有效的噬菌体混合物。项目目的：开发E.大肠杆菌特异性抗体对广泛的SCI特异性大肠杆菌有效。大肠杆菌分离株从我们的VA医院在小鼠模型的导管相关性尿路感染（CITTI）和/或败血症目的：1.测定噬菌体对大肠杆菌耐药株的杀伤效果。小鼠感染模型中的大肠杆菌感染E.大肠杆菌是抗性（1C）。目的2是开发和测试有效抗当代E.杆菌分离株从脊髓损伤退伍军人那里在目标2A中，我们将积极收集E.大肠杆菌临床分离的退伍军人与SCI，创造 SCI特异性细菌菌株库。在目标2B中，我们将收集并实验性地生成具有宽寄主范围对E.构建了一个覆盖80%以上SCI E.大肠杆菌菌株。在目标2C我们将从我们的噬菌体库中产生噬菌体鸡尾酒，并在小鼠中测试鸡尾酒的功效用SCI E.杆菌目的3研究抗噬菌体E.大肠杆菌在的治疗，并确定如何克服噬菌体耐药性。目的3A：确定E.大肠杆菌持久性噬菌体处理后的结果是细菌对噬菌体的抗性。目标3Bb：确定“再充电”剂量是否为噬菌体治疗几天可防止E.杆菌方法：我们建议研究噬菌体在体外和体内使用我们建立的模型，小鼠ESTTI和菌血症的所有三个目标。在这些我们将跟踪微生物结果和临床结果。微生物结果包括细菌和噬菌体的定量计数，[用噬菌体处理前后的微生物组多样性和/或抗生素和导尿管相关生物膜的图像。]我们的临床结果旨在概括人类的经验，特别是进行日常生活活动的能力。我们有两临床结果的测量：疾病严重程度指数（评估健康状况）和行为评分（评估动物是否仍然进行日常活动）。目的1中的实验将使用细菌（E. coli JJ 2528）和噬菌体（HP 3）从我们现有的收藏，使工作可以立即开始。在本提案的最后，我们将拥有一个针对SCI的细菌菌株库，我们还将开发、表征和测试体内噬菌体文库有效裂解超过80%的这些SCI分离物。我们的团队汇集了在临床感染、流行病学、SCI临床管理、SCI研究、微生物学、病毒学、[宏基因组学、生物膜成像]和动物研究来完成所提出的工作。