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脊髓损伤患者（SCI）的两个紧急临床问题。这第一个问题是尿路感染（UTI）和细菌和败血症的死亡率的持续发病率由尿路中的病原体产生。尿路感染和相关并发症是常见的威胁脊髓损伤（SCI）的人甚至生存的威胁。第二个临床困境 SCI的不成比例的危害人是来自多种耐药细菌的经历，尤其是大肠杆菌，最常见的尿病原体。我们计划开发细菌，杀死特定的病毒细菌菌株，作为对SCI中多药耐药性大肠杆菌和败血症的治疗。噬菌体有很多表明它们将在此角色中有效的特性，包括缺乏抗生素的交叉抗性，能力在感染部位攻击生物膜，体外发展性并成为自我更新的剂。噬菌体疗法抗尿液生物在UTI治疗以外的SCI人群中具有潜在的应用总体而言，退伍军人人口，例如在泌尿外科之前进行膀胱灭菌。噬菌体疗法与VHA抗生素管理工作保持一致，并可能减轻艰难梭菌的燃烧由退伍军人。我们在这里提出的工作是SCI中最常见的尿病原体，大肠杆菌将随后，将其应用于其他科学尿道病原体，以创建广泛有效的噬菌体鸡尾酒。项目目标：我们将开发出针对广泛的科幻E. E.大肠杆菌特异性噬菌体。与导管相关的尿路感染（CAUTI）和/或败血症。 AIM 1是确定在鼠类感染模型中杀死抗生素耐药大肠杆菌中噬菌体的效率 Cauti（1a），细菌（1B）和与感染大肠杆菌病原体的抗生素结合抗性（1C）。 AIM 2是开发和测试一批有效的噬菌体，以防止当代大肠杆菌分离物来自有科幻的退伍军人。在AIM 2A中，我们将积极从具有SCI的退伍军人那里收集大肠杆菌临床分离株，创建科学特异性细菌菌株库。在AIM 2B中，我们将收集并实验生成庞大的噬菌体寄主范围针对大肠杆菌，创建了一组测序的噬菌体，占SCI大肠杆菌菌株的80％以上。在 AIM 2C我们将从我们的噬菌体库中创建噬菌体鸡尾酒，并测试鼠标鸡尾酒的效率由Sci E. coli诱导的CAUTI模型。 AIM 3是检查耐噬菌体大肠杆菌的出现治疗cauti并确定如何克服噬菌体耐药性。目标3a：确定大肠杆菌是否持久噬菌体处理后，细菌抗噬菌体。 AIM 3BB：确定是否有“补给”剂量噬菌体进行几天治疗可防止大肠杆菌的复发。方法：我们建议研究细菌。在所有三个目标中，使用我们已建立的小鼠cauti和细菌模型的体外和体内模型。在这些实验我们将跟踪微生物结果和临床结果。微生物学结果包括细菌和噬菌体的定量计数，[用噬菌体和/或处理前后的微生物组多样性抗生素和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，尤其是从事日常生活活动的能力。我们有两个临床结局的度量：疾病严重程度指数（评估健康）和行为评分（评估）动物是否仍然进行常规活动）。 AIM 1中的实验将使用细菌（大肠杆菌JJ2528）和我们现有收藏中的噬菌体（HP3），以便可以立即开始工作。在此提案的结尾，我们将有一个特定于SCI的细菌应变库，我们还将开发，表征和测试在体内，噬菌体库有效地将超过80％的SCI分离株裂解。我们的团队聚集在一起在临床感染，流行病学，SCI临床管理，SCI研究中完全专业知识，微生物学，病毒学，[宏基因组学，生物膜成像]和动物研究，以完成提出的工作。