Bacteriophage to treat UTI caused by multidrug-resistant P. aeruginosa

噬菌体治疗多重耐药铜绿假单胞菌引起的尿路感染

基本信息

批准号：
9187430
负责人：
ROBERT Franklin RAMIG
金额：
$ 21.79万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187430
关键词：
Adjuvant Antibiotic Resistance Antibiotics Bacteria Bacteriophages Bladder Blood Catheter Management Catheterization Catheters Clinical Combined Antibiotics Development Drug Kinetics Excision Excretory function Geographic Locations Goals Half-Life Host Defense Human In Vitro Infection Intestines Investigational Drugs Life Louisiana Measures Medical Device Methods Microbial Biofilms Modeling Multi-Drug Resistance Mus Nosocomial Infections Organ Organism Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacodynamics Phase Positioning Attribute Predisposition Preparation Production Protocols documentation Pseudomonas aeruginosa Quality Control Resistance Safety Series Symbiosis Testing Texas Therapeutic Urinary tract Urinary tract infection Virus Work alternative treatment antimicrobial antimicrobial drug bacterial resistance catheter associated UTI clinically relevant effective therapy efficacy testing experimental study in vivo killings mouse model multi-drug resistant pathogen multidrug-resistant Pseudomonas aeruginosa novel therapeutic intervention novel therapeutics pathogen product development public health relevance research clinical testing resistant strain technique development urinary virtual

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our work is to develop bacteriophage as a paradigm-shifting approach for treating infections caused by multidrug-resistant (MDR) Gram-negative pathogens. As a first step towards this new therapeutic approach, we will explore the use of bacteriophage in the treatment of catheter-associated urinary tract infection (CAUTI), caused by MDR Pseudomonas aeruginosa (Psa). Psa is the second most commonly identified causative organism in CAUTI, and clinical outcomes are worse when it is MDR. With the lack of new antibiotic drugs, Psa is increasingly resistant to available antibiotics and some resistant strains are virtually untreatable with currently available drugs. Phage offer an alternative treatment that has numerous advantages over antibiotics, including that they can kill MDR bacteria by a different mechanism than antibiotics; they can target the infecting Psa without harming other intestinal commensals; they are a self-replicating drug and amplify during treatment; and that they are generally regarded as non-toxic compared to antibiotics. Phage are also likely to be excellent adjuvants to traditional antimicrobials, as tey can disrupt biofilms, and reversion to antibiotic sensitivity has been observed in phage-resistant bacteria. In this R21/R33, we propose to develop the first therapeutic phage to treat multi-drug resistant CAUTI infections caused by P. aeruginosa (Psa). We chose Psa CAUTI as a target because the intrinsic resistance of Psa makes infections difficult to treat, setting a high bar in our studies. Psa also forms biofilms on medical devices, further complicating management. In proof of concept experiments, we will test a Psa-specific phage cocktail in a murine model of CAUTI against a human Psa isolate susceptible to the cocktail (R21). We will also use the mouse CAUTI model to test the concept that phage cocktail and antibiotic may be synergistic (R21). We will then use a phage host range expansion protocol developed by our group to generate phage that can kill a broad-spectrum of clinically-relevant Psa isolates (R21) and confirm that (i) the resulting phage are efficacious in vivo and (ii) are efficacious against contemporary Psa clinical isolates from the Texas- Louisiana region and across the U.S. Finally, in the R33 phase of this work, we will define good manufacturing practice (GMP) for the isolation, administration, and storage of our therapeutic phage, thereby paving a path for regulatory approval for clinical use of our phage in humans. The phage development techniques in this proposal may then be applied to other MDR pathogens.

描述（由适用提供）：我们工作的长期目标是开发细菌性作为治疗由多药耐药（MDR）革兰氏阴性病原体引起的感染的范式转移方法。作为迈向这种新的治疗方法的第一步，我们将探讨通过MDR Pseudomonas aeruginosa（PSA）引起的与导管相关的尿路感染（CAUTI）的治疗中的使用。 PSA是第二常见的计算 cauti的有机体和临床结果是MDR时的情况。由于缺乏新的抗生素，PSA对可用的抗生素具有抗药性，并且某些抗性菌株实际上是无法治疗的，目前可用毒品。噬菌体提供了一种替代治疗方法，比抗生素具有许多优势，包括它们可以通过与抗生素不同的机制杀死MDR细菌。他们可以瞄准受感染的PSA而不会损害其他肠道分子。它们是一种自我复制的药物，并在治疗过程中得到扩增；与抗生素相比，它们通常被认为是无毒的。噬菌体也可能是传统抗菌剂的出色调节器，因为TEY可能会破坏生物膜，并且在耐噬菌体的细菌中观察到了抗生素敏感性。在此R21/R33中，我们提议开发第一个治疗铜绿假单胞菌（PSA）引起的抗多药cauti感染的治疗噬菌体。我们选择PSA CAUTI作为目标，因为PSA的固有阻力使感染难以治疗，在我们的研究中设定了很高的标准。 PSA还在医疗设备上形成生物膜，使管理更加复杂。在概念实验证明中，我们将在小鼠模型中测试PSA特定的噬菌体鸡尾酒，以针对易受鸡尾酒的人类PSA分离物（R21）。我们还将使用小鼠CAUTI模型来测试噬菌体鸡尾酒和抗生素可能具有协同作用的概念（R21）。然后，我们将使用我们的小组开发的噬菌体宿主范围扩展协议来产生噬菌体，该噬菌体可以杀死广泛的临床上的PSA隔离株（R21），并确认（i）（i）所得的噬菌体在体内有效，并且（ii）对现代PSA临床隔离株有效地从德克萨斯州 - 路易斯安那州地区以及跨美国的范围进行了遵守，我们将在美国的范围内进行R3阶段。（GMP）用于分离，给药和存储我们的治疗性噬菌体，从而掩盖了在人类中使用噬菌体临床使用的调节性批准的途径。然后，该提案中的噬菌体发展技术可以应用于其他MDR病原体。