Development of B-Lock, an antibiofilm catheter lock product

开发抗生物膜导管锁产品 B-Lock

基本信息

批准号：
7481941
负责人：
KRZYSZTOF APPELT
金额：
$ 10万
依托单位：
GREAT LAKES PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481941
关键词：
Acute Address Adult Age Animals Anticoagulants Bacteremia Bacteria Binding Biological Biological Assay Biological Preservation Biology Blood Budgets Candida Candida albicans Caring Catheter-related bloodstream infection Catheters Chelating Agents Chemicals Chicago Childhood Clinical Clinical Management Clinical Research Clinical Trials Clinics and Hospitals Coagulants Coagulation Process Collaborations Color Combined Antibiotics Complex Conduct Clinical Trials Contracts Cyclic GMP Data Set Deposition Development Devices Disease Double-Blind Method Drug Formulations Drug resistance Edetic Acid End Point Endothelial Cells Ensure Ethanol Evaluation Excipients Exhibits Exposure to Failure Fee-for-Service Plans Fibrin Fluconazole resistance Flushing Funding Fungemia Guidelines Health Personnel Hematologic Neoplasms Hemodialysis Heparin High Pressure Liquid Chromatography Immunocompromised Host In Vitro Incidence Study Industry Indwelling Catheter Infection Inflammation Injury International Kentucky Kidney Failure Laboratories Laboratory Research Life Malignant Neoplasms Marketing Mechanics Medical Device Medical center Methods Microbial Biofilms Modeling Monitor Morbidity - disease rate Numbers Ohio Organism Oryctolagus cuniculus Outpatients Patient Recruitments Patients Pharmaceutical Preparations Pharmacologic Substance Phase Pilot Projects Placement Polysaccharides Positioning Attribute Precipitation Preparation Prevention Property Public Health Randomized Randomized Clinical Trials Range Rate Rattus Research Research Personnel Resistance Review Literature Risk Safety Saline Science Secure Sepsis Serial Passage Site Small Business Funding Mechanisms Small Business Innovation Research Grant Solutions Source Staging Standardization Standards of Weights and Measures Sterility Structure Supportive care Surrogate Markers Systemic infection Technology Temperature Test Result Testing The science of Mycology Therapeutic Intervention Thrombosis TimeLine Toxic effect Toxicology Trimethoprim United States Food and Drug Administration United States National Institutes of Health Universities University Hospitals Urination Vancomycin resistant enterococcus Vascular Endothelial Cell Veins Venous abstracting antimicrobial antimicrobial drug attributable mortality base cancer therapy candida biofilm cell injury chemical release chemical stability chemotherapy clinical efficacy clinical research site clinically relevant commercialization cost design drug discovery drug resistant microorganism experience extracellular fungus human SLPI protein in vivo in vivo Model insight killings member methicillin resistant Staphylococcus aureus microorganism oncology pathogen pre-clinical prevent professor programs prospective prototype resistance mechanism size success symposium tool

项目摘要

DESCRIPTION (provided by applicant): Increasing use of intravascular (IV) catheters put patients at risk for catheter occlusion as well as systemic infections. Failure to prevent and treat device-related infections is due to the ability of microorganisms (fungi and bacteria) to produce biofilms, resulting in catheter-associated infection and occlusion. Biofilms formed on catheters are complex structures composed of host-derived fibrin deposits and stranding as well as pathogen- derived, extracellular polysaccharide-rich matrix. There is a significant unmet need to prevent and treat biofilm- related infections. To address this unmet need, in this SBIR application, we will develop and commercialize an antibiofilm product that possesses anti-biofilm and anti-coagulation/anti-catheter occlusion properties. Our product, B-LockTM, discovered using our previously established in vitro and in vivo assays meets the above criteria. We demonstrated that B-LockTM has broad-spectrum activity against biofilms formed by clinically relevant pathogens, both in vitro and in vivo, and also possesses anti-coagulant activity. Since the last submission, we successfully identified six prototype formulations that remained physically and chemically stable for several months, showed that clinical candidate was active against biofilms in vitro and in vivo, including biofilms formed by fluconazole-resistant C. albicans and C. parapsilosis, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). In this Fast-Track SBIR application, we propose a two-phase plan to develop B-LockTM as a product directed at prevention and treatment of CRBSIs and occlusion. Phase 1 of this SBIR application describes in vivo efficacy testing, stability testing, toxicology and compatibility studies, while Phase 2 details a clinical trial to test the safety and efficacy of B-LockTM. PHASE 1 SPECIFIC AIMS: The objective of Phase 1 of this Fast-Track application is to perform expanded in vivo efficacy testing, evaluate the in vitro activity of B-LockTM against biofilms formed by drug-resistant microorganisms, and determine the long-term stability of the clinical candidate. Furthermore, we will also evaluate the safety profile of B-LockTM and determine its compatibility with catheter material. The following specific aims are proposed: Aim 1. Determine efficacy of clinical B-LockTM formulation in vivo. Aim 2. Evaluate long-term stability of B-LockTM. Aim 3. Evaluate the in vitro activity of B-LockTM against biofilms formed by drug-resistant microorganisms. Aim 4. Demonstrate that B-LockTM is safe and non-toxic in vivo. Aim 5. Demonstrate compatibility of B-LockTM with catheter materials. PHASE 2 SPECIFIC AIM. Conduct a randomized, double-blind clinical trial to evaluate B-LockTM solution compared with heparin lock solution in the preservation of in-dwelling catheter sterility and potency in patients receiving chemotherapy for hematologic malignancies. PUBLIC HEALTH RELEVANCE: Central venous catheters (CVCs) are essential tools for the appropriate treatment and support of patients with life-threatening diseases such as cancer and end-stage kidney failure. However, intravascular catheters put patients at risk for systemic infections, which are caused by microbial biofilms formed within the catheter lumens. In this Fast-Track SBIR application, we propose a two-phase plan to develop an antibiofilm and anticoagulant product (B-LockTM) directed at prevention and treatment of CVC-associated infections and occlusion.

描述（由申请人提供）：增加使用血管内（IV）导管的使用使患者处于导管闭塞和全身感染的风险。无法预防和治疗与装置相关的感染是由于微生物（真菌和细菌）产生生物膜的能力，从而导致导管相关的感染和闭塞。在导管上形成的生物膜是由宿主衍生的纤维蛋白沉积物和滞留以及病原体衍生的，细胞外多糖富含的基质组成的复杂结构。预防和治疗与生物膜相关的感染有很大的未满足需求。为了满足这种未满足的需求，在此SBIR应用中，我们将开发和商业化具有抗生物膜和抗凝集/抗凝集/抗导管闭塞特性的抗生素产品。我们的产品B-LockTM使用我们先前建立的体外和体内测定法符合上述标准。我们证明，B-LockTM具有针对由临床相关病原体形成的生物膜的广谱活性，无论是体外和体内，还具有抗凝集活性。自上次提交以来，我们成功地鉴定了六个原型制剂，这些原型制剂在身体和化学上保持了几个月的稳定，表明临床候选者在体外和体内对生物膜有效，包括抗氟康唑的抗氟康唑C. c. bilpicans和C. parapapsilosis，包括生物膜，耐甲氧西林金黄色葡萄球菌（MRSA）和抗性霉素肠球菌（VRE）。在此Fast-Track SBIR应用中，我们提出了一个两相计划，以开发B-lockTM作为针对预防和治疗CRBSIS和遮挡的产品。 SBIR应用的第1阶段描述了体内功效测试，稳定性测试，毒理学和兼容性研究，而第2阶段详细介绍了一项临床试验，以测试B-LockTM的安全性和功效。第1阶段的特定目的：此快速应用的阶段1的目标是在体内效力测试中进行扩展，评估B-LockTM对由药物耐药微生物形成的生物膜的体外活性，并确定长期稳定性临床候选人。此外，我们还将评估B-LockTM的安全性并确定其与导管材料的兼容性。提出了以下具体目的：目标1。确定体内临床B-lockTM公式的功效。 AIM 2。评估B-LockTM的长期稳定性。 AIM 3。评估B-LockTM对耐药微生物形成的生物膜的体外活性。 AIM 4。证明B-LockTM在体内是安全且无毒的。 AIM 5。证明B-LockTM与导管材料的兼容性。第2阶段的特定目标。与肝素锁定溶液相比，进行了随机的双盲临床试验，以评估B-LockTM溶液，以保存室内导管不育和接受血液学恶性肿瘤化学疗法的患者。公共卫生相关性：中央静脉导管（CVC）是适当治疗和支持威胁生命疾病（如癌症和终末期肾脏衰竭）的重要工具。然而，血管内导管使患者处于系统性感染的风险，这是由导管流明中形成的微生物生物膜引起的。在此快速轨道SBIR应用中，我们提出了一个两相计划，以开发用于预防和治疗与CVC相关的感染和闭塞的抗凝胶产物（B-LockTM）。