Development of B-Lock an antibiofilm catheter lock product

开发抗生物膜导管锁定产品 B-Lock

• 批准号: 7641502
• 负责人: KRZYSZTOF APPELT
• 金额: $ 135.4万
• 依托单位: GREAT LAKES PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641502
• 关键词: Acute; Address; Adult; Age; Animals; Anticoagulants; Bacteremia; Bacteria; Binding; Biological; Biological Assay; Biological Preservation; Blood; Budgets; Candida; Candida albicans; Catheters; Childhood; Clinical; Clinical Management; Clinical Research; Clinical Trials; Clinics and Hospitals; Coagulants; Coagulation Process; Collaborations; Complex; Conduct Clinical Trials; Cyclic GMP; Data Set; Deposition; Development; Devices; Disease; Double-Blind Method; Drug Formulations; Drug resistance; Endothelial Cells; Ensure; Evaluation; Exposure to; Failure; Fee-for-Service Plans; Fibrin; Fluconazole resistance; Funding; Fungemia; Guidelines; Health Personnel; Hematologic Neoplasms; Hemodialysis; Heparin; 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 center; Methods; Microbial Biofilms; Modeling; Monitor; Ohio; Organism; Oryctolagus cuniculus; Outpatients; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Polysaccharides; Positioning Attribute; Preparation; Prevention; Property; Randomized; Randomized Clinical Trials; Rattus; Research; Research Contracts; Resistance; Risk; Safety; Science; Secure; Serial Passage; Site; Small Business Innovation Research Grant; Solutions; Source; Staging; Standardization; Sterility; Structure; Supportive care; Surrogate Markers; Systemic infection; Technology; Temperature; Test Result; Testing; The science of Mycology; Thrombosis; TimeLine; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Vancomycin resistant enterococcus; Vascular Endothelial Cell; Veins; Venous; base; cancer therapy; candida biofilm; cell injury; chemical release; chemical stability; chemotherapy; clinical efficacy; clinical research site; clinically relevant; commercialization; cost; design; drug resistant microorganism; efficacy testing; experience; extracellular; fungus; high risk; in vitro activity; in vivo; meetings; member; methicillin resistant Staphylococcus aureus; microorganism; oncology; pathogen; pre-clinical; prevent; professor; programs; prospective; prototype; safety testing; stability testing; standard of care; success; symposium; tool

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）：血管内 (IV) 导管的使用增加使患者面临导管闭塞和全身感染的风险。未能预防和治疗装置相关感染是由于微生物（真菌和细菌）产生生物膜的能力，导致导管相关感染和闭塞。导管上形成的生物膜是复杂的结构，由宿主来源的纤维蛋白沉积和绞合以及病原体来源的富含细胞外多糖的基质组成。预防和治疗生物膜相关感染的需求尚未得到满足。为了解决这一未满足的需求，在此 SBIR 应用中，我们将开发并商业化一种具有抗生物膜和抗凝血/抗导管闭塞特性的抗生物膜产品。我们的产品 B-LockTM 通过我们之前建立的体外和体内测定发现符合上述标准。我们证明，B-LockTM 在体外和体内均具有针对临床相关病原体形成的生物膜的广谱活性，并且还具有抗凝血活性。自上次提交以来，我们成功鉴定了六种在数月内保持物理和化学稳定性的原型制剂，表明临床候选药物在体外和体内对生物膜具有活性，包括由耐氟康唑白色念珠菌和近平滑念珠菌、耐甲氧西林金黄色葡萄球菌 (MRSA) 和耐万古霉素形成的生物膜 肠球菌（VRE）。 在此 Fast-Track SBIR 应用中，我们提出了一个两阶段计划，将 B-LockTM 开发为针对 CRBSI 和闭塞预防和治疗的产品。 该 SBIR 申请的第一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，而第二阶段详细介绍了测试 B-LockTM 安全性和有效性的临床试验。第一阶段具体目标：该快速通道应用第一阶段的目标是进行扩大的体内功效测试，评估 B-LockTM 针对耐药微生物形成的生物膜的体外活性，并确定临床候选药物的长期稳定性。 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。提出以下具体目标： 目标 1. 确定临床 B-LockTM 制剂的体内功效。目标 2. 评估 B-LockTM 的长期稳定性。目标 3. 评估 B-LockTM 针对耐药微生物形成的生物膜的体外活性。目标4.证明B-LockTM在体内安全无毒。目标 5. 展示 B-LockTM 与导管材料的兼容性。第 2 阶段的具体目标。进行一项随机、双盲临床试验，以评估 B-LockTM 解决方案与肝素封管溶液相比，在接受血液恶性肿瘤化疗的患者中保留留置导管无菌性和效力方面的效果。 公共健康相关性：中心静脉导管 (CVC) 是对癌症和终末期肾衰竭等危及生命的疾病患者进行适当治疗和支持的重要工具。然而，血管内导管使患者面临全身感染的风险，这是由导管腔内形成的微生物生物膜引起的。 在此 Fast-Track SBIR 应用中，我们提出了一个两阶段计划，开发抗生物膜和抗凝产品 (B-LockTM)，旨在预防和治疗 CVC 相关感染和闭塞。