Development of B-Lock an antibiofilm catheter lock product

描述（由申请人提供）：越来越多地使用血管内（IV）导管使患者面临导管闭塞和全身感染的风险。预防和治疗器械相关感染的失败是由于微生物（真菌和细菌）产生生物膜的能力，导致导管相关感染和闭塞。在导管上形成的生物膜是由宿主来源的纤维蛋白沉积和搁浅以及病原体来源的细胞外富含多糖的基质组成的复杂结构。在预防和治疗与生物膜相关的感染方面还存在着显著的未满足的需求。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具有抗生物膜和抗凝血/抗导管阻塞特性的抗菌膜产品。我们的产品B-LockTM是通过我们之前建立的体外和体内检测发现的，符合上述标准。我们证明了B-LockTM在体外和体内对临床相关病原体形成的生物膜具有广谱活性，并且具有抗凝血活性。自上次提交以来，我们成功鉴定了6个物理和化学稳定数月的原型制剂，表明临床候选药物在体外和体内对生物膜有活性，包括耐氟康唑的白色念珠菌和副嗜氧梭菌、耐甲氧西林的金黄色葡萄球菌（MRSA）和耐万古霉素的肠球菌（VRE）形成的生物膜。在这个快速通道SBIR申请中，我们提出了一个两阶段的计划来开发B-LockTM作为一个产品，用于预防和治疗CRBSIs和闭塞。该SBIR申请的第一阶段描述了体内疗效测试、稳定性测试、毒理学和相容性研究，而第二阶段详细介绍了B-LockTM的安全性和有效性的临床试验。具体目的：该快速通道申请的1期目的是进行扩展的体内功效测试，评估B-LockTM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。提出了以下具体目标：目标1。确定临床B-LockTM制剂在体内的疗效。目标2。评估B-LockTM的长期稳定性。目标3。评价B-LockTM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。证明B-LockTM与导管材料的兼容性。第二阶段的具体目标。开展一项随机、双盲临床试验，评估B-LockTM溶液与肝素锁液在血液恶性肿瘤化疗患者留置导管无菌保护和效力方面的比较。

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.