Development of B-Lock, an antibiofilm catheter lock product

描述（由申请人提供）：血管内（IV）导管使用的增加使患者面临导管闭塞和全身感染的风险。未能预防和治疗器械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。在导管上形成的生物膜是由宿主来源的纤维蛋白沉积物和绞合物以及病原体来源的富含胞外多糖的基质组成的复杂结构。预防和治疗生物膜相关感染存在显著的未满足的需求。为了解决这一未满足的需求，在SBIR应用中，我们将开发并商业化一种具有抗生物膜和抗凝/抗导管阻塞特性的生物膜产品。我们的产品，B-LockTM，使用我们以前建立的体外和体内试验发现符合上述标准。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，并且还具有抗凝活性。自上次提交以来，我们成功鉴定了6种原型制剂，这些制剂在几个月内保持物理和化学稳定，表明临床候选制剂在体外和体内对生物膜具有活性，包括由氟康唑耐药的C.白色念珠菌和C.耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素肠球菌（VRE）。 在此快速通道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和闭塞的预防和治疗产品。 SBIR申请的第一阶段描述了体内功效测试、稳定性测试、毒理学和相容性研究，而第二阶段详细介绍了测试B-LockTM安全性和功效的临床试验。第1阶段具体目标：该快速通道申请的第1阶段的目的是进行扩展的体内有效性测试，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制剂在体内的功效。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。第二阶段具体目标。进行一项随机、双盲临床试验，以评价B-LockTM溶液与肝素封管液相比在血液系统恶性肿瘤化疗患者中保持留置导管无菌性和效力方面的效果。 公共卫生相关性：中心静脉导管（CVC）是适当治疗和支持癌症和终末期肾衰竭等危及生命的疾病患者的重要工具。然而，血管内导管使患者处于全身感染的风险中，这是由导管腔内形成的微生物生物膜引起的。 在这项快速通道SBIR应用中，我们提出了一个两阶段计划，以开发一种针对预防和治疗CVC相关感染和闭塞的抗凝血膜和抗凝产品（B-LockTM）。

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.