Development of B-Lock, an antibiofilm catheter lock product

描述(由申请人提供)：越来越多的血管内(IV)导管的使用使患者面临导管堵塞和全身感染的风险。未能预防和治疗与设备相关的感染是由于微生物(真菌和细菌)产生生物膜的能力，导致导管相关性感染和闭塞。导管上形成的生物膜是由宿主来源的纤维蛋白沉积和缠绕以及病原体来源的富含细胞外多糖的基质组成的复杂结构。预防和治疗与生物膜有关的感染有一个重要的未得到满足的需求。为了满足这一未得到满足的需求，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血/抗导管堵塞特性的抗生物膜产品。我们的产品B-LockTM，使用我们之前建立的体外和体内测试发现，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被膜具有广谱活性，并具有抗凝血活性。自上次提交以来，我们成功地鉴定了6个物理和化学稳定的原型制剂，表明临床候选在体外和体内对生物被膜具有活性，包括由氟康唑耐药白色念珠菌和近缘念珠菌形成的生物膜、耐甲氧西林金黄色葡萄球菌(MRSA)和万古霉素耐药肠球菌(VRE)。在这个快速通道SBIR应用中，我们提出了一个分两个阶段的计划，将B-LockTM开发为一种针对CRBSI和咬合的预防和治疗产品。这种SBIR应用的第一阶段包括体内疗效测试、稳定性测试、毒理学和兼容性研究，而第二阶段详细说明了测试B-LockTM的安全性和有效性的临床试验。第一阶段的具体目标：这一Fast-Track应用的第一阶段的目标是进行扩大的体内疗效测试，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。具体目标如下：目的1.确定B-LockTM临床制剂的体内疗效。目的2.评价B-LockTM的长期稳定性。目的3.评价B-LockTM对耐药微生物生物被膜的体外抗菌活性。目的4.证明B-LockTM在体内是安全无毒的。目的5.验证B-LockTM与导管材料的相容性。阶段2特定目标。进行一项随机、双盲临床试验，以评价B-LockTM溶液与肝素锁定溶液在保存血液系统恶性肿瘤化疗患者留置导管的无菌性和有效性方面的比较。 公共卫生相关性：中心静脉导管(CVCs)是适当治疗和支持癌症和终末期肾功能衰竭等威胁生命的疾病患者的基本工具。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，我们提出了一个分两个阶段的计划，以开发一种针对预防和治疗CVC相关感染和闭塞的抗生物膜和抗凝剂产品(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.