Ceragenin-based antimicrobial coating to tackle hemodialysis catheter-related infections.

项目总结 不断增加的血液透析患者数量(美国每年增加2%)领先 与随后日益加重的导管相关感染负担，以及直接和间接的住院费用 每集17,000-32,000美元不等，30天内死亡率为18%。当前的抗菌剂 基于局部药膏的策略导致了抗药性细菌菌株的选择，而锁定溶液则 溶栓和心脏并发症的风险。抗生素(米诺环素+利福平)涂层导管能够 减少革兰氏阳性菌(金黄色葡萄球菌和表皮葡萄球菌)的增殖 但对革兰氏阴性杆菌(铜绿假单胞菌)和真菌(念珠菌)缺乏抗菌活性。 应变，而金属基涂层(银及其与其他金属的结合)表现出不一致 杀菌效果和不良反应的诱发(例如，肺栓塞)。有一个迫切的需要 寻找预防和治疗导管相关感染的有效方法。N8医疗提出一种创新的涂料 对于这些导管，使用的是角蛋白(CSA)，旨在模仿自然产生的抗菌素 多肽及其杀菌能力。此外，CSA还能渗透细菌细胞膜和 让他们对疏水抗生素敏感。该涂层将被设计成具有抗感染活性 纳入CSA，初步研究表明其对革兰氏阳性菌有效 (耐甲氧西林表皮葡萄球菌和金黄色葡萄球菌)和革兰氏阴性(铜绿假单胞菌)细菌和真菌 预防感染(白色念珠菌)，防止生物被膜的形成。CSA的抗菌活性将促进 彻底根除导致导管感染的细菌种群(包括耐药菌株)， 降低住院费用和死亡率。在这个SBIR第一阶段项目中，N8 Medical将开发一种CSA- 适用于血液透析导管的负载型聚氨酯水凝胶及其抗菌性能研究 在与血液剪切力直接接触的情况下的疗效和CsA释放情况(目标1)。经过验证的 涂层导管将在动物模型中进行测试，以评估其有效性和安全性(目标2)。这件事的成功 该项目将降低第二阶段活动的风险，在该阶段，公司将专注于临床前、支持IDE的安全性、 多重挑战病原菌(葡萄球菌、铜绿假单胞菌、C. 白念珠菌)。

PROJECT SUMMARY The constantly increasing number of hemodialysis patients (2% increase every year in the United States) leads to the subsequent increasing burden of catheter-related infections, with direct and indirect hospitalization costs ranging between $17,000-$32,000 per episode and a mortality rate at 30 days of 18%. Current antimicrobial strategies based on topical ointments lead to the selection of resistant bacterial strains, while lock solutions carry the risk of thrombolytic and cardiac complications. Antibiotic (minocycline + rifampin)-coated catheters are able to reduce the proliferation of Gram-positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis) but lack antimicrobial activity against Gram-negative (Pseudomonas aeruginosa) and fungal (Candida spp.) strains, while metal-based coatings (silver and its combination with other metals) have shown inconsistent bactericidal efficacy and the induction of adverse effects (e.g., pulmonary embolism). There is an urgent need for an effective way to prevent and treat catheter-related infections. N8 Medical proposes an innovative coating for these catheters based on the use of ceragenins (CSAs), designed to mimic naturally occurring antimicrobial peptides and their bactericidal capabilities. Moreover, CSAs permeabilize the membranes of bacterial cells and sensitize them to hydrophobic antibiotics. The coating will be designed to exert an anti-infective activity with the incorporation of CSAs, investigated in preliminary studies demonstrating its effectiveness against Gram-positive (methicillin-resistant S. epidermidis and S. aureus) and Gram-negative (P. aeruginosa) bacteria and fungal infections (C. albicans), and to prevent the formation of biofilms. The antimicrobial activity of CSAs will promote the complete eradication of bacterial populations (including resistant strains) responsible for catheter infections, reducing hospitalization costs and mortality rates. In this SBIR Phase I project, N8 Medical will develop a CSA- loaded, polyurethane-based hydrogel applicable to hemodialysis catheters and investigate its antimicrobial efficacy and CSA release profile in the context of direct contact with blood shear forces (Aim 1). The validated coated catheter will be tested in an animal model to assess its efficacy and safety (Aim 2). The success of this project will de-risk Phase II activities where the company will focus on preclinical, IDE-enabling safety, biocompatibility and efficacy studies against multiple challenge pathogens (Staphylococci, P. aeruginosa, C. albicans).