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

项目摘要 血液透析患者数量的不断增加（在美国每年增加2%）导致 随后导管相关感染的负担增加，直接和间接的住院费用 每次发作的费用在17，000 - 32，000美元之间，30天的死亡率为18%。当前抗菌剂 基于局部软膏的策略导致耐药菌株的选择，而封闭溶液携带 血栓溶解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 但缺乏对革兰氏阴性菌（铜绿假单胞菌）和真菌（念珠菌属）的抗微生物活性。 应变，而金属基涂层（银及其与其他金属的组合）表现出不一致 杀菌功效和副作用的诱导（例如，肺栓塞）。迫切需要 寻找预防和治疗导管相关感染的有效方法。N8 Medical提出了一种创新的涂层 对于这些导管，基于使用ceragenins（CSA），旨在模拟天然存在的抗菌剂 肽及其杀菌能力。此外，CSA使细菌细胞的膜透化， 使它们对疏水性抗生素敏感。该涂层将被设计为发挥抗感染活性， 在初步研究中研究了CSA的掺入，证明其对革兰氏阳性菌的有效性 （耐甲氧西林S. epidermidis和S.金黄色葡萄球菌）和革兰氏阴性（铜绿假单胞菌）细菌和真菌 感染（C.白色念珠菌），并防止生物膜的形成。CSA的抗微生物活性将促进 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SBIR第一阶段项目中，N8 Medical将开发CSA- 负载，聚丙烯酰胺基水凝胶适用于血液透析导管，并研究其抗菌性 在与血液剪切力直接接触的情况下的有效性和CSA释放曲线（目的1）。经验证的 将在动物模型中对涂层导管进行试验，以评估其有效性和安全性（目标2）。的成功 该项目将降低II期活动的风险，公司将专注于临床前，IDE使能安全性， 针对多种挑战病原体（葡萄球菌、铜绿假单胞菌、C. 白色念珠菌）。

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).