A Niclosamide-releasing hot-melt extruded catheter prevents Staphylococcus aureus experimental biomaterial-associated infection

Biomaterial-associated infections are a major healthcare challenge as they are responsible for high disease burden in critically ill patients. In this study, we have developed drug-eluting antibacterial catheters to prevent catheter-related infections. Niclosamide (NIC), originally an antiparasitic drug, was incorporated into the polymeric matrix of thermoplastic polyurethane (TPU) via solvent casting, and catheters were fabricated using hot-melt extrusion technology. The mechanical and physicochemical properties of TPU polymers loaded with NIC were studied. NIC was released in a sustained manner from the catheters and exhibited <em>in vitro</em> antibacterial activity against <em>Staphylococcus aureus</em> and <em>Staphylococcus epidermidis</em>. Moreover, the antibacterial efficacy of NIC-loaded catheters was validated in an <em>in vivo</em> biomaterial-associated infection mouse model using a methicillin-susceptible and methicillin-resistant strain of <em>S. aureus. </em>The released NIC from the produced catheters reduced bacterial colonization of the catheter as well as of the surrounding tissue. In summary, the NIC-releasing hot-melt extruded catheters prevented implant colonization and reduced the bacterial colonization of peri-catheter tissue by methicillin sensitive as well as resistant <em>S. aureus</em> in a biomaterial-associated infection mouse model and has good prospects for preclinical development.

生物材料相关感染（biomaterial-associated infections）是医疗卫生领域的重大挑战，因其会给重症患者带来沉重的疾病负担。本研究开发了用于预防导管相关感染的药物洗脱抗菌导管。将原本作为抗寄生虫药物的氯硝柳胺（niclosamide, NIC）通过溶剂浇铸法载入热塑性聚氨酯（thermoplastic polyurethane, TPU）的聚合物基质中，并采用热熔挤出技术制备导管。研究了负载NIC的TPU聚合物的力学与理化性能。NIC可从导管中持续释放，并在体外（in vitro）对金黄色葡萄球菌（Staphylococcus aureus）和表皮葡萄球菌（Staphylococcus epidermidis）展现出抗菌活性。此外，本研究采用甲氧西林敏感型（methicillin-susceptible）与甲氧西林耐药型（methicillin-resistant）金黄色葡萄球菌菌株，在体内（in vivo）生物材料相关感染小鼠模型中验证了负载NIC导管的抗菌效果。所制备导管释放的NIC可减少导管及周围组织的细菌定植。综上，释放NIC的热熔挤出导管可在生物材料相关感染小鼠模型中抑制植入物定植，并降低甲氧西林敏感型及耐药型金黄色葡萄球菌所致的导管周围组织细菌定植，具备良好的临床前开发前景。