Treatment of Multidrug-Resistant Staphylococcus aureus Orthopaedic-Device Related Biofilm Infections with Local Delivery of Lytic Bacteriophage

通过局部递送裂解性噬菌体治疗多重耐药金黄色葡萄球菌骨科器械相关生物膜感染

• 批准号: 10649057
• 负责人: CATHERINE G AMBROSE
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-22 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649057
• 关键词: Age; American Type Culture Collection; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacteriophages; Biodegradable microsphere; Cell Culture Techniques; Classification; Clinical; Clinical Trials; Complication; Cytolysis; Debridement; Devices; Economic Burden; Encapsulated; Ensure; Excision; Exposure to; Glycolates; Goals; Human; Immune system; Implant; In Vitro; Individual; Infection; Intramuscular Injections; Intravenous; Investigation; Irrigation; Laboratories; Life; Lytic; Medicine; Microbial Biofilms; Microspheres; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Nanotechnology; Operative Surgical Procedures; Oral Administration; Orthopedic Surgery; Orthopedics; Osteoblasts; Osteomyelitis; Patient-Focused Outcomes; Patients; Penetration; Polymethyl Methacrylate; Population; Predisposition; Protocols documentation; Rattus; Regimen; Research; Resistance; Site; Staphylococcus aureus; Staphylococcus aureus infection; Surface; System; Testing; Therapeutic; Tissues; Titanium; Treatment Efficacy; Virus; bacterial resistance; biomaterial compatibility; bone; college; efficacy evaluation; experimental group; improved; in vivo; innovation; manufacture; manufacturing process; methicillin resistant Staphylococcus aureus; microsphere delivery; pathogenic bacteria; resistance mechanism

ABATRACT: Osteomyelitis due to orthopaedic device-related infections (ODRIs), is a major complication in orthopaedic medicine, resulting in approximately 200,000 cases in the US per year (~3% of the estimated 6 million elective orthopaedic surgeries), and is predicted to rise as the US population ages. Current treatment requires 4 to 6 weeks of IV antibiotic administration and multiple surgeries to remove the infected implants and surrounding tissue and restore the device, resulting in a large economic burden and significant patient morbidity. ODRIs are extremely recalcitrant to antibiotic treatment as these are biofilm infections, in which the bacterial pathogens are attached to surfaces surrounded by a self-produced matrix. A hallmark of biofilms is their resistance to antibiotics and the host immune system. Furthermore, antibiotics administered orally or parenterally (intravenously or through intramuscular injection) have poor bone penetration. Another treatment complication is the rise in ODRIs due to antibiotic- and multidrug-resistant (MDR) bacteria. Local delivery of antibiotics by their incorporation into polymethylmethacrylate (PMMA) beads has improved treatment. We developed and tested a local antibiotic delivery system of biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres that retain the advantages of PMMA antibiotic delivery, but do not require removal. An emerging strategy to treat MDR infections is to directly target and lyse the bacterial pathogen using IV administration of bacteriophage (viruses that kill bacteria) or `phage'. Phage self-replicate at the site of infection, do not share resistance mechanisms with antibiotics, and may even restore bacterial susceptibility to antibiotics. As IV phage administration has drawbacks including the loss of phage during delivery and long-term exposure to the immune system, we propose here an innovative nanotechnology strategy using our biodegradable delivery system to locally administer lytic phage to treat ODRIs. We have recently demonstrated that phage K, which effectively lyses many strains of Staphylococcus aureus, the most common cause of ODRIs, can be incorporated into PLGA microspheres. Further, eluted phage are able to kill S. aureus within in vitro biofilms on orthopaedic materials. Our long-term goal is to develop effective local delivery of lytic phage to treat MDR ODRIs. We plan the following short-term goals: 1) optimize the phage incorporation into PLGA microspheres, 2) generate lytic phage cocktails to treat S. aureus ODRI that eliminate bacterial phage resistance, 3) test of the optimized phage-containing microspheres in in-vitro cell culture and an in-vivo rat model of ODRI. It is anticipated that the investigations proposed in this application will pave the way for clinical trials using local delivery of lytic phage to treat ODRI infections thereby improving patient outcomes.

ABATRACT： 由骨科器械相关感染（ODRIs）引起的骨髓炎是骨科手术的主要并发症， 美国每年约有20万例（约占估计的600万例择期手术的3%）。 骨科手术），并预计将随着美国人口老龄化而上升。目前的治疗需要4到6个 数周的静脉注射抗生素和多次手术以移除感染的植入物和周围组织。 组织和恢复装置，导致巨大的经济负担和显著的患者发病率。ODRI是 由于这些是生物膜感染，其中细菌病原体 被附着在由自制基质包围的表面上。生物膜的一个标志是它们对细菌的抗性。 抗生素和宿主免疫系统。此外，口服或胃肠外给予的抗生素 （静脉内或通过肌内注射）具有差的骨渗透性。另一个治疗并发症 是由于抗生素和多药耐药（MDR）细菌引起的ODRI增加。抗生素的局部递送， 将它们结合到聚甲基丙烯酸甲酯（PMMA）珠粒中改善了处理。我们开发并 测试了可生物降解的聚（乳酸-共-乙醇酸）（PLGA）微球的局部抗生素递送系统， 保留PMMA抗生素递送的优点，但不需要移除。一种新兴的治疗策略 MDR感染是使用噬菌体的IV施用直接靶向并裂解细菌病原体 （杀死细菌的病毒）或“噬菌体”。噬菌体在感染部位自我复制，不共享耐药性 抗生素的作用机制，甚至可能恢复细菌对抗生素的敏感性。As IV噬菌体 施用具有缺点，包括在递送期间噬菌体的损失和长期暴露于 免疫系统，我们在这里提出了一个创新的纳米技术战略，使用我们的生物降解交付 本发明提供了局部施用裂解性噬菌体以治疗ODRI系统。 我们最近已经证明，噬菌体K，有效地溶解许多菌株的金黄色葡萄球菌， ODRIs的最常见原因，可以掺入PLGA微球中。此外，洗脱的噬菌体是 可以杀死S。金黄色葡萄球菌在骨科材料上的体外生物膜内。我们的长期目标是开发有效的 局部递送裂解性噬菌体以治疗MDR ODRI。我们计划以下短期目标：1）优化噬菌体 掺入PLGA微球中，2）产生裂解性噬菌体混合物以治疗S.金黄色葡萄球菌ODRI， 细菌噬菌体抗性，3）在体外细胞培养中测试优化的含噬菌体的微球， ODRI的体内大鼠模型。预计本申请中提出的调查将为 使用溶解性噬菌体的局部递送治疗ODRI感染从而改善患者的临床试验的方法 结果。