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.

删减： 骨科器械相关感染（OD​​RI）引起的骨髓炎是骨科的主要并发症 医学，导致美国每年约 200,000 例病例（约占估计 600 万选修课的 3%） 骨科手术），并且预计随着美国人口老龄化而增加。目前治疗需要4到6次 数周的静脉注射抗生素和多次手术以去除受感染的植入物和周围环境 组织并恢复装置，导致巨大的经济负担和显着的患者发病率。 ODR 是 对抗生素治疗极其顽固，因为这些是生物膜感染，其中细菌病原体 附着在由自产基质包围的表面上。生物膜的一个特点是它们的抵抗力 抗生素和宿主免疫系统。此外，口服或肠胃外施用抗生素 （静脉注射或肌肉注射）骨渗透性较差。另一种治疗并发症 是由于抗生素和多重耐药 (MDR) 细菌导致的 ODRI 增加。抗生素的局部递送 将它们纳入聚甲基丙烯酸甲酯 (PMMA) 珠中可改善治疗效果。我们开发并 测试了可生物降解的聚乳酸-乙醇酸 (PLGA) 微球的局部抗生素输送系统， 保留PMMA抗生素输送的优点，但不需要去除。一种新兴的治疗策略 MDR感染是通过静脉注射噬菌体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，不共享抵抗力 抗生素的机制，甚至可能恢复细菌对抗生素的敏感性。作为IV噬菌体 施用有缺点，包括在递送过程中噬菌体的损失以及长期暴露于噬菌体 免疫系统，我们在这里提出了一种利用我们的可生物降解的交付的创新纳米技术策略 系统局部施用裂解噬菌体来治疗 ODRI。 我们最近证明噬菌体 K 可以有效裂解许多金黄色葡萄球菌菌株， ODRIs 最常见的原因，可以掺入 PLGA 微球中。此外，洗脱的噬菌体是 能够杀死骨科材料上体外生物膜内的金黄色葡萄球菌。我们的长期目标是开发有效的 局部递送裂解噬菌体以治疗 MDR ODRI。我们计划以下短期目标：1）优化噬菌体 掺入 PLGA 微球，2) 生成裂解噬菌体混合物来处理金黄色葡萄球菌 ODRI，消除 细菌噬菌体抗性，3）优化的含噬菌体微球在体外细胞培养中的测试和 ODRI 体内大鼠模型。预计本申请中提出的调查将为 使用局部递送裂解噬菌体来治疗 ODRI 感染从而改善患者病情的临床试验方法 结果。