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; 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.

at ract： 由于骨科相关感染（OD​​RIS）引起的骨髓炎是骨科的主要并发症 医学，每年大约有200,000例案例（估计600万选修课的3％ 骨科手术），预计随着美国人口年龄的增长。当前的治疗需要4至6 静脉内抗生素给药和多次手术，以去除感染的植入物和周围 组织并恢复设备，导致巨大的经济负担和严重的患者发病率。 Odris是 对抗生素治疗极为顽固，因为这些是生物膜感染，其中细菌病原体 附着在被自生矩阵包围的表面上。生物膜的标志是他们对 抗生素和宿主免疫系统。此外，口服或肠胃外施用抗生素 （静脉注射或通过肌内注射）骨穿透性差。另一个治疗并发症 是由于抗生素和多药（MDR）细菌引起的ODRI的上升。局部分娩抗生素 它们掺入聚甲基丙烯酸酯（PMMA）珠已改善治疗方法。我们开发了 测试了可生物降解聚（乳酸 - 乙醇酸）（PLGA）微球的局部抗生素递送系统 保留PMMA抗生素递送的优势，但不需要去除。治疗的新兴策略 MDR感染是使用噬菌体的静脉注射直接靶向和裂解细菌病原体 （杀死细菌的病毒）或“噬菌体”。噬菌体在感染部位自我复制，请勿共享抵抗力 具有抗生素的机制，甚至可能恢复细菌对抗生素的敏感性。作为IV噬菌体 管理有缺点 免疫系统，我们在这里提出了一种创新的纳米技术策略，该策略使用我们的可生物降解交付 系统以局部管理裂解噬菌体来治疗ODRI。 我们最近证明，噬菌体K有效地裂解了金黄色葡萄球菌的许多菌株 ODRI的最常见原因可以纳入PLGA微球。此外，洗脱的噬菌体是 能够在骨科材料上杀死体外生物膜内的金黄色葡萄球菌。我们的长期目标是发展有效 裂纹噬菌体的局部输送以治疗MDR ODRI。我们计划以下短期目标：1）优化噬菌体 掺入PLGA微球，2）生成裂解噬菌体鸡尾酒来处理消除的金黄色葡萄球菌。 细菌噬菌体耐药性，3）在体外细胞培养和 ODRI的体内大鼠模型。预计本申请中提出的调查将铺平 使用局部输送裂解噬菌体治疗ODRI感染，从而改善患者的临床试验方法 结果。