Intramedullary antibiotic therapy for the treatment of osteomyelitis

髓内抗生素疗法治疗骨髓炎

• 批准号: 9273890
• 负责人: Jayant Prasad Agarwal
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273890
• 关键词: Adverse effects; Affect; Anatomy; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Bacteria; Bacterial Counts; Bacterial Infections; Bioluminescence; Blast Injuries; Bone Morphogenetic Proteins; Caring; Characteristics; Clinical; Comminuted Fracture type; Control Groups; Debridement; Detection; Development; Devices; Diagnostic radiologic examination; Dose; Drug Delivery Systems; Focal Infection; Fracture; Fracture Healing; Histologic; Histology; Human Resources; Implant; Incidence; Infection; Infection prevention; Inflammatory; Infusion procedures; Injury; Intervention; Intravenous; Invaded; Limb structure; Medical; Methods; Microbial Biofilms; Military Personnel; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Musculoskeletal; Musculoskeletal System; Nephrotoxic; Osteoblasts; Osteomyelitis; Outcome; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Population; Prevalence; Prevention; Process; Property; Prophylactic treatment; Rattus; Recovery; Recurrence; Relapse; Renal function; Residual state; Resolution; Resort; Saline; Societies; Soldier; Staphylococcus aureus; System; Techniques; Technology; Testing; Therapeutic; Tibial Fractures; Time; Tissues; Toxic effect; Translating; Trauma; Vancomycin; Veterans; Wound Healing; antimicrobial; bacterial resistance; bone; bone healing; clinical practice; combat; cost; drug administration rate; improved; innovation; killings; local drug delivery; long bone; methicillin resistant Staphylococcus aureus; microCT; mortality; musculoskeletal injury; nephrotoxicity; novel; ototoxicity; pathogen; prevent; public health relevance; service member; soft tissue; standard care; systemic toxicity; tibia; treatment group

 DESCRIPTION (provided by applicant): Osteomyelitis is an inflammatory process caused by bacterial infection of the bone. The infection is generally limited to a local area of bone and surrounding soft tissue resulting from bacterial contamination following musculoskeletal injury. Treatment of bone infections can be difficult due to poor penetration of antibiotics into the infected tissue owing to the physiologica and anatomical characteristics of bone, the increased prevalence of infections caused by antibiotic resistant pathogens, and the protective properties of biofilms formed by the infecting bacteria. Extremity injuries are the most common injuries associated with infection complications in the battlefield. Approximately 15% of these patients develop osteomyelitis, and of those, ~17% suffer from infection relapse or recurrence. An increasing number of active duty personnel are receiving their care at VA facilities and a significant proportion of these patients suffer from musculoskeletal infections. With the increasing prevalence of pathogens resistant to antibiotics, treatment of infections has become more challenging. Current standard treatments for infected bones require adequate debridement of the involved or exposed bone with systemic administration of antibiotics, which can last for weeks and have potential toxicities. Despite current infection intervention strategies implemented to treat combat-related injuries in soldiers, one- third of such injuries have been complicated by infection. The direct medical costs relating to the treatment of osteomyelitis has previously been found to be approximately $35,000 per patient. Our lab has challenged the current paradigm that bone infections require long durations of systemic antibiotics. We have developed a model for local intramedullary delivery of antibiotics into long bones. Our delivery system allows for the repeated dosing of antibiotic to an infected rat tibia model. We have shown that local delivery of antibiotic can result in high therapeutic levels of drug locally while maintaining low systemic levels. Using this model, we will test whether local antibiotic delivery results in improved resolution of infection in a rat tibial osteomyelitis model while maintaining bone integrity and reducing systemic drug concentrations and resultant toxicities compared to traditional systemic delivery. Additionally, we will evaluate this local delivery method in the setting of a contaminated fracture model to determine whether local antibiotic delivery can prevent infection and allow for fracture healing compared to controls Outcomes will be evaluated by radiographic resolution of infection, bioluminescent resolution of infection, bone culture and histology. We expect that local antibiotic delivery will result in fastr and more effective resolution of osteomyelitis and will prevent the development of infection in the contaminated fracture model, without the untoward effects of lengthy systemic antibiotic therapy. The results of this study will allow us to translate this technique to clinical practice ad offer patients that suffer from osteomyelitis or contaminated fractures as the result of combat or non-combat trauma a chance at improved recovery and easier re-integration into society and normal activities.

 描述（由申请人提供）： 骨髓炎是由骨骼细菌感染引起的炎症过程。感染通常仅限于肌肉骨骼损伤后细菌污染造成的骨骼和周围软组织的局部区域。由于骨的生理和解剖特征、抗生素抗性病原体引起的感染患病率增加以及感染细菌形成的生物膜的保护特性，抗生素难以渗透到感染组织中，因此骨感染的治疗可能很困难。四肢损伤是战场上最常见的与感染并发症相关的损伤。这些患者中大约 15% 出现骨髓炎，其中约 17% 出现感染复发或复发。越来越多的现役人员在退伍军人管理局的设施中接受治疗，其中很大一部分患者患有肌肉骨骼感染。随着对抗生素耐药的病原体越来越普遍，感染的治疗变得更具挑战性。目前针对受感染骨骼的标准治疗方法需要对受累或暴露的骨骼进行充分清创，并全身施用抗生素，这可能会持续数周并具有潜在的毒性。尽管目前实施的感染干预策略是为了治疗士兵的战斗相关伤害， 三分之一的此类伤害因感染而复杂化。此前发现，与治疗骨髓炎相关的直接医疗费用约为每位患者 35,000 美元。我们的实验室挑战了当前的观念，即骨感染需要长时间的全身抗生素治疗。我们开发了一种将抗生素局部髓内输送到长骨的模型。我们的输送系统允许对抗生素重复给药 感染大鼠胫骨模型。我们已经证明，抗生素的局部递送可以导致局部药物的高治疗水平，同时保持较低的全身水平。使用这个模型，我们将 测试与传统的全身给药相比，局部抗生素给药是否可以提高大鼠胫骨骨髓炎模型中感染的解决率，同时保持骨完整性并降低全身药物浓度和由此产生的毒性。此外，我们将在受污染的骨折模型的背景下评估这种局部给药方法，以确定与对照相比，局部抗生素给药是否可以预防感染并允许骨折愈合。结果将通过感染的放射线分辨率、感染的生物发光分辨率、骨培养和组织学来评估。我们期望局部抗生素递送能够更快、更有效地解决骨髓炎，并防止受污染的骨折模型中感染的发展，而不会产生长期全身抗生素治疗的不良影响。这项研究的结果将使我们能够将这项技术转化为临床实践，为因战斗或非战斗创伤而患有骨髓炎或污染性骨折的患者提供改善康复的机会，并更容易重新融入社会和正常活动。