Intramedullary antibiotic therapy for the treatment of osteomyelitis

 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。感染一般仅限于局部骨骼和周围软组织，是肌肉骨骼损伤后细菌污染造成的。由于骨骼的生理学和解剖学特征，抗生素对感染组织的渗透性差，耐药病原体引起的感染增加，以及感染细菌形成的生物膜的保护特性，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。这些患者中约有15%发展为骨髓炎，其中约17%感染复发或复发。越来越多的现役人员在退伍军人管理局接受护理，其中很大一部分患者患有肌肉骨骼感染。随着越来越多的病原体对抗生素产生抗药性，感染的治疗变得更具挑战性。目前对受感染骨骼的标准治疗方法需要对受感染或暴露的骨骼进行充分的清创，并全身应用抗生素，这可能会持续数周，并具有潜在的毒性。尽管目前实施了感染干预策略来治疗士兵的战斗相关伤害， 三分之一的此类损伤是由感染引起的。以前发现，与骨髓炎治疗有关的直接医疗费用约为每个患者35,000美元。我们的实验室挑战了目前的模式，即骨感染需要长时间的全身抗生素。我们已经开发了一种局部髓内注射抗生素进入长骨的模型。我们的递送系统允许反复给抗生素剂量 感染大鼠胫骨模型。我们已经证明，局部给予抗生素可以导致局部药物治疗水平的提高，同时保持较低的全身水平。使用此模型，我们将 与传统的全身给药相比，测试局部给药是否能改善大鼠胫骨骨髓炎模型的感染消退，同时保持骨骼的完整性，并降低全身药物浓度和由此产生的毒性。此外，我们将在污染骨折模型的背景下评估这种局部给药方法，以确定与对照组相比，局部给药是否可以预防感染并促进骨折愈合。结果将通过感染的放射学分辨率、感染的生物发光分辨率、骨培养和组织学来评估。我们预计，局部给予抗生素将导致FASTR并更有效地解决骨髓炎，并将防止污染骨折模型中感染的发展，而不会出现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，并为因战斗或非战斗创伤而遭受骨髓炎或污染骨折的患者提供改善康复和更容易重新融入社会和正常活动的机会。

 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.