Intramedullary antibiotic therapy for the treatment of osteomyelitis

 描述（由申请人提供）： 骨髓炎是一种由细菌感染引起的炎症过程。感染通常局限于骨骼和周围软组织的局部区域，由肌肉骨骼损伤后的细菌污染引起。骨感染的治疗可能是困难的，因为由于骨的生理和解剖特征，抗生素对感染组织的渗透性差，由抗生素抗性病原体引起的感染的患病率增加，以及由感染细菌形成的生物膜的保护特性。创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15%发生骨髓炎，其中约17%患有感染复发或复发。越来越多的现役人员在VA设施接受护理，这些患者中有很大一部分患有肌肉骨骼感染。随着耐抗生素病原体的日益流行，感染的治疗变得更具挑战性。目前对感染骨的标准治疗需要对受累或暴露的骨进行充分清创，全身给予抗生素，这可能持续数周并具有潜在毒性。尽管目前实施了感染干预策略来治疗士兵中与战斗有关的伤害， 三分之一的受伤者因感染而并发症。以前发现，治疗骨髓炎的直接医疗费用约为每名病人35 000美元。我们的实验室已经挑战了目前的范式，即骨感染需要长时间的全身抗生素。我们已经开发了一种模型，用于将抗生素局部髓内递送到长骨中。我们的输送系统允许重复给药抗生素， 感染大鼠胫骨模型。我们已经表明，抗生素的局部递送可以导致局部高治疗水平的药物，同时保持低的全身水平。利用这个模型，我们将 测试局部抗生素递送是否导致在大鼠胫骨骨髓炎模型中改善的感染消退，同时与传统的全身递送相比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中评价这种局部给药方法，以确定与对照组相比，局部抗生素给药是否可以预防感染并促进骨折愈合。将通过感染的放射学消退、感染的生物发光消退、骨培养和组织学来评价结局。我们期望局部抗生素的应用能更快、更有效地解决骨髓炎的问题，并能防止污染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反应。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患有骨髓炎或污染性骨折的患者提供改善恢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.