Ultrasound-Triggered Prophylaxis as a Novel Paradigm for Preventing Spinal Infection

超声触发预防作为预防脊柱感染的新范例

• 批准号: 10704163
• 负责人: Lauren Jo Delaney
• 金额: $ 24.9万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704163
• 关键词: Address; Adherence; Antibiotic Therapy; Antibiotics; Area; Bacteria; Bacterial Infections; Bolus Infusion; Career Mobility; Clinical; Combined Antibiotics; Ensure; Excision; Gram-Negative Bacteria; Hospitalization; Hydrogels; Implant; In Vitro; Infection; Infection prevention; Kinetics; Left; Microbial Biofilms; Modality; Operative Surgical Procedures; Patients; Perioperative; Postoperative Period; Powder dose form; Prophylactic treatment; Research; Research Personnel; Risk Reduction; Site; Spinal; Spinal Fusion; Spine surgery; System; Time; Tobramycin; Training; Translating; Vancomycin; Vertebral column; Work; antimicrobial; disability; drug resistant pathogen; experience; in vivo Model; infection rate; innovation; mortality; novel; pain reduction; pathogen; persistent bacteria; prevent; prophylactic; skills; spatiotemporal; ultrasound; wound

Bacterial infection following spinal fusion surgery is a major clinical concern, with 1-10% of patients developing infection despite aggressive peri-operative antibiotic treatments. Upwards of 5 million annual spinal surgeries are predicted by 2030. Current clinical standards involve the use of aseptic drains and packing of ~1g of powdered vancomycin (VAN) into the wound space; however, this prophylaxis is short-lived (24-48 h). Left untreated, persistent bacteria form biofilms on the spinal hardware, complicating treatment of the infection by requiring aggressive systemic antibiotic treatment and removal of the infected hardware, prolonging hospital admission and patient debilitation. More effective means to prevent infection are a clinical imperative. New treatment modalities must eradicate pathogens prior to their adherence to the spinal hardware to be effective in preventing infection. Based on our previous work, our hypothesis is that a time-dependent augmentation of the initial VAN levels with a combination of antibiotics effective against both Gram-positive AND Gram-negative bacteria will reduce spinal infection rates. We propose to develop an implantable hydrogel, which will augment the standard period of aggressive antimicrobial prophylaxis through (1) sustained release of VAN at the surgical site while surgical drains are still present to maintain prophylactic levels of antibiotics, and (2) following surgical drain removal, external ultrasound-triggered release of a bolus of complementary broad-spectrum antibiotics (VAN + tobramycin) from within the hydrogel to provide broad spectrum coverage against surviving bacteria. Use of a combination of antibiotics is expected to reduce the risk of antibiotic resistant pathogens, while also ensuring that all contaminating pathogens are eradicated from the surgical site. The scientific premise of this work is that the proposed system will allow rapid, spatiotemporally-controlled, and complete release of antibiotics at supra-therapeutic levels to reduce bacterial colonization of the surgical hardware. There are three specific aims: 1) Characterize the release kinetics and stability of the hydrogel as well as the ultrasound-triggered prophylactic release system using optimized ultrasound parameters, 2) Assess the ability of the ultrasound- triggered system to prevent bacterial colonization of spinal hardware under in vitro conditions, and 3) Determine the prophylactic utility of the ultrasound-triggered system in eradicating bacteria and preventing infection in an in vivo model of spinal surgery. This proposed project addresses the clinical problem of postoperative spinal infections using innovative applications of proven materials, and can quickly and effectively be translated to the clinical area upon completion of the project. We anticipate that the project will result in an adjunctive therapy capable of lowering infection rates in spinal fusion patients, effectively reducing the pain, disability, and mortality associated with postoperative infection following spinal fusion surgery. Throughout this proposed project, the applicant will receive training and support in each area as appropriate to perform the research tasks, gaining invaluable skills and experiences to help advance her career as an independent researcher.

脊柱融合手术后的细菌感染是一个主要的临床问题，有 1-10% 的患者 尽管进行了积极的围手术期抗生素治疗，仍出现感染。每年超过500万条脊柱 预计到 2030 年进行手术。当前的临床标准涉及使用无菌引流管和约 1 克的包装 将粉状万古霉素 (VAN) 注入伤口空间；然而，这种预防措施的效果是短暂的（24-48 小时）。左边 未经治疗的持久性细菌会在脊柱硬件上形成生物膜，使感染的治疗变得复杂 需要积极的全身抗生素治疗并去除受感染的硬件，延长住院时间 入院和患者虚弱。临床上迫切需要采取更有效的手段来预防感染。新的 治疗方式必须在病原体粘附到脊柱硬件之前根除病原体才能有效 预防感染。基于我们之前的工作，我们的假设是，时间依赖性增强 抗生素组合对革兰氏阳性菌和革兰氏阴性菌均有效的初始 VAN 水平 细菌会降低脊柱感染率。我们建议开发一种可植入的水凝胶，这将增强 通过 (1) 在手术时持续释放 VAN 进行积极抗菌药物预防的标准期 手术引流管仍存在以维持预防性抗生素水平的情况下，以及（2）手术后 去除引流管，外部超声触发释放补充广谱抗生素 （VAN + 妥布霉素）来自水凝胶内，可提供针对存活细菌的广谱覆盖。 抗生素组合的使用有望降低抗生素耐药病原体的风险，同时也 确保从手术部位根除所有污染病原体。这样做的科学前提 工作的重点是，所提出的系统将允许抗生素快速、时空控制和完全释放 在超治疗水平，以减少手术硬件的细菌定植。具体有以下三点 目标：1）表征水凝胶的释放动力学和稳定性以及超声触发的 使用优化的超声参数的预防性释放系统，2) 评估超声的能力 触发系统以防止体外条件下脊柱硬件的细菌定植，以及 3) 确定 超声波触发系统在消灭细菌和预防感染方面的预防作用 脊柱手术的体内模型。该项目解决了术后脊柱的临床问题 使用经过验证的材料的创新应用来感染，并且可以快速有效地转化为 项目完成后的临床领域。我们预计该项目将产生辅助治疗 能够降低脊柱融合患者的感染率，有效减少疼痛、残疾和死亡率 与脊柱融合手术后的术后感染有关。在整个拟议项目中， 申请人将在适当的情况下接受每个领域的培训和支持以执行研究任务，获得 宝贵的技能和经验有助于推进她作为独立研究员的职业生涯。