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

点击翻译按钮获取中文摘要

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.