Development of an Antimicrobial Pedicle Screw System: Studies Designed to Mitigate the Risk of Bacterial Resistance

项目总结/摘要 植入部位的慢性疼痛，“腰椎手术失败综合征（FBSS）”，是脊柱融合的常见原因 失败然而，在过去的五年里，多项研究已经确定了FBSS和低血糖之间的明确联系。 植入物表面的细菌污染水平。特别是，这些研究表明， 在从FBSS患者中取出的40%的硬件病例中， 手术部位感染的迹象。为了满足这种临床需求，Orthobond开发了一种抗菌剂， 使用高密度共价结合季铵的椎弓根螺钉植入物系统 化合物（QAC）。该椎弓根螺钉系统已经证明具有广谱抗菌性 有效性和良好的生物相容性;然而，为了使产品商业化，有必要 证明抗菌植入物不会促进耐药性的出现， 细菌 近世纪来，QAC在诸如漱口水、洗发水等消费品中是众所周知的， 表面消毒剂喷雾;他们遭受细菌耐药性的报告很少。然而，当抵抗 QAC确实发生，它是通过表达一种或多种类型的外排泵来清除QAC 在它们破坏细胞内目标之前。我们认为，在水面系留的质保期内， 通过外排泵降低功效;预期这些表面结合的分子不会进入 细菌，而是通过正电荷促进机制作用于其细胞壁。全球 这项拟议研究的目的还包括实施快速测定，以确定我们的倾向， QAC处理的椎弓根螺钉植入物，以允许出现对它们和其他 接触型抗菌剂第一阶段的提案包括两个具体目标，简而言之： ·目的1是测试Orthobond抗菌椎弓根螺钉表面是否反复暴露于 革兰氏阳性或革兰氏阴性细菌导致这些细菌对抗生素的敏感性降低。 植入物或对常用抗生素的交叉耐药性。 ·目标2是测试QAC与椎弓根螺钉系统的表面粘合是否消除了阻力 溶解QAC的机制-QacA外排泵基因的表达。 这些试验的设计和实施将允许评价Orthobond的倾向 抗菌椎弓根螺钉系统，以促进细菌抵抗力。这些研究可能会提供 向医生和患者销售抗菌椎弓根螺钉系统所需的关键数据。

PROJECT SUMMARY/ABSTRACT Chronic pain at the implant site, “failed back surgery syndrome (FBSS),” is a common cause of spine fusion failure. Over the past five years, though, multiple studies have defined a clear link between FBSS and low levels of bacterial contamination on implant surfaces. In particular, these studies showed bacterial contamination in 40% of cases of hardware retrieved from FBSS patients who have otherwise no clinical signs of surgical site infection. In response to this clinical need, Orthobond has developed an antimicrobial pedicle screw implant system utilizing a high density of covalently bound quaternary ammonium compounds (QACs). This pedicle screw system has already demonstrated broad-spectrum antimicrobial efficacy and good biocompatibility; however, in order to commercialize the product, it is necessary to demonstrate that the antimicrobial implants will not promote the emergence of antibiotic-resistant bacteria. QACs are well-known for nearly a century in consumer products such as mouthwashes, shampoos and surface disinfectant sprays; they suffer few reports of bacterial resistance. However, when resistance to QACs does occur, it is through expression of one or more types of efflux pumps that work to remove QACs before they disrupt intracellular targets. We believe that surface-tethered QACs should not be subject to decreased efficacy by efflux pumps; these surface-bound molecules are expected to not enter the bacterium, but rather to act on its cell wall through positive-charge promoted mechanisms. The global aim of this proposed research also includes to implement rapid assays to determine the propensity for our QAC-treated pedicle screw implants to allow emergence of bacterial resistance to them and to other contact-based antimicrobials. This Phase 1 proposal consists of two specific aims, in brief: • Aim 1 is to test whether repeated exposure of Orthobond antimicrobial pedicle screw surfaces to gram positive or gram negative bacteria results in decreased susceptibility of these bacteria to the implants or cross-resistance to commonly used antibiotics. • Aim 2 is to test if surface-bonding the QAC to the pedicle screw system obviates the resistance mechanism to dissolved QACs - expression of the QacA efflux pump gene. The design and implementation of these tests will allow for evaluation of the propensity of the Orthobond antimicrobial pedicle screw system to promote bacterial resistance. These studies will potentially provide critical data needed to market the antimicrobial pedicle screw system to physicians and their patients.