Using implantable biomaterial and bio-orthogonal chemistry to guide delivery of antibiotics

摘要 抗药性细菌的增加是对美国人口和其他国家健康的主要威胁。 世界每年有200万美国人患有耐药性感染。根据疾控中心的数据， 2013年，由于这些感染的直接结果，23，000人丧生，更多人死于相关疾病。 并发症每年抗生素耐药性使医疗保健系统损失超过200亿美元， 住院时间为6.4-12.7天，并使社会损失了350亿美元的生产力。减少20%， 耐药性感染每年将节省32亿至52亿美元的医疗费用。但却具有抗真菌性 由于滥用和不必要地使用广谱抗生素， 医疗保健和农业。如果没有有效的抗生素，标准药物治疗后的轻微感染可能 会带来毁灭性的后果基于植入物的表面活性剂是一个特别令人关切的问题。手术部位 在美国，每年有超过780，000名患者发生感染（SSI），并导致8，205人死亡。植入物 相关感染占这些SSI的20%，即，超过35，000起事件和估计2，000起 死亡在美国，仅髋关节和膝关节置换手术每年就导致20,000例SSI，而这些 患者在医院多呆了两周，医疗费用增加了两倍， 生活质量随着美国人口的不断老龄化，髋关节和膝关节置换术的发生率将越来越高。 频率，抗药性感染的数量也会增加。不幸的是，大多数全身性抗生素 治疗指数有限，目前使用的剂量可能会促使细菌生长， 阻力全身性抗生素还损害身体其他部位的正常细菌植物群，这进一步 鼓励耐药性并允许机会性感染不受控制地蔓延。此外，大多数系统 药物以及局部抗生素在穿透术后组织方面较差。理想情况下， 确切剂量的抗生素只需要在感染区域，这将使药物能够对抗 细菌，同时避免全身副作用和减少细菌耐药性的可能性。虽然 是作为药物仓库的可植入材料，药物不能被调节或修改 植入后。这些方法通常需要物理植入和移除，并且导致 药物的初始爆发随后是药物以亚治疗水平释放的数天或数周， 可能导致抗药性细菌的产生。Shasqi正在开发一种基于"捕获“的技术， 两种生物正交化学品之间的“释放”反应，导致局部药物释放。这种方法 将可注射生物材料的空间控制与全身性无活性前药的时间控制相结合 交付.在该项目下，Shasqi将利用该技术开发可释放的万古霉素前药， 达托霉素，通常用作MRSA感染的“最后药物”。具体目标是 项目是建立受试化合物的体外最低抑菌浓度（MIC）;并研究 在局部MRSA感染的小鼠模型中使用化合物。

Abstract The rise of antibiotic-resistant bacteria is a major threat to the health of the U.S. population and the rest of the world. 2 million Americans suffer from antibiotic-resistant infections yearly. According to the CDC at least 23,000 lives were lost in 2013 as a direct result of these infections and many more die due to related complications. Every year antibiotic resistance costs the healthcare system more than $20 billion, extends hospital stays by 6.4-12.7 days, and costs society another $35 billion in lost productivity. A 20% reduction in antibiotic-resistant infections would save $3.2-$5.2 billion each year in healthcare costs. But antibiotic-resistant infections are on the rise due to the indiscriminate and unnecessary use of broad-spectrum antibiotics in healthcare and agriculture. Without effective antibiotics, trivial infections after standard medical therapies could have devastating consequences. Surgeries based on implants are a particular source of concern. Surgical-site infections (SSIs) occur in more than 780,000 patients and cause 8,205 deaths in the U.S. each year. Implant associated infections account for 20% of those SSIs, i.e., more than 35,000 incidents and an estimated 2,000 deaths. Hip and knee replacement surgeries alone lead to 20,000 SSIs each year in the U.S., and these patients suffer an additional two weeks in the hospital, a tripled cost of healthcare, and a significantly reduced quality of life. As the U.S. population continues to age, hip and knee replacements will occur with greater frequency, and so will the number of antibiotic-resistant infections. Unfortunately, most systemic antibiotics have a limited therapeutic index, and the doses that are currently used may drive bacteria to develop resistance. Systemic antibiotics also harm normal bacterial flora in other parts of the body, which further encourages resistance and allows opportunistic infections to flourish unchecked. Furthermore, most systemic drugs as well as topical antibiotics are poor at penetrating post-operative tissue. Ideally one would provide the exact dose of antibiotic needed exclusively at the area of infection, which would enable the drug to fight the bacteria while avoiding systemic side effects and reducing the likelihood of bacterial resistance. While there are implantable materials that serve as depots of medication, the medications cannot be modulated or modified after implantation. These methods usually require physical implantation and removal, as well as result in an initial burst of medication followed by days or weeks where the drug is released at sub-therapeutic levels, potentially leading to antibiotic-resistant bacteria. Shasqi is developing a technology based on a `catch and release' reaction between two bio-orthogonal chemicals that results in a localized drug release. This approach combines the spatial control of injectable biomaterials with the temporal control of systemic inactive prodrug delivery. Under this project, Shasqi will use this technology to develop releasable prodrugs of vancomycin and daptomycin, which are commonly used as “drugs of last resort” for MRSA infections. The specific aims of this project are to establish minimum inhibitory concentration (MIC) of the test compounds in vitro; and study the compounds in a mouse model of local MRSA infection.