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

点击翻译按钮获取中文摘要

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.