Hemostatic-antibiotic Combination for Prevention of MRSA Surgical Site Infections

描述（由申请人提供）：osteene是一种柔软的，合成的，可成型的止血材料，可以很好地粘附在切割的骨表面，并通过机械闭塞止血。Ostene是一种生物相容性水溶性聚合物的组合，在植入后24至48小时内被完全吸收；它是非炎症的，并且由于它能够防止细菌粘附在表面上而具有内在的抗感染作用。这种特性的结合使骨骨素成为在任何涉及切割骨头的外科手术过程中直接向伤口输送抗生素的理想材料。该项目的目的是研制一种含有万古霉素的奥斯汀制剂（奥斯汀- v）。Ostene- v与Ostene完全一样用于骨止血，但在手术中和术后立即在手术部位提供高浓度的万古霉素。作为全身抗生素预防的辅助手段，该抗生素将在术后立即提供补充保护，以减少耐甲氧西林葡萄球菌（如MRSA或MRSE）对伤口或骨骼感染（骨髓炎）的可能性。本申请描述了制剂开发、体外验证、生物相容性测试和体内动物药代动力学研究。该临床前试验计划是在与FDA协商后制定的，将用于支持510(k)或IDE提交，随后进行II期临床研究，以评估在MRSA/MRSE感染高风险患者中，术中预防性使用ostee - v以降低手术伤口感染的发生率和严重程度。oone - v有可能显著降低MRS伤口感染的发生率，并对术后感染相关的死亡、残疾和总体治疗成本产生重大影响。

DESCRIPTION (provided by applicant): Ostene is a soft, synthetic, moldable hemostatic material that sticks well to cut bone surfaces and stops bleeding by mechanical occlusion. Ostene is a combination of biocompatible water-soluble polymers which are absorbed completely within 24 to 48 hours of implantation; it is non-inflammatory and also has an intrinsic anti-infective effect due to its ability to prevent bacterial adhesion to surfaces. This combination of properties makes Ostene an ideal material for delivery of antibiotics directly to the wound during any surgical procedure that involves the cutting of bone. The objective of this project is to develop a formulation of Ostene that contains vancomycin (Ostene-V). Ostene-V is intended to be used for bone hemostasis exactly like Ostene, but will also provide a high local concentration of vancomycin at the surgical site during surgery and the immediate post-operative period. The antibiotic will provide supplemental protection during the immediate post-operative period to reduce the probability of against infection of the wound or the bone (osteomyelitis) by methicillin- resistant Staphylococci (e.g., MRSA or MRSE), as an adjunct to systemic antibiotic prophylaxis. This application describes the formulation development, in vitro validations, biocompatibility testing, and in vivo animal pharmacokinetic studies. This preclinical testing plan, developed in consultation with the FDA, will be used to support a 510(k) or IDE submission, followed by a clinical study in phase II to evaluate the interoperative prophylactic use of Ostene-V to reduce the incidence and severity of surgical wound infections in patients at high risk for MRSA/MRSE infection. Ostene-V has the potential to significantly reduce the incidence of MRS wound infection, and have a major impact on post-operative infection related deaths, disability, and overall cost of treatment. PUBLIC HEALTH RELEVANCE: Sternal wound infections (SWIs) are a relatively common complication of cardiac surgery. In recent studies, the reported incidence of SWI after sternotomy was 6-9%, of which about two- thirds were classified as superficial, and one-third of (2-3% in total) as deep SWI or mediastinitis, which are associated with significant morbidity, often require prolonged in-patient treatment, and have a mortality rate between 10 and 20%. Over 50% of all SWI are Staphylococcal infections, the majority of which are caused by drug-resistant variants such as methicillin-resistant S. Aureus and coagulase-negative Staph species. Assuming a current average treatment cost of one SWI in the US to be $25,000, with 650,000 cardiac operations per year, a SWI incidence of 5%, of which >25% are caused by methicillin- resistant staphylococci, the total additional health care cost due to this one potentially preventable complication amounts to about $200,000,000 annually. Local delivery of vancomycin to the surgical site has the potential to significantly reduce the incidence of Staphylococcal SWI. The Ostene and vancomycin combination product to be developed under this proposal will require no additional effort to use than Ostene alone, and is expected to be effective as an adjuvant therapy to systemic antibiotic prophylaxis for prevention of SWI. Ostene is increasingly being used for hemostasis in cardiac surgery as a preferred alternative to bonewax or other hemostatic materials (e.g., thrombin, collagen, fibrin). Thus, once developed and proven effective for SWI prevention, the Ostene+ Gentamicin combination would be not expected to meet any major barrier to acceptance.