Hemostatic-antibiotic Combination for Prevention of MRSA Surgical Site Infections

止血-抗生素组合预防 MRSA 手术部位感染

• 批准号: 8001471
• 负责人: TIMOTHY C FISHER
• 金额: $ 10万
• 依托单位: CEREMED, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001471
• 关键词: Adjuvant Therapy; Adverse effects; Aging; Animals; Anti-Infective Agents; Antibiotic Prophylaxis; Antibiotics; Bacterial Adhesion; Biocompatible; Bone Surface; Buffers; Cardiac; Cardiac Surgery procedures; Cessation of life; Clinical; Clinical Research; Coagulase; Collagen; Combined Antibiotics; Complication; Consultations; Defect; Development; Drug Formulations; Drug Kinetics; Drug resistance; Ensure; Evaluation; FDA approved; Femur; Fibrin; Gentamicins; Genus staphylococcus; Goals; Gram-Positive Bacteria; Health Care Costs; Hemorrhage; Hemostatic Agents; Hemostatic function; High Pressure Liquid Chromatography; Hour; Immunoassay; In Vitro; Incidence; Infection; Infection prevention; Inflammatory; Intramuscular; Kinetics; Measurement; Measures; Mechanics; Mediastinitis; Methicillin Resistance; Microscopic; Modeling; Monitor; Morbidity - disease rate; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Osteomyelitis; Particle Size; Patients; Performance; Phase; Polymers; Postoperative Period; Preclinical Testing; Prevention; Probability; Process; Property; Reporting; Research; Sampling; Severities; Site; Staging; Staphylococcal Infections; Sterilization; Sternotomy; Structure; Surface; Surgical Wound Infection; Temperature; Testing; Thrombin; Time; Toxic effect; Treatment Cost; Validation; Vancomycin; Variant; Viscosity; Water; Wound Infection; biomaterial compatibility; bone; cytotoxicity; disability; genotoxicity; high risk; implantation; in vivo; manufacturing process; meetings; methicillin resistant Staphylococcus aureus; mortality; operation; preclinical study; prevent; prophylactic; public health relevance; stability testing; wound

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.

描述（由申请人提供）：ostene是一种柔软，合成的，可塑的止血物质，可以很好地粘贴骨表面并通过机械闭塞停止出血。 Ostene是生物相容性水溶性聚合物的组合，它们在植入的24至48小时内完全被吸收。它是非炎症性的，并且由于其能够防止细菌粘附到表面的能力，因此具有内在的抗感染作用。这种特性的组合使奥蛋白成为在任何涉及切割骨骼的手术过程中直接输送抗生素向伤口传递的理想材料。该项目的目的是开发含有万古霉素（ostene-V）的ostene的配方。 Ostene-V旨在与Ostene一样用于骨止血，但在手术期间和术后直接术中，手术部位也将在手术部位提供高局部浓度的万古霉素。抗生素将在术后立即提供补充保护，以降低甲氧西林 - 耐甲氧西林葡萄球菌（例如MRSA或MRSE）的伤口或骨骼（骨髓炎）的可能性，作为全身性抗生素预防的辅助性。该应用描述了配方的发展，体外验证，生物相容性测试和体内动物药代动力学研究。该临床前测试计划与FDA协商开发，将用于支持510（k）或IDE提交，然后在II期中进行临床研究，以评估Ostene-V对术的预防性使用，以减少MRSA/MRSE感染高风险的患者手术伤口感染的发病率和严重性。 Ostene-V有可能显着降低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。 公共卫生相关性：胸骨伤口感染（SWIS）是心脏手术的相对常见并发症。在最近的研究中，据报道，胸骨切开术后SWI的发生率为6-9％，其中约三分之二被归类为表面，其中三分之一（总计2-3％）为深SWI或纵隔炎，这通常与明显的发病率有关，通常需要长时间的患者治疗，并且具有10％和20％的死亡率。超过50％的SWI是葡萄球菌感染，其中大多数是由抗药性变体（如耐甲氧西林的金黄色葡萄球菌和凝结酶阴性的葡萄球菌）引起的。假设美国目前的平均治疗费用为美国25,000美元，每年有650,000个心脏操作，SWI发病率为5％，其中> 25％是由耐甲氧西林抗甲氧西林葡萄球菌引起的，这是由于这一潜在预防的并发症的总额外医疗保健成本，每年约200,000美元。万古霉素局部递送到手术部位有可能显着降低葡萄球菌SWI的发生率。在该提案下要开发的Ostene和Vansomycin组合产品将不需要单独使用的额外努力，并且有望作为一种用于预防SWI的全身性抗生素预防的辅助治疗。在心脏手术中，Ostene越来越多地用于止血，作为骨膜或其他止血物质（例如凝血酶，胶原蛋白，纤维蛋白）的首选替代品。因此，一旦开发并证明对SWI预防有效，Ostene+庆大霉素的组合将不会遇到任何主要的接受障碍。