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(申请人提供)：Ostene是一种柔软的、合成的、可模塑的止血材料，能很好地粘连在切割的骨表面，并通过机械闭塞止血。Ostene是一种生物相容的水溶性聚合物的组合，在植入后24至48小时内完全吸收；它是非炎症性的，由于其能够防止细菌附着到表面，还具有内在的抗感染作用。这种特性的结合使Ostene成为在任何涉及切割骨骼的外科手术中将抗生素直接输送到伤口的理想材料。该项目的目标是开发一种含有万古霉素(Ostene-V)的Ostene配方。Ostene-V旨在用于骨止血，与Ostene完全一样，但也将在手术期间和手术后立即在手术部位提供高浓度的万古霉素。该抗生素将在术后立即提供补充保护，以减少伤口或骨骼(骨髓炎)感染甲氧西林耐药葡萄球菌(例如，MRSA或MRSE)的可能性，作为全身抗生素预防的辅助措施。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。这项与FDA协商制定的临床前测试计划将用于支持510(K)或IDE提交，随后将进行第二阶段的临床研究，以评估术中预防性使用Ostene-V以降低MRSA/MRSE感染高危患者手术伤口感染的发生率和严重程度。Ostene-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)是心脏手术中相对常见的并发症。在最近的研究中，报道的胸骨切开术后SWI的发生率为6-9%，其中约三分之二被归类为浅表SWI，三分之一(总计2-3%)为深部SWI或纵隔炎，它们与显著的发病率相关，通常需要长期住院治疗，死亡率在10%至20%之间。超过50%的SWI是葡萄球菌感染，其中大部分是由耐药变种引起的，例如耐甲氧西林金黄色葡萄球菌和凝固酶阴性葡萄球菌。假设目前美国一个SWI的平均治疗费用为25,000美元，每年有650,000例心脏手术，SWI的发病率为5%，其中25%是由耐甲氧西林葡萄球菌引起的，那么这种潜在的可预防的并发症每年导致的额外医疗费用总计约为2亿美元。手术部位局部应用万古霉素有可能显著降低葡萄球菌SWI的发生率。根据这项建议开发的Ostene和万古霉素联合产品将不需要比单独使用Ostene更多的努力，预计将作为预防SWI的系统性抗生素预防的辅助治疗有效。Ostene作为骨蜡或其他止血材料(如凝血酶、胶原、纤维蛋白)的首选替代品，越来越多地被用于心脏手术的止血。因此，一旦开发并被证明对预防SWI有效，Ostene+庆大霉素的组合预计不会遇到任何主要的接受障碍。