Sporocidal Mechanism and Inline Monitoring of Peracetic Acid in Supercritical CO2

 描述(由申请人提供)：由于医院获得性感染(HAI)中抗生素耐药性的迅速上升，对生物医学设备、异种移植和异体移植材料进行灭菌至关重要。对于HAI的一种主要病原体艰难梭菌，抗生素的使用增加了感染率和更糟糕的结果，因为使用的强力抗生素消除了本地肠道菌群(Songer和Anderson，2006)。艰难梭菌、金黄色葡萄球菌和铜绿假单胞菌是2002年造成100,000多人死亡的约200万医院感染中的许多原因，估计每20名医院患者中就有一人会感染HAI(www.cdc.gov/hai/burden.html，www.cdc.gov/HAI/pdfs/hai/infections_deaths.pdf).卫生保健费用估计超过250-350亿美元，预防费用估计不到70亿美元(www.cdc.gov/HAI/pdfs/hai/Scott_CostPaper.pdf).在使用任何灭菌系统或抗生素时，需要确定所涉及的分子或因素的杀菌作用的机制。从抗生素耐药性、艰难梭菌感染的抗生素促进和杀生剂耐药性中吸取的经验教训推动了对新的和长期使用的杀生剂的杀灭机制进行表征的要求。了解杀生剂的关键细胞靶标，能够开发出创新、安全的方法来控制或消除HAI的发生。[对于内外使用的医疗设备和药品，要接受一种新的灭菌方法，美国食品和药物管理局(FDA)现在要求确定杀菌作用的机制。]NovaSterilis，Inc.已经完成了NIH第二阶段的两笔赠款，从而在市场上推出了一种经过验证的超临界二氧化碳-过氧乙酸(scCO2-PAA)软组织和硬组织灭菌系统，并正在开发可吸收缝合线的灭菌。这项建议涉及FDA对SCCO2中PAA杀死微生物的机制进行表征的要求。NovaSterilis的商用Nova 2200系统监测超临界二氧化碳的形成和维持所需的条件，但目前不监测溶解在scCO2中的过氧乙酸(和稳定剂过氧化氢)的浓度。[NovaSterilis第一阶段计划的目标是识别PAA和SCCO2中的氢对枯草芽孢杆菌芽胞的生物杀灭作用机制，枯草杆菌是最具抗药性的生命形式之一，并开发和测试一种在线仪表，以监测系统中PAA的杀菌水平。]这项工作将大大促进FDA监管机构对使用PAA和过氧化氢作为医疗器械和生物制品以及使用PAA作为灭菌剂或辅助灭菌剂的食品和环境系统的scCO2灭菌的监管接受。

 DESCRIPTION (provided by applicant): It is critical to sterilize biomedical devices, xenograft and allograft materials, due to the rapid rise of antibiotic resistance in hospital-acquired infections (HAI). For one major HAI pathogen, Clostridium difficile, the use of antibiotics promotes greater infection rates and worse outcome, as the native intestinal flora is eliminated by the strong antibiotics used (Songer and Anderson, 2006). C. difficile, Staphylococcus aureus and Pseudomonas aeruginosa are responsible for many of the estimated 2 million nosocomial infections resulting in over 100,000 deaths in 2002 and with the estimate that one in twenty hospital patients will acquire an HAI (www.cdc.gov/HAI/burden.html, www.cdc.gov/HAI/pdfs/hai/infections_deaths.pdf). The estimated costs of HAI are well over $25-35 billion, with prevention costs estimated at below $7 billion (www.cdc.gov/HAI/pdfs/hai/Scott_CostPaper.pdf). With the use of any sterilization system or antibiotic, there is a need to identify the mechanism of microbicidal action of the molecule or factor involved. Lessons learned from antibiotic resistance, antibiotic promotion of C. difficile infection and biocide resistance drive the requirement for characterizing new and long-used biocide's mechanisms of kill. Understanding the critical cellular targets for biocides enables the development of innovative, safe methods to control or eliminate the incidence of HAI. [For a novel sterilization method to be accepted for medical devices for internal and external use and for pharmaceuticals, the U.S. Food and Drug Administration (FDA) now require identification of the mechanism of biocide action.] NovaSterilis, Inc., has completed two NIH Phase II grants, resulting in a validated supercritical Carbon dioxide- peracetic acid (scCO2-PAA) sterilization system on the market for soft and hard tissue and is developing sterilization of absorbable sutures. This proposal addresses the FDA requirement for characterization of the mechanism of microbial kill by PAA in scCO2. NovaSterilis' commercial Nova 2200 system monitors the conditions required for formation and maintenance of supercritical CO2, but does not currently monitor concentrations of peracetic acid (and stabilizer hydrogen peroxide) solubilized in scCO2. [The goals of the NovaSterilis Phase I program are to identify the mechanism of biocidal action of PAA and hydrogen in scCO2 on spores of the bacterium Bacillus subtilis, one of the most resistant forms of life, and to develop and test an inline meter to monitor microbicidal levels of PAA in the system.] This work will significantly advance FDA regulatory acceptance of scCO2 sterilization with PAA and hydrogen peroxide as co-sterilants for medical devices and biologicals, as well as for food and environmental systems utilizing PAA as a sterilant or co- sterilant.