Surgical site infections and the role of anesthesia and bacterial ion transporters

项目概要/摘要 这项拟议的研究题为“手术部位感染以及麻醉和细菌离子转运蛋白的作用” 研究日常使用的麻醉药物对手术部位感染（SSI）的影响（暴露时间和 麻醉剂类型）和抗生素在体内的有效性，并在体外研究其潜在机制 假设挥发性麻醉剂（VA）而不是静脉麻醉剂（IA）增加细菌负荷 通过与细菌离子转运蛋白直接相互作用增加生物膜形成， 也通过减弱宿主免疫细胞。SSI是围手术期最常见的外科感染 占院内感染的20%，并与显著的发病率、死亡率和 医疗费用。高达80%的SSI是由生物膜形式的细菌引起的，而不是由细菌引起的。我们 先前在革兰氏阴性菌大肠埃希菌中报告，1）常用的VA异氟烷和 七氟醚，而不是IA丙泊酚增加生物膜形成，和2）一组细菌离子转运蛋白， VA通过影响离子转运蛋白促进生物膜的形成。在这 建议我们计划使用革兰氏阳性菌金黄色葡萄球菌和粪肠球菌菌株， SSI的常见菌株。在目标1中，我们将确定常用麻醉剂对生物膜形成的影响， 在低氧下在体外模拟伤口处的氧水平。离子转运蛋白在生物膜形成中的作用及其对生物膜的影响 将审查与自愿捐款机构的直接互动。在目标2中，我们将确定常用麻醉剂对 宿主防御，包括在体外缺氧和直接 VA与革兰氏阳性受体Toll样受体2的结合。在目标3中，我们将确定 麻醉剂对生物膜相关SSI的影响以及抗生素在体内的有效性。我们将研究 在该模型中，麻醉剂对细菌生物膜形成和先天免疫细胞功能的影响。完成后 在这项研究中，我们希望了解麻醉剂的类型和暴露时间是否会影响 细菌负荷、生物膜形成和抗生素的有效性。所有测试的麻醉剂都在临床上 我们希望我们的研究具有高度临床相关性，并且易于翻译。继成功 完成这项研究，我们希望有基础来检查麻醉方案的影响， 接受高感染风险手术的患者中的SSI。对麻醉药直接捆绑的认识 细菌离子转运蛋白的生物膜形成和宿主防御受体toll样受体2，如果学习， 这一建议不仅将增加我们对挥发性麻醉剂如何工作的理解，而且还可以引导我们 我想开发筛选试验来排除这些相互作用，并开发没有不良反应的麻醉剂。 方面的影响.

Project Summary/ Abstract The proposed research titled “Surgical site infections and the role of anesthesia and bacterial ion transporters” is to study the impact of daily used anesthetic drugs on surgical site infections (SSIs) (exposure duration and type of anesthetics) and the effectiveness of antibiotics in vivo and examine its underlying mechanism in vitro under the hypothesis that volatile anesthetics (VAs), not intravenous anesthetic (IA) increase bacteria burden in surgical wound by increasing biofilm formation via their direct interaction with bacterial ion transporters, and also by attenuating host immune cells. SSIs are the most common surgical infections in the perioperative setting, occupying 20% of in-hospital infections, and associated with significant morbidities, mortalities and healthcare expenses. Up to 80% of SSIs are due to bacteria in biofilm form, not in planktonic form. We previously reported in gram-negative bacteria Escherichia coli that 1) commonly used VAs isoflurane and sevoflurane, not IA propofol increased biofilm formation, and 2) a group of bacterial ion transporters were involved in biofilm formation, and 3) VAs enhanced the biofilm formation via affecting ion transporters. In this proposal we plan to use gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis strains, common strains for SSIs. In Aim 1, we will determine the effect of common anesthetics on biofilm formation in vitro under hypoxia to mimic oxygen level at wounds. The role of ion transporters in biofilm formation and their direct interaction with VAs will be examined. In Aim 2, we will determine the effect of common anesthetics on host defense, including phagocytosis of planktonic or biofilm bacteria cells in vitro under hypoxia and direct binding of VA to gram-positive receptor toll-like receptor 2. In Aim 3, we will determine the impact of anesthetics on biofilm-associated SSIs and the effectiveness of antibiotics in vivo. We will study the effect of anesthetics on bacterial biofilm formation and innate immune cell functions in this model. Upon the completion of the study, we expect to learn whether or not the type of anesthetics and the duration of their exposure affect bacterial loads, biofilm formation and the effectiveness of antibiotics. All the anesthetics tested are in clinical use and we expect that our study is highly clinically-relevant and readily translatable. Following the successful completion of this study, we expect to have the foundation to examine the impact of anesthetic regimens on SSIs in patients undergoing procedures with high risk of infection. The knowledge of anesthetic direct binding to bacterial ion transporters for biofilm formation and to host defense receptor toll-like receptor 2, if learned in this proposal, will not only increase our understanding of how volatile anesthetics work but also can lead us to think of developing screening assays to rule out these interactions and develop anesthetics devoid of adverse effects.