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

项目摘要/摘要 这项拟议的研究题为“手术部位感染与麻醉和细菌离子转运蛋白的作用”。 是研究日常使用的麻醉药对手术部位感染(SSI)的影响(暴露时间和 麻醉药的种类)和抗生素的体内有效性，并在体外研究其潜在的机制 在挥发性麻醉剂(VAS)而不是静脉麻醉剂(IA)增加细菌负荷的假设下 通过它们与细菌离子转运体的直接相互作用增加生物膜的形成，以及 也可以通过削弱宿主免疫细胞来实现。SSI是围手术期最常见的外科感染 环境，占医院感染的20%，并与显著的发病率、死亡率和 医疗保健费用。高达80%的SSI是由生物膜形式的细菌引起的，而不是浮游生物形式的细菌。我们 以前在革兰氏阴性菌中报道过1)常用的VAS异氟醚和 七氟醚而不是IA异丙酚增加了生物被膜的形成，2)一组细菌离子转运体 3)VAS通过影响离子转运体促进生物膜的形成。在这 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的常见毒株。在目标1中，我们将确定常见麻醉药对生物被膜形成的影响。 在体外低氧条件下模拟伤口的氧气水平。离子转运体在生物膜形成中的作用及其研究进展 将考察与VAS的直接交互。在目标2中，我们将确定常见麻醉药对 宿主防御，包括体外低氧和直接作用下浮游细菌或生物膜细菌细胞的吞噬作用 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 麻醉药对生物膜相关SSIs的影响及体内抗生素的有效性。我们将研究这些措施的效果 麻醉剂对该模型中细菌生物膜形成和天然免疫细胞功能的影响。在完成后 在这项研究中，我们希望了解麻醉剂的类型和接触时间是否会影响 细菌载量、生物被膜形成和抗生素的有效性。所有测试的麻醉药均为临床用药 我们希望我们的研究具有高度的临床相关性和可译性。继成功的 这项研究的完成，我们希望有基础来检查麻醉方案的影响 感染风险较高的手术患者的性传播感染。对麻醉药物直接捆绑的认识 细菌离子转运体形成生物膜和宿主防御受体Toll样受体2，如果在 这一建议，不仅将增加我们对挥发性麻醉剂如何起作用的理解，而且还可以引导我们 考虑开发筛查分析来排除这些相互作用，并开发无不良反应的麻醉药 效果。

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.