Serial Endoscopic Surveillance (SES) and Direct Topical Antibiotics (DTA) to prev

系列内窥镜监测 (SES) 和直接局部抗生素 (DTA)

基本信息

批准号：
8756542
负责人：
John C Alverdy
金额：
$ 15.84万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2015-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8756542
关键词：
Address Adverse event Advocate Anastomosis - action Anterior Antibiotics Bacteria Bioinformatics Biological Biological Assay Biology Budgets Cessation of life Chicago Cleaved cell Clinical Data Clinical Paths Clinical Research Clinical Trials Collagen Colon Colorectal Surgery Communication Complication Computers Consent Forms Data Development Direct Repeats Dose Electronics Eligibility Determination Endoscopy Enrollment Ensure Enzymes Esophagus Ethics Ethics Consultation Excision Feces Frequencies Fright Gastrointestinal tract structure Goals Healed Health Insurance Portability and Accountability Act Hospitalization Human Ileostomy Image Immune Incidence Indigenous Inflammatory disease of the intestine Informed Consent Inpatients Institutional Review Boards Instruction Intestinal Content Intestines Laboratories Long-Term Care MMP9 gene Manuals Methods Microbe Modeling Molecular Operative Surgical Procedures Participant Pathogenesis Patients Peptide Hydrolases Performance Peritoneum Peritonitis Phase Phase II Clinical Trials Phenotype Placebos Play Postoperative Period Preparation Procedures Process Property Protocols documentation Publishing Qualifying Randomized Rattus Recovery Rectum Regimen Reporting Research Research Design Research Ethics Research Personnel Research Subjects Resected Resolution Ribosomal RNA Risk Role Sampling Schedule Secure Sepsis Services Sigmoidoscopy Site Staging Standardization Stomas Surgeon Surgical sutures System Testing Tissues Topical Antibiotic Topical application Universities Virulence Visit Work authority base collagenase cost cyber infrastructure data management data sharing design direct application disability driving force enema administration evidence base healing high risk in vivo microbial microbiome mortality operation pathogen prevent primary outcome public health relevance rectal sample collection seal secondary outcome

项目摘要

DESCRIPTION (provided by applicant): When surgeons remove (resect) a diseased segment of the gastrointestinal tract, its continuity is reestablished by carefully suturing or stapling th remaining ends together to create a viable and well- sealed connection referred to as an "anastomosis." The most devastating and disability complication following anastomotic construction is a "leak" where anastomotic tissues fail to heal, separate, and intestinal contents escape into the peritoneum causing sepsis, peritonitis and even death. Anastomotic leak rates have not changed in decades and remain at 10% for the highest risk cases involving the esophagus and rectum. We have generated compelling evidence that intestinal microbes are the driving force behind the pathogenesis of anastomotic leak. Our work demonstrates that certain intestinal microbes become activated in vivo to produce a high degree of collagenase that is capable of expressing a "tissue destroying phenotype" leading to anastomotic non- healing, separation, and leak. We show that intestinal microbes become transformed in vivo to express high collagenase over the course of recovery that can cleave intestinal MMP9 to its active form and breakdown the collagen needed for healing. Importantly our data demonstrate that currently used IV antibiotic regimens do not eliminate these offending microbes whereas direct application of topical antibiotics (DTA) to anastomotic tissues completely protects against anastomotic leak by suppressing collagenase and preventing MMP9 cleavage to its active form. We have generated preliminary data in humans that strongly suggests that patients harboring pathogens expressing the "leak phenotype" are most at risk when their normal indigenous microbiota can no longer constrain the tissue damaging effects of these renegade pathogens. In this planning proposal we will develop a trial to directly test this hypothesis. We will plan a tril in which patients undergoing a low colo- rectal resection, termed a low anterior resection (LAR) with a diverting protective stoma (ileostomy), are subjected to serial endoscopic examination (SES) by sigmoidoscopy with image capture and microbial analysis at 3 separate intervals following surgery. Images of anastomotic healing will be correlated to compositional and functional changes in the microbiota via 16s rRNA sequencing and phenotype assay including collagenase and MMP9 cleavage activity. In the SES-DTA trial, patients will be randomized to application of direct topical antibiotics (DTA) versus placebo and anastomotic healing tracked at 3 SES episodes over the course of 21 days (postoperative days 2-3, 7-10, and 14-21). This planning proposal has assembled uniquely qualified investigators who are leading authorities on intestinal microbiome research, the pathogenesis of anastomotic leak colorectal surgery, multi-centered trials on patients undergoing colorectal surgery, and all facets of biostastistics and bioinformatics to operationalize the trial. This trial will be the first of its kind to directly exmine anastomotic tissues as they heal and correlate healing to microbial composition and function. It will change the practice of colo-rectal surgery by providing a clinical path to predict and prevent anastomotic leak.

描述（由申请人提供）：当外科医生切除（切除）胃肠道的患病部分时，通过仔细地将剩余末端缝合或钉在一起以形成可行且密封良好的连接（称为“吻合术”）来重新建立其连续性。 ”吻合构造后最具破坏性和致残性的并发症是“渗漏”，即吻合组织无法愈合、分离，肠内容物逸入腹膜，导致败血症、腹膜炎甚至死亡。几十年来，吻合口漏率没有变化，对于涉及食管和直肠的最高风险病例，吻合口漏率仍保持在 10%。我们已经获得了令人信服的证据，证明肠道微生物是吻合口瘘发病机制背后的驱动力。我们的工作表明，某些肠道微生物在体内被激活，产生高度的胶原酶，能够表达“组织破坏表型”，导致吻合口不愈合、分离和渗漏。我们发现肠道微生物在恢复过程中在体内发生转化，表达高胶原酶，可以将肠道 MMP9 裂解为其活性形式并分解愈合所需的胶原蛋白。重要的是，我们的数据表明，目前使用的静脉注射抗生素疗法并不能消除这些有害微生物，而直接将局部抗生素（DTA）应用于吻合组织可以通过抑制胶原酶并防止 MMP9 裂解为其活性形式来完全防止吻合口渗漏。我们已经在人类中获得了初步数据，这些数据强烈表明，当携带表达“泄漏表型”的病原体的患者的正常本土微生物群不再能够限制这些叛变病原体的组织破坏作用时，他们面临的风险最大。在这个规划提案中，我们将开发一个试验来直接检验这个假设。我们将计划一项试验，其中接受低位结直肠切除术（称为低位前切除术（LAR）并带有转向保护性造口（回肠造口术））的患者将通过乙状结肠镜进行系列内窥镜检查（SES），并进行图像捕获和微生物分析手术后 3 个独立的时间间隔。通过 16s rRNA 测序和表型测定（包括胶原酶和 MMP9 裂解活性），吻合口愈合的图像将与微生物群的组成和功能变化相关联。在 SES-DTA 试验中，患者将被随机分配使用直接局部抗生素 (DTA) 与安慰剂，并在 21 天内（术后第 2-3 天、7-10 天和 14 天）跟踪 3 次 SES 发作时的吻合口愈合情况。 21）。该规划提案汇集了具有独特资格的研究人员，他们是肠道微生物组研究、吻合口瘘结直肠手术发病机制、接受结直肠手术患者的多中心试验以及生物统计学和生物信息学各个方面的领先权威，以实施该试验。该试验将是同类试验中首次直接检查吻合组织的愈合情况，并将愈合情况与微生物组成和功能联系起来。它将通过提供预测和预防的临床路径来改变结直肠手术的实践吻合口漏。