POR Program on Genomic Prediction of Antimicrobial Resistance in VRE

VRE 抗菌素耐药性基因组预测 POR 程序

• 批准号: 9906161
• 负责人: Cesar Augusto Arias
• 金额: $ 17.03万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-25 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906161
• 关键词: Affect; Alleles; Americas; Ampicillin Resistance; Animal Model; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotic-resistant organism; Antibiotics; Antimicrobial Resistance; Antimicrobial susceptibility; Area; Award; Bacteremia; Bacterial Antibiotic Resistance; Blood Circulation; Bone Marrow Transplantation; Cancer Center; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Data; Clinical Research; Collaborations; Colombia; Combined Modality Therapy; Communicable Diseases; Congresses; Critical Illness; DNA sequencing; Daptomycin; Data; Decision Making; Development; ESKAPE pathogens; Enterococcus; Enterococcus faecium; Failure; Funding; Future; Gene Mutation; Generations; Genes; Genetic; Genetic Determinism; Genomics; Gentamicins; Goals; Grant; Health; Health Sciences; Hematologic Neoplasms; Hospitals; Human; In Vitro; Infection; International; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Medical center; Memorial Sloan-Kettering Cancer Center; Mentors; Methods; Microbiology; Molecular; Molecular Genetics; Multiple Bacterial Drug Resistance; Mutation; Organism; Outcome; Patient Care; Patient Isolators; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Predisposition; Public Health; Publishing; Reporting; Research; Resistance; Resistance development; Resources; Retrospective cohort; Sampling; Science; Scientist; Site; Societies; South America; Technology; Testing; Texas; Therapeutic; Training Programs; Translations; United States National Institutes of Health; Universities; University of Texas M D Anderson Cancer Center; Vacuum; Vancomycin; Vancomycin Resistance; Vancomycin resistant enterococcus; World Health Organization; antimicrobial; bactericide; base; beta-Lactams; clinical practice; cohort; cost; fight against; genome sequencing; genomic platform; genomic tools; grasp; healthcare-associated infections; mortality; multi-drug resistant pathogen; new technology; novel therapeutics; oritavancin; pathogen; pathogenic bacteria; patient oriented research; predict clinical outcome; predicting response; programs; prospective; public health relevance; research facility; sequencing platform; success; synergism; therapy outcome; tool; validation studies; whole genome

ABSTRACT My major goal through this mid-career development award (K24) is to increase my ability to conduct patient oriented research (POR) on antibiotic resistance and mentor a new generation of clinicians as to how to approach this important public health threat. The emergence of antibiotic resistant bacteria is one of the greatest threats to human health in the 21st century and vancomycin-resistant enterococci (VRE) are some of the most challenging organisms in clinical settings. Indeed, vancomycin-resistant Enterococcus faecium have been designated by the Infectious Diseases Society of America and CDC as a serious threat and one of the “super- bugs” against which new therapies are urgently needed. My current NIH funding is directed to the investigation of the genetic and mechanistic bases of daptomycin (DAP) resistance in VRE. During the course of our investigations, we have provided compelling data that the emergence of DAP resistance results from the accumulation of specific gene mutations and demonstrated that some of the genetic changes do not often correlate with changes in in vitro susceptibility of the organisms (as defined by standard MIC breakpoint) leading to therapeutic failure. Based on major advances in sequencing technologies, I hypothesize that a genetic platform will predict antibiotic susceptibilities in a more accurate manner and that such an approach is feasible and may be better equipped to predict therapeutic success than standard MIC determination in critically ill patients. This hypothesis is supported by robust data suggesting that MIC is not an accurate tool to predict clinical outcomes and the fact that sequencing technologies are likely to be widely implemented in clinical laboratories in the near future. During the course of this award, I plan to use VRE as the model organism to develop a whole genome platform for antibiotic susceptibility with the aim of testing this platform in a cohort of patients with VRE bacteremia. Additionally, I plan to develop a robust mentoring program that integrates the molecular and genetic bases of resistance into clinical practice and seeks to engage young clinicians in a new and expanding area of infectious diseases. The specific aims of this program include, i) development of a genomic antimicrobial susceptibility profile (GASP) to predict antibiotic resistances in enterococci, and ii) prediction of clinical outcomes in a cohort of patients with VRE bacteremia treated with DAP (both retrospectively and prospectively) using GASP. The POR program will be developed at The University of Texas Health Science Center at Houston (UTHealth) taking advantage of the strong clinical research facilities and resources (including one of the original NIH CTSAs) and the numerous training programs at UTHealth and UT MD Anderson Cancer Center with collaborations at Memorial Sloan Kettering Cancer Center and Detroit Medical Center (Henry Ford Hospital). Additionally, this application also has an important international component based on the multiple previous collaborations and an additional research site established by the candidate in Colombia (South America).

抽象的 我通过这个职业中期发展奖（K24）的主要目标是提高我指导患者的能力 抗生素耐药性导向研究（POR）并指导新一代超级明星如何应对这一重要的公共卫生威胁抗生素耐药性细菌的出现是最大的威胁之一。 耐万古霉素肠球菌 (VRE) 是 21 世纪对人类健康威胁最大的威胁之一 事实上，耐万古霉素屎肠球菌已成为临床环境中的挑战性微生物。 被美国传染病学会和疾病预防控制中心指定为严重威胁和“超级威胁”之一 我目前的 NIH 资金用于调查 VRE 中达托霉素 (DAP) 耐药性的遗传和机制基础 在我们的研究过程中，我们提供了令人信服的数据，表明 DAP 耐药性的出现是由于特定基因突变的积累造成的，并证明了一些基因变化确实导致了这种情况。不经常与 生物体体外敏感性的变化（由标准 MIC 断点定义）导致治疗失败 基于测序技术的重大进展，我渴望基因平台能够实现这一点。 以更准确的方式预测抗生素敏感性，并且这种方法是可行的 可能比危重患者的标准 MIC 测定更能预测治疗成功。 这一假设得到了强有力的数据的支持，这些数据表明 MIC 并不是预测临床结果的准确工具，而且测序技术可能在临床实验室中广泛应用的事实 在不久的将来，我计划使用VRE作为模型生物来开发一个整体。 抗生素敏感性基因组平台，目的是在一组 VRE 患者中测试该平台 菌血症。 该计划的具体目标包括，i）开发基因组抗菌药物敏感性谱（GASP）以预测肠球菌的抗生素耐药性，以及 ii）预测接受治疗的 VRE 菌血症患者队列的临床结果。与 DAP（回顾性和前瞻性）使用 GASP POR 计划将在德克萨斯大学健康科学中心开发。 休斯顿 (UTHealth) 利用强大的临床研究设施和资源（包括其中之一） 最初的 NIH CTSA）以及 UTHealth 和 UT MD 安德森癌症中心与纪念斯隆凯特琳癌症中心和底特律医疗中心（亨利·福特）合作的众多培训项目 此外，该应用程序还具有基于多个的重要国际组件 先前的合作以及候选人在哥伦比亚（南美洲）建立的额外研究地点。