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).

摘要 我通过这个中期职业发展奖（K24）的主要目标是提高我的能力， 我们正在开展关于抗生素耐药性的导向研究（POR），并指导新一代临床医生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人类历史上 在21世纪世纪，万古霉素耐药肠球菌（VRE）是对人类健康的最大威胁之一， 在临床环境中挑战微生物。事实上，耐万古霉素的屎肠球菌已经被 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 这些细菌迫切需要新的治疗方法。我目前的国家卫生研究院资金是用于 达托霉素（DAP）耐药的遗传和机制基础VRE。在我们的研究过程中，我们提供了令人信服的数据，即DAP抗性的出现是由特定基因突变的积累引起的，并证明了一些遗传变化通常与DAP抗性无关。 导致治疗失败的微生物体外敏感性变化（如标准MIC断点所定义）。基于测序技术的重大进展，我假设基因平台将 以更准确的方式预测抗生素敏感性，这种方法是可行的， 可能比标准MIC测定更适合预测危重患者的治疗成功。 这一假设得到了稳健的数据的支持，这些数据表明MIC不是预测临床结果的准确工具，并且测序技术可能在临床实验室中广泛实施。 不久的将来在这个奖项的过程中，我计划使用VRE作为模式生物来开发一个整体 抗生素敏感性的基因组平台，目的是在VRE患者队列中测试该平台 菌血症此外，我计划开发一个强大的指导计划，将耐药的分子和遗传基础整合到临床实践中，并寻求让年轻的临床医生参与一个新的和不断扩大的 传染病领域。该项目的具体目标包括：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; ii）使用GASP预测接受DAP治疗的VRE菌血症患者队列的临床结局（回顾性和前瞻性）。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 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 医院）。此外，该应用程序还具有一个重要的国际组件， 候选人在哥伦比亚（南美洲）建立了一个额外的研究中心。