POR Program on Genomic Prediction of Antimicrobial Resistance in VRE

摘要 我通过这个职业中期发展奖(K24)的主要目标是提高我引导患者的能力 针对抗生素耐药性的定向研究(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。抗生素抗药性细菌的出现是最伟大的 21世纪对人类健康的威胁和对万古霉素耐药的肠球菌(VRE)是最严重的 在临床环境中挑战生物体。事实上，对万古霉素耐药的粪肠球菌 被美国传染病学会和疾控中心指定为严重威胁和“超级威胁”之一 虫子“，迫切需要新的治疗方法。我目前在美国国立卫生研究院的资金是用来调查 阐明VRE对达托霉素(DAP)耐药的遗传和机制基础。在我们的研究过程中，我们提供了令人信服的数据，即DAP耐药性的出现是特定基因突变积累的结果，并证明了一些基因变化通常与 导致治疗失败的生物体体外敏感性的变化(由标准MIC断点定义)。基于测序技术的重大进步，我假设一个遗传平台将 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 可能比标准最低抑菌浓度测定更能预测危重患者的治疗成功。 这一假设得到了强有力的数据的支持，这些数据表明MIC不是预测临床结果的准确工具，而且测序技术很可能在#年在临床实验室中广泛实施 在不久的将来。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 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到一个新的和不断扩大的 传染病疫区。该计划的具体目标包括：i)开发基因组抗菌素敏感性图谱(GAP)以预测肠球菌的抗生素耐药性；ii)使用GAP预测一组接受DAP治疗的VRE菌血症患者的临床结果(包括回顾性和前瞻性)。POR计划将在德克萨斯大学健康科学中心开发，地址为 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)以及在UTHealth和UT MD Anderson癌症中心与纪念斯隆·凯特琳癌症中心和底特律医疗中心(Henry Ford)合作的众多培训计划 医院)。此外，此应用程序还具有一个重要的国际组件，它基于多个 以前的合作和候选人在哥伦比亚(南美洲)建立的另一个研究网站。

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).