Antimicrobial Synergy for Carbapenem-Resistant Enterobacteriaceae - Administrative Supplement

项目总结/摘要 – 家长 K08 拟议的项目是对抗菌组合的协同活性的研究 对抗碳青霉烯类耐药肠杆菌科细菌（CRE）。首席研究员 Thea 博士 Brennan-Krohn，最近完成了儿科传染病和医学方面的研究金 微生物学，现为哈佛医学院讲师和博士后研究员 贝斯以色列女执事医疗中心。她对改进检测方法和 抗菌药物协同作用的表征，以指导感染患者的治疗 高度耐药的病原体。她的职业目标是成为该领域的领先研究员 抗菌协同作用检测测试的开发、实施和解释。 在获奖期间，她将获得药理学理学硕士学位，并将继续攻读 临床和转化研究课程。拟议的研究将在 James Kirby, MD, D(ABMM) 的指导，他是 NIH 资助的贝斯以色列研究员 女执事医疗中心，其实验室调查与拟议项目高度相关的主题 项目，包括开发新型抗菌药物敏感性测试方法和 CRE 新疗法的研究。 Brennan-Krohn 博士将在获奖期间得到支持 由包括世界著名专家 George Eliopoulos 博士在内的咨询委员会负责 关于抗菌协同作用。在拟议的项目中，Brennan-Krohn 博士将首先测试抗菌药物 针对全面收集的临床 CRE 分离株进行组合，以便建立 活性的组合谱。对于项目的这一部分，她将使用自动化的 使用基于 HP D300 喷墨打印机的棋盘阵列微量稀释方法 分配系统。接下来，她将开发一种新颖的荧光时间杀死协同测定法，以便 研究协同组合的杀菌动力学。最后，她将调查此事 最有效组合的体内功效和 PK/PD 参数 CRE 感染的免疫功能低下小鼠模型。最终加深了对 协同作用以及拟议研究期间开发和验证的技术 预计将为联合抗生素治疗的前瞻性临床试验的设计提供信息 建立简单、快速的协同测试平台，首次提供协同数据 可在临床可行的时间范围内用于指导患者护理。

Project Summary/Abstract – Parent K08 The proposed project is an investigation of the synergistic activity of antimicrobial combinations against carbapenem-resistant Enterobacteriaceae (CRE). The principal investigator, Dr. Thea Brennan-Krohn, recently completed fellowships in Pediatric Infectious Diseases and in Medical Microbiology and is now an Instructor at Harvard Medical School and a post-doctoral fellow at Beth Israel Deaconess Medical Center. She is interested in improving methods for detection and characterization of antimicrobial synergy in order to guide the treatment of patients infected with highly resistant pathogens. Her career goal is to become a leading investigator in the development, implementation and interpretation of tests for detection of antimicrobial synergy. During the award period, she will obtain a Master of Science in Pharmacology and will pursue coursework in clinical and translational research. The proposed research will be carried out under the mentorship of James Kirby, MD, D(ABMM), an NIH-funded investigator at Beth Israel Deaconess Medical Center whose laboratory investigates topics highly relevant to the proposed project, including the development of novel antimicrobial susceptibility testing methods and the investigation of new therapeutics for CRE. Dr. Brennan-Krohn will be supported during the award period by an advisory committee that includes Dr. George Eliopoulos, a world-renowned expert on antimicrobial synergy. In the proposed project, Dr. Brennan-Krohn will initially test antimicrobial combinations against a comprehensive collection of clinical CRE isolates in order to establish combinatorial spectra of activity. For this part of the project, she will use an automated checkerboard array microdilution method that makes use of the HP D300 inkjet printer-based dispensing system. She will next develop a novel, fluorescent time-kill synergy assay in order to investigate the bactericidal kinetics of synergistic combinations. Finally, she will investigate the in vivo efficacy and PK/PD parameters of the most effective combinations using an immunocompromised mouse model of CRE infection. Ultimately, the enhanced understanding of synergy as well as the technology developed and validated during the proposed study are expected to inform the design of prospective clinical trials of combination antibiotic therapy and to establish simple, rapid synergy testing platforms that will for the first time provide synergy data that can be used in a clinically actionable timeframe to guide patient care.