Antimicrobial Synergy for Carbapenem-Resistant Enterobacteriaceae - Administrative Supplement

项目总结/摘要-母公司K 08 该项目的目的是研究抗菌剂组合的协同作用 抗碳青霉烯耐药肠杆菌科（CRE）。首席调查员西娅医生 Brennan-Krohn最近完成了儿科传染病和医学 现为哈佛医学院讲师， 贝斯以色列女执事医疗中心。她对改进检测方法感兴趣， 抗菌协同作用的表征，以指导感染 高抗性病原体她的职业目标是成为一名领先的调查员， 开发、实施和解释抗菌协同作用检测试验。 在获奖期间，她将获得药理学硕士学位，并将继续 临床和转化研究课程。拟议的研究将在 詹姆斯·柯比，医学博士，D（ABMM），在贝斯以色列NIH资助的研究员的指导 女执事医疗中心，其实验室研究的主题高度相关的建议 项目，包括开发新的抗菌药物敏感性测试方法和 CRE新疗法研究。Brennan-Krohn博士将在颁奖期间获得支持 由一个咨询委员会，其中包括博士乔治埃利奥普洛斯，世界著名的专家， 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剂 针对临床CRE分离株的综合集合的组合，以建立 活性的组合谱。对于项目的这一部分，她将使用自动化的 棋盘阵列微量稀释法，利用惠普D300喷墨打印机为基础的 分配系统她下一步将开发一种新的荧光时间杀伤协同测定法， 研究协同组合的杀菌动力学。最后，她将调查 使用最有效组合的体内功效和PK/PD参数 CRE感染的免疫受损小鼠模型。最后，加强对 协同作用以及在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 可以在临床上可操作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.