Characterization and suppression of resistance to new CRE agents

新 CRE 药物耐药性的表征和抑制

• 批准号: 9884732
• 负责人: Ryan K Shields
• 金额: $ 7.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-04 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884732
• 关键词: Address; Advocate; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Applications Grants; Award; Aztreonam; Bacteremia; Carbapenems; Ceftazidime; Characteristics; Clinical; Colistin; Combined Antibiotics; Communicable Diseases; Data; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Effectiveness; Environment; Enzymes; Epithelial; Epithelium; Equilibrium; Exposure to; Fiber; Fosfomycin; Foundations; Frequencies; Funding; Future; Gene Mutation; Genetic; Genotype; Goals; Hospitals; In Vitro; Infection; Investigation; Klebsiella pneumoniae; Knowledge; Laboratories; Lead; Liquid substance; Measurement; Mediating; Medical center; Medicine; Meropenem; Minimum Inhibitory Concentration measurement; Modeling; Molecular; Morbidity - disease rate; Mutation; Observational Study; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacists; Pharmacodynamics; Plasmids; Pneumonia; Positioning Attribute; Predisposition; Public Health; Regimen; Reporting; Research; Resistance; Resistance development; Role; Scientist; Serum; Site; Superbug; Techniques; Testing; Time; Toxic effect; Training; Transition Career Development Award (K22); Translating; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; VDAC1 gene; Variant; Vertebral column; antimicrobial; bacterial resistance; base; beta-Lactamase; beta-Lactams; carbapenem-resistant Enterobacteriaceae; carbapenemase; career; career development; clinically relevant; cost; drug resistant pathogen; drug testing; effective therapy; experience; exposed human population; improved; improved outcome; inhibitor/antagonist; mathematical model; mid-career faculty; mortality; multi-drug resistant pathogen; mutant; novel; optimal treatments; pathogen; preservation; prevent; resistance mechanism; resistance mutation; restoration; simulation; skills; success; synergism; tigecycline; tool; treatment duration; treatment strategy

ABSTRACT I am an infectious diseases pharmacist who aspires to pursue an academic career devoted to translating scientific discoveries into safe and effective antimicrobial strategies to prevent and treat infections caused by drug-resistant pathogens. I have recently been promoted to Associate Professor of Medicine at the University of Pittsburgh, where I have trained in the labs of Drs. Neil Clancy, Hong Nguyen, and Raman Venkataramanan to study antimicrobial resistance and the pharmacokinetics-pharmacodynamics of antibacterial drugs. In doing so, I have learned basic and advanced laboratory techniques and pursued NIH career development funding. As a K08 award recipient, I am now submitting an application for R03 funding to provide new preliminary data and hypotheses in support of a subsequent R01 application. The goals of the proposed project are to 1) understand the frequency and mechanisms by which KPC- producing Klebsiella pneumoniae (KPC-Kp) clinical isolates develop resistance to newly-approved antibiotics, ceftazidime-avibactam (CAZ-AVI) and meropenem-vaborbactam (MER-VAB), and 2) identify strategies that effectively suppress the emergence of resistance. KPC-Kp infections continue to be a major cause of morbidity and mortality among patients. The recent availability of ceftazidime-avibactam treatment has improved outcomes among KPC-Kp infected patients, but has come at the cost of the emergence of resistance in some cases. We anticipate that resistance emerges through distinct molecular mechanisms for CAZ-AVI and MER- VAB based upon the genetic characteristics of isolates. The central hypothesis of this proposal is that combination regimens of CAZ-AVI or MER-VAB with synergistic antibiotics will suppress the emergence of resistance seen following exposures to either agent alone. To test this hypothesis, we will compare the KPC-Kp mutational frequency rates against CAZ-AVI and MER- VAB, and determine mechanisms mediating the emergence of resistance. We will screen antibiotic combinations by time-kill analysis using antibiotics that may have synergistic mechanisms of action with CAZ- AVI and/or MER-VAB (aim 1). Next, we will validate effective combinations for their ability to eradicate KPC-Kp and suppress the emergence of resistance over a 10-day treatment course in an in vitro hollow-fiber infection model that accurately simulates humanized exposures of antibiotics (aim 2). The model features site-specific exposures that are achieved at sites of infection, from which we will develop mathematical models to define the best combinations. Through these objectives, we will generate timely, clinically-relevant data that cannot be obtained through other approaches, and will open new lines of investigation for future grant applications. I am well-positioned to carry out the proposed aims within a medical center that has accumulated much of the world's experience with CAZ-AVI and a research environment that has allowed me to develop the advanced laboratory and analytical skills needed to study antimicrobial resistance.

抽象的 我是一名传染病药剂师，渴望从事翻译学术事业 科学发现安全有效的抗菌策略，以预防和治疗由以下原因引起的感染 耐药病原体。我最近晋升为大学医学副教授 匹兹堡，我在博士的实验室接受过培训。尼尔·克兰西、洪·阮和拉曼·文卡塔拉马南 研究抗菌药物耐药性和抗菌药物的药代动力学-药效学。在做 因此，我学习了基本和先进的实验室技术，并寻求 NIH 职业发展资助。 作为 K08 获奖者，我现在正在提交 R03 资助申请，以提供新的初步数据 以及支持后续 R01 应用的假设。 拟议项目的目标是 1) 了解 KPC- 产生肺炎克雷伯菌（KPC-Kp）临床分离株对新批准的抗生素产生耐药性， 头孢他啶-阿维巴坦 (CAZ-AVI) 和美罗培南-瓦硼巴坦 (MER-VAB)，以及 2) 确定策略 有效抑制反抗的产生。 KPC-Kp 感染仍然是发病的主要原因 和患者的死亡率。最近头孢他啶-阿维巴坦治疗的可用性有所改善 KPC-Kp 感染患者的结果，但代价是一些人出现了耐药性 案例。我们预计 CAZ-AVI 和 MER- 会通过不同的分子机制出现耐药性 VAB 基于分离株的遗传特征。该提案的中心假设是 CAZ-AVI 或 MER-VAB 与协同抗生素的联合治疗方案将抑制出现 单独接触任一药物后出现耐药性。 为了检验这一假设，我们将 KPC-Kp 突变频率与 CAZ-AVI 和 MER 进行比较 VAB，并确定介导耐药性出现的机制。我们将筛选抗生素 使用可能与 CAZ- 具有协同作用机制的抗生素进行时间杀灭分析的组合 AVI 和/或 MER-VAB（目标 1）。接下来，我们将验证有效组合消除 KPC-Kp 的能力 并在体外中空纤维感染的 10 天治疗过程中抑制耐药性的出现 准确模拟人源化抗生素暴露的模型（目标 2）。该模型具有特定于站点的功能 在感染部位实现的暴露，我们将据此开发数学模型来定义 最佳组合。通过这些目标，我们将生成及时的、临床相关的数据，而这些数据无法被 通过其他方法获得，并将为未来的资助申请开辟新的调查路线。我是 处于有利地位，可以在医疗中心内实现拟议的目标，该中心已经积累了很多 CAZ-AVI 的世界经验和研究环境使我能够开发先进的 研究抗菌素耐药性所需的实验室和分析技能。

项目成果

Fosfomycin for treatment of multidrug-resistant pathogens causing urinary tract infection: A real-world perspective and review of the literature.

磷霉素治疗引起尿路感染的多重耐药病原体：现实世界的视角和文献综述。

• 发表时间: 2019-11
• 影响因子: 2.9
• 作者: Babiker, Ahmed;Clarke, Lloyd;Doi, Yohei;Shields, Ryan K
• 通讯作者: Shields, Ryan K