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.

摘要 我是一名传染病药剂师，渴望从事翻译学术事业。 科学发现转化为安全有效的抗菌策略，以预防和治疗 耐药病原体我最近被提升为大学的医学副教授 我曾在尼尔·克兰西、洪·阮和拉曼·文卡塔拉曼南博士的实验室接受过培训 研究细菌的耐药性及抗菌药物的药动学-药效学。做 因此，我学习了基本的和先进的实验室技术，并寻求国家卫生研究院的职业发展基金。 作为K 08获奖者，我现在提交R 03资助申请，以提供新的初步数据 以及支持后续R 01应用的假设。 拟议项目的目标是：（1）了解科索沃保护团- 产生肺炎克雷伯氏菌（KPC-Kp）的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-伐硼巴坦（MER-VAB），以及2）确定 有效地抑制了阻力的产生。KPC-Kp感染仍然是发病的主要原因 和患者死亡率之间的关系。最近头孢他啶-阿维巴坦治疗的可用性有所改善 KPC-Kp感染患者中的结果，但在一些患者中出现耐药性的代价是 例我们预计耐药性是通过CAZ-AVI和MER-1不同的分子机制出现的。 VAB基于分离株的遗传特征。这一提议的核心假设是， CAZ-AVI或MER-VAB与协同抗生素的联合方案将抑制 在单独暴露于任一试剂后观察到的抗性。 为了检验这一假设，我们将比较KPC-Kp突变频率率与CAZ-AVI和MER-1的差异。 VAB，并确定介导耐药性出现的机制。我们会筛选抗生素 使用可能与CAZ具有协同作用机制的抗生素通过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根除KPC-Kp的能力 并在体外中空纤维感染的10天疗程中抑制耐药性的出现 精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 暴露在感染部位，我们将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， 通过其他途径获得，并将为未来的赠款申请开辟新的研究方向。我是 有能力在一个积累了大量经验的医疗中心内实现所提出的目标。 世界的经验与CAZ-AVI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。