Targeting MDR hetero-resistant Gram-negatives: PK/PD for rational combinations

靶向多重耐药异质耐药革兰氏阴性菌：合理组合的 PK/PD

• 批准号: 7890472
• 负责人: Roger L. Nation
• 金额: $ 60.65万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890472
• 关键词: Accounting; Acinetobacter baumannii; Address; Americas; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Attention; Bacteria; Biological Phenomena; Cells; Cessation of life; Characteristics; Clinical; Colistin; Combined Antibiotics; Communicable Diseases; Competence; Complex; Critical Illness; Data; Development; Disease Outbreaks; Dose; Drug Kinetics; Exhibits; Exposure to; FDA approved; Future; Genus staphylococcus; Gram-Negative Bacteria; Gram-Positive Bacteria; Growth; Human body; Imipenem; Immune; Immune system; In Vitro; Individuality; Infection; Institution; Intermediate resistance; Klebsiella pneumonia bacterium; Knowledge; Lead; Learning; Left; Life; Marketing; Membrane; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Nosocomial pneumonia; Organism; Outcome; Outcomes Research; Paper; Parents; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pneumonia; Polymyxin B; Polymyxins; Population; Predisposition; Pseudomonas aeruginosa; Public Health; Publishing; Regimen; Relative (related person); Reporting; Research; Resistance; Resistance to infection; Screening procedure; Series; Simulate; Site; Societies; Staging; Testing; Therapeutic; Time; Vancomycin resistant enterococcus; bacterial resistance; base; clinical practice; colistin resistance; data modeling; design; dosage; drug discovery; experience; fight against; in vitro Model; in vitro activity; in vivo; in vivo Model; killings; man; mathematical model; meetings; member; microbial; microorganism; model development; novel; novel strategies; novel therapeutics; pathogen; pharmacodynamic model; preclinical study; prevent; process optimization; programs; research and development; research study; tigecycline

DESCRIPTION (provided by applicant): The Gram-negative bacteria Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae are causing significant problems in the USA and other parts of the world. These bacteria are opportunistic pathogens that cause pneumonia and other serious infections in critically-ill patients and those with impaired immune systems. Because these bacteria are increasingly displaying high levels of resistance to almost all currently available antibiotics and because of the shortage of new antibiotics coming into clinical use, clinicians are often left with little option but to use colistin, which is an antibiotic of the polymyxin class. Colistin first came onto the market nearly 50 years ago and has been used relatively rarely, until recent times. Unfortunately, although the resistance rates to colistin are much lower than for other antibiotics, there is mounting evidence that resistance to colistin is increasing. Since colistin is, in essence, the 'last-line' antibiotic for treatment of many infections, resistance to it implies resistance to virtually all antibiotics. It has become clear that even bacteria that seem to be susceptible to colistin harbor a highly colistin-resistant sub-population. Exposure to colistin leads to death of the susceptible bacteria in the total population, but unfortunately this leads to a situation where the highly colistin-resistant bacteria multiply to much larger numbers. Although two or more antibiotics are often prescribed in an attempt to overcome antibiotic resistance, this has been an empiric clinical practice, based on little or no evidence. The central aim of the present project is to use a series of very systematic studies to identify antibiotics that can be prescribed together with colistin to kill all members of the total bacterial population. The research strategy starts with the novel approach of identifying other antibiotics that are most active against the colistin-resistant sub-population of bacteria, as there is good evidence that the sub-population may be much more susceptible than previously thought to other antibiotics. These experiments are followed by screening of combinations, involving colistin and many other antibiotics, to determine which combinations and relative concentrations result in the highest activity. Then, a systematic series of in vitro studies will be conducted to simulate the conditions of infection and drug concentrations in the human body to devise regimens that optimize the combination regimens (each involving colistin plus another antibiotic) that most effectively kill both the colistin-susceptible and the colistin-resistant bacteria. Finally, once an optimal regimen is determined in vitro, animal studies will be performed to provide proof of concept. Each progressive stage in the research plan provides key information to develop understanding of the combinations and is driven by the development of mathematical mechanistic models to guide the optimization process. The outcome will be identification and optimization of colistin combination regimens to prevent amplification of resistant sub- populations in the very troublesome Gram-negative bacteria above. The world is facing an enormous and growing threat from the emergence of bacteria that are resistant to almost all available antibiotics and in the past two decades there has been a marked decline in discovery of novel antibiotics. As described in the 'Bad Bugs, No Drugs' paper published by the Infectious Diseases Society of America, "as antibiotic discovery stagnates, a public health crisis brews". This highlights the relevance of the current project which aims to preserve the usefulness of colistin through the study of novel approaches in the fight against very difficult to treat infections caused by Gram-negative bacteria to minimize the emergence of resistance.

描述（由申请人提供）：革兰氏阴性细菌baumannii，铜绿假单胞菌和肺炎克雷伯氏菌在美国和世界其他地区都引起了重大问题。这些细菌是机会性病原体，引起肺炎和其他严重感染的患者以及免疫系统受损的患者。由于这些细菌越来越多地表现出对目前几乎所有可用的抗生素的耐药性，而且由于缺乏新的抗生素临床使用，因此临床医生通常几乎没有选择，但是使用colistin，这是多发性粘液蛋白类别的抗生素。 Colistin首次在近50年前进入市场，直到最近才相对较少使用。不幸的是，尽管对大肠菌素的耐药率远低于其他抗生素，但有越来越多的证据表明对菌群的抗性正在增加。由于本质上是colistin是用于治疗许多感染的“最后一条”抗生素，因此对其的抗药性意味着对几乎所有抗生素的耐药性。很明显，即使是大肠杆菌蛋白含有高度菌群耐药的亚人群的细菌也是如此。暴露于大肠菌素会导致易感细菌在总人群中死亡，但不幸的是，这导致了高度抗colis菌蛋白的细菌繁殖的情况。尽管通常开处方两种或多种抗生素以克服抗生素抗性，但这是基于几乎没有证据的经验性临床实践。本项目的核心目的是使用一系列非常系统的研究来识别可以与大肠菌素一起开处方的抗生素，以杀死所有细菌总人群的所有成员。研究策略始于鉴定其他抗生素对细菌抗colist菌素的亚种群最活跃的新方法，因为有充分的证据表明，亚构型可能比以前认为对其他抗生素的抗生素更容易受到敏感。这些实验之后是筛选涉及大肠菌素和许多其他抗生素的组合，以确定哪些组合和相对浓度会导致最高活性。然后，将进行一系列系统的体外研究，以模拟人体的感染和药物浓度的条件，以设计优化组合方案（每种涉及肠球菌加另一种抗生素）的方案，这些方案最有效地杀死了菌群敏感性和抗体蛋白耐药菌。最后，一旦在体外确定最佳方案后，将进行动物研究以提供概念证明。研究计划中的每个渐进阶段都提供了关键信息，以发展对组合的理解，并由数学机械模型的发展驱动以指导优化过程。结果将是鉴定和优化结肠素组合方案，以防止在上面非常麻烦的革兰氏阴性细菌中扩增耐药的亚种。由于细菌的出现，世界正面临着对几乎所有可用抗生素具有抗药性的巨大威胁，在过去的二十年中，新型抗生素的发现显着下降。正如美国传染病学会发表的“坏虫子”中所述，“抗生素发现停滞不前，公共卫生危机酿造”。这凸显了当前项目的相关性，该项目旨在通过研究新方法来维护colistin的有用性，以与革兰氏阴性细菌引起的非常难以治疗的感染，以最大程度地减少抗性的出现。