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）：革兰氏阴性菌鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌正在美国和世界其他地区造成严重问题。这些细菌是机会性病原体，会导致危重患者和免疫系统受损的患者出现肺炎和其他严重感染。由于这些细菌对几乎所有目前可用的抗生素越来越表现出高水平的耐药性，并且由于进入临床使用的新抗生素短缺，临床医生通常别无选择，只能使用粘菌素（一种多粘菌素类抗生素）。粘菌素大约 50 年前首次进入市场，直到最近才被使用相对较少。不幸的是，尽管对粘菌素的耐药率远低于其他抗生素，但越来越多的证据表明对粘菌素的耐药性正在增加。由于粘菌素本质上是治疗许多感染的“最后一线”抗生素，对它的耐药性意味着对几乎所有抗生素的耐药性。很明显，即使是看似对粘菌素敏感的细菌也含有高度粘菌素抗性的亚群。接触粘菌素会导致总体中易感细菌的死亡，但不幸的是，这会导致高度粘菌素耐药的细菌繁殖到更多的数量。尽管经常开出两种或多种抗生素来试图克服抗生素耐药性，但这只是一种经验性的临床实践，基于很少或没有证据。本项目的中心目标是利用一系列非常系统的研究来确定可以与粘菌素一起使用的抗生素，以杀死总细菌群中的所有成员。该研究策略从识别对粘菌素耐药细菌亚群最有效的其他抗生素的新方法开始，因为有充分的证据表明，该亚群可能比以前认为的其他抗生素更容易受到影响。这些实验之后是筛选组合，涉及粘菌素和许多其他抗生素，以确定哪些组合和相对浓度产生最高的活性。然后，将进行一系列系统的体外研究，模拟人体内的感染条件和药物浓度，以设计优化组合方案（每种方案涉及粘菌素加另一种抗生素）的方案，以最有效地杀死粘菌素敏感的细菌。和耐粘菌素的细菌。最后，一旦在体外确定了最佳方案，将进行动物研究以提供概念证明。研究计划中的每个进展阶段都提供了关键信息以加深对组合的理解，并由数学机制模型的开发驱动以指导优化过程。结果将是确定和优化粘菌素组合方案，以防止上述非常麻烦的革兰氏阴性细菌中耐药亚群的扩增。世界正面临着对几乎所有可用抗生素都具有抗药性的细菌的出现所带来的巨大且日益严重的威胁，并且在过去二十年中，新型抗生素的发现量显着下降。正如美国传染病学会发表的《没有坏虫，没有药物》论文中所描述的，“随着抗生素发现的停滞，一场公共卫生危机正在酝酿”。这凸显了当前项目的相关性，该项目旨在通过研究对抗非常难以治疗的革兰氏阴性菌引起的感染的新方法来保留粘菌素的有用性，以尽量减少耐药性的出现。