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: 8101260
• 负责人: Roger L. Nation
• 金额: $ 51.67万
• 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/8101260
• 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; Hospitals; 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; 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 development; 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）：革兰氏阴性细菌鲍曼不动杆菌、铜绿假单胞菌和肺炎克雷伯菌在美国和世界其他地区引起了重大问题。这些细菌是机会致病菌，可在危重病人和免疫系统受损者中引起肺炎和其他严重感染。由于这些细菌越来越多地对几乎所有目前可用的抗生素显示出高水平的耐药性，并且由于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，这是一种多粘菌素类抗生素。粘菌素在近50年前首次进入市场，直到最近才被相对较少地使用。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，即使是似乎对粘菌素敏感的细菌也有一个高度耐粘菌素的亚群。接触粘菌素会导致整个人群中的易感细菌死亡，但不幸的是，这会导致高度耐粘菌素的细菌繁殖到更大的数量。虽然经常开两种或两种以上的抗生素以试图克服抗生素耐药性，但这是一种经验性的临床实践，基于很少或没有证据。目前项目的中心目标是使用一系列非常系统的研究来确定可以与粘菌素一起开处方的抗生素，以杀死所有细菌种群的成员。研究策略从确定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，因为有充分证据表明，该亚群可能比以前认为的对其他抗生素更敏感。在这些实验之后，筛选涉及粘菌素和许多其他抗生素的组合，以确定哪种组合和相对浓度可产生最高活性。然后，将进行一系列系统的体外研究，模拟感染条件和人体内药物浓度，以设计出最有效地杀死粘菌素敏感菌和粘菌素耐药菌的联合方案（每种方案都包括粘菌素加另一种抗生素）。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，并由数学机制模型的发展驱动，以指导优化过程。结果将是鉴定和优化粘菌素联合方案，以防止在非常麻烦的革兰氏阴性菌中扩增耐药亚群。世界正面临着对几乎所有现有抗生素都具有耐药性的细菌的出现所带来的巨大和日益严重的威胁，在过去二十年中，新型抗生素的发现明显减少。正如美国传染病学会发表的一篇题为《有害细菌，无药可医》的论文所描述的那样，“随着抗生素的发现停滞不前，一场公共卫生危机正在酝酿”。这突出了当前项目的相关性，该项目旨在通过研究新的方法来对抗革兰氏阴性菌引起的非常难以治疗的感染，以尽量减少耐药性的出现，从而保持粘菌素的有用性。

项目成果

Investigating the Interaction of Octapeptin A3 with Model Bacterial Membranes.

• DOI: 10.1021/acsinfecdis.7b00065
• 发表时间: 2017-08-11
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Han ML;Shen HH;Hansford KA;Schneider EK;Sivanesan S;Roberts KD;Thompson PE;Le Brun AP;Zhu Y;Sani MA;Separovic F;Blaskovich MAT;Baker MA;Moskowitz SM;Cooper MA;Li J;Velkov T
• 通讯作者: Velkov T

Structure, Function, and Biosynthetic Origin of Octapeptin Antibiotics Active against Extensively Drug-Resistant Gram-Negative Bacteria.

• DOI: 10.1016/j.chembiol.2018.01.005
• 发表时间: 2018-04-19
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Velkov T;Gallardo-Godoy A;Swarbrick JD;Blaskovich MAT;Elliott AG;Han M;Thompson PE;Roberts KD;Huang JX;Becker B;Butler MS;Lash LH;Henriques ST;Nation RL;Sivanesan S;Sani MA;Separovic F;Mertens H;Bulach D;Seemann T;Owen J;Li J;Cooper MA
• 通讯作者: Cooper MA

Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use.

• DOI: 10.1002/phar.1537
• 发表时间: 2015-01
• 期刊: PHARMACOTHERAPY
• 影响因子: 4.1
• 作者: Bergen, Phillip J.;Bulman, Zackery P.;Saju, Sarith;Bulitta, Juergen B.;Landersdorfer, Cornelia;Forrest, Alan;Li, Jian;Nation, Roger L.;Tsuji, Brian T.
• 通讯作者: Tsuji, Brian T.

Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing.

• DOI: 10.1592/phco.30.12.1279
• 发表时间: 2010-12
• 期刊: Pharmacotherapy
• 影响因子: 4.1
• 作者: Lim LM;Ly N;Anderson D;Yang JC;Macander L;Jarkowski A 3rd;Forrest A;Bulitta JB;Tsuji BT
• 通讯作者: Tsuji BT

Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens.

• DOI: 10.1038/srep26233
• 发表时间: 2016-05-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cheah SE;Johnson MD;Zhu Y;Tsuji BT;Forrest A;Bulitta JB;Boyce JD;Nation RL;Li J
• 通讯作者: Li J