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

描述（由申请方提供）：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在美国和世界其他地区引起严重问题。这些细菌是机会性病原体，可导致重症患者和免疫系统受损患者的肺炎和其他严重感染。由于这些细菌越来越多地显示出对几乎所有目前可用的抗生素的高水平抗性，并且由于进入临床使用的新抗生素的短缺，临床医生通常别无选择，只能使用多粘菌素类的抗生素粘菌素。粘菌素首次进入市场近50年前，一直使用相对较少，直到最近。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，即使是对粘菌素敏感的细菌，也有一个高度耐粘菌素的亚群。暴露于粘菌素导致总种群中的敏感细菌死亡，但不幸的是，这导致了高度粘菌素耐药细菌繁殖到更大数量的情况。虽然两种或两种以上的抗生素往往是为了克服抗生素耐药性，这一直是一个经验性的临床实践，很少或没有证据的基础上。本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处方的抗生素，以杀死总细菌种群的所有成员。研究策略始于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，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敏感。这些实验之后是筛选组合，包括粘菌素和许多其他抗生素，以确定哪些组合和相对浓度导致最高的活性。然后，将进行一系列系统的体外研究，以模拟人体内的感染条件和药物浓度，以设计优化联合方案的方案（每种方案涉及粘菌素加另一种抗生素），最有效地杀死粘菌素敏感和粘菌素耐药细菌。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验证。研究计划中的每个渐进阶段都提供了关键信息，以加深对组合的理解，并由数学机理模型的开发驱动，以指导优化过程。结果将是鉴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耐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，新型抗生素的发现明显减少。正如美国传染病学会发表的“Bad Bugs，No Drugs”论文中所描述的那样，“随着抗生素发现的停滞，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方法来保护粘菌素的有用性，以对抗革兰氏阴性菌引起的非常难以治疗的感染，以最大限度地减少耐药性的出现。

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.