Novel PK/PD Strategies for Polymyxin Combinations against Gram-negative Superbugs

描述(申请人提供)：耐多药的革兰氏阴性‘超级细菌’正在造成全球健康危机。由于抗生素发现的显著减少和目前新抗生素的短缺，临床医生通常别无选择，只能使用多粘菌素(多粘菌素B和粘菌素，即多粘菌素E)。多粘菌素在50多年前首次进入市场，直到最近才被很少使用。不幸的是，越来越多的证据表明，对多粘菌素的耐药性正在增加。一个促进耐药性的主要因素是，在相当大比例的危重患者中，推荐每日剂量的多粘菌素的血浆浓度是次佳的。不幸的是，简单地增加TH多粘菌素的日剂量不是一种选择，因为肾脏毒性(在目前的方案中高达60%的发生率)是主要的剂量限制不良反应。出现对多粘菌素的耐药性是单一疗法的一个重大风险，由于处于最后一线状态，意味着对所有 目前的抗生素。这凸显了探索新的、高活性的多粘菌素组合给药策略的迫切需要。本项目的中心目标是评估多粘菌素组合的新给药方案，以最大限度地提高抗菌活性，并将耐药性和毒性的出现降至最低。我们的研究策略包括对新的“突发式”、“前置式”(例如，治疗开始时的大剂量、短持续剂量)和“顺序”多粘菌素联合给药策略的有效性进行系统评估。该研究计划结合了一系列体外和兔感染模型的多层次方法。首先，体外模型将被用来模拟人体内的感染条件和药物浓度-时间曲线，以设计出最有效地杀死多粘菌素敏感和多粘菌素耐药细菌的组合给药策略。接下来，将在中空纤维感染模型中测试多粘菌素联合给药策略对临床分离株的耐药性抑制。尖端基因组学/转录组/代谢组学研究将通过表征全球细菌对新的联合剂量策略的反应(包括出现耐药性)来指导最佳方案的选择。最后，我们将在10天的免疫受损和合格的兔感染模型中对我们的优势方案进行前瞻性验证研究，以前瞻性评估耐药性抑制和毒性。每个进步阶段将提供关键信息，以独特的方式为创新的基于机制的数学模型的开发提供信息，这些模型将用于在所有实验层之间进行转换。最终的翻译将通过基于机制的蒙特卡罗模拟来执行，以提出多粘菌素组合的新剂量策略，以最大限度地提高抗菌活性，并将耐药性和毒性降至最低，用于未来的人体试验。

DESCRIPTION (provided by applicant): Multidrug-resistant Gram-negative 'superbugs' are causing a global health crisis. Due to a marked decline in the discovery of antibiotics and the current shortage of new antibiotics, clinicians are often left with little option but to use the polymyxins (polymyxin B and colistin, i.e. polymyxin E). Polymyxins first came onto the market more than 50 years ago and have been used rarely, until recent times. Unfortunately, there is mounting evidence that resistance to polymyxins is increasing. A major factor promoting resistance is that plasma concentrations of polymyxins at recommended daily doses are sub-optimal in a significant proportion of critically-ill patients. Unfortunately, simply increasing th polymyxin daily dose is not an option because kidney toxicity (up to 60% incidence with current regimens) is the major dose-limiting adverse effect. Emergence of resistance to polymyxins is a significant risk with monotherapy and, because of the 'last-line' status, implies resistance to all current antibiotics. This highlights the urgent need to explore novel, highly active dosing strategies with polymyxin combinations. The central aim of the present project is to evaluate novel dosing regimens for polymyxin combinations to maximize antibacterial activity and minimize emergence of resistance and toxicity. Our research strategy involves a systematic evaluation of the effectiveness of novel 'burst', 'front-loading' (e.g. high dose, short duration dosing at the beginning of therapy) and 'sequential' polymyxin combination dosing strategies. The research plan incorporates a multi-tiered approach across a range of in vitro and rabbit infection models. First, in vitro models will be used to simulate the conditions of infection and drug concentration-time profiles in the human body to devise combination dosing strategies that most effectively kill both polymyxin-susceptible and polymyxin-resistant bacteria. Next, promising dosing strategies for the polymyxin combinations will be tested for resistance suppression against clinical isolates in a hollow-fiber infection model. Cutting-edge genomics/transcriptomics/metabolomics studies will guide selection of optimal regimens by characterizing the global bacterial responses (including emergence of resistance) to the novel combination dosing strategies. Finally, prospective validation studies for our superior regimens will be conducted in 10-day immune-compromised and -competent rabbit infection models for prospective evaluation of resistance suppression and toxicity. Each progressive stage will provide key information to uniquely inform the development of innovative mechanism-based mathematical models that will be used to translate across all experimental tiers. The final translation will be performed by mechanism-based Monte Carlo Simulations to propose novel dosing strategies for polymyxin combinations that maximize antibacterial activity and minimize resistance and toxicity for future testing in humans.