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

描述（由申请人提供）：多重耐药革兰氏阴性“超级细菌”正在造成全球健康危机。由于抗生素发现的显著下降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多年前首次上市，直到最近才很少使用。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。促进耐药性的一个主要因素是，在相当大比例的危重患者中，推荐日剂量的多粘菌素的血浆浓度是次优的。不幸的是，简单地增加多粘菌素日剂量不是一种选择，因为肾毒性（在当前方案中高达60%的发生率）是主要的剂量限制性不良反应。对多粘菌素耐药的出现是单药治疗的一个重大风险，由于其“最后一线”地位，意味着对所有药物的耐药。 当前抗生素这突出了迫切需要探索新的，高活性的多粘菌素组合给药策略。本项目的主要目的是评估多粘菌素联合用药的新给药方案，以最大限度地提高抗菌活性，并最大限度地减少耐药性和毒性的出现。我们的研究策略涉及对新型“爆发”、“前负荷”（例如，在治疗开始时高剂量、短时间给药）和“序贯”多粘菌素联合给药策略的有效性进行系统评价。该研究计划包括一系列体外和兔感染模型的多层次方法。首先，将使用体外模型来模拟人体内的感染条件和药物浓度-时间曲线，以设计最有效地杀死多粘菌素敏感细菌和多粘菌素耐药细菌的联合给药策略。接下来，将在中空纤维感染模型中测试多粘菌素组合的有希望的给药策略对临床分离株的耐药性抑制。尖端的基因组学/转录组学/代谢组学研究将通过表征对新型组合给药策略的总体细菌反应（包括耐药性的出现）来指导最佳方案的选择。最后，我们的上级方案的前瞻性验证研究将在10天免疫受损和免疫能力低下的兔感染模型中进行，以前瞻性评价耐药性抑制和毒性。每个渐进阶段将提供关键信息，以独特地告知创新机制为基础的数学模型的开发，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进行，以提出多粘菌素组合的新给药策略，最大限度地提高抗菌活性，并最大限度地减少耐药性和毒性，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.