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

多粘菌素组合对抗革兰氏阴性超级细菌的新 PK/PD 策略

• 批准号: 8709383
• 负责人: Jian Li
• 金额: $ 82.5万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709383
• 关键词: Acinetobacter baumannii; Adverse effects; Americas; Anti-Bacterial Agents; Antibiotics; Bacteria; Carbapenems; Clinic; Clinical; Colistin; Communicable Diseases; Critical Illness; Data; Development; Dose; Dose-Limiting; Drug Exposure; Drug Kinetics; Effectiveness; Evaluation; Fiber; Future; Genomics; Goals; Human; Human body; Immune; In Vitro; Incidence; Infection; Inorganic Sulfates; Kidney; Klebsiella pneumonia bacterium; Left; Marketing; Mesylates; Modeling; Monte Carlo Method; Multi-Drug Resistance; Oryctolagus cuniculus; Paper; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Polymyxin B; Polymyxin Resistance; Polymyxins; Prodrugs; Product Labeling; Pseudomonas aeruginosa; Regimen; Reporting; Research; Resistance; Rifampin; Risk; Simulate; Societies; Staging; Testing; Therapeutic; Time; Toxic effect; Translating; Translations; Unspecified or Sulfate Ion Sulfates; base; combat; global health; in vitro Model; innovation; insight; interdisciplinary approach; killings; mathematical model; metabolomics; nephrotoxicity; novel; pathogen; prospective; public health relevance; resistance mechanism; response; transcriptomics; validation studies

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.

描述（由申请人提供）：多重耐药革兰氏阴性“超级细菌”正在引发全球健康危机。由于抗生素发现的显着下降以及当前新抗生素的短缺，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）。多粘菌素于 50 多年前首次进入市场，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，在相当一部分危重患者中，推荐每日剂量的多粘菌素血浆浓度并非最佳。不幸的是，简单地增加多粘菌素每日剂量并不是一种选择，因为肾毒性（当前治疗方案中发生率高达 60%）是主要的剂量限制性不良反应。出现多粘菌素耐药性是单一疗法的一个重大风险，并且由于处于“最后一线”状态，意味着对所有药物均产生耐药性 目前的抗生素。这突出表明迫切需要探索多粘菌素组合的新型、高活性给药策略。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“突发”、“前负荷”（例如治疗开始时的高剂量、短持续时间给药）和“顺序”多粘菌素组合给药策略的有效性进行系统评估。该研究计划采用了一系列体外和兔子感染模型的多层方法。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组合的有前途的剂量策略，以抑制对临床分离株的耐药性。尖端的基因组学/转录组学/代谢组学研究将通过表征全球细菌对新型组合给药策略的反应（包括耐药性的出现）来指导最佳治疗方案的选择。最后，我们的优越方案的前瞻性验证研究将在 10 天的免疫受损且有能力的兔子感染模型中进行，以前瞻性评估耐药性抑制和毒性。每个进展阶段都将提供关键信息，为基于机制的创新数学模型的开发提供独特的信息，这些模型将用于跨所有实验层进行转化。最终的翻译将通过基于机制的蒙特卡罗模拟来进行，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最大限度地降低耐药性和毒性，以供未来的人体测试使用。