Combating Deadly Gram-negative Lung Infections: An Inhalation and Systems Approach

美国疾病控制和预防中心（CDC）最近升级了抗生素耐药性威胁 在美国，革兰氏阴性“超级细菌”铜绿假单胞菌、肺炎克雷伯菌和 鲍曼不动杆菌为严重至紧急。由细菌“超级细菌”引起的肺部感染 是全球健康和经济的主要负担。由于干燥的抗生素发现管道，多粘菌素 被用作对抗革兰氏阴性肺部感染的最后手段;然而， 由于药物到达肺部感染部位的途径非常有限，因此不是最佳的。简单地增加 由于剂量限制性肾毒性，多粘菌素剂量不是一种选择。令人担忧的是， 单一疗法可引起耐药性的发展。协同多粘菌素组合的肺部递送 具有显著的药代动力学/药效学/毒理学优势， 治疗多药耐药（MDR）肺部感染。不幸的是，传统的吸入制剂具有低的 递送效率;更糟糕的是，目前的吸入多粘菌素疗法是经验性的，并且从未被应用于临床。 系统优化。因此，吸入性多粘菌素疗法的安全性、功效和患者依从性是值得关注的。 严重受损。令人兴奋的是，我们已经确定了几种多粘菌素组合， 根除泛耐药革兰氏阴性菌而不会再生长我们的首要假设是， 通过新的粉末气雾剂制剂的优化的多粘菌素组合的肺部递送 毒性、上级疗效（与临床使用的雾化CMS相比）和最小化对 MDR革兰氏阴性肺部感染。具体目的是：（1）优化增效多粘菌素 用于吸入对抗由革兰氏阴性“超级细菌”引起的肺部感染的组合;（2）开发新的 使用创新的颗粒工程技术的吸入粉末制剂;（3）研究处置 多粘菌素在肺部与其他抗生素，并检查潜在的肺部不良反应 应用系统药理学方法优化吸入多粘菌素及其联合用药的给药方案 基于动物肺部感染模型中的PK/PD。我们必须开发新的疗法来防止细菌 战胜抗生素并产生耐药性。由于没有新的抗生素可用于MDR， 革兰阴性病原体在不久的将来，NIAID已突出合理应用'老' 抗生素联合治疗是一种实用、快速和经济的策略。我们的创新 多学科项目将采用尖端的制药工程，分子成像和系统 药理学，以产生急需的信息，以优化使用吸入多粘菌素， 患者的组合。重要的是，我们的项目及时响应国家计划， 对抗抗药性细菌。

The Centers for Disease Control and Prevention (CDC) has recently escalated the antibiotic resistance threat level in the USA with the Gram-negative ‘superbugs’ Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii as being Serious to Urgent. Lung infections caused by bacterial ‘superbugs’ represent a major global health and economic burden. Due to the dry antibiotic discovery pipeline, polymyxins are used as a last-resort against Gram-negative lung infections; however, parenteral polymyxins are suboptimal due to very limited access of the drug to the infection site in the lungs. Simply increasing the polymyxin dose is not an option because of the dose-limiting nephrotoxicity. Alarmingly, polymyxin monotherapy can cause development of resistance. Pulmonary delivery of synergistic polymyxin combinations holds a great promise with significant pharmacokinetic/pharmacodynamic/toxicodynamic advantages for treating multidrug-resistant (MDR) lung infections. Unfortunately, traditional inhaled formulations have low delivery efficiency; even worse, current inhaled polymyxin therapies are empirical and have never been systematically optimized. Hence, safety, efficacy and patient compliance of inhaled polymyxin therapies are significantly compromised. Excitingly, we have identified several polymyxin combinations which can completely eradicate pandrug-resistant Gram-negatives without any regrowth. Our overarching hypothesis is that the pulmonary delivery of optimized polymyxin combinations via novel powder aerosol formulations has negligible toxicity, superior efficacy (compared to the clinically used nebulized CMS) and minimized resistance against MDR Gram-negative lung infections. The Specific Aims are: (1) To optimize synergistic polymyxin combinations for inhalation against lung infections caused by Gram-negative ‘superbugs’; (2) To develop novel inhaled powder formulations using innovative particle engineering techniques; (3) To investigate the disposition of polymyxins in the lungs with and without other antibiotics, and examine potential pulmonary adverse effects using systems pharmacology; (4) To optimize dosage regimens for inhaled polymyxins and their combinations based on the PK/PD in animal lung infection models. We must develop novel therapies to prevent bacteria from outsmarting antibiotics and developing resistance. As no new antibiotic will be available for the MDR Gram-negative pathogens in the near future, the NIAID has highlighted rational applications of ‘old’ antibiotics through combination therapy as a practical, swift and economical strategy. Our innovative multi-disciplinary project will employ cutting-edge pharmaceutical engineering, molecular imaging and systems pharmacology to generate urgently needed information for the optimal use of inhaled polymyxins and combinations in patients. Importantly, our project responds in a timely manner to the National Plan for Combating Antibiotic-resistant Bacteria.