Clinical Pharmacology of Polymyxin B

描述（由申请人提供）：细菌对抗生素的耐药性正在以惊人的速度上升。特别令人关注的是耐多药革兰氏阴性细菌（如铜绿假单胞菌）的流行，对这种细菌，所有现有的一线抗生素都无效。新药开发的速度不太可能跟上多药耐药性的增长。因此，迫切需要其他有效的治疗策略。毒性更强的药物（如多粘菌素B）在临床上作为最后手段使用。然而，批准临床使用的多粘菌素B制剂是几种结构相关成分的未指定混合物（例如，多粘菌素B1、B2、B3等）；没有关于单个成分的药理学和毒性的信息。我们的长期目标是改善多粘菌素B的临床应用，以对抗耐药性的出现。本应用程序的目的是研究商业配方中每种主要多粘菌素B成分的药理学和毒性概况。如果我们了解每一种主要多粘菌素B成分的性质，就可以合理地开发改进的配方和/或有效的给药方案，以提供最大的细菌杀灭和最小的药物诱导毒性。我们计划通过比较不同多粘菌素B组分在以下方面实现应用的目标：(1)体外和体内对临床耐多药铜绿假单胞菌的效力；(2)体外和体内肾毒性谱；(3) 2种动物感染模型的药代动力学。我们期望将产生急需的信息，以改进耐多药革兰氏阴性感染的治疗。

DESCRIPTION (provided by applicant): Bacterial resistance to antibiotics is rising at an alarming rate. Of particular concern is the prevalence of multidrug resistant Gram-negative bacteria (e.g., Pseudomonas aeruginosa), for which all available first-line antibiotics are ineffective. The rate of new drug development is unlikely to keep pace with the increase in multidrug resistance. Consequently, there is a dire need for alternative effective treatment strategies. More toxic agents (e.g., polymyxin B) are used clinically as a last resort. However, formulations of polymyxin B approved for clinical use are available as an unspecified mixture of several structurally related components (e.g., polymyxin B1, B2, B3, etc.); no information is available on the pharmacology and toxicity of individual components. Our long-term goal is to improve the clinical use of polymyxin B to combat the emergence of resistance. The objective of this application is to investigate the pharmacological and toxicity profiles of each of the major polymyxin B component in commercial formulations. If we understand the properties of each of the major polymyxin B component, an improved formulation and / or effective dosing regimens could be developed rationally to provide maximal bacterial killing and minimal drug-induced toxicity. We plan to accomplish the objective of the application by comparing various polymyxin B components with respect to the following: (1) in-vitro and in-vivo potency against clinical multidrug resistant P. aeruginosa; (2) in- vitro and in-vivo nephrotoxicity profiles; and (3) pharmacokinetics in 2 animal infection models. It is our expectation that much-needed information will be generated to improve the treatment of multidrug resistant Gram-negative infections. PUBLIC HEALTH RELEVANCE: As the prevalence of multidrug resistant bacteria increases, many available antibiotics are no longer effective. New effective agents are unlikely to be available in time to solve this crisis. It is critical that we develop alternative treatment strategy and maximize the therapeutic potential of existing agents (e.g., polymyxin B) for multidrug resistant infections. Otherwise, we are at risk of returning to the pre-antibiotic era in the not too distant future.