Central nervous system (CNS) infections caused by multi-drug resistant (MDR) Gram-negative bacteria present a major health and economic burden worldwide. Due to the nearly empty antibiotic discovery pipeline, polymyxins (i.e. polymyxin B and colistin) are used as the last-line therapy against Gram-negative 'superbugs' when all other treatment modalities have failed. The treatment of CNS infections due to multi-drug resistant Gram-negative bacteria is problematic and associated with high mortality rates. Colistin shows significant efficacy for the treatment of CNS infections caused by MDR Gram-negative bacteria that are resistant to all other antibiotics. In particular, MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae which are resistant to expanded-spectrum and fourth-generation cephalosporins, carbapenems and aminoglycosides, represent a major therapeutic challenge, although they can be treated with colistin or polymyxin B. However, current dosing recommendations of intrathecal/intraventricular polymyxins are largely empirical, as we have little understanding of the pharmacokinetics/pharmacodynamics and, importantly, we are only starting to understand the mechanisms of potential neurotoxicity. This review covers the current knowledge-base on the mechanisms of disposition and potential neurotoxicity of polymyxins as well as the combined use of neuroprotective agents to alleviate polymyxins-related neurotoxicity. Progress in this field will provide the urgently needed pharmacological information for safer and more efficacious intrathecal/intraventricular polymyxin therapy against life-threatening CNS infections caused by Gram-negative 'superbugs'.

中文翻译：

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中枢神经系统感染的多粘菌素：药理学和神经毒性。

由多重耐药性（MDR）革兰氏阴性细菌引起的中枢神经系统（CNS）感染在全球范围内构成了重大的健康和经济负担。由于几乎没有空的抗生素发现渠道，当所有其他治疗方式均告失败时，多粘菌素（即多粘菌素B和粘菌素）被用作对抗革兰氏阴性“超级细菌”的最后一线治疗方法。由于多重耐药性革兰氏阴性菌引起的中枢神经系统感染的治疗存在问题，并且死亡率高。Colistin在治疗由耐所有其他抗生素的MDR革兰氏阴性细菌引起的中枢神经系统感染中显示出显着的疗效。尤其是MDR鲍曼不动杆菌，铜绿假单胞菌和肺炎克雷伯菌，它们对广谱和第四代头孢菌素都有抗药性，碳青霉烯类和氨基糖苷类药物虽然可以用大肠菌素或多粘菌素B进行治疗，但仍代表着主要的治疗挑战。但是，鞘内/脑室内多粘菌素的当前剂量推荐主要是经验性的，因为我们对药代动力学/药效学了解甚少，而且重要的是，才刚刚开始了解潜在的神经毒性机制。这篇综述涵盖了关于多粘菌素的处置和潜在神经毒性机制以及结合使用神经保护剂减轻多粘菌素相关的神经毒性的最新知识。