Towards minimising polymyxin nephrotoxicity

Antibiotics underpin modern medicine; however, the emergence of multi-drug resistant bacterial ‘superbugs’ coupled with the absence of novel antibiotics pose a significant threat to public health. In the midst of a ‘perfect storm’, polymyxin has emerged as the last-line defence for life-threatening Gram-negative infections. Unfortunately, polymyxin-induced nephrotoxicity is dose-limiting and there is an urgent need to optimise their clinical efficacy and minimise resistance. Despite being approved for clinical use since the late 1950s, there remains a paucity of pharmacological information for the rational use of polymyxins. The data garnered in this thesis provides new information for the safer use of polymyxins, and sheds new light on the mechanisms underlying polymyxin-induced nephrotoxicity.