Polymyxin pharmacokinetics and pharmacodynamics

Polymyxin B and E (the latter more commonly known as colistin) were originally introduced into clinicalmedicine in the late 1950s for the treatment of infections caused by gram-negative pathogens. They fellinto relative disuse during the next decade as concern about their potential to cause nephrotoxicity grewand other new antibiotics regarded at the time as less toxic became available. In more recent times, thepolymyxins have been resurrected as an important component of the therapeutic armamentarium becauseof rising rates of resistance to other available antibiotics and the limited number of new antibacterial agentswith activity against gram-negative pathogens emerging from the drug development pipeline. At the timeof their original regulatory approval for clinical use the rigor of drug development and approval processeswas substantially less than it is today and there was little information to guide clinicians in the optimal useof these agents. Over the last decade, the polymyxins have been subject to a “redevelopment” process, ledby academic researchers and clinicians, and funded largely by public grant bodies around the world. Theresult has been a considerable increase in knowledge of the preclinical and clinical pharmacology of thepolymyxins. This chapter reviews key aspects of the chemistry, microbiology, and especially the pharmacokineticsand pharmacodynamics of both of the clinically available polymyxins. The similarities and differencesbetween colistin and polymyxin B are highlighted as are the clinical implications for use of theseimportant last-line antibiotics.