Polymyxin pharmacokinetics and pharmacodynamics

Abstract

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