Pharmacokinetics and pharmacodynamics of colistin

The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has resulted in colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), being increasingly used as a last-line therapy to treat infections caused by these pathogens. Developed well before contemporary drug development procedures, substantial improvements in the understanding of its chemistry, pharmacokinetics (PK), pharmacodynamics (PD) and PK/PD relationships have occurred over the last decade which have enabled substantial progress towards optimising its clinical use in different patient populations. This has resulted in the first scientifically based dosing algorithm for various categories of critically ill patients receiving CMS to generate a desired target steady-state plasma concentration of formed colistin. It has become clear that monotherapy with CMS is unlikely to generate plasma colistin concentrations that are reliably efficacious. With nephrotoxicity preventing simply increasing the dose of CMS, combination therapy may be required in order to maximise efficacy and minimise the emergence of resistance.