Editorial Commentary: Colistin and a New Paradigm in Drug Development.

Abstract

In this issue of Clinical Infectious Diseases, Nation and colleagues (from a consortium of academic institutions in Australia, the United States, Thailand, and Greece) present a critical analysis of the United States (Food and Drug Administration [FDA]) and European (European Medicines Agency [EMA]) dosing recommendations for the intravenous administration of colistin in relation with pharmacokinetic/pharmacodynamic target attainment rates [1]. Together with the large number of recent publications from members of this consortium and other academic institutions, this analysis and the efforts of both regulatory agencies come at an appropriate time and also illustrate a new paradigm in drug development. Colistin is indeed a quite old antibiotic (isolated in Japan in 1949 from Bacillus polymyxa var colistinus). It was only sparingly used in human clinical practice for parenteral administration until the emergence of multi- and panresistant gram-negative organisms in the beginning of this century [2]—that is, at a time when it was no longer under patent protection. In parallel, colistin has been and is still used in large amounts in animals both for curative treatments and for prevention of disease [3]. As a result, there was no or little interest for the pharmaceutical industry to meet the expectations of clinicians when requesting information and hard data about optimal human dosages. Likewise, no effort was made at re-registering colistin for treatment of infections caused by resistant organisms. This may be understandable in a context of drug development made essentially by profit-making industries, which has been and is still largely the system in which most industrial countries have been able to obtain modern medicines. There was also a fear from industry that regulatory agencies would never approve colistin for the indications required by clinicians given the many uncertainties about its true pharmacokinetics (complicated by the fact that colistin is used in humans as prodrug [colistimethate], which hydrolyzes to liberate active colistin rather slowly), its ability to control infections alone (thus requiring combination therapies), and the potential for nephro- and neurotoxic reactions. Thus, colistin may be unique so far in having known a development for human