Diabetes and lung function: part of a wider spectrum.

www.chestpubs.org authors) showed that after IV administration of colistin methanesulfonate (CMS), the plasma concentration of colistin is apparently suboptimal. The adverb “apparently” is necessary because the values of the pharmacodynamic indices that best predict the effi cacy of (free) colistin have been determined in in vitro and animal studies, 2 , 3 but are not yet known for humans. The results of in vitro pharmacodynamic studies of antibiotics, although very useful for correlating drug concentrations and pharmacologic effects, might not be directly translatable to the clinical setting. In the case of colistin, the picture is even more complex. In fact, colistin (like polymyxin B) binds to the lipopolysaccharides (LPS) released by killed bacteria also at concentrations below the minimum inhibitory concentration and which, therefore, have no effect on bacterial counts. 4 This colistin-LPS binding could inhibit the toxic effects of the bacterial products, or contrariwise, could reduce the amount of available colistin and its bactericidal activity. The balance between the benefi cial and harmful effects of LPS binding has not yet been defi ned. De Pascale et al also emphasize another worrisome risk of suboptimal antibiotic concentrations: the risk of favoring the emergence of resistance to colistin. Resistance to colistin is not very common. This might be due, in part, to the fact that colistinresistant bacteria present downregulation of several proteins (outer membrane proteins, chaperones, protein biosynthesis factors, metabolic enzymes), which reduce their biologic fi tness and induce phenotype instability. 5 Nevertheless, resistance to colistin is being increasingly described, 6 8 likely because of the increasing use of CMS, and heteroresistance to colistin among clinical strains of multidrug-resistant Acinetobacter baumannii has also been reported recently. 9 Combination therapy (eg, CMS plus another antibiotic, or CMS administered via two different routes) might reduce the risk of the emergence of resistance to colistin. In the next 8 to 10 years we might only be able to combat pan-resistant gram-negative bacterial infections with the use of colistin, this “old” and neglected, but complex and interesting, antibiotic. The defi nition of the optimum dosing regimen, including total daily dose, dosing intervals, and combination therapy, will, therefore, be of paramount importance to maximize bacterial killing and minimize emergence of resistance.