Réévaluation de la colistine

Colistin (polymyxin E) designates two different drugs, colistin sulfate, an oral digestive decontaminant, and colismethate sodium (CMS) intended for intravenous, intrathecal/intraventricular, or inhaled therapy. Colistin interferes with bacterial membranes creating cytoplasmic leaks lethal to bacteria through interactions with membrane proteins and phospholipids (including LPS). This mechanism of action confers bactericidal activity to colistin on frequently multiresistant pathogens such as Acinetobacter spp., P. aeruginosa, and Klebsiella spp. It also leads to specific resistance mechanisms, which arise from modifications in bacterial membrane proteins. New methods applied to pharmacokinetic studies of colistin take into account the in-solution and plasmatic hydrolysis of CMS, the inactive prodrug, into active compounds among which colistin. These studies show that current therapeutic regimens may be optimized. Colistin being a concentration dependent bactericidal antibiotic, the area under the curve (AUC)/MIC was proven the best PK/PD parameter associated with in vivo efficacy, opening new perspectives in alternate dosing regimens. Nephrotoxicity occurs at a rate comparable to aminoglycosides and neurotoxicity is more often benign; both being reversible upon discontinuation of therapy. In multiresistant Gram negative, mostly A. baumanii or P. aeruginosa, nosocomial infections as well as in chronic P. aeruginosa infections and exacerbations in cystic fibrosis patients, the efficacy of colistin has been demonstrated within the limitations inherent to studies of an antibiotic which can only be used after determination of susceptibility in severe infections nonetheless requiring urgent adequate therapy. Further clarifications are required concerning the added benefit of combination with antibiotics considered as synergistic such as rifampicin and carbapenems.