The threat of colistin resistance among carbapenem-resistant Klebsiella pneumoniae isolates in Iran

Colistin belongs to polymyxin family of antibiotics which are polypeptide bactericidal agents acting mainly by disruption of outer-membrane in Gram-negative bacteria (GNB). This antibiotic group (including polymyxin B and colistin) was approved for clinical use in the late 1950s but fell out of favour soon because of the reported high incidence of nephrotoxicity. With increasing the emergence of extensively-drug resistant (XDR)-GNB and paucity of new marketed antibiotics, polymyxins have recently regained significant clinical interest. They are currently considered as the last-line defense against problematic XDR-GNB notably carbapenem-resistant Enterobacteriaceae (CRE) and Acinetobacter baumannii. Colistin revival in clinical settings has increased the inevitable risk of emerging resistance. Resistance to colistin in GNB is known to be mediated by chemical modification or complete loss of the antibiotic target, LPS. Recently the transmissible plasmid mediated resistance mechanism has been identified in Enterobacteriaceae posing a significant threat to infection control programs. Despite having a very similar chemical structure and indistinguishable antimicrobial activity in vitro, colistin and polymyxin B (PMB) differ mainly in the form administered parenterally. While PMB is administered directly as its active form, colistin is formulated as an inactive prodrug, colistin methanesulfonate (CMS) which itself lacks antibacterial activity and requires to be converted in vivo to colistin in a reaction which occurs slowly and incompletely. As a consequence, plasma concentrations of colistin rise slowly resulting in lower plasma concentrations in renally competent patients. Indeed, it is estimated that only