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Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis. Current data supports the use of intravenous colistimethate for the treatment of acute pulmonary exacerbations involving MDR P. aeruginosa and inhaled therapy for initial colonization. The frequency of nephrotoxicity and severity of neurotoxicity seem to be substantially less than previously believed. In addition, recent pharmacokinetic and pharmacodynamic data suggests new intravenous dosing regimens may enhance efficacy while minimizing toxicities; such regimens deserve further evaluation. Pre- and post-treatment spirometry is recommended at initiation of inhaled colistin therapy to identify sensitized individuals. Judicious use of colistin where the benefits have been clearly documented will retain this as a useful agent in the management of P. aeruginosa infections in patients with cystic fibrosis.