Colistin (Polymyxin E)

Overview

Colistin is administered intravenously as an inactive prodrug, colistimethate sodium (CMS), which is hydrolysed in the body to the active colistin. Its polycationic structure targets the lipopolysaccharide of the Gram-negative outer membrane, making it one of the few agents still reliably active against carbapenem-resistant organisms.

Because of complex prodrug pharmacokinetics, modern practice (Nation et al.) emphasises a loading dose followed by maintenance dosing based on target plasma colistin exposure and renal function. Doses are often expressed in international units (IU); approximately 1 million IU of CMS corresponds to about 80 mg of CMS or roughly 30 mg of colistin base activity (CBA).

The principal toxicities are dose-dependent nephrotoxicity and, less commonly, neurotoxicity. Colistin is also used by inhalation for chronic Pseudomonas airway infection (e.g. cystic fibrosis) and topically. Emergence of plasmid-mediated mcr-1 colistin resistance is a growing global concern.

Mechanism of Action

Electrostatic binding to lipid A and competitive displacement of calcium and magnesium bridges destabilise the outer membrane (self-promoted uptake), after which colistin permeabilises the cytoplasmic membrane. Additional proposed effects include neutralisation of endotoxin and inhibition of respiratory enzymes. Resistance arises chiefly through lipid A modifications (e.g. pmrCAB, mgrB mutations, or plasmid-borne mcr genes) that reduce the membrane's negative charge.