Colistimethate sodium

In plain language

Colistimethate is a last-resort antibiotic for infections by Gram-negative bacteria that resist nearly everything else, including carbapenem-resistant Acinetobacter and Pseudomonas. It is the injectable form of colistin, a drug from the 1950s that was shelved for toxicity and has returned because of superbugs.

It is a prodrug: the body slowly converts it to the active colistin over hours, which must be factored into dosing. Its serious risks are kidney and nerve damage, so doctors reserve it for when few or no alternatives exist. An inhaled form is used in cystic fibrosis.

For students

Colistimethate sodium is the penta-methanesulfonate prodrug of colistin (polymyxin E), a cyclic decapeptide with an N-terminal fatty acid (about 1,743 Da as the sodium salt). Soluble and inactive itself, it is hydrolyzed in vivo by tissue and plasma esterases to colistin, the active cationic lipopeptide that binds lipid A in the outer membrane of Gram-negative bacteria, permeabilizing both membranes.

Colistin was isolated from Bacillus polymyxa in 1949 (Japan) and abandoned clinically in the 1970s due to nephrotoxicity and neurotoxicity; the spread of carbapenemases revived it as a last-line agent, and its pharmacokinetics (slow conversion, renal handling of the prodrug but not active drug) made dosing a research field of its own, culminating in the 2019 multicenter randomized AIDA trial (n=406) showing colistin monotherapy inferior to meropenem for carbapenem-resistant infections, cementing its use only in combination.

For researchers and instructors

Biochemistry. Polymyxin E's cyclic heptapeptide plus tripeptide tail with a 6-methyloctanoyl group is a natural antibiotic whose cationic surface mirrors host antimicrobial peptides, a parallel often taught with LL-37 and defensins.

Pharmacology. CMS dosed in mg of colistin base activity; conversion to colistin takes hours, so a loading dose is recommended; nephrotoxicity occurs in roughly 30-40% of courses; inhaled CMS is standard for Pseudomonas in cystic fibrosis.

Human evidence. AIDA (JAMA 2019, n=406) showed higher clinical failure with colistin monotherapy; observational PK/PD studies underpin combination therapy recommendations; overall evidence quality remains limited by old trials and heterogeneity.

Teaching point. A drug revived by resistance: teaches prodrug pharmacokinetics, toxicity-driven dosing culture, and how a "last resort" designation coexists with inferior comparative efficacy.