Colistin
Colistin (polymyxin E) is a lipopeptide antibiotic effective against multidrug-resistant gram-negative bacteria, used as a last-resort treatment for resistant infections.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C52H98N16O13 |
| Molecular Weight | 1155.46 g/mol |
| CAS Number | 1066-17-7 |
| IUPAC Name | Polymyxin E1/E2 mixture |
| Peptide Class | Polymyxin Lipopeptide |
| Origin | Paenibacillus polymyxa |
Structure
Colistin is a cationic lipopeptide antibiotic of the polymyxin family, produced by Paenibacillus polymyxa var. colistinus. It consists of a cyclic heptapeptide ring with a tripeptide side chain acylated at the N-terminus by a fatty acid (6-methyloctanoic acid or 6-methylheptanoic acid). The cationic charges from five L-diaminobutyric acid residues and the lipophilic fatty acid tail are critical for its membrane-disrupting mechanism.
Mechanism of Action
Colistin acts through a multi-step mechanism against gram-negative bacteria:
- LPS displacement: The cationic peptide displaces divalent cations (Mg2+, Ca2+) from lipopolysaccharide (LPS) in the outer membrane
- Outer membrane disruption: Insertion of the fatty acid tail destabilizes the outer membrane bilayer
- Cytoplasmic membrane damage: The peptide crosses the periplasm and disrupts the inner membrane
- Cell death: Results in osmotic lysis and cell death (rapid bactericidal activity)
Clinical Applications
Colistin is used as a last-resort antibiotic for:
- Multidrug-resistant gram-negative infections: Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae
- Carbapenem-resistant Enterobacterales (CRE): When no other options exist
- Cystic fibrosis pulmonary exacerbations: Inhaled colistin for chronic Pseudomonas infection
Available as colistimethate sodium (prodrug) for IV and inhaled use, and colistin sulfate for oral/topical use.
Pharmacokinetics
- Half-life: 2-3 hours (colistimethate); colistin 14-18 hours
- Protein binding: Colistimethate 50%; colistin >90%
- Metabolism: Colistimethate hydrolyzed to active colistin in vivo
- Elimination: Primarily renal (60-70% as unchanged colistimethate)
- Renal adjustment: Essential; significant accumulation in renal impairment
Safety and Side Effects
Nephrotoxicity (20-60%, dose-limiting), neurotoxicity (peripheral neuropathy, paresthesias, neuromuscular blockade), and hypersensitivity reactions. Dose optimization strategies (loading dose, extended-interval dosing) have improved the safety profile. Therapeutic drug monitoring is increasingly used to balance efficacy and toxicity.
References
- Nation, R.L., et al. (2017). Dose optimization of polymyxins. Antimicrobial Agents and Chemotherapy, 61, e01484-15.
- Falagas, M.E., & Kasiakou, S.K. (2006). Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Critical Care, 10, R27.
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