Colistin Classification and Mechanism of Action
Colistin (polymyxin E) is a positively charged polypeptide antibiotic that disrupts the outer membrane of gram-negative bacteria by binding to the lipid A moiety of lipopolysaccharides, resulting in cell death. 1
Drug Classification
- Colistin belongs to the polymyxin class of antibiotics, specifically classified as polymyxin E 1
- The drug is administered as colistimethate sodium (CMS), an inactive prodrug that is less toxic and preferred for parenteral administration 2, 3
- Colistimethate sodium is a polypeptide antibiotic with an approximate molecular weight of 1750 and the empirical formula C58H105N16Na5O28S5 3
Mechanism of Action
Primary Bactericidal Effect
- Colistin is an amphipathic molecule that interacts with lipopolysaccharide (LPS) in the bacterial outer membrane 4
- The positively charged decapeptide structure binds specifically to the lipid A moiety of LPS, disrupting the integrity of the outer membrane of gram-negative bacteria 1
- This binding leads to disruption of both the outer and cytoplasmic membranes, resulting in bacterial death and lysis 5
Secondary Antiendotoxic Properties
- The endotoxic activity of lipopolysaccharides is simultaneously inhibited during colistin's bactericidal action 1
- Polymyxins have potent antiendotoxic properties that contribute to their therapeutic effect 4
Antibacterial Spectrum
- Colistin demonstrates potent antibacterial activity against Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and many Enterobacteriaceae 6, 4
- The antibiotic has resurfaced as a last-line treatment option for multidrug-resistant gram-negative organisms 6
Important Clinical Considerations
Resistance Mechanism Implications
- Colistin resistance occurs through LPS modifications that protect the cytoplasmic membrane but not the outer membrane from damage 5
- Resistance can develop via chromosomal mutations or acquisition of mobilized colistin-resistance (mcr) genes, both resulting in chemical modifications to LPS with positively charged moieties 5, 7
- Resistance seems to emerge often unless colistin is combined with another antibiotic, though further studies are needed 1
Pharmacodynamic Properties
- The ratio between the area under the curve (AUC) of free colistin and the pathogen's Minimal Inhibitory Concentration (MIC) best predicts microbiological and clinical responses 1