Colistin is a polymyxin antibiotic, a class of cationic polypeptide antibiotics discovered in the late 1940s. It is produced by the soil bacterium Paenibacillus polymyxa. For decades, its clinical use was limited due to perceived nephrotoxicity and neurotoxicity, but it has experienced a critical resurgence as a last-line therapeutic agent against multidrug-resistant (MDR) Gram-negative bacterial infections, particularly those caused by carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. Its significance lies in its ability to disrupt the outer membrane of these ‘superbugs’ where most other antibiotics fail, making it an essential component of the antimicrobial arsenal despite its toxicity profile.
Quick Facts
| Also Known As | Polymyxin E, Colistimethate Sodium, Colistin Sulfate, Coly-Mycin |
|---|---|
| Sequence | Cyclic: (Dab-Thr-Dab-Dab-Dab-Dab-Dab-Ser-Dab-Dab). Linear tail: Dab-Dab-Thr-Dab-Thr (Dab = L-α,γ-diaminobutyric acid). |
| Molecular Formula | C52H98N16O13 |
| Molecular Weight | 1155.4 Da |
| PubChem CID | 5311054 |
Research Parameters
| Half-Life | Approximately 2-3 hours for the active colistin after IV administration of colistimethate sodium. The half-life can be significantly prolonged in patients with renal impairment. |
|---|---|
| Stability | Lyophilized colistimethate sodium powder is stable at recommended storage temperatures. After reconstitution in sterile water, solutions are typically stable for 24 hours at room temperature or up to 7 days if refrigerated (2-8°C), though specific product labeling should be consulted. |
| Solubility | Colistimethate sodium is typically reconstituted with Sterile Water for Injection. Further dilution for IV infusion is done in compatible IV solutions like 0.9% Sodium Chloride. |
| Vial Size | 150 mg |
| Storage (Lyophilized) | Store at 2-8°C (refrigerated), protect from light. Some formulations may be stored at room temperature for limited periods; consult specific product information. |
| Storage (Reconstituted) | Refrigerate at 2-8°C if not used immediately. Use within the time specified by the manufacturer (often 24 hours to 7 days). |
| Typical Research Dose | Research/clinical dosing is in mg/kg, not mcg. Typical IV dose range for colistimethate sodium is 2.5-5 mg/kg/day, divided. |
| Cycle Parameters | Not applicable in the traditional 'cycle' sense. In research and clinical practice, treatment is typically administered via IV infusion 2-4 times daily for a defined course of 7-14 days or longer based on clinical response and renal function monitoring. |
| Amino Acid Count | 16 |
Mechanism of Action
Colistin is a cationic, amphipathic peptide that acts primarily by disrupting the structure and function of the bacterial outer membrane (OM) of Gram-negative bacteria. Its mechanism involves a multi-step, detergent-like interaction with lipopolysaccharide (LPS), a key component of the OM.
Electrostatic Binding: The positively charged diaminobutyric acid (Dab) residues of colistin interact electrostatically with the negatively charged lipid A component of LPS in the outer leaflet of the bacterial outer membrane.
Displacement of Divalent Cations: This binding competitively displaces magnesium (Mg2+) and calcium (Ca2+) ions that normally stabilize the LPS layer by cross-linking adjacent phosphate groups.
Membrane Destabilization: The displacement of cations destabilizes the OM, allowing the hydrophobic fatty acid tail of colistin to insert into the membrane. This causes increased permeability, leakage of intracellular contents, and ultimately bacterial cell death. At higher concentrations, it may also have secondary effects like inhibition of vital respiratory enzymes.
Research Applications
Antimicrobial Resistance Research: Colistin is a cornerstone agent in studies of last-resort therapies against pan-drug-resistant Gram-negative pathogens. Research focuses on optimizing dosing regimens (including inhaled administration), understanding pharmacokinetics/pharmacodynamics (PK/PD), and defining breakpoints for susceptibility testing.
Combination Therapy Studies: Significant research investigates colistin in combination with other antibiotics (e.g., carbapenems, rifampin, fosfomycin) to achieve synergistic effects, lower the required dose of colistin, and potentially slow the emergence of resistance.
Toxicity and Nephroprotection Research: A major area of investigation involves understanding the molecular mechanisms of colistin-induced nephrotoxicity and neurotoxicity. Studies explore novel, less toxic derivatives (like colistin methanesulfonate) and co-administration of protective agents to mitigate kidney damage while preserving antimicrobial efficacy.
Mechanisms of Resistance: Research is intensely focused on elucidating the genetic and biochemical basis of plasmid-mediated mobile colistin resistance (mcr) genes, which threaten to render this last-line antibiotic ineffective, driving surveillance and novel drug discovery.
Safety & Side Effects
The primary dose-limiting toxicity is nephrotoxicity (acute kidney injury), observed in up to 50% of patients in some studies, characterized by increased serum creatinine and tubular damage. Neurotoxicity (dizziness, muscle weakness, paresthesia, and rarely respiratory paralysis from neuromuscular blockade) is another significant concern. These effects are dose-dependent and more common with high doses or prolonged use. Hypersensitivity reactions and bronchospasm (with inhaled form) have been reported. Anecdotally, side effects may also include fever and gastrointestinal upset. Theoretical concerns include the potential for promoting further antibiotic resistance and superinfections.
Dosage Information
Disclaimer: The following information is derived from clinical and preclinical research literature and is presented for educational purposes only. Colistin is a prescription antibiotic with significant toxicity risks and must only be used under medical supervision.
In research and clinical settings, colistin is typically administered as its prodrug, colistimethate sodium (CMS), which is hydrolyzed in vivo to the active colistin. Dosing is complex and based on ideal body weight. Typical intravenous (IV) research/clinical dose ranges for CMS are 2.5-5 mg/kg per day (equivalent to 30,000-75,000 IU/kg/day), divided into 2-4 doses. Inhaled administration for pulmonary infections is also studied, with typical doses of 75-150 mg of CMS twice daily. Frequency is daily, with duration varying from 7 to 14 days or longer depending on infection severity and renal function, which must be closely monitored.
References
Li, J., Nation, R.L., Turnidge, J.D., et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006.
Nation, R.L., Velkov, T., Li, J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis. 2014.
Bergen, P.J., Landersdorfer, C.B., Zhang, J., et al. Pharmacokinetics and pharmacodynamics of 'old' antibiotics: new tricks? Clin Pharmacokinet. 2012.
Liu, Y.Y., Wang, Y., Walsh, T.R., et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016.
Garonzik, S.M., Li, J., Thamlikitkul, V., et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011.
Pogue, J.M., Lee, J., Marchaim, D., et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011.