The Polymyxin Drug Class
Colistin is a member of the polymyxin family, a class of polycationic polypeptide antibiotics originally discovered in the late 1940s. The two main polymyxins used clinically are colistin (polymyxin E) and polymyxin B, both of which are produced by the bacterium Paenibacillus polymyxa. These antibiotics are distinct from other classes due to their unique mechanism of action, which targets the outer membrane of Gram-negative bacteria. Their initial clinical use declined significantly in the 1970s and 1980s due to concerns over toxicity, particularly to the kidneys. However, the rise of extensive drug resistance in Gram-negative bacteria has prompted their revival as critical therapeutic options.
Mechanism of Action Against Gram-Negative Bacteria
Colistin is a cyclic lipopeptide that exhibits its bactericidal effect by targeting the outer and inner membranes of susceptible Gram-negative bacteria. The primary steps of its mechanism are as follows:
- Binding to Lipopolysaccharide (LPS): The molecule’s positively charged residues of diaminobutyric acid (Dab) are electrostatically attracted to the negatively charged phosphate groups on the lipid A component of the LPS layer in the bacterial outer membrane.
- Displacing Divalent Cations: This binding process displaces essential divalent cations, such as magnesium ($Mg^{2+}$) and calcium ($Ca^{2+}$), which are crucial for maintaining the structural integrity of the outer membrane.
- Outer Membrane Disruption: The removal of these cations destabilizes the LPS, which increases the permeability of the outer membrane. This allows colistin to cross this barrier and reach the inner cytoplasmic membrane.
- Detergent-Like Action and Lysis: Colistin then inserts its hydrophobic fatty acyl chain into the inner membrane, acting like a detergent to disrupt the phospholipid bilayer. This leads to membrane leakage, the loss of intracellular contents, and ultimately, cell death.
Additionally, colistin has potent anti-endotoxin activity by binding to and neutralizing the toxic lipid A component of LPS, which can cause severe systemic inflammation.
Therapeutic Uses and Administration
Colistin's use is generally reserved for serious, life-threatening infections caused by multidrug-resistant (MDR) Gram-negative bacteria that have few other treatment options. These include pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae. It is not effective against Gram-positive bacteria.
Two main forms of colistin are used clinically: colistin sulfate and colistimethate sodium (CMS).
- Colistin Sulfate: This is the active form used for oral, topical, and inhalational applications. It is poorly absorbed from the gastrointestinal tract, making it suitable for treating intestinal infections.
- Colistimethate Sodium (CMS): This is an inactive prodrug that is administered intravenously. It is less toxic than colistin sulfate and undergoes gradual conversion into the active colistin compound in the body. Due to poor penetration of the blood-brain barrier, it may also be given intrathecally or intraventricularly for central nervous system infections.
Adverse Effects: Nephrotoxicity and Neurotoxicity
Despite its necessity for treating severe infections, colistin is associated with significant adverse effects, which led to its initial decline in use. The primary toxicities are nephrotoxicity and neurotoxicity.
- Nephrotoxicity: A major dose-dependent risk is kidney damage, which is often reversible after the drug is discontinued. A meta-analysis of randomized controlled trials reported a nephrotoxicity incidence of approximately 36% with colistin therapy, significantly higher than with other antibiotics.
- Neurotoxicity: Less common but also reported are neurological side effects, including paresthesia (tingling or numbness), vertigo, confusion, and muscle weakness. These effects are generally reversible upon stopping treatment.
The Resurgence and Challenge of Resistance
The reintroduction of colistin has been a critical strategy in combating the global rise of antimicrobial resistance. However, the overuse and misuse of colistin in both human medicine and animal agriculture have led to the emergence of colistin resistance.
Resistance to colistin can arise from several mechanisms:
- Chromosomal Mutations: Changes in genes like pmrAB and phoPQ can alter the LPS structure by adding cationic groups, which reduces the negative charge and weakens colistin binding.
- Efflux Pumps and Capsules: Some bacteria employ efflux pump systems or produce an overabundance of capsular polysaccharide to protect themselves from the drug.
- Plasmid-Mediated Resistance: A major concern is the horizontal transfer of resistance via mobile genetic elements. The discovery of the mcr-1 gene, which encodes a phosphoethanolamine transferase, on plasmids allows resistance to be rapidly spread among different bacterial species. As of 2024, at least 10 different mobile colistin resistance (mcr) genes (mcr-1 to mcr-10) have been identified globally.
Comparison of Colistin and Polymyxin B
Although both colistin (polymyxin E) and polymyxin B belong to the same drug class, they have key differences in clinical application and properties.
| Feature | Colistin (Polymyxin E) | Polymyxin B |
|---|---|---|
| Mechanism | Disrupts bacterial cell membranes by binding to LPS. | Disrupts bacterial cell membranes by binding to LPS. |
| Active Form | Inactive prodrug (CMS) for IV, requires conversion. | Active drug for IV. |
| Administration | IV (via CMS prodrug), inhalation, oral (sulfate). | IV, topical, ophthalmic, otic. |
| Pharmacokinetics | Prodrug conversion can be complex; dosage requires careful calculation. | Better defined pharmacokinetics than colistin. |
| Toxicity | Higher risk of nephrotoxicity and neurotoxicity. | Generally considered less nephrotoxic than colistin. |
| Clinical Context | Revived as a last-resort option for MDR Gram-negative infections. | Used for similar MDR Gram-negative infections as well as topically. |
Conclusion
In conclusion, colistin is a crucial polymyxin antibiotic used as a last-resort treatment for severe multidrug-resistant Gram-negative bacterial infections. Its re-emergence into clinical practice is a direct response to the global antimicrobial resistance crisis, as it provides a therapeutic option when most other antibiotics have failed. While its mechanism of action—targeting the bacterial cell membrane—is highly effective, its use is tempered by the significant risk of nephrotoxicity and neurotoxicity. The spread of plasmid-mediated resistance, particularly the mcr genes, presents a growing challenge to its effectiveness. The judicious use of colistin, often in combination therapy, is essential to prolong its clinical utility and preserve it as a vital tool in the fight against antibiotic-resistant superbugs. For more information on antimicrobial resistance strategies, see the World Health Organization's page on the topic [Authoritative Link to WHO.int on AMR].
