What are polymyxins?
Polymyxins are a group of cationic lipopeptide antibiotics produced by the Gram-positive bacterium Paenibacillus polymyxa. There are several types of polymyxins, but only polymyxin B and polymyxin E (also known as colistin) are used in clinical practice today. These antibiotics were discovered in the late 1940s and saw wide use before being largely abandoned in the 1970s due to concerns about their toxicity, particularly to the kidneys. However, the rise of multidrug-resistant (MDR) Gram-negative bacteria, especially carbapenem-resistant organisms, has led to their re-emergence as a critical last-resort treatment option.
Mechanism of action: Attacking the bacterial membrane
The polymyxin mechanism of action is distinct from many other antibiotics. Rather than targeting internal processes like protein synthesis, polymyxins exert their bactericidal effect by disrupting the bacterial cell membrane.
The process can be broken down into these steps:
- Electrostatic interaction: The positively charged polymyxin molecules are attracted to and bind with the negatively charged lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria.
- Membrane disruption: This binding displaces essential divalent cations like calcium ($Ca^{2+}$) and magnesium ($Mg^{2+}$) that help stabilize the outer membrane. The disruption of the outer membrane increases its permeability.
- Leakage and lysis: The process continues to the inner cytoplasmic membrane. The detergent-like hydrophobic tail of the polymyxin inserts into the membrane, increasing its permeability further. This leads to the leakage of intracellular contents and ultimately, bacterial cell death by lysis.
- Endotoxin neutralization: An additional benefit is that polymyxins can bind to and neutralize endotoxins released from the LPS of dead bacteria, potentially mitigating some of the inflammatory effects of the infection.
Polymyxin B vs. Colistin (Polymyxin E)
While polymyxin B and colistin have very similar antimicrobial properties, they have significant differences in how they are administered and how they behave in the body.
| Feature | Polymyxin B | Colistin (Polymyxin E) |
|---|---|---|
| Administration Form | Administered directly in its active form. | Administered as an inactive prodrug called colistimethate sodium (CMS). |
| Activation | No activation needed; is already active upon administration. | Needs to be converted to its active form (colistin) in the body, which is a gradual process. |
| Systemic Pharmacokinetics | Achieves therapeutic concentrations rapidly and predictably. It is eliminated primarily through non-renal mechanisms. | Achieves peak serum concentration slowly (up to 7 hours) and concentrations are less predictable due to variable conversion from CMS. |
| Renal Function Impact | Does not require dose adjustment for renal impairment. | Requires careful dose adjustment in patients with renal impairment. |
| Excretion | Slow excretion due to extensive tissue binding. | CMS is rapidly excreted by the kidneys, with only a portion converted to active colistin. |
Clinical uses and indications
Polymyxins are reserved for treating severe infections where other, less toxic antibiotics are ineffective. The main indications include:
- Multi-drug Resistant (MDR) Infections: Used against susceptible strains of Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and members of the Enterobacteriaceae family.
- Specific Infection Sites: Depending on the infection, polymyxins can be administered via different routes:
- Intravenous (IV): For systemic infections like bloodstream infections and pneumonia.
- Inhalation (Aerosolized): Especially useful for treating lung infections, such as those in cystic fibrosis patients.
- Topical and Ophthalmic: For localized infections like external ear infections (otitis externa) and eye infections.
Side effects and toxicity
Despite their effectiveness, polymyxins are known for significant toxicities, which led to their decline in use decades ago. Systemic use is associated with a black box warning due to the potential for serious adverse effects.
- Nephrotoxicity (Kidney Injury): This is the most common and serious side effect, characterized by a decrease in urine output or general kidney dysfunction. It is reversible but requires careful monitoring of kidney function.
- Neurotoxicity: Affects the nervous system, potentially causing:
- Sensory disturbances such as tingling or numbness in extremities (paresthesia).
- Dizziness and confusion.
- Muscle weakness and even temporary paralysis.
- Blurry vision.
- Allergic Reactions: Patients may experience rashes, itching, hives, or swelling of the face, lips, and throat.
- Injection Site Reactions: Pain, redness, or irritation at the site of injection.
The battle with polymyxin resistance
Polymyxin resistance is an emerging and serious problem, posing a threat to their use as a last-line defense. The main mechanisms of resistance include:
- Lipid A Modification: Bacteria can alter the structure of the lipid A portion of their LPS. This modification reduces the negative charge, which lowers the binding affinity of the positively charged polymyxin and prevents it from disrupting the membrane effectively.
- Plasmid-Mediated Resistance: The discovery of the mcr-1 gene in 2015 confirmed that resistance could be transferred between different bacteria via mobile genetic elements (plasmids). This poses a significant threat of rapid, global spread of resistance.
- Complete LPS Loss: Some bacteria, particularly Acinetobacter baumannii, can acquire resistance by completely losing their LPS.
Conclusion
Polymyxins are a class of "old" antibiotics that have made a crucial comeback to combat the modern threat of multidrug-resistant Gram-negative bacteria. While their effectiveness in treating severe infections is undeniable, their use requires careful risk-benefit analysis due to the potential for significant toxic side effects, especially nephrotoxicity and neurotoxicity. The emergence and spread of polymyxin resistance, particularly through plasmid-mediated genes like mcr-1, further complicate their clinical application and underscore the urgent need for new antimicrobial agents. Ongoing research is focused on developing novel derivatives with improved efficacy and reduced toxicity, and on surveillance to monitor resistance patterns.
Outbound Link: Polymyxin - StatPearls - NCBI Bookshelf
