The Resurgence of a "Last-Line" Antibiotic
Polymyxins are a class of polypeptide antibiotics first discovered in the 1940s. Their use was largely abandoned in the 1970s due to concerns over significant nephrotoxicity (kidney damage) and neurotoxicity (nerve damage), with safer, less toxic alternatives becoming available. However, the landscape of infectious disease has dramatically shifted. The widespread emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, particularly those resistant to carbapenems, has severely limited treatment options. This dire situation forced a reevaluation and reintroduction of polymyxins, primarily polymyxin B and colistin (also known as polymyxin E), as crucial therapies for life-threatening infections.
Targeting the Bacterial Cell Membrane
Polymyxins exert their potent bactericidal effect by targeting the outer membrane of Gram-negative bacteria. Their mechanism of action can be summarized as follows:
- Polymyxins are cationic, or positively charged, lipopeptides.
- They are attracted to and bind to the negatively charged lipopolysaccharide (LPS) molecules present on the outer membrane of Gram-negative bacteria.
- This binding is achieved by competitively displacing divalent cations like calcium ($Ca^{2+}$) and magnesium ($Mg^{2+}$), which stabilize the LPS layer.
- This displacement disrupts the integrity and permeability of both the outer and inner bacterial cell membranes.
- The resulting cellular leakage of essential cytoplasmic contents, including ions, proteins, and ATP, leads to rapid cell death.
Clinical Uses of Polymyxin
Polymyxins are indicated for a range of severe infections caused by susceptible Gram-negative bacteria. Their use is typically reserved for hospitalized patients with serious conditions for which safer antibiotics are ineffective.
Systemic Infections
Intravenous polymyxin B or colistin is used to treat serious systemic infections such as:
- Bloodstream infections (bacteremia) caused by susceptible Gram-negative pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacteriaceae.
- Urinary tract infections (UTIs).
- Central nervous system (CNS) infections, including meningitis and ventriculitis, often requiring intrathecal or intraventricular administration due to poor systemic penetration.
- Ventilator-associated pneumonia (VAP), often using nebulized (inhaled) therapy in combination with intravenous administration to achieve high local concentrations in the lungs.
Topical and Local Applications
Polymyxins are also used topically for localized infections to minimize systemic toxicity:
- Ophthalmic preparations: Polymyxin B is commonly combined with other antibiotics like trimethoprim in eye drops for treating bacterial conjunctivitis and blepharoconjunctivitis.
- Topical ointments: Used for treating skin infections and preventing infection in minor cuts and burns.
Polymyxin B vs. Colistin (Polymyxin E)
While polymyxin B and colistin share a similar spectrum of activity, key differences in their formulation and pharmacokinetics can influence clinical choice. The comparison below highlights the primary distinctions:
| Feature | Polymyxin B | Colistin (Polymyxin E) | Key Clinical Implication |
|---|---|---|---|
| Parenteral Formulation | Administered as the active, antibacterial sulfate salt. | Administered as an inactive prodrug, colistimethate sodium (CMS). | Polymyxin B is active immediately upon administration, while CMS requires in-vivo conversion. |
| Rate to Peak Concentration | Reaches desired plasma concentration relatively quickly. | Rises slowly and may take hours to reach effective concentrations. | Delayed action of CMS can lead to suboptimal killing and potential resistance. |
| Renal Function Impact | Clearance is not significantly affected by renal impairment, so dose adjustment is not typically needed. | Clearance is highly dependent on renal function; dose adjustment is required in patients with renal impairment. | Dosing is more predictable and less variable for Polymyxin B. |
| Nephrotoxicity | Recent studies suggest potentially lower rates of nephrotoxicity compared to colistin. | Historically associated with higher nephrotoxicity rates, possibly due to intrarenal conversion of CMS. | Polymyxin B may offer a safer profile for certain patients, though both require careful monitoring. |
| Urinary Concentration | Excreted to a very minor extent, leading to low urinary concentrations. | Excreted extensively into the urine, where it converts to active colistin. | Colistin is generally preferred for lower urinary tract infections. |
Significant Risks: Nephrotoxicity and Neurotoxicity
The major drawback of polymyxin use is the risk of serious side effects, which is why these drugs are used with caution, particularly in critical care settings.
Acute Kidney Injury (AKI)
- Mechanism: Polymyxins accumulate extensively within the renal proximal tubular cells, primarily mediated by transporter proteins like megalin and PEPT2. This accumulation can trigger cell damage, leading to dose-dependent AKI.
- Monitoring: Frequent monitoring of renal function, including blood urea nitrogen (BUN) and creatinine, is essential during treatment.
- Reversibility: AKI associated with polymyxins is often reversible upon discontinuation of the drug.
Neurological Effects
- Symptoms: Neurotoxicity can manifest as facial and peripheral paresthesias (tingling or numbness), dizziness, confusion, vertigo, seizures, and visual disturbances.
- Mechanism: The exact mechanism is not fully understood but is thought to involve neuromuscular blockade and potential accumulation in nerve tissues.
- Management: Like nephrotoxicity, these effects are usually reversible once the medication is stopped.
The Threat of Antimicrobial Resistance
Despite their last-resort status, resistance to polymyxins is an ongoing concern that threatens their continued effectiveness. Resistance mechanisms include:
- Modification of LPS: The most common mechanism involves altering the lipid A component of LPS by adding cationic groups, which reduces the negative charge and weakens the binding affinity of the positively charged polymyxin.
- Mobile Resistance Genes: The discovery of plasmid-mediated resistance genes, such as mcr, is particularly alarming as it allows for the horizontal transfer of polymyxin resistance between bacteria.
- LPS Loss: Some strains, particularly Acinetobacter baumannii, can acquire resistance by completely losing their LPS via genetic mutations.
Prudent use of polymyxins, often in combination with other antibiotics, is critical to slow the development of further resistance and preserve these vital drugs for future use.
Conclusion
Polymyxins serve as a critical line of defense against severe, multidrug-resistant Gram-negative bacterial infections in an era of growing antimicrobial resistance. What is polymyxin good for is ultimately defined by its ability to tackle these hard-to-treat pathogens when other options have failed. Their potent bactericidal mechanism, which targets the bacterial cell membrane, provides a life-saving option. However, the use of polymyxins is balanced against significant risks of nephrotoxicity and neurotoxicity, demanding careful patient selection and monitoring. The important pharmacokinetic differences between polymyxin B and colistin, particularly in their administration and renal handling, further emphasize the need for informed clinical decisions. As resistance continues to evolve, preserving the efficacy of these last-resort antibiotics through responsible use remains a major priority in modern infectious disease management.
[National Institutes of Health (NIH) | (.gov) https://www.ncbi.nlm.nih.gov/books/NBK557540/]
