Polymyxins are a class of antibiotics composed of polypeptides derived from the soil bacterium Paenibacillus polymyxa. Although their use was historically limited by potential side effects, they have seen a resurgence in modern medicine. This renewed interest is a response to the challenge of infections caused by multidrug-resistant bacteria, making polymyxins an important option as other antibiotics lose effectiveness.
Mechanism of Action and Bacterial Targets
Polymyxins are cationic molecules, meaning they carry a positive electrical charge. This charge is attracted to the negatively charged components of the bacterial outer membrane, specifically a molecule called lipopolysaccharide (LPS). This interaction is the basis of their antibacterial activity.
The binding of polymyxins to LPS displaces calcium and magnesium ions that stabilize the membrane’s structure. This displacement disrupts the outer membrane’s integrity, making it more permeable. This allows essential molecules to leak out of the cell and the polymyxin to enter, leading to cell death.
This targeted action means polymyxins are effective against Gram-negative bacteria, which have an outer membrane rich in LPS. Common examples include Pseudomonas aeruginosa and Acinetobacter baumannii. Conversely, they are not effective against Gram-positive bacteria or fungi because these organisms lack the LPS-containing outer membrane for the antibiotic to target.
Clinical Use and Administration
Polymyxins are reserved as “last-resort” antibiotics due to their potency and potential for side effects. They are used to treat severe infections caused by bacteria that have developed resistance to most other available drugs. Infections caused by pathogens such as Klebsiella pneumoniae and Acinetobacter baumannii are common targets for this therapy, especially in hospital settings.
For systemic infections that have spread throughout the body, they are given intravenously to reach the bloodstream directly. Topical formulations are used for skin infections, and in these products, polymyxin is often combined with other antibiotics. An inhaled form can be used to treat lung infections, particularly in patients with cystic fibrosis.
A limitation of these drugs is that they cannot be taken orally. Polymyxins are poorly absorbed from the gastrointestinal tract, so an oral dose would not effectively fight a systemic infection. This lack of oral bioavailability necessitates direct administration methods.
Associated Toxicities
The same membrane-disrupting action that makes polymyxins effective against bacteria can also affect human cells, leading to adverse effects. The two most recognized forms of toxicity are damage to the kidneys and the nervous system. These side effects are a primary reason their use is limited.
Nephrotoxicity, or kidney damage, is the most common side effect associated with systemic polymyxin use. This toxicity is dose-dependent, meaning the risk increases with higher doses or longer treatment durations. The damage is often reversible, and kidney function can recover after the medication is stopped. Healthcare providers closely monitor kidney function during treatment.
Neurotoxicity, or damage to the nervous system, can also occur. Patients may experience symptoms like dizziness, muscle weakness, and numbness or tingling, particularly around the face and in the extremities. In more severe instances, this can affect the respiratory muscles, potentially leading to respiratory paralysis. Careful monitoring for these symptoms is a standard part of patient care.
Mechanisms of Bacterial Resistance
Some bacteria have developed ways to resist the effects of polymyxins. The primary strategy involves altering the lipopolysaccharide (LPS) molecule in their outer membrane, which prevents the antibiotic from binding effectively.
The most common mechanism of resistance is the modification of the lipid A component of LPS. Bacteria can enzymatically add positively charged molecules, such as phosphoethanolamine or 4-amino-4-deoxy-L-arabinose, to the lipid A structure. This addition reduces the outer membrane’s negative charge, which repels the positively charged polymyxin molecules and prevents them from binding.
This resistance can arise from mutations in the bacteria’s own chromosomal genes. More concerning is the acquisition of resistance genes through mobile genetic elements called plasmids. The gene known as mcr-1, for example, can be transferred between different species of bacteria on a plasmid. This horizontal gene transfer allows resistance to spread rapidly, posing a challenge to the continued use of these antibiotics.