Polymyxin
Introduction
Polymyxin is a class of antibiotics that target Gram-negative bacteria. These antibiotics are derived from the bacterium Bacillus polymyxa and are known for their effectiveness against a range of pathogenic bacteria, including Pseudomonas aeruginosa and Acinetobacter baumannii. Polymyxins are considered last-resort antibiotics due to their nephrotoxicity and neurotoxicity, making their clinical use limited to severe infections where other antibiotics have failed.
Chemical Structure and Mechanism of Action
Polymyxins are cyclic polypeptides with a unique structure that includes a polycationic peptide ring and a fatty acid tail. This structure allows polymyxins to interact with the lipopolysaccharides (LPS) in the outer membrane of Gram-negative bacteria. The primary mechanism of action involves the disruption of the bacterial cell membrane, leading to cell lysis and death.
Polymyxins bind to the LPS and phospholipids in the outer membrane, displacing divalent cations such as calcium and magnesium that stabilize the membrane. This displacement results in increased membrane permeability and leakage of intracellular contents, ultimately causing bacterial cell death.
Types of Polymyxins
There are several types of polymyxins, but the most clinically relevant are polymyxin B and polymyxin E (colistin).
Polymyxin B
Polymyxin B is primarily used for treating infections caused by multidrug-resistant Gram-negative bacteria. It is administered intravenously or topically and is effective against a variety of pathogens, including Klebsiella pneumoniae and Escherichia coli.
Polymyxin E (Colistin)
Colistin is another important polymyxin used in clinical settings. It is often administered as colistin methanesulfonate, a prodrug that is converted to colistin in the body. Colistin is particularly effective against Carbapenem-resistant Enterobacteriaceae (CRE) and is used as a last-resort treatment for severe infections.
Pharmacokinetics and Pharmacodynamics
Polymyxins exhibit complex pharmacokinetics and pharmacodynamics. They are poorly absorbed from the gastrointestinal tract, necessitating intravenous administration for systemic infections. Once administered, polymyxins distribute primarily to the kidneys, liver, and lungs. They exhibit a concentration-dependent bactericidal effect, meaning their efficacy increases with higher drug concentrations.
Clinical Applications
Polymyxins are used to treat a variety of infections, including:
Due to their nephrotoxicity, polymyxins are often reserved for cases where other antibiotics have failed. They are also used in combination therapy to enhance efficacy and reduce the risk of resistance development.
Resistance Mechanisms
The emergence of polymyxin-resistant bacteria is a growing concern. Resistance mechanisms include modifications to the LPS structure, efflux pumps, and enzymatic degradation. The mcr-1 gene, which encodes a phosphoethanolamine transferase, is one of the most well-known resistance mechanisms. This gene modifies the LPS, reducing polymyxin binding and efficacy.
Adverse Effects
The use of polymyxins is associated with several adverse effects, primarily nephrotoxicity and neurotoxicity. Nephrotoxicity manifests as acute kidney injury, characterized by elevated serum creatinine and reduced urine output. Neurotoxicity can present as dizziness, weakness, and paresthesia. These adverse effects limit the use of polymyxins to severe, multidrug-resistant infections.
Future Directions and Research
Research is ongoing to develop new polymyxin derivatives with reduced toxicity and enhanced efficacy. Studies are also exploring combination therapies to mitigate resistance and adverse effects. The development of rapid diagnostic tools to identify polymyxin-resistant bacteria is another area of active research.