Polymyxins are a class of antibiotics that play a significant role in medical practice, particularly as challenges from increasingly resistant bacteria continue to emerge globally. Understanding these compounds provides insight into how certain severe infections can be managed.
Understanding Polymyxin
Polymyxins are a group of polypeptide antibiotics. These antibiotics were first discovered in the late 1940s, originating from the soil bacterium Bacillus polymyxa. Their unique origin from soil microorganisms sets them apart from many other antibiotic classes.
The chemical structure of polymyxins features a cyclic peptide portion and a long fatty acid chain. This arrangement contributes to their mechanism of action against bacterial cells. Two primary forms, polymyxin B and polymyxin E (also known as colistin), are the most clinically relevant. These structural characteristics allow polymyxins to interact specifically with certain bacterial components for their antimicrobial effects.
How Polymyxin Targets Bacteria
Polymyxins disrupt the bacterial cell membrane. Gram-negative bacteria possess an outer membrane that serves as a protective barrier, which is rich in a molecule called lipopolysaccharide (LPS). Polymyxins are positively charged molecules that are attracted to the negatively charged LPS on the outer membrane of these bacteria.
Once polymyxin binds to the LPS, it displaces ions like magnesium and calcium. This displacement destabilizes the outer membrane, leading to increased permeability. The antibiotic then inserts itself into the bacterial cell membrane, causing disruption and leakage of cellular contents. This damage to the cell membrane ultimately leads to bacterial cell death.
Polymyxins are effective against Gram-negative bacteria because of their outer membrane structure. Bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are vulnerable to this mechanism of action. The ability of polymyxins to directly compromise the bacterial membrane makes them effective against these pathogens.
Polymyxin’s Role in Medicine
Polymyxins are used for treating severe infections caused by multi-drug resistant (MDR) Gram-negative bacteria. These include pathogens like Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Enterobacteriaceae (CRE), such as Klebsiella pneumoniae. These bacteria often cause serious conditions like pneumonia, bloodstream infections, and urinary tract infections that are difficult to treat with other antibiotics.
The use of polymyxins as a “last resort” antibiotic is due to increasing antibiotic resistance. When other, less toxic antibiotics are ineffective against these resistant strains, polymyxins may be one of the few remaining options. This careful consideration of their use helps to preserve their effectiveness for the most critical situations.
For systemic infections, polymyxins are commonly administered intravenously. In some cases, for localized infections like certain eye or ear infections, polymyxins can be applied topically. The route of administration depends on the type and severity of the infection being treated.
Important Considerations
Despite their effectiveness against resistant bacteria, polymyxins are associated with significant side effects that necessitate careful patient monitoring. The most notable adverse effect is nephrotoxicity, which refers to damage to the kidneys. This can manifest as acute kidney injury and requires close monitoring of kidney function during treatment.
Neurotoxicity involves adverse effects on the nervous system. This can include symptoms such as dizziness, weakness, or a tingling sensation in the limbs. Healthcare providers must carefully balance the benefits of polymyxin treatment against these potential risks, adjusting dosages as needed to minimize harm.
The emergence of polymyxin resistance impacts these last-resort antibiotics. A mechanism of resistance involves a gene called MCR-1 (mobilized colistin resistance). This gene can be transferred between bacteria, including different species, through mobile genetic elements like plasmids.
The MCR-1 gene modifies the lipopolysaccharide (LPS) on the bacterial outer membrane, reducing polymyxin binding. This modification prevents the antibiotic from disrupting the membrane, allowing the bacteria to survive. The spread of MCR-1 globally highlights the urgent need for continued surveillance and the development of new antimicrobial strategies to combat these highly resistant pathogens.