Polymyxin

Polymyxins are a group of polypeptide antibiotics primarily used as a last-resort treatment for multidrug-resistant Gram-negative bacterial infections. They disrupt the bacterial cell membrane, leading to cell death. Polymyxins are cyclic lipopeptides with a positively charged amino acid chain, which allows them to interact with the negatively charged lipopolysaccharides (LPS) present in the outer membrane of Gram-negative bacteria. This interaction disrupts the integrity of the membrane, increasing its permeability and ultimately causing leakage of intracellular contents and bacterial death.

There are several types of polymyxins, with polymyxin B and polymyxin E (colistin) being the most clinically relevant. Polymyxin B is available in formulations for intravenous and topical use, while colistin is typically administered as its prodrug, colistimethate sodium (CMS), which is converted to colistin in vivo.

Due to their potential for nephrotoxicity (kidney damage) and neurotoxicity (nerve damage), polymyxins were largely abandoned in favor of less toxic antibiotics. However, the rise of antibiotic resistance, particularly among Gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii, has led to a resurgence in their use.

The mechanisms of resistance to polymyxins are still being elucidated, but include modifications to the lipid A portion of LPS, which reduces the affinity of polymyxins for the bacterial membrane. Resistance can be mediated by chromosomal mutations or by the acquisition of mobile genetic elements, such as the mcr genes, which encode phosphoethanolamine transferases that modify lipid A.

Because of their toxicity and the increasing development of resistance, polymyxins are reserved for use in cases where other antibiotics are ineffective or inappropriate. Therapeutic drug monitoring is often employed to optimize dosing and minimize the risk of adverse effects. Research is ongoing to develop new polymyxin analogs with improved safety profiles and to understand and combat polymyxin resistance.