polymyxins

Polymyxins are a group of cationic, amphipathic cyclic peptide antibiotics produced by Paenibacillus polymyxa. The clinically used members are polymyxin B and polymyxin E (colistin). Colistin is administered as its inactive prodrug colistin methanesulfonate (CMS), which is converted to active colistin in vivo. Polymyxins are primarily employed as last-resort agents for severe infections caused by multidrug-resistant Gram-negative bacteria.

Mechanism of action: Polymyxins bind to lipid A and other phospholipids in the outer membrane of Gram-negative bacteria, displacing divalent cations and disrupting membrane integrity. This leads to increased permeability of both the outer and inner membranes, leakage of cellular contents, and rapid bacterial death. The activity is largely bactericidal and concentration-dependent, with a post-antibiotic effect observed for some organisms.

Spectrum and resistance: Polymyxins have activity mainly against Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, and many Enterobacterales. They are generally inactive against most Gram-positive bacteria and anaerobes. Resistance can arise via modification of lipid A (for example, by chromosomal pmrAB mutations) or via plasmid-mediated mcr genes, which reduce binding of the drug to the bacterial outer membrane. Heteroresistance and emerging resistance to polymyxins have been reported in several species.

Pharmacology and administration: Polymyxin B is used in its active form, while colistin is given as CMS and activated in patients. Dosing is complex and guided by weight, organ function, and infection type; loading doses are often used to achieve therapeutic levels promptly. Treatments are associated with substantial toxicity risks and are typically reserved for severe MDR Gram-negative infections. Routes include intravenous for systemic infections and inhaled formulations for respiratory infections in certain contexts.

Safety and clinical use: Nephrotoxicity and neurotoxicity are the major adverse effects, which can be dose-related and exacerbated by concomitant nephrotoxic agents. Careful monitoring of renal function and neurologic status is essential. Polymyxins remain critical tools for treating difficult-to-treat Gram-negative infections when other options are unavailable.