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Colistin
A polymyxin-class lipopeptide antibiotic used as a last-resort treatment for multidrug-resistant Gram-negative infections, particularly carbapenem-resistant Enterobacterales.
Overview
Colistin, also known as polymyxin E, is a cyclic lipopeptide antibiotic discovered in 1949 from Bacillus polymyxa subsp. colistinus. Like polymyxin B, colistin fell out of favor in the 1970s due to nephrotoxicity and neurotoxicity concerns. However, the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) Gram-negative bacteria, particularly carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii, and Pseudomonas aeruginosa, has forced clinicians to revive this "last-resort" antibiotic.
Colistin is typically administered as the inactive prodrug colistimethate sodium (CMS), which is hydrolyzed in vivo to the active colistin. This prodrug formulation was developed to reduce toxicity, but it introduces pharmacokinetic complexity. The conversion of CMS to active colistin is slow and variable, leading to challenges in achieving adequate plasma and tissue concentrations. This is a key pharmacokinetic disadvantage compared to polymyxin B, which is administered directly in its active form.
The antibacterial mechanism mirrors that of polymyxin B: colistin binds to the lipid A component of lipopolysaccharide in Gram-negative bacterial outer membranes, disrupting membrane integrity and causing cell death. It also neutralizes endotoxin. Colistin is active against most Gram-negative bacilli but is intrinsically inactive against Proteus, Providencia, Serratia, Morganella, and Gram-positive organisms.
A significant global concern emerged in 2015 with the discovery of the mcr-1 gene in China, the first plasmid-mediated colistin resistance mechanism. Unlike chromosomal resistance mechanisms, plasmid-mediated resistance can spread rapidly between bacterial species. The mcr gene family has since been detected worldwide, raising concerns about the loss of colistin as an effective last-resort therapy. This discovery has accelerated efforts to develop new antibiotics against resistant Gram-negative bacteria.