Colistin is an antibiotic used against bacterial infections, particularly those resistant to multiple other drugs. Understanding how it works and why bacteria develop resistance is crucial for addressing antimicrobial resistance.
What Colistin Is and Why It’s Used
Colistin, also known as polymyxin E, belongs to the polymyxin class of antibiotics. It was identified in 1947 and approved in the United States in 1970 for various infections. Its widespread use declined in the 1970s and early 1980s due to concerns about potential side effects.
However, the emergence of multi-drug resistant (MDR) Gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and carbapenem-resistant Klebsiella pneumoniae, led to colistin’s re-emergence as a “last-resort” treatment in the mid-1990s. These bacteria often resist nearly all other available antibiotics, making colistin an important option when other therapies fail. The World Health Organization (WHO) now classifies colistin as an antibiotic of “very high importance for Human Medicine.”
How Colistin Works Against Bacteria
Colistin works by disrupting the outer membrane of Gram-negative bacteria. As a polycationic polypeptide, colistin carries a net positive charge, allowing it to strongly interact with the negatively charged components of the bacterial outer membrane, specifically the phosphate groups of lipid A, which is part of the lipopolysaccharide (LPS) molecule.
The outer membrane of Gram-negative bacteria is stabilized by divalent cations like magnesium (Mg2+) and calcium (Ca2+), which bridge adjacent LPS molecules. Colistin displaces these essential divalent cations from the LPS, weakening the outer membrane’s structural integrity. Following this displacement, the hydrophobic acyl chain of colistin inserts itself into the now disorganized outer membrane.
This insertion increases its permeability. The disruption leads to leakage of intracellular components, such as ions, ATP, and nucleic acids, from the bacterial cell. This leakage results in cell death. There is also evidence suggesting that polymyxins, including colistin, may enter the cell and precipitate cytoplasmic components, further contributing to their bactericidal action.
Why Bacteria Become Resistant to Colistin
Bacteria develop resistance to colistin through modifications to the lipopolysaccharide (LPS) structure in their outer membrane, colistin’s main target. These modifications involve adding positively charged groups to the lipid A component of LPS, such as phosphoethanolamine (PEtn) or 4-amino-4-deoxy-L-arabinose (L-Ara4N). This reduces the overall negative charge of the bacterial surface.
This reduction in negative charge diminishes colistin’s electrostatic attraction to the bacterial membrane, preventing effective binding and disruption. Such modifications can be regulated by two-component systems like PmrA/PmrB and PhoP/PhoQ, which are involved in adapting to environmental stresses. A significant development in colistin resistance was the discovery of mobile colistin resistance (mcr) genes, particularly mcr-1, in late 2015.
The mcr-1 gene encodes a phosphoethanolamine transferase enzyme that directly catalyzes the addition of phosphoethanolamine to lipid A. This plasmid-mediated gene can be easily transferred between different bacterial species, facilitating the rapid spread of colistin resistance globally. The emergence of mcr-1 has posed a serious threat to the continued effectiveness of colistin as a last-resort antibiotic.
Important Considerations for Colistin Use
Despite its efficacy against highly resistant Gram-negative bacteria, colistin’s use is limited by its side effects. The primary concern is nephrotoxicity, or kidney damage. Colistin is excreted by the kidneys, and elevated drug levels can further impair renal function. The incidence of kidney injury can be higher in patients with pre-existing renal dysfunction or those with factors like shock or hypoalbuminemia.
Another side effect is neurotoxicity, which involves nerve tissue damage. While less common and severe than nephrotoxicity, neurotoxicity can manifest as peripheral or orofacial paresthesias, visual disturbances, dizziness, muscle weakness, or confusion. These neurological symptoms typically resolve upon discontinuation of the drug.
Due to these toxicities, colistin administration requires careful consideration. Dosage adjustments are often necessary, especially in patients with impaired kidney function, to balance therapeutic efficacy with minimizing adverse effects. Monitoring for signs of nephrotoxicity and neurotoxicity is a standard practice during colistin therapy.