Colistin is an antibiotic belonging to the polymyxin class. This drug was first introduced for clinical use in the 1950s for treating infections caused by Gram-negative bacteria. However, its systemic use was largely discontinued within a decade due to reports of significant organ toxicity. New, less toxic antibiotics became available, causing colistin to be mostly relegated to topical applications.
The rise of multi-drug resistant bacteria, particularly highly resistant Gram-negative organisms, has necessitated the re-evaluation and re-introduction of colistin in modern medicine. This agent has become a therapeutic option against pathogens that have developed resistance to nearly all other available drugs. Colistin is now recognized globally as an antibiotic of last resort, a position that underscores its efficacy and the risks associated with its use.
How Colistin Kills Bacteria
Colistin exerts its antibacterial effect by targeting the outer structure of Gram-negative bacteria. The drug acts as a cationic agent, carrying a positive electrical charge that is attracted to the negatively charged lipopolysaccharide (LPS) molecules forming the outer membrane.
The binding occurs at the lipid A component of the LPS, where colistin displaces the divalent cations, such as calcium and magnesium, that normally stabilize the membrane structure. This displacement destabilizes the outer membrane, increasing its permeability. Once the outer barrier is compromised, colistin accesses the inner membrane, leading to the leakage of cellular contents and resulting in rapid bacterial death.
Use Against Multi-Drug Resistant Infections
The resurgence of colistin is directly linked to the global crisis of antimicrobial resistance. Colistin is primarily reserved for treating infections caused by highly resistant Gram-negative bacteria that are no longer susceptible to carbapenems. These organisms include carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and various carbapenem-resistant Enterobacteriaceae (CRE).
For patients facing these infections, colistin functions as a salvage therapy when few other effective options remain. It is often administered intravenously to treat systemic infections like pneumonia or bloodstream infections. Colistin can also be given via inhalation for respiratory infections, or directly into the central nervous system through intraventricular or intrathecal injection for cases of meningitis or ventriculitis unresponsive to intravenous therapy.
Managing Significant Organ Toxicity
The high risk of toxicity was the reason colistin was initially abandoned, a concern that persists even with modern dosing strategies. The two primary dose-limiting toxicities are nephrotoxicity (kidney damage) and neurotoxicity (nervous system effects). Nephrotoxicity, the more common adverse effect, results from colistin’s direct damage to the renal tubular epithelial cells.
The incidence of colistin-associated kidney damage can range from 20% or lower in current clinical practice, and it is often reversible upon drug cessation. Neurotoxicity is less frequent, typically manifesting as mild symptoms like dizziness, facial tingling, or paresthesia. In rare instances, however, it can cause more severe effects such as neuromuscular blockade.
Clinicians must balance the risk of organ damage against the necessity of treating an otherwise untreatable infection. This involves careful dosing adjustments based on the patient’s kidney function and body weight. Close monitoring of renal function, through regular measurement of serum creatinine levels, is performed throughout the treatment course to detect and manage early signs of toxicity.
The Threat of Mobile Resistance
Despite its status as a last-resort drug, resistance to colistin is an emerging global health threat. For many years, resistance was thought to arise only through chromosomal mutations, which are relatively slow to spread. However, the discovery of the mobile colistin resistance gene, mcr-1, in 2015 changed this perspective.
The mcr-1 gene is carried on a plasmid, a small, circular piece of DNA easily transferred between different species of bacteria. This mechanism, known as horizontal gene transfer, allows resistance to spread rapidly among diverse bacterial populations, including E. coli and Klebsiella pneumoniae. The gene works by producing an enzyme that modifies the lipid A component of the LPS target, preventing colistin from binding and rendering the drug ineffective.