What is colistin?

Colistin: An Overview of a Last-Resort Antibiotic for Multidrug-Resistant Gram-Negative Infections

Colistin (polymyxin E) is a polypeptide antibiotic primarily used as a last-resort treatment for multidrug-resistant (MDR) gram-negative bacterial infections, particularly those caused by Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales. 1

Mechanism and Formulation

• Colistin is available as colistimethate sodium (CMS), a prodrug that is converted to the active form colistin in the body 2
• The drug has a molecular weight of approximately 1750 Da with the empirical formula C58H105N16Na5O28S5 2
• Colistin acts by disrupting the bacterial outer membrane of gram-negative bacteria, leading to increased permeability and cell death 3

Clinical Indications

• Primarily used for treating infections caused by carbapenem-resistant, non-fermenting gram-negative bacteria, including P. aeruginosa and A. baumannii 1
• Indicated for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) infections with limited treatment options 1
• Used for carbapenem-resistant Acinetobacter baumannii (CRAB) infections when other options are unavailable 1
• Common infection sites include pneumonia (especially ventilator-associated), bloodstream infections, urinary tract infections, and intra-abdominal infections 4, 5

Dosing Recommendations

• A loading dose of 9 MU (5 mg/kg) of colistin followed by a maintenance dose of 4.5 MU twice daily is strongly recommended in critically ill patients 1
• Dose adjustment is required in patients with renal impairment 1, 2
• For pediatric patients, the FDA and EMA recommend a loading dose of 0.15 MU/kg followed by a maintenance dose of 0.075 MU/kg every 12 hours, though this may be inadequate for pathogens with MIC ≥1 mg/L 1
• Optimal dosing is essential as higher doses correlate with better microbiological success but also with increased nephrotoxicity 6

Efficacy

• Clinical cure rates with colistin range from 42.7% to 71.7% across various studies 4, 7
• Microbiological eradication rates vary widely, from 13.3% to higher percentages depending on the infection site and pathogen 5, 7
• Poorest outcomes are typically observed in pneumonia cases, with success rates as low as 25% 5
• Higher colistin doses are independently associated with better microbiological success (adjusted odds ratio per 1 mg/kg/day = 1.74) 6

Toxicity and Adverse Effects

• Nephrotoxicity is the most significant adverse effect, occurring in 10.9-53.7% of patients 2, 4, 7
• Risk factors for nephrotoxicity include pre-existing renal impairment, older age, and concomitant nephrotoxic medications 2, 1
• Neurotoxicity can manifest as muscle weakness, paresthesia, and rarely respiratory paralysis due to neuromuscular blockade 2
• Drug interactions with aminoglycosides, polymyxins, and neuromuscular blocking agents can potentiate neurotoxicity 2

Monotherapy vs. Combination Therapy

• The use of colistin-based combination therapy remains controversial with weak recommendations and very low-quality evidence 1
• Some studies suggest combination therapy may be beneficial for certain infections, particularly with carbapenem-resistant Acinetobacter baumannii 1
• Colistin-carbapenem combinations show the highest success rates in network meta-analyses for carbapenem-resistant A. baumannii bacteremia (SUCRA 83.6%) 1
• Colistin-rifampin combination has not shown significant advantages over colistin monotherapy in randomized controlled trials 1

Clinical Considerations and Pitfalls

• Renal function should be closely monitored during colistin therapy due to the high risk of nephrotoxicity 1, 2
• Colistin should be reserved for multidrug-resistant infections where other options are limited to prevent resistance development 8
• For carbapenem-resistant A. baumannii susceptible to sulbactam, ampicillin-sulbactam is preferred over colistin due to its better safety profile 8, 1
• Inhaled colistin may be considered as adjunctive therapy for respiratory infections, with some studies showing improved clinical cure rates (57.4% vs. 37.0%) 7
• Therapeutic drug monitoring is recommended when available to optimize dosing and minimize toxicity 1

Special Populations

• In elderly patients, dose selection should be cautious, starting at the lower end of the dosing range due to the higher likelihood of decreased renal function 2
• Colistin crosses the placental barrier and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 2
• Colistin is excreted in human breast milk and caution should be exercised when administered to nursing women 2