Colistin

Colistin (polymyxin E) is a last-line polypeptide antibiotic for carbapenem-resistant Gram-negative bacteria, given IV or by inhalation as the prodrug colistimethate sodium. It has a narrow safety margin: nephrotoxicity and neurotoxicity are frequent. Doses are labelled in three different units, which is a common cause of prescribing error.

Classification. Polymyxin.

Mechanism. Binds lipopolysaccharide in the outer membrane of Gram-negative bacteria, displacing calcium and magnesium and disrupting the membrane; bactericidal, concentration-dependent.

Spectrum. Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Enterobacter (including carbapenem-resistant strains). Not active against Proteus, Providencia, Serratia, Morganella, Burkholderia, Gram-positive bacteria or anaerobes. Resistance (mcr genes, chromosomal mutations) is emerging.

Pharmacokinetics. Colistimethate is inactive and converts slowly to active colistin, so plasma levels rise slowly (hence the loading dose). Half-life of colistin 9 to 18 hours in normal function. Poor lung, bone and CSF penetration after IV use. Colistimethate is cleared by the kidneys; colistin itself is cleared non-renally.

Reserve agent; combine with a second active drug (usually a carbapenem or other agent). Maximum daily dose about 360 mg colistin base activity (about 10.9 million IU).

Unit conversion. 1 million IU colistimethate sodium = about 80 mg colistimethate = about 33 mg colistin base activity. Check which unit the vial label uses before prescribing.

Adults, IV.

• Loading dose 9 million IU (300 mg colistin base activity), given as a single dose over 30 minutes (use ideal body weight; maximum 300 mg base activity).
• Maintenance, starting 12 hours later: 4.5 million IU every 12 hours (9 million IU daily) with creatinine clearance 80 mL/min or more.
• Reduce stepwise with falling clearance. Give about 3.5 to 4 million IU every 12 hours at 50 to 79 mL/min, 2.5 to 3 million IU every 12 hours at 30 to 49 mL/min, and 2 million IU every 12 hours at 10 to 29 mL/min. Lower in dialysis; use specialist advice.
• Duration 7 to 14 days, depending on site, response and tolerance.
• Hospital-acquired and ventilator-associated pneumonia: add nebulised colistimethate 1 to 2 million IU every 8 to 12 hours.
• Cystic fibrosis, chronic Pseudomonas suppression: nebulised colistimethate 1 to 2 million IU every 12 hours.

Children. 75 000 to 150 000 IU/kg/day (2.5 to 5 mg colistin base activity/kg/day) in 2 to 3 divided doses; loading dose 5 mg/kg base activity in critical illness under specialist direction.

Alternatives. Polymyxin B, ceftazidime avibactam, meropenem vaborbactam, cefiderocol, tigecycline, aminoglycosides, fosfomycin.

Contraindications. Hypersensitivity; myasthenia gravis (relative); concurrent neuromuscular blockers (relative).

Adverse effects. Nephrotoxicity (up to 30 to 50%, dose related, usually reversible), neurotoxicity (paraesthesia, dizziness, ataxia, visual disturbance), neuromuscular blockade and apnoea, bronchospasm and cough with inhalation, rash, pain on IM injection. Serious: acute kidney injury, respiratory arrest.

Interactions. Aminoglycosides, vancomycin, amphotericin B, NSAIDs, loop diuretics, contrast and other nephrotoxins; neuromuscular blockers and muscle relaxants; drugs affecting neuromuscular transmission.

Common prescribing errors. Confusing mg and million IU, no loading dose, no renal adjustment, monotherapy, concurrent nephrotoxins, and giving a nebulised dose without a bronchodilator.

Special groups. - Pregnancy: use only when no alternative. Breastfeeding: avoid if possible (limited data). - Older adults: higher risk of kidney injury and neurotoxicity. - Kidney impairment: maintenance 3.5 to 4 million IU every 12 hours at creatinine clearance 50 to 79 mL/min, 2.5 to 3 million IU every 12 hours at 30 to 49 mL/min, and 2 million IU every 12 hours at 10 to 29 mL/min; monitor creatinine daily.

Haemodialysis: specialist dosing, giving the dose after dialysis. - Liver impairment: no adjustment. - Region: access is limited and cost is high for newer agents, so colistin remains the main option for carbapenem-resistant infection in many East African hospitals; stewardship and renal monitoring are essential.

Preparation. IV: reconstitute with water for injection and dilute in 50 mL of 0.9% sodium chloride; infuse over 30 minutes. Nebulised: dissolve in 3 to 4 mL of 0.9% sodium chloride or sterile water and use a vibrating-mesh or jet nebuliser, after a bronchodilator; use within 24 hours.

Baseline and monitoring. - Baseline: creatinine and creatinine clearance, weight, electrolytes, neurological examination, medication review. - During treatment: creatinine daily (at least every 48 hours); neurological symptoms; respiratory function with nebulised use.

Stop rules. Stop for creatinine rising by 0.3 mg/dL (26 micromol/L) or more without another cause, neurotoxicity, neuromuscular weakness, apnoea or severe bronchospasm.

Referral and escalation. Infectious diseases consultation before and during use; nephrology for acute kidney injury; intensive care for respiratory depression.