Polymyxins

Polymyxins (colistin, also called polymyxin E, and polymyxin B) are cationic cyclic lipopeptides that act on the outer membrane of Gram-negative bacteria. They were abandoned because of toxicity and revived as last-resort agents for carbapenem-resistant Enterobacterales, Acinetobacter baumannii and Pseudomonas aeruginosa. The therapeutic margin is narrow and dosing is complex.

Mechanism. The positively charged peptide displaces calcium and magnesium bridges on lipopolysaccharide, disrupts the outer and inner membranes and causes leakage and cell death. Killing is rapid and concentration-dependent (AUC to MIC). Resistance arises by lipid A modification (pmrAB, mgrB mutations, mcr plasmid genes), and is intrinsic in Proteus, Providencia, Morganella, Serratia and Burkholderia.

Pharmacokinetics. Not absorbed orally. Colistin is given as the inactive prodrug colistimethate sodium, which is converted slowly to colistin in plasma, so initial concentrations are low and loading doses are essential. Polymyxin B is given directly as the active drug. Colistin is cleared partly by the kidney as prodrug; polymyxin B is cleared non-renally and needs no renal adjustment. Poor penetration into lung, CSF and bone.

Dose expression. One million international units of colistimethate equals about 80 mg of colistimethate sodium and about 33 mg of colistin base activity. One milligram of polymyxin B equals about 10,000 international units.

• Colistin (colistimethate sodium): IV, nebulised, intrathecal; renal dose adjustment required.
• Polymyxin B: IV, intrathecal; no renal adjustment; poor urinary concentrations, so colistin is preferred for urinary infection.

Adult regimens (normal renal function; specialist-supervised).

• Colistimethate: loading dose 9 million international units (about 300 mg colistin base activity), then 4.5 million international units every 12 hours starting 12 to 24 hours later. Reduce the maintenance dose stepwise as creatinine clearance falls under about 80 mL/min, following product information or a formula-based dosing method; haemofiltration and dialysis need additional dosing.
• Polymyxin B: loading dose 2 to 2.5 mg/kg over 1 hour, then 1.25 to 1.5 mg/kg every 12 hours.
• Nebulised colistimethate: 1 to 2 million international units every 8 to 12 hours, as an adjunct for ventilator-associated pneumonia, after a bronchodilator to limit bronchospasm.
• Intrathecal or intraventricular therapy for resistant Gram-negative meningitis: specialist dosing.

Selection. Reserve for carbapenem-resistant organisms when no safer active drug exists, ideally combined with a second active agent. Monotherapy is avoided in pneumonia and bacteraemia because of poor tissue concentrations and resistance emergence. Newer agents (ceftazidime-avibactam, cefiderocol, meropenem-vaborbactam) are preferred when available and active.

Contraindications. Hypersensitivity; myasthenia gravis; concurrent neuromuscular blockers unless closely monitored.

Serious effects. Nephrotoxicity (acute kidney injury in 30 to 50 percent; dose- and duration-related, usually reversible); neurotoxicity (perioral and limb paraesthesia, ataxia, confusion, visual disturbance, neuromuscular blockade with respiratory arrest); bronchospasm with nebulised use; skin hyperpigmentation with polymyxin B; injection-site pain.

Interactions. Aminoglycosides, vancomycin, amphotericin, NSAIDs, contrast media and loop diuretics (nephrotoxicity); neuromuscular blockers and aminoglycosides (respiratory paralysis); drugs that cause nephrotoxicity should be avoided.

Monitoring. Creatinine and urine output daily; electrolytes; neurological symptoms; respiratory function; drug levels where available.

Special groups. Pregnancy: used only when essential. Breastfeeding: limited data. Children: weight-based specialist dosing. Renal impairment: adjust colistin; polymyxin B unchanged. Obesity: dose by ideal or adjusted body weight for colistin loading, with specialist advice. Region: availability varies; colistin use in livestock has spread plasmid-mediated mcr resistance, so stewardship in both sectors matters.