Colistimethate (CMS)

• Approved Indications:
• Treatment of infections caused by multidrug-resistant Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.
• Particularly used in infections of the respiratory tract, urinary tract, bloodstream, skin and soft tissue, and intra-abdominal infections when susceptible organisms are involved.
• Often reserved for severe, life-threatening infections where alternative antibiotics are ineffective or contraindicated.
• Off-label Uses:
• Inhalation therapy for cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infections to reduce bacterial load and exacerbations.
• Use in ventilator-associated pneumonia due to multidrug-resistant pathogens.

• Adults:
• Intravenous (IV): Dose varies based on infection severity and renal function; usual initial dose ranges from 2.5 to 5 mg/kg colistin base activity daily, divided into 2-3 doses.
• Inhalation: Nebulized dose typically 75 mg (colistimethate sodium) every 12 hours for cystic fibrosis lung infections.
• Pediatrics:
• Dosing individualized; approximately 2.5 to 5 mg/kg/day colistin base activity IV divided doses; inhalation dosing per specialist recommendations.
• Elderly:
• Dose adjustment may be necessary due to renal impairment; monitor renal function closely.
• Renal Impairment:
• Dosage adjustments mandatory; dosing interval may be extended or dose reduced depending on creatinine clearance.
• Administration:
• IV administration diluted in compatible fluids; inhalation via nebulizer with sterile preparations.
• Duration:
• Typically 7 to 14 days, depending on clinical response and infection site.

Colistimethate sodium is an inactive prodrug that is converted in vivo to colistin, a polymyxin antibiotic. Colistin acts by binding to the lipopolysaccharide (LPS) and phospholipids in the outer membrane of Gram-negative bacteria, disrupting membrane integrity. This leads to increased permeability, leakage of intracellular contents, and bacterial cell death. Its bactericidal effect targets multidrug-resistant Gram-negative pathogens by compromising their cell membrane structure.

• Absorption: Poor oral absorption; administered parenterally or by inhalation.
• Distribution: Widely distributed in extracellular fluids; limited penetration into cerebrospinal fluid.
• Metabolism: Colistimethate sodium is a prodrug hydrolyzed to active colistin after administration.
• Elimination: Primarily excreted unchanged by the kidneys; clearance depends on renal function.
• Half-life: Colistimethate sodium ~2–3 hours; colistin ~14 hours in patients with normal renal function.
• Onset: Antibacterial effects begin shortly after conversion to active colistin.

• Pregnancy: Category C; animal studies have shown adverse effects, but no adequate human studies exist. Use only if benefits outweigh risks.
• Lactation: Unknown if excreted in human milk; caution advised. Avoid use unless clearly necessary.

• Primary Class: Antibiotic
• Subclass: Polymyxin Antibiotic

• Known hypersensitivity to colistimethate sodium, colistin, or polymyxins.
• Pre-existing neuromuscular disorders that may be exacerbated (e.g., myasthenia gravis).

• Nephrotoxicity and neurotoxicity risks; monitor renal function and neurological status regularly.
• Potential for respiratory paralysis with concurrent use of neuromuscular blocking agents.
• Use cautiously in patients with renal impairment; dose adjustment necessary.
• Avoid concomitant nephrotoxic drugs if possible.
• Monitor for signs of hypersensitivity reactions.
• Not recommended for intrathecal or intraventricular administration unless specialized use.

Common:

• Nephrotoxicity: elevated serum creatinine, acute kidney injury.
• Neurotoxicity: paresthesia, dizziness, confusion, neuromuscular blockade.
• Injection site reactions (pain, inflammation).
• Respiratory distress with inhalation (cough, bronchospasm).

Rare/Serious:

• Anaphylaxis or severe hypersensitivity reactions.
• Respiratory paralysis (rare).
• Superinfection with resistant organisms or fungi.

• Increased nephrotoxicity risk with other nephrotoxic agents (e.g., aminoglycosides, vancomycin, amphotericin B).
• Additive neurotoxic effects with neuromuscular blockers (e.g., succinylcholine).
• Use caution with loop diuretics and other drugs affecting renal function.
• No significant CYP450 interactions known.

• Guidelines recommend colistimethate sodium as a last-resort agent for multidrug-resistant Gram-negative infections.
• New dosing protocols emphasize renal function-based adjustments to minimize toxicity.
• Inhaled colistimethate sodium approved and recommended for cystic fibrosis lung infections.
• Monitoring protocols for nephrotoxicity and neurotoxicity have been emphasized in recent FDA safety communications.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from light and moisture.
• Use reconstituted solution immediately or store refrigerated (2°C to 8°C) and discard after 24 hours.
• Keep out of reach of children.