Colistimethate - Drug Monograph

Introduction

Colistimethate sodium is a polymyxin antibiotic that has regained clinical importance due to the increasing prevalence of multidrug-resistant Gram-negative bacterial infections. It is the inactive prodrug of colistin, which is converted in vivo to the active antibacterial agent colistin. This medication represents a last-line treatment option for serious infections caused by susceptible Gram-negative organisms when other alternatives are not suitable or available.

Mechanism of Action

Colistimethate undergoes hydrolysis in the body to form colistin, the active antibacterial compound. Colistin acts as a cationic detergent that binds to the anionic lipopolysaccharide molecules in the outer membrane of Gram-negative bacteria. This binding disrupts the integrity of the bacterial cell membrane, increasing permeability and causing leakage of intracellular contents. The bactericidal effect occurs through the detergent-like action on the cytoplasmic membrane, ultimately leading to cell death.

Indications

• Treatment of infections caused by susceptible Gram-negative bacteria, particularly:

- Pseudomonas aeruginosa - Acinetobacter baumannii - Klebsiella pneumoniae - Escherichia coli - Enterobacter species

• FDA-approved for the treatment of acute or chronic infections due to sensitive strains of these organisms in the:

- Urinary tract - Respiratory tract - Bloodstream - Meninges

• Particularly valuable for multidrug-resistant Gram-negative infections when other treatment options are limited

Dosage and Administration

• IV: 2.5-5 mg/kg/day (based on colistin base activity) divided into 2-4 doses
• Maximum daily dose: 300 mg colistin base activity
• Inhalation: 75-150 mg twice daily for patients with cystic fibrosis

• CrCl 30-80 mL/min: Reduce dose frequency to every 12-24 hours
• CrCl 10-30 mL/min: Administer every 24-36 hours
• CrCl <10 mL/min: Administer every 36-48 hours
• Hemodialysis: Administer post-dialysis with supplemental dose

• Pediatrics: 2.5-5 mg/kg/day divided into 2-4 doses
• Elderly: Dose adjustment based on renal function
• Obesity: Use ideal body weight for dosing calculations

• IV infusion over 30-60 minutes
• Reconstitute with sterile water for injection
• Further dilute in appropriate IV solution (typically 50-100 mL)

Pharmacokinetics

Contraindications

• Hypersensitivity to colistimethate sodium, colistin, or any component of the formulation
• Patients with myasthenia gravis (due to neuromuscular blocking potential)

Warnings and Precautions

• Nephrotoxicity: Can cause acute kidney injury; monitor renal function closely
• Neurotoxicity: Can cause neuromuscular blockade resulting in respiratory paralysis; monitor for muscle weakness

• Use with caution in patients with renal impairment
• Risk of superinfection including Clostridium difficile-associated diarrhea
• Potential for bronchospasm with inhalation therapy
• Cross-hypersensitivity with other polymyxins may occur
• Not recommended during pregnancy unless potential benefit justifies potential risk

Drug Interactions

• Aminoglycosides, vancomycin, loop diuretics: Increased risk of nephrotoxicity
• Neuromuscular blocking agents: Enhanced neuromuscular blockade
• Other nephrotoxic drugs: Additive renal toxicity
• Corticosteroids: May mask early symptoms of colistin toxicity

Adverse Effects

• Nephrotoxicity (elevated serum creatinine, reduced urine output)
• Neurotoxicity (dizziness, vertigo, paresthesia, visual disturbances)
• Respiratory: Bronchospasm (with inhalation)
• Gastrointestinal: nausea, vomiting
• Injection site reactions

• Acute kidney injury requiring dialysis
• Neuromuscular blockade leading to respiratory failure
• Anaphylaxis
• Apnea
• Seizures

Monitoring Parameters

• Renal function: Serum creatinine, BUN, urine output (baseline and every 2-3 days)
• Neurological status: Monitor for paresthesias, muscle weakness, respiratory distress
• Clinical response: Signs and symptoms of infection
• Microbiological cultures: Follow-up cultures when appropriate
• Drug levels: Consider therapeutic drug monitoring in serious infections or renal impairment
• Electrolytes: Particularly in patients with renal impairment
• Pulmonary function: For patients receiving inhalation therapy

Patient Education

• Report any tingling sensations, numbness, or muscle weakness immediately
• Maintain adequate hydration unless contraindicated
• Report changes in urinary output or color
• Complete the full course of therapy unless instructed otherwise
• Do not skip doses and take at evenly spaced intervals
• Report any difficulty breathing, especially with inhalation therapy
• Inform all healthcare providers about colistimethate use
• Store medication according to manufacturer recommendations
• Understand potential side effects and when to seek medical attention

References

1. Nation RL, Li J. Colistin in the 21st century. Curr Opin Infect Dis. 2009;22(6):535-543. 2. FDA Prescribing Information: Coly-Mycin M (colistimethate sodium). Revised 2019. 3. Elias LS, Konzen D, Krebs JM, Zavascki AP. The impact of polymyxin B dosage on in-hospital mortality of patients treated with this antibiotic. J Antimicrob Chemother. 2010;65(10):2231-2237. 4. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284-3294. 5. Tsuji BT, Pogue JM, Zavascki AP, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins. Pharmacotherapy. 2019;39(1):10-39. 6. American Society of Health-System Pharmacists. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2023. 7. European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. Version 13.0, 2023.