What is the recommended dosage and treatment protocol for Colistin in treating multidrug-resistant gram-negative bacterial infections?

Colistin Dosing and Treatment Protocol for Multidrug-Resistant Gram-Negative Infections

For critically ill adults with multidrug-resistant gram-negative infections, administer a loading dose of 9 MU (5 mg/kg) of colistin methanesulfonate followed by a maintenance dose of 4.5 MU twice daily, calculated as 2.5 mg × [(1.5 × CrCl) + 30] IV every 12 hours. 1, 2

Standard Adult Dosing Protocol

Loading and Maintenance Doses

• Loading dose: 9 MU (equivalent to 5 mg/kg colistin base activity) administered intravenously 1, 2
• Maintenance dose: 4.5 MU (2.5 mg CBA × [(1.5 × CrCl) + 30]) IV every 12 hours 1, 2
• This regimen is supported by pharmacodynamic studies in critically ill patients and international consensus guidelines 1
• One MU of colistin methanesulfonate equals approximately 33 mg colistin base activity 1

FDA-Approved Dosing Range

• The FDA label specifies 2.5 to 5 mg/kg per day of colistin base divided into 2 to 4 doses for patients with normal renal function 3
• However, the higher loading dose regimen (9 MU loading, then 4.5 MU twice daily) is strongly recommended by recent guidelines over the FDA's older dosing recommendations 1
• Dosing should be based on ideal body weight in obese individuals 3

Renal Dose Adjustments

Patients with Renal Impairment

Renal function must be closely monitored throughout therapy, as acute kidney injury is a major risk factor for clinical failure and mortality. 1, 4

The FDA provides specific dose reductions based on creatinine clearance 3:

• CrCl ≥80 mL/min: 2.5 to 5 mg/kg divided into 2-4 doses per day
• CrCl 50-79 mL/min: 2.5 to 3.8 mg/kg divided into 2 doses per day
• CrCl 30-49 mL/min: 2.5 mg/kg once daily or divided into 2 doses per day
• CrCl 10-29 mL/min: 1.5 mg/kg every 36 hours

Nephrotoxicity Risk Factors

• Nephrotoxicity occurred in 29.4% of patients in UTI-specific studies, with higher risk in patients with pre-existing chronic renal insufficiency, diabetes mellitus, and concurrent aminoglycoside use 5
• Higher colistin doses (median 3.8 vs 1.6 mg/kg/day) were associated with development of acute kidney injury 6
• Despite these risks, most studies report nephrotoxicity rates of only 8-11% when used appropriately 7, 8

Pediatric Dosing

• Loading dose: 0.15 MU/kg of colistin 1
• Maintenance dose: 0.075 MU/kg every 12 hours (equivalent to 2.5-5 mg CBA per kg per day) 1, 2
• Important caveat: These FDA/EMA-recommended pediatric doses may be inadequate when the pathogen MIC is ≥1 mg/L or in patients with augmented renal clearance 1

Combination vs. Monotherapy

The evidence for combination therapy is controversial and of very low quality, but combination with one or more additional agents is suggested when available. 1

Combination Therapy Recommendations

• Colistin should be combined with one or more additional agents to which the pathogen displays in vitro susceptibility 1
• If no susceptible second agent is available, combine colistin with a second and/or third non-susceptible agent (e.g., a carbapenem) with the lowest MIC 1
• Colistin-carbapenem combinations have shown high success rates (SUCRA 83.6% for clinical cure) in network meta-analyses 5
• One randomized trial showed no superiority of colistin-meropenem combination over monotherapy (14-day mortality 25% vs 31%, p=1.0), though this conflicts with other studies showing benefit 1

Evidence Quality Note

• The recommendation for combination therapy carries a weak recommendation with very low quality of evidence (2D) 1
• In clinical practice, 87% of patients received combination therapy with other antibiotics such as beta-lactams, aminoglycosides, or ciprofloxacin 7

Treatment Duration by Infection Type

Urinary Tract Infections

• Complicated UTI: 5-10 days 1
• Standard colistin dosing applies: 5 mg CBA/kg IV loading dose, then 2.5 mg CBA (1.5 CrCl + 30) IV every 12 hours 1, 2

Bloodstream Infections

• Duration: 10-14 days 1
• Same dosing regimen as above 1

Hospital-Acquired or Ventilator-Associated Pneumonia

• Duration: 10-14 days 1
• Consider adjunctive nebulized colistin (2 million IU every 8-12 hours) in combination with IV therapy for non-responsive cases 4
• Higher nebulized doses of 5 million IU every 8 hours may be considered for non-resolving pneumonia 4

Intra-Abdominal Infections

• Duration: 5-10 days 1

Administration Routes

Intravenous Administration

Two methods are FDA-approved 3:

1. Direct intermittent administration: Inject one-half of total daily dose over 3-5 minutes every 12 hours 3

2. Continuous infusion:

   • Inject one-half of total daily dose over 3-5 minutes 3
   • Add remaining half to compatible IV solution (0.9% NaCl, 5% dextrose in water, lactated Ringer's, etc.) 3
   • Infuse over 22-23 hours, starting 1-2 hours after initial dose 3

Intramuscular Administration

• Administer by deep IM injection into large muscle mass (gluteal muscles or lateral thigh) 3
• Reconstituted solution stable for 7 days when refrigerated at 2-8°C or at room temperature 20-25°C 3

Nebulized/Inhaled Colistin

• Nebulized colistin should always be used in combination with IV antimicrobial therapy for pneumonia 4
• Standard dose: 2 million IU every 8-12 hours via ultrasonic or vibrating plate nebulizers 4
• Higher doses (5 million IU every 8 hours) for non-resolving cases 4
• Particularly beneficial for carbapenem-resistant Acinetobacter baumannii and multidrug-resistant Pseudomonas aeruginosa 4

Clinical Efficacy Data

Dose-Response Relationship

• Higher colistin doses independently predict microbiological success: median dose 2.9 vs 1.5 mg/kg/day in successful vs unsuccessful cases (adjusted OR 1.74 per 1 mg/kg/day increase, p=0.015) 6
• Higher doses also correlated with 7-day survival (2.7 vs 1.5 mg/kg/day, p=0.007) but not 28-day survival 6
• Overall favorable response rates of 67-72% have been reported 7, 8

Microbiological Clearance

• Causative organisms were cleared in 92% of patients from whom post-treatment specimens were obtained 9
• Clinical response (cure or improvement) observed in 66.7% of infection episodes 8

Common Pitfalls to Avoid

1. Underdosing: Many clinicians still use outdated lower doses; the loading dose of 9 MU followed by 4.5 MU twice daily is critical for optimal outcomes 1, 6

2. Failure to adjust for renal function: 43% of cases in one study did not follow dose adjustment recommendations, mainly in patients with renal impairment 10

3. Inadequate monitoring: Renal function must be monitored closely throughout therapy, not just at baseline 1, 4

4. Using monotherapy when combination is feasible: While controversial, combination therapy should be attempted when susceptible agents are available 1

5. Inadequate dosing in pediatrics with high MIC pathogens: Standard pediatric doses may be insufficient when pathogen MIC ≥1 mg/L 1

Alternative Agents for Carbapenem-Resistant Organisms

When available and susceptible, consider these alternatives 1:

• Ceftazidime-avibactam 2.5 g IV every 8 hours
• Ceftolozane-tazobactam 1.5-3 g IV every 8 hours
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours
• Meropenem-vaborbactam 4 g IV every 8 hours