What is the treatment protocol for infections caused by multidrug-resistant gram-negative bacteria using colistin?

Colistin Treatment Protocol for Multidrug-Resistant Gram-Negative Infections

Dosing Regimen

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

Adult Dosing Specifics

• Loading dose: 9 MU of CMS as initial dose 1
• Maintenance dose: 4.5 MU CMS twice daily (every 12 hours) 1
• This regimen is supported by pharmacodynamic studies in critically ill patients and international consensus 1

Pediatric Dosing

• Loading dose: 0.15 MU/kg 1
• Maintenance dose: 0.075 MU/kg every 12 hours (equivalent to 2.5-5 mg colistin base activity per kg per day) 1
• Important caveat: FDA/EMA pediatric dosing may be inadequate when pathogen MIC ≥1 mg/L or in patients with augmented renal clearance 1

Monotherapy vs. Combination Therapy

Combination therapy with colistin plus one or more additional agents is recommended when available agents show in vitro susceptibility, though evidence remains controversial. 1

When to Use Combination Therapy

• Severe infections: Particularly carbapenem-resistant Pseudomonas aeruginosa (CRPA) or carbapenem-resistant Acinetobacter baumannii (CRAB) 3
• High-risk infections: Two in vitro active antibiotics suggested for severe CRAB infections 3
• If no susceptible second agent exists, combine colistin with a second/third non-susceptible agent (e.g., carbapenem) with the lowest MIC 1

When Monotherapy is Acceptable

• Non-severe or low-risk infections caused by multidrug-resistant gram-negative bacteria 3
• Evidence shows no significant mortality difference between colistin monotherapy and colistin-meropenem combination (14-day mortality 25% vs 31%, p=1.0) 1
• Strong recommendation against polymyxin-meropenem combination specifically for CRAB infections 3

Optimal Combinations

• For CRAB bacteremia: Colistin-carbapenem combinations show highest success rates (SUCRA 83.6%) 2
• For CRAB pneumonia: Polymyxin-meropenem combination recommended when carbapenem MIC ≤32 mg/L 4

Route of Administration

For respiratory tract infections, add aerosolized colistin to intravenous therapy to improve clinical outcomes. 4, 5

• Combining intravenous and inhaled CMS improves clinical cure rates (57.4% vs 37.0%, p=0.003) 5
• Aerosolized polymyxin reduces mortality (RR=0.86), clinical treatment failure (RR=0.82), and pathogen eradication failure (RR=0.84) 4

Renal Function Monitoring

Monitor renal function closely throughout colistin therapy, as nephrotoxicity is the most significant adverse effect and independently predicts treatment failure and mortality. 1, 2

Nephrotoxicity Risk

• Occurs in 10.9-53.7% of patients 2, 5
• Risk factors include: pre-existing renal impairment, older age, concomitant nephrotoxic medications, shock, hypoalbuminemia 2, 6
• Colistin plasma concentration >2.42 mg/L predicts nephrotoxicity 7
• Total cumulative dose correlates with kidney damage, suggesting shorter treatment duration when possible 6

Dose Adjustment

• Adjust maintenance dose based on creatinine clearance using formula: 2.5 mg × (1.5 × CrCl + 30) 1
• In patients on renal replacement therapy (RRT), higher dosing regimens are recommended as colistin is easily removed by dialysis/hemofiltration 8
• Therapeutic drug monitoring is recommended when available to optimize dosing and minimize toxicity 2

Clinical Indications

Colistin is indicated for infections caused by sensitive strains of gram-negative bacilli, particularly Pseudomonas aeruginosa, when other options are limited. 9

FDA-Approved Organisms

• Enterobacter aerogenes 9
• Escherichia coli 9
• Klebsiella pneumoniae 9
• Pseudomonas aeruginosa 9
• Not indicated for Proteus or Neisseria 9

Preferred Alternatives When Available

• For CRAB susceptible to sulbactam: Use ampicillin-sulbactam over colistin due to better safety profile 2, 4
• For CRPA: Newer agents like ceftazidime-avibactam, ceftolozane-tazobactam, or imipenem-cilastatin-relebactam are preferred when active in vitro 1, 2
• 80% of imipenem-resistant P. aeruginosa bloodstream isolates remain susceptible to amikacin and novel agents 1

Treatment Duration and Follow-Up

• Mean treatment duration typically 10±4 days 5
• Shorter durations may decrease nephrotoxicity incidence 6
• Obtain follow-up cultures in case of treatment failure to detect resistance development 3
• Prioritize source control to optimize outcomes and shorten antibiotic treatment durations 3

Critical Pitfalls to Avoid

• Do not omit the loading dose in critically ill patients, as it is essential for achieving therapeutic concentrations rapidly 1
• Do not use colistin as first-line therapy when other effective options exist; reserve for multidrug-resistant infections to prevent resistance development 2
• Do not neglect renal function monitoring in elderly patients or those with chronic kidney disease, as they have higher risk of developing kidney injury 1
• Do not underdose in patients on RRT, as colistin is efficiently removed by dialysis/hemofiltration 8
• Do not continue therapy without reassessing if nephrotoxicity develops, as it predicts fewer cures and increased mortality 6