What are the advantages of colistin (colistimethate) nebulisation in patients with respiratory infections caused by multi-drug resistant gram-negative bacteria, particularly those with cystic fibrosis or chronic obstructive pulmonary disease (COPD)?

Advantages of Colistin Nebulisation

Nebulized colistin delivers high antibiotic concentrations directly to the site of infection in the lungs while minimizing systemic toxicity, making it particularly valuable as adjunctive therapy for multidrug-resistant gram-negative respiratory infections and as maintenance therapy for chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients. 1

Primary Clinical Advantages

Superior Drug Delivery and Concentration

• Nebulized colistin achieves lung tissue concentrations exceeding five times the minimum inhibitory concentration (MIC) of gram-negative bacteria in regions with bronchopneumonia, far surpassing levels achievable through intravenous administration alone 2
• Direct deposition at the infection site improves efficacy while reducing systemic exposure, as colistin's high molecular mass and hydrophilic properties impair crossing of the alveolo-capillary membrane 2
• Intravenous colistimethate sodium (CMS) undergoes rapid renal clearance with only 20-25% conversion to active colistin, often resulting in subtherapeutic lung concentrations that risk treatment failure 2

Enhanced Safety Profile

• Nebulized colistin eliminates or minimizes the risk of nephrotoxicity and neurotoxicity that commonly occurs with systemic administration 3, 4
• A real-world study of 30 patients treated with nebulized colistin for pneumonia reported no serious adverse events, with no nephrotoxicity or neurotoxicity observed 3
• Long-term nebulized colistin therapy in 18 patients with chronic bronchial sepsis showed no side effects and no development of colistin-resistant isolates 5

Evidence-Based Clinical Benefits

Improved Mortality and Treatment Outcomes

• When added to intravenous polymyxin therapy for carbapenem-resistant gram-negative respiratory infections, nebulized colistin reduces mortality by approximately 50 deaths per 1000 patients treated (RR 0.86,95% CI 0.72-1.03) 1
• Clinical treatment failure decreases by 77 per 1000 patients (RR 0.82,95% CI 0.70-0.96) when nebulized colistin is added to systemic therapy 1
• Pathogen eradication failure is reduced by 62 per 1000 patients (RR 0.84,95% CI 0.69-1.03) with combination therapy 1

Pulmonary Function Preservation

• In patients with chronic bronchial sepsis, nebulized colistin significantly slowed the decline in FEV1 (44 mL/year vs 104 mL/year without colistin, P=0.035) 5
• Forced vital capacity decline was also significantly slower (48 mL/year vs 110 mL/year, P=0.033) 5
• Patient-reported quality of life improved significantly following initiation of nebulized colistin therapy (P=0.001) 5

Reduced Mechanical Ventilation Duration

• One study demonstrated that nebulized plus intravenous colistin therapy was associated with significantly fewer days of mechanical ventilation compared to intravenous therapy alone (8 vs 12 days, P=0.001) 1
• Combination therapy was an independent predictor of clinical cure in ventilator-associated pneumonia 1

Specific Clinical Indications

Carbapenem-Resistant Gram-Negative Pneumonia

• Nebulized colistin is recommended as adjunctive therapy to intravenous polymyxin for respiratory tract infections caused by carbapenem-resistant gram-negative bacilli, particularly when clinical efficacy with systemic therapy alone is suboptimal 1
• This approach is particularly valuable for infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Enterobacterales (CRE) 1

Cystic Fibrosis Maintenance Therapy

• For CF patients with chronic Pseudomonas aeruginosa colonization, nebulized colistin 1-2 million units twice daily administered continuously throughout the year is recommended as an alternative to tobramycin 6
• Nebulized antibiotics achieve higher concentrations than systemic administration while minimizing nephrotoxicity and ototoxicity 6

Ventilator-Associated Pneumonia

• Nebulized colistin should be used in combination with intravenous antimicrobial therapy for VAP caused by multidrug-resistant gram-negative bacteria, particularly in patients who are non-responsive to systemic antibiotics alone, have recurrent VAP, or have isolates with MICs close to susceptibility breakpoints 1
• A retrospective case-control study demonstrated higher clinical cure rates (61.5%) with nebulized colistin in microbiologically documented VAP caused by colistin-only susceptible gram-negative bacteria 1

Ventilator-Associated Tracheobronchitis

• Nebulized antibiotics show encouraging efficacy for microbiological eradication and clinical cure in patients with multidrug-resistant A. baumannii tracheobronchitis 1
• For tracheobronchitis specifically, nebulized antibiotics are recommended, though whether concurrent intravenous therapy is necessary requires further study 1

Critical Implementation Considerations

Optimal Dosing and Administration

• The recommended dose is 2 million international units (MIU) every 8-12 hours, though higher doses can be used in non-resolving cases 1
• The most common dosing schedule in real-world practice is 1 MIU every 8 hours 3
• For CF patients, the standard dose is 2 million units twice daily dissolved in 3 mL water and 3 mL physiological saline to create an isotonic solution 1

Nebulizer Selection

• Nebulized antibiotics should be delivered using ultrasonic or vibrating plate nebulizers rather than jet nebulizers 1
• The nebulizer must produce particles with a mass median aerodynamic diameter of 2-5 μm for optimal bronchiolar deposition 6, 7
• Particles larger than 5 μm do not reach the lower respiratory tract, while particles smaller than 1 μm are exhaled 1

Prevention of Bronchospasm

• Patients must receive a bronchodilator before nebulized colistin administration to prevent bronchospasm, which is the major side effect 7
• Use isotonic solutions exclusively, as hypotonic or hypertonic solutions can cause bronchoconstriction and inflammation 1
• Monitor lung function before and immediately after nebulization 1
• Colistimethate sodium (CMS) is strongly preferred over colistin sulphate for nebulization, as colistin sulphate causes significantly greater decreases in lung function and severe throat irritation 8

Airway Clearance

• Perform airway clearance techniques before nebulization to improve drug delivery, as sputum can impair uniform deposition and decrease therapeutic effects 1, 7
• In CF patients, mucus plugs can bind aminoglycosides and reduce efficacy 7

Important Caveats and Limitations

Not for Monotherapy in Pneumonia

• Nebulized colistin should always be used in combination with intravenous antimicrobial therapy for pneumonia and should never be used as monotherapy 1
• In general, aerosolized polymyxin is not used alone for respiratory tract infections 1

Avoid in Simple Colonization

• Nebulized antibiotics should not be used in patients with A. baumannii colonization without active infection 1

Monitoring Requirements

• When patients receive both intravenous and high-dose nebulized colistin, close monitoring for relevant adverse events (especially bronchospasm) is essential 1
• Regular surveillance cultures should be performed to assess bacterial load and resistance patterns 6

Resistance Considerations

• Emergence of drug resistance after aerosol therapy has been documented in several studies, though susceptibility is often regained after drug-free periods 1
• This observation supports the concept of intermittent dosing for chronic maintenance therapy 1

Quality of Evidence

• While the clinical benefits are substantial, the certainty of evidence supporting nebulized colistin as adjunctive therapy ranges from low to very low, indicating these effects might be altered by future studies 1
• The recommendation for adjunctive nebulized polymyxin is classified as a weak recommendation with low-quality evidence 1