Why is colistin not given as monotherapy?

Why Colistin Should Not Be Given as Monotherapy

Colistin monotherapy rapidly selects for resistant bacterial subpopulations, making combination therapy the standard of care for severe multidrug-resistant gram-negative infections. 1

The Core Problem: Rapid Resistance Development

The fundamental issue with colistin monotherapy is its propensity to select resistant subpopulations during treatment:

• Colistin monotherapy rapidly selects resistant subpopulations, which is the primary reason combination therapy is advised for clinical use 1
• This resistance development occurs even during active treatment, compromising therapeutic efficacy and limiting future treatment options 2

Current Guideline-Based Recommendations

For Severe Infections Requiring Colistin

The most recent high-quality guidelines (2022-2025) provide pathogen-specific recommendations:

• For carbapenem-resistant Pseudomonas aeruginosa (CRPA): Combination therapy with two in vitro active drugs (including colistin) is strongly recommended 3, 4
• For carbapenem-resistant Acinetobacter baumannii (CRAB): Combination therapy with two in vitro active antibiotics is suggested for severe and high-risk infections 4, 5
• For carbapenem-resistant Enterobacterales (CRE): Colistin should be used in combination with at least one additional agent to which the pathogen is susceptible 3

When Monotherapy May Be Acceptable

The 2022 ESCMID guidelines make a nuanced distinction:

• Colistin monotherapy is recommended only for non-severe infections or low-risk infections caused by multidrug-resistant gram-negative bacteria 4
• This represents a pragmatic approach balancing resistance prevention with antibiotic stewardship in less critical situations 4

Evidence from High-Quality Trials

Despite the theoretical concerns about monotherapy, recent randomized controlled trials have shown mixed results:

• The OVERCOME trial (high-quality RCT) showed no significant difference in 28-day mortality between colistin monotherapy and colistin-meropenem combination for hospital-acquired/ventilator-associated pneumonia and bloodstream infections caused by carbapenem-resistant gram-negative bacteria 4
• The AIDA RCT demonstrated no advantage of colistin-meropenem over colistin monotherapy for CRAB infections regarding clinical failure or 14-day mortality 4
• However, microbiological eradication was significantly higher with combination therapy in some studies, even when clinical outcomes were similar 6

The Disconnect: Clinical Outcomes vs. Resistance Prevention

This creates an important clinical paradox:

• While combination therapy may not always improve mortality or clinical cure rates in individual patients, it serves a broader purpose of preventing resistance emergence that could compromise future treatment options 6, 2
• The theoretical benefit of preventing resistance development during therapy has not been definitively confirmed in clinical trials, but remains a compelling rationale 6

Practical Algorithm for Clinical Decision-Making

Use this approach when considering colistin therapy:

1. Assess infection severity:

   • Severe/high-risk infections (septic shock, VAP, bacteremia) → Mandatory combination therapy 3, 4
   • Non-severe infections → Monotherapy may be acceptable 4

2. Identify the pathogen and susceptibilities:

   • CRPA → Colistin + one additional active agent 3
   • CRAB → Colistin + one additional active agent (avoid colistin-meropenem specifically) 4, 5
   • CRE → Colistin + tigecycline or other active agent 3

3. Ensure source control is achieved to optimize outcomes and shorten treatment duration 3, 4

4. Monitor for resistance development with follow-up cultures if treatment failure occurs 3, 5

Critical Dosing Considerations

When colistin is used (whether monotherapy or combination):

• Loading dose is essential: 9 MU (5 mg/kg) colistin methanesulfonate, followed by maintenance dosing of 4.5 MU twice daily for critically ill patients 3
• Without a loading dose, plasma concentrations remain insufficient before steady state is reached 3
• Unit conversion is critical: 1 million IU colistin methanesulfonate = 33 mg colistin base activity 3

Common Pitfalls to Avoid

• Do not use colistin-meropenem combination for CRAB - this is a strong recommendation against this specific combination based on high-certainty evidence from multiple RCTs 4, 5
• Do not skip the loading dose - suboptimal dosing has been linked to resistance development 7
• Do not ignore nephrotoxicity monitoring - regular renal function assessment is mandatory, though nephrotoxicity is generally reversible 7, 8
• Do not use monotherapy for severe infections - even if individual trial results are equivocal, the resistance prevention rationale remains compelling 1, 2