Why is polymixin B (Polymyxin B) given to patients with severe Carbapenem-Resistant Enterobacteriaceae (CRE) infections?

Why Polymyxin B is Given for CRE Infections

Polymyxin B is given for carbapenem-resistant Enterobacteriaceae (CRE) infections because it remains one of the few antibiotics with in vitro activity against these multidrug-resistant organisms, particularly when newer agents like ceftazidime-avibactam are unavailable or inactive. 1

Primary Mechanism and Rationale

Polymyxin B serves as a last-resort antibiotic for CRE infections because these organisms have developed resistance to carbapenems (meropenem, imipenem, doripenem), which are typically the most potent beta-lactams available. 1 The Infectious Diseases Society of America specifically recommends polymyxins for carbapenem-resistant gram-negative bacteria including CRE when first-line agents cannot be used. 2

When Polymyxin B Should Be Used

Polymyxin-based combination therapy is recommended as the preferential choice over monotherapy for treating CRE infections in patients who require polymyxin treatment. 1 The specific clinical scenarios include:

Bloodstream Infections (BSI)

• Polymyxin-based combination therapy is recommended for CRE bloodstream infections, with the combination agent selected based on susceptibility testing results. 1
• Meta-analysis data shows combination therapy reduces 28-30 day mortality (35.7% vs 55.5% for monotherapy; OR 0.46,95% CI 0.30-0.69). 2
• For BSI secondary to intra-abdominal infections, polymyxin-based combinations showed lower mortality (39.3% vs 56.4%; OR: 0.52,95% CI 0.33-0.83). 1

Complicated Intra-Abdominal Infections (cIAI)

• Polymyxin-based combination therapy is recommended for cIAI caused by CRE, with combination selection based on susceptibility testing. 1
• Common combinations include polymyxin with tigecycline, meropenem, or fosfomycin. 1

Urinary Tract Infections

• While newer agents like ceftazidime-avibactam, meropenem-vaborbactam, or plazomicin are preferred for CRE urinary tract infections, polymyxins remain an option when these are unavailable. 1

Why Combination Therapy is Critical

Polymyxin B should never be used as monotherapy for severe CRE infections. 1, 2 The rationale for combination therapy includes:

• Prevention of resistance emergence: Polymyxin monotherapy is associated with rapid development of resistance during treatment. 1, 3
• Synergistic effects: Combinations demonstrate synergistic activity against CRE in vitro and may prevent emergence of resistant sub-populations. 2
• Improved clinical outcomes: Combination therapy reduces mortality, treatment failure, and pathogen eradication failure compared to monotherapy. 2

Preferred Combination Partners

The most commonly used and evidence-supported combinations include: 1

• Polymyxin B + carbapenem (meropenem): Particularly effective when carbapenem MIC is ≤8 mg/L for CRE, using extended 3-hour infusion of meropenem. 1
• Polymyxin B + tigecycline: Demonstrated rapid and sustained bactericidal killing in hollow-fiber infection models against carbapenem-resistant E. coli. 4
• Polymyxin B + fosfomycin: Supported by observational data for various CRE infections. 1
• Polymyxin B + aminoglycosides: Based on susceptibility testing results. 1

Dosing Considerations

For critically ill patients, a loading dose approach is essential: 1

• Loading dose: 9 million units (approximately 5 mg/kg) as a 3-hour infusion
• Maintenance dose: 4.5 million units twice daily (or 1.25 mg/kg every 12 hours as 2-hour infusions) 5
• Therapeutic drug monitoring should be performed when available to optimize dosing and minimize toxicity. 1, 2

Critical Safety Monitoring

Renal function must be monitored closely during polymyxin B treatment, as nephrotoxicity occurs in approximately 45-55% of patients. 5 Key safety considerations include:

• Polymyxin B appears to have less nephrotoxicity than colistin (adjusted HR 2.27 for colistin vs polymyxin B). 1
• Avoid concurrent use of other nephrotoxic or ototoxic drugs. 1
• Neurotoxicity can occur in up to 55% of patients, including hyperpigmentation. 5, 6
• Baseline renal insufficiency is a significant risk factor for treatment failure (OR 6.0,95% CI 1.22-29.59). 3

When NOT to Use Polymyxin B

Newer agents should be prioritized over polymyxins when available and active in vitro: 2

• First-line preference: Ceftazidime-avibactam, meropenem-vaborbactam, or imipenem-relebactam for CRE infections 1, 2
• Reason: These newer beta-lactam/beta-lactamase inhibitor combinations have superior clinical cure rates and dramatically lower nephrotoxicity (adjusted OR 0.08,95% CI 0.03-0.22) compared to polymyxins. 2

Common Pitfalls to Avoid

• Never use polymyxin B monotherapy for severe CRE infections: This is associated with higher treatment failure rates and rapid resistance development. 2, 3
• Do not combine polymyxin with tigecycline for bacteremia: Tigecycline achieves inadequate serum concentrations for bloodstream infections. 2
• Avoid using polymyxins without susceptibility testing: Resistance can develop rapidly, and breakthrough infections with polymyxin-resistant organisms occur in up to 45% of patients. 3
• Do not use standard dosing without a loading dose in critically ill patients: Subtherapeutic levels increase risk of treatment failure. 1, 5