What is the recommended use and dosage of Polymyxin B for treating severe infections caused by multidrug-resistant gram-negative bacteria?

Polymyxin B for Multidrug-Resistant Gram-Negative Infections

Direct Recommendation

For severe infections caused by carbapenem-resistant gram-negative bacteria, use polymyxin B in combination with another in vitro active agent rather than monotherapy, with dosing of 15,000-25,000 units/kg/day IV (divided every 12 hours, not exceeding 25,000 units/kg/day total) for patients with normal renal function. 1, 2, 3

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Clinical Indications and Pathogen Coverage

Polymyxin B is reserved for severe infections when newer, less toxic agents are unavailable or inactive in vitro 3:

• Carbapenem-resistant Enterobacterales (CRE): Polymyxin-based combination therapy is recommended for bloodstream infections 4
• Carbapenem-resistant Pseudomonas aeruginosa (CRPA): Combination therapy with two in vitro active drugs is suggested for severe infections 4, 2, 5
• Carbapenem-resistant Acinetobacter baumannii (CRAB): Polymyxin B is appropriate when sulbactam resistance is present 2, 3

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Dosing Regimens

Standard IV Dosing (Normal Renal Function)

Adults and children: 15,000-25,000 units/kg/day divided every 12 hours 1

• Loading dose: 9 MU (approximately 5 mg/kg) for critically ill patients 2
• Maintenance dose: 4.5 MU twice daily 2
• Maximum daily dose: Do not exceed 25,000 units/kg/day 1

Infants: May receive up to 40,000 units/kg/day without adverse effects 1

Renal Impairment

Reduce dosing from 15,000 units/kg downward based on degree of kidney impairment 1

Preparation

Dissolve 500,000 polymyxin B units in 300-500 mL of 5% Dextrose Injection for continuous IV drip 1

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Combination Therapy Strategy

When to Use Combination Therapy

For severe infections, always combine polymyxin B with a second in vitro active agent 4, 2, 5:

• Meta-analysis of CRE infections showed combination therapy reduced 28-30 day mortality (35.7% vs 55.5% for monotherapy; OR 0.46,95% CI 0.30-0.69) 4
• Clinical study in critically ill patients demonstrated combination therapy independently associated with lower 30-day mortality (HR 0.33,95% CI 0.17-0.64) compared to polymyxin B monotherapy 6

Combination Partner Selection

Choose based on antimicrobial susceptibility testing 4, 5:

• Carbapenems (meropenem preferred): Use high-dose extended-infusion if MIC ≤8 mg/L 4, 3, 5
• Aminoglycosides: Appropriate for combination therapy 4, 5
• Tigecycline: Most commonly used for CRE-BSI, but avoid for primary bacteremia due to low serum concentrations 4
• Fosfomycin: Can be used as combination partner 4, 5
• Aztreonam plus ceftazidime-avibactam: For metallo-β-lactamase-producing CRE 4

Combinations to Avoid

Do not use polymyxin-rifampin combinations for CRAB or CRPA—no evidence supports this regimen 3, 5

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Pathogen-Specific Algorithms

For CRE Infections

1. First-line: Prefer newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) if active in vitro 4
2. If newer agents unavailable or inactive: Polymyxin B combination therapy 4
3. Combination partners: Tigecycline (avoid for BSI), carbapenem (if MIC ≤8 mg/L), or aminoglycosides 4

For CRPA Infections

1. First-line: Ceftolozane-tazobactam if active in vitro 4, 5
2. If unavailable: Polymyxin B plus second active agent (aminoglycoside, fosfomycin, or carbapenem if MIC ≤8 mg/L) 4, 5
3. Non-severe infections: Monotherapy with in vitro active agent acceptable 4, 5

For CRAB Infections

1. If sulbactam-susceptible: Ampicillin-sulbactam preferred over polymyxins 2
2. If sulbactam-resistant: Polymyxin B plus meropenem (especially if carbapenem MIC ≤32 mg/L) 2
3. For pneumonia: Consider adding aerosolized polymyxin B to IV therapy 2, 3

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Special Administration Routes

Aerosolized Polymyxin B

For respiratory tract infections, add aerosolized polymyxin B to IV therapy 2, 3:

• Reduces mortality (RR 0.86), clinical treatment failure (RR 0.82), and pathogen eradication failure (RR 0.84) 2

Intrathecal Administration

For Pseudomonas aeruginosa meningitis 1:

• Adults and children >2 years: 50,000 units once daily for 3-4 days, then every other day for ≥2 weeks after CSF cultures negative
• Children <2 years: 20,000 units once daily for 3-4 days, then 25,000 units every other day

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Critical Management Principles

Antimicrobial Stewardship

Obtain antimicrobial susceptibility testing immediately to guide therapy 5:

• Use newer β-lactam/β-lactamase inhibitors over polymyxin B when available and active due to lower nephrotoxicity 2, 3
• For non-severe infections, monotherapy with an in vitro active older agent is acceptable 4, 5

Monitoring and Support

• Renal function monitoring: Essential throughout therapy—nephrotoxicity occurs but may be less frequent than historically reported 7, 8
• Therapeutic drug monitoring: Utilize when available 3, 5
• Source control: Optimize drainage of abscesses and removal of infected devices 5
• Infectious disease consultation: Obtain early in management 5

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Common Pitfalls and Caveats

Avoid These Errors

• Do not use polymyxin B monotherapy for severe infections—associated with higher treatment failure rates 2, 3, 5
• Do not use tigecycline for bacteremia or pneumonia as monotherapy—inadequate serum concentrations 4
• Do not combine polymyxin with rifampin—no supporting evidence 3, 5
• Do not use combination therapy with newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) if organism is susceptible—monotherapy is sufficient 4

Storage and Stability

Solutions for parenteral use should be refrigerated, and unused portions discarded after 72 hours 1

Toxicity Considerations

Polymyxin B appears to have less nephrotoxicity than colistin (adjusted HR 2.27 for colistin, 95% CI 1.35-3.82) 2