How should Polymyxin B be used in adults, including its indications, dosing regimens (intravenous, inhalation, ophthalmic), renal dose adjustments, contraindications, adverse effects, and monitoring recommendations?

Polymyxin B: Clinical Use in Adults

Polymyxin B should be reserved exclusively for serious infections caused by multidrug-resistant gram-negative bacteria (carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa) when less toxic agents are ineffective or unavailable, and must always be used in combination therapy—never as monotherapy. 1, 2

Primary Indications

Polymyxin B is indicated for:

• Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by carbapenem-resistant pathogens sensitive only to polymyxins 3
• Bloodstream infections due to carbapenem-resistant Enterobacterales (CRE) 2
• Severe infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) when newer agents like ceftolozane-tazobactam are unavailable 2
• Carbapenem-resistant Acinetobacter baumannii (CRAB) infections 3, 2

Critical caveat: Polymyxins should only be used in settings with high prevalence of multidrug resistance and local expertise in dosing and monitoring. 3

Intravenous Dosing Regimen

Loading Dose (Mandatory for All Patients)

Administer 2–2.5 mg/kg IV as a loading dose regardless of renal function status. 1, 4 This corresponds to 20,000–25,000 units/kg or approximately 1.4–1.75 million international units (MIU) for a 70-kg adult. 4 The loading dose achieves therapeutic plasma concentrations on day one and must be given even in severe renal dysfunction or continuous renal replacement therapy (CRRT). 4

Maintenance Dosing

Standard maintenance dose: 1.5–3 mg/kg/day (or 2.5–3.0 mg/kg/day per IDSA guidelines) divided into two doses every 12 hours. 3, 1, 4 For a 70-kg patient, this equals 105–210 mg/day or 1.05–2.1 MIU/day. 4

Critical distinction from older FDA labeling and colistin: Polymyxin B does NOT require dose reduction for renal impairment. 4 Maintain standard dosing (1.5–3 mg/kg/day) even in severe renal dysfunction or CRRT. 4 This is the most important dosing principle that contradicts older FDA labeling which recommended dose reduction. 5

Dosing Conversion Reference

• 1 mg polymyxin B sulfate = 10,000 units 3, 4
• 1 MIU = 100 mg polymyxin B sulfate 4

Therapeutic Drug Monitoring (TDM)

TDM is strongly recommended and should be performed whenever available. 1, 4, 2

Target concentrations:

• Steady-state average concentration: ~3.35 mg/L 4
• AUC₀₋₂₄h: 50–100 mg·h/L 4, 2

Rationale: Only 65–75% of critically ill patients with normal renal function achieve target concentrations with standard dosing. 1, 2 TDM optimizes efficacy and reduces nephrotoxicity. 1, 2

Combination Therapy Requirements

Polymyxin B must NEVER be used as monotherapy for serious infections. 2 Always combine with at least one additional in vitro active agent. 2

Pathogen-Specific Combinations

For CRE bloodstream infections:

• Combine with tigecycline OR extended-infusion meropenem (if MIC ≤8 mg/L) 3, 4, 2

For CRAB infections:

• Combine with extended-infusion meropenem if carbapenem MIC ≤32 mg/L 1, 2
• Strong recommendation AGAINST polymyxin-meropenem combination if meropenem MIC >16 mg/L 2
• Strong recommendation AGAINST polymyxin-rifampin combination (no mortality benefit demonstrated) 2

For CRPA infections:

• Combine with aminoglycoside, fosfomycin, or carbapenem if MIC ≤8 mg/L 2
• Fosfomycin combination shows synergistic activity with 54.2% treatment efficacy in ICU patients 1

Avoid these combinations:

• Do NOT add glycopeptides (vancomycin) due to increased nephrotoxicity without benefit 2
• Do NOT use rifampin combination 2

Inhaled Polymyxin Therapy

For HAP/VAP caused by carbapenem-resistant pathogens sensitive only to polymyxins: Add adjunctive inhaled colistin (NOT inhaled polymyxin B) to intravenous polymyxin B. 3, 4

Rationale: Inhaled colistin has better clinical evidence and pharmacokinetic advantages for pulmonary delivery compared to inhaled polymyxin B, which has only anecdotal data. 3 Aerosolized polymyxin added to IV therapy may reduce mortality (RR 0.86), clinical treatment failure (RR 0.82), and pathogen eradication failure (RR 0.84). 2

Dosing for inhaled colistin: 2–6 million IU daily, administered promptly after mixing with sterile water. 3, 2

Intrathecal Administration

For Pseudomonas aeruginosa meningitis:

• Adults and children >2 years: 50,000 units (≈5 mg) intrathecally once daily for 3–4 days, then every other day for at least 2 weeks after CSF cultures are negative 4, 5
• Children <2 years: 20,000 units once daily for 3–4 days, then 25,000 units every other day 5

Ophthalmic Use

For Pseudomonas aeruginosa eye infections:

• Dissolve 500,000 units in 20–50 mL sterile water to achieve 10,000–25,000 units/mL concentration 5
• Administer 1–3 drops every hour, increasing intervals as response indicates 5
• Subconjunctival injection up to 100,000 units/day may be used for corneal/conjunctival infections 5
• Avoid total systemic and ophthalmic instillation exceeding 25,000 units/kg/day 5

Contraindications

Absolute contraindications:

• Known hypersensitivity to polymyxins 6

Relative contraindications (use with extreme caution):

• Myasthenia gravis (neuromuscular blockade risk) 6
• Concurrent use of other nephrotoxic agents (aminoglycosides, vancomycin) increases toxicity risk 1, 2

Adverse Effects and Monitoring

Nephrotoxicity

Incidence: Approximately 14% in patients with normal baseline renal function, significantly lower than colistin (11.8% vs 39.3%). 1, 7 Colistin shows higher RIFLE-defined kidney injury (adjusted HR 2.27,95% CI 1.35–3.82). 2

Monitoring protocol:

• Baseline serum creatinine and creatinine clearance 1
• Daily serum creatinine during therapy 1, 4
• Avoid concurrent nephrotoxic drugs 1

Neurotoxicity

Manifestations: Paresthesias (numbness, tingling), dizziness, ataxia, neuromuscular blockade 6, 7

Incidence: Reversible numbness observed in approximately 3% of cases 7

Monitoring: Assess for neurological symptoms daily, particularly paresthesias and muscle weakness 6

Skin Hyperpigmentation

Rare but documented: Diffuse skin darkening, most prominent on face and forearms, peaks around 2 weeks after initiation 8

Mechanism: Hypermelanosis of basal layer with melanin deposition in dermis 8

Management: Typically improves within 4 weeks of discontinuation 8

Hypersensitivity Reactions

Monitor for rash, fever, and allergic reactions 6

Duration of Therapy

Standard duration: 7 days for HAP/VAP 3, 4

For CRE bloodstream infections: 7–14 days 4

Adjust based on:

• Rate of clinical improvement 3
• Radiologic resolution 3
• Follow-up cultures to confirm pathogen eradication and detect emerging resistance 2

De-escalation Strategy

De-escalate therapy when antimicrobial susceptibilities are known rather than maintaining fixed broad-spectrum coverage. 3 This reduces adverse effects, C. difficile infections, and antibiotic resistance. 3

Common Pitfalls and How to Avoid Them

1. Using monotherapy: Always combine with another active agent for serious infections 2

2. Reducing dose in renal failure: Unlike older recommendations and colistin, polymyxin B does NOT require renal dose adjustment 4

3. Omitting loading dose: The loading dose is mandatory for all patients, including those with renal dysfunction 4

4. Using inhaled polymyxin B instead of inhaled colistin: For adjunctive inhalation therapy, use colistin due to superior evidence 3

5. Combining with rifampin or high-dose meropenem for CRAB when MIC >16 mg/L: These combinations lack mortality benefit and should be avoided 2

6. Not performing TDM: Only 50–75% of patients achieve therapeutic concentrations with standard dosing; TDM is essential 1, 2

7. Confusing polymyxin B with colistin dosing: Polymyxin B is dosed in mg/kg, not based on colistin base activity (CBA), and does not require renal adjustment 4

Storage and Preparation

Solutions for parenteral use should be stored under refrigeration, and unused portions discarded after 72 hours. 5