What is the coverage and usage of Polymyxin B (antibiotic) for multidrug-resistant Gram-negative bacteria infections?

Polymyxin B Coverage and Usage

Spectrum of Activity

Polymyxin B is bactericidal against almost all multidrug-resistant gram-negative bacilli, including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), Klebsiella pneumoniae, Escherichia coli, and Haemophilus influenzae, but has no activity against Proteus species, gram-positive bacteria, fungi, or gram-negative cocci. 1

Primary Indications

• Serious infections caused by multidrug-resistant gram-negative bacteria when less toxic drugs are ineffective or contraindicated 2, 1
• Bloodstream infections, urinary tract infections, meningeal infections, and respiratory tract infections caused by susceptible organisms 1, 3
• Specifically indicated for carbapenem-resistant Acinetobacter baumannii when resistant to sulbactam 4
• Carbapenem-resistant Enterobacterales infections 2

Dosing Recommendations

Administer a loading dose of 2-2.5 mg/kg followed by maintenance dosing of 1.5-3 mg/kg/day divided into two doses, based on total body weight regardless of renal function. 2

Key Dosing Principles

• The loading dose must be given to all patients, including those with renal dysfunction 2
• Dosing is NOT adjusted for renal function initially, though maintenance may require adjustment 2
• Continuous infusion may be suitable in select cases 2
• Unit conversion: 1 mg polymyxin B sulfate = 10,000 units 2

Combination Therapy vs Monotherapy

Combination therapy is strongly recommended over monotherapy for multidrug-resistant gram-negative infections, reducing treatment failure rates by approximately 119 cases per 1000 patients. 2, 4

Recommended Combinations by Pathogen

• For CRAB with meropenem MIC ≤32 mg/L: Polymyxin B plus extended-infusion meropenem (3-hour infusion) 2, 5
• For CRE bloodstream infections: Polymyxin B plus tigecycline or meropenem 2
• For CRPA infections: Polymyxin B plus another in vitro active agent (conditional recommendation, very low certainty) 4
• For fosfomycin combinations: Polymyxin B plus fosfomycin shows synergistic activity against CRKP 6

Combinations to AVOID

• Strong recommendation AGAINST polymyxin-meropenem combination for CRAB with high-level carbapenem resistance (MIC >16 mg/L) 5
• Strong recommendation AGAINST polymyxin-rifampin combination for CRAB infections 4, 5

Therapeutic Drug Monitoring

TDM should be performed whenever available due to high interpatient variability in achieving therapeutic concentrations. 6, 2

• Even with FDA/EMA recommended doses, only 65-75% of critically ill patients with normal renal function achieve target concentrations (Css,avg ≥1 mg/L) 6
• TDM optimizes dosing, improves clinical efficacy, and reduces adverse reactions 6

Nephrotoxicity and Monitoring

Nephrotoxicity occurs in approximately 14% of patients with normal baseline renal function, which is lower than colistin. 2, 7

Risk Factors and Monitoring

• Older age is significantly associated with development of renal failure (76 vs 59 years, p=0.02) 7
• Nephrotoxicity is independent of daily dose, cumulative dose, or treatment duration 7
• Monitor renal function throughout treatment 2
• Avoid concurrent nephrotoxic or ototoxic drugs 2
• Mortality increases to 57% in patients who develop renal failure 7

Clinical Efficacy

Microbiological clearance rates of 88% have been reported for multidrug-resistant gram-negative infections treated with polymyxin B. 7, 8

• Overall mortality ranges from 20-48% in critically ill patients, though this reflects severity of underlying illness 7, 3, 8
• Treatment efficacy of 54.2% reported in ICU patients with CRKP and CRPA when combined with fosfomycin 6
• Good clinical outcomes observed in majority of patients in recent studies 9

Important Clinical Pearls

• Polymyxin B is NOT a prodrug (unlike colistin methanesulfonate), allowing for immediate antibacterial activity 2
• Loses 50% of activity in presence of serum, resulting in low active blood levels 1
• Poor tissue diffusion and does NOT cross blood-brain barrier; intrathecal administration required for meningeal infections 1
• Newer agents like ceftolozane-tazobactam should be prioritized when available and active due to lower nephrotoxicity 4
• Optimal source control must always be prioritized to improve outcomes 4