What is the role of polymyxin B in the treatment of infections caused by multidrug-resistant gram-negative bacteria?

Role of Polymyxin B in Treatment of Multidrug-Resistant Gram-Negative Bacteria

Polymyxin B is a critical last-resort antibiotic for treating infections caused by multidrug-resistant gram-negative bacteria when newer or less toxic agents are ineffective or contraindicated. 1, 2

Indications and Antimicrobial Activity

• Polymyxin B is effective against most gram-negative bacilli, particularly carbapenem-resistant Pseudomonas aeruginosa (CRPA), Acinetobacter baumannii (CRAB), and Enterobacterales, with the exception of Proteus species 1
• FDA-approved indications include infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of P. aeruginosa, as well as serious infections caused by susceptible strains of H. influenzae, E. coli, Aerobacter aerogenes, and Klebsiella pneumoniae 1
• Polymyxin B increases bacterial cell membrane permeability, leading to cell death, but has poor tissue diffusion and does not cross the blood-brain barrier (except when administered intrathecally) 1
• Acquired resistance to polymyxins remains relatively rare among target pathogens, making them valuable for treating multidrug-resistant infections 3

Clinical Use in Multidrug-Resistant Infections

For Carbapenem-Resistant Pseudomonas aeruginosa (CRPA):

• For severe CRPA infections, when polymyxins are used, treatment with two in vitro active drugs is suggested (conditional recommendation, very low certainty of evidence) 2
• For non-severe or low-risk CRPA infections, monotherapy with polymyxin B (if active in vitro) may be appropriate, selected according to the source of infection 2
• When newer agents like ceftolozane-tazobactam are available and active in vitro, they are preferred over polymyxin B due to lower nephrotoxicity 2

For Carbapenem-Resistant Acinetobacter baumannii (CRAB):

• For CRAB resistant to sulbactam, polymyxin B can be used if active in vitro 2
• For severe and high-risk CRAB infections, combination therapy including two in vitro active antibiotics (which may include polymyxin B) is suggested 2
• Polymyxin-meropenem combination therapy is not recommended for CRAB infections (strong recommendation against use) 2

Dosing Considerations

• Standard dosing is 1.5-2.5 mg/kg/day divided into two doses 4
• Dose adjustment is required in renal impairment as the drug is primarily eliminated by the kidneys 1, 4
• For respiratory infections, aerosolized polymyxin (nebulized) in addition to intravenous administration may be considered to improve efficacy, especially when clinical response is suboptimal with intravenous therapy alone 2, 5

Toxicity and Monitoring

• Nephrotoxicity is the most significant adverse effect, occurring in approximately 14% of patients with normal baseline renal function 6
• Older patients (mean age 76 vs. 59 years) are at significantly higher risk for developing renal failure during polymyxin B therapy 6
• Development of renal failure during polymyxin B treatment is associated with increased mortality (57% vs. 20% overall) 6
• Nephrotoxicity appears to be less common with polymyxin B compared to colistin (polymyxin E), with one study showing higher RIFLE-defined nephrotoxicity with colistin (adjusted HR 2.27,95% CI 1.35-3.82) 2
• Regular monitoring of renal function is strongly recommended during treatment 2

Combination Therapy Considerations

• For severe CRPA infections treated with polymyxins, combination therapy with two in vitro active drugs is suggested, though specific combinations cannot be definitively recommended 2
• Very low-certainty evidence suggests an advantage of polymyxin combined with another active antibiotic over polymyxin alone for CRPA infections 2
• In a small subgroup of patients with extensively drug-resistant (XDR) P. aeruginosa, mortality was lower with combination therapy (0/3) compared to polymyxin monotherapy (14/15) 2
• For CRAB infections, polymyxin-meropenem and polymyxin-rifampin combinations are specifically not recommended 2

Clinical Pearls and Pitfalls

• Polymyxin B should be reserved for multidrug-resistant gram-negative infections when newer, less toxic agents are ineffective or unavailable 7
• Optimized dosage regimens for polymyxin B are still not definitively established, highlighting the need for therapeutic drug monitoring when available 3, 7
• Polymyxin B has poor penetration into cerebrospinal fluid and should only be administered intrathecally for meningeal infections 1
• Despite concerns about toxicity, recent studies suggest that polymyxin B has a lower nephrotoxicity rate than historically reported 6
• For respiratory tract infections, consider adding aerosolized polymyxin to intravenous therapy to improve clinical outcomes 2, 5