Mechanism of Action
LPS Binding and Outer Membrane Permeabilization
Polymyxin B binds the lipid A component of lipopolysaccharide (LPS) with high affinity through electrostatic interactions between its five positively charged diaminobutyric acid (Dab) residues and the negatively charged phosphate groups of lipid A. This displaces divalent cations (Mg2+, Ca2+) that normally stabilize the outer membrane, causing outer membrane permeabilization. The hydrophobic fatty acid tail then inserts into the disrupted membrane, causing self-promoted uptake and inner membrane disruption by the same mechanism.
LPS Neutralization
Beyond killing bacteria, polymyxin B also neutralizes free LPS (endotoxin) in circulation. LPS activates TLR4 on innate immune cells, triggering the inflammatory cascade leading to septic shock. Polymyxin B sulfate-immobilized fiber (PMX-F, Toraymyxin) is used in Japan for extracorporeal endotoxin adsorption in sepsis, exploiting this LPS-binding property without the nephrotoxicity of systemic polymyxin. This "endotoxin adsorption" approach has shown benefit in septic shock trials.
Research Summary
Last-Resort MDR Gram-Negative Infections
FDA ApprovedPolymyxin B is used for carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Klebsiella pneumoniae (CRKP), and multidrug-resistant P. aeruginosa when all other options have failed. Combination therapy with rifampicin, carbapenems, or tigecycline is used to reduce nephrotoxicity through lower polymyxin doses and exploit synergistic killing. Polymyxin B is preferred over colistin for IV use in some guidelines due to more predictable PK.
Nephrotoxicity and Dosing Optimization
ApprovedNephrotoxicity (acute kidney injury in 20-60% of patients) remains the main dose-limiting toxicity of polymyxin B. PK/PD optimization using AUC-guided dosing and therapeutic drug monitoring (TDM) is being investigated to achieve bacterial killing while minimizing renal toxicity. Novel delivery approaches including inhaled polymyxin for lung infections and polymyxin-loaded nanoparticles aim to improve local concentrations and reduce systemic exposure.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| MDR Gram-negative (IV) | 1.25-1.5 mg/kg IV every 12h | Every 12 hours | IV infusion |
| Intrathecal/intraventricular | 50,000 units daily | Daily | Intrathecal |
| Topical (Neosporin) | Component at 5000-10000 units/g | As needed | Topical |
Systemic use requires TDM where available. Dose adjustments for renal impairment. Reserve for MDR infections.
Interactions
Safety Profile
Nephrotoxicity in 20-60% of patients (AKI, tubular necrosis). Neurotoxicity (paresthesias, facial numbness, dizziness) in 7-14%. Neuromuscular blockade. No dose adjustment needed for hepatic impairment. TDM emerging to reduce toxicity. Despite significant toxicity, polymyxin B is lifesaving for truly pan-resistant Gram-negative infections where alternatives do not exist.
References
- [1]Falagas ME, et al. (2010). Effectiveness and nephrotoxicity of colistin monotherapy vs. colistin-meropenem combination therapy for multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis, 51(10), e182-e185.
- [2]Zavascki AP, et al. (2007). Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antimicrob Chemother, 60(6), 1206-1215.