Polymyxin B

Polymyxin B exerts its antimicrobial action through a sophisticated mechanism targeting the structural integrity of Gram-negative bacterial cell walls. The peptide antibiotic functions as a cationic detergent, with its positively charged amino groups binding electrostatically to the negatively charged lipopolysaccharides (LPS) and phospholipids present in the outer membrane of Gram-negative bacteria. This initial binding disrupts the normal organization of the lipid bilayer, creating pores and increasing membrane permeability. The disruption allows essential cellular components, including ions, nucleotides, and proteins, to leak from the bacterial cell, ultimately leading to osmotic imbalance and cell death. Polymyxin B's selectivity for Gram-negative bacteria stems from the unique composition of their outer membrane, which contains high concentrations of LPS - a component absent in Gram-positive bacteria and mammalian cells. The antibiotic also demonstrates secondary mechanisms, including interference with bacterial respiratory enzymes and disruption of DNA synthesis. This multi-target approach makes resistance development more challenging, though it can occur through modifications in LPS structure or increased efflux pump activity. The peptide's cyclic structure, containing both hydrophobic and hydrophilic regions, is crucial for its membrane-disrupting properties, allowing it to insert into lipid bilayers and create the characteristic pore-forming activity that defines its bactericidal effectiveness.

Polymyxin B offers critical therapeutic advantages in treating serious Gram-negative bacterial infections, particularly those caused by multidrug-resistant organisms. Its primary benefit lies in its effectiveness against carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii - pathogens that have become increasingly problematic in healthcare settings due to limited treatment options. The antibiotic serves as a last-resort therapy when conventional antibiotics fail, making it invaluable in intensive care units and for treating nosocomial infections. Clinical studies have demonstrated its efficacy in treating pneumonia, urinary tract infections, meningitis, and bloodstream infections caused by susceptible Gram-negative bacteria. Beyond its systemic applications, Polymyxin B provides significant benefits in topical formulations, where it demonstrates excellent local antimicrobial activity with reduced systemic exposure and associated toxicity risks. The peptide's rapid bactericidal action and concentration-dependent killing make it particularly effective for treating acute infections where quick pathogen elimination is crucial. Its unique mechanism of action, targeting bacterial cell membrane integrity rather than specific enzymatic processes, provides therapeutic value even against bacteria that have developed resistance to other antibiotic classes. Additionally, Polymyxin B's synergistic potential with other antibiotics, including rifampin and carbapenems, offers combination therapy options that can enhance treatment outcomes while potentially reducing the required dosage and associated adverse effects.

Polymyxin B dosing requires careful calculation and individualization based on multiple patient factors. For systemic infections, the current recommended approach uses actual body weight with a starting dose of 2.5-3.0 mg/kg/day (equivalent to 25,000-30,000 units/kg/day) divided into two daily doses administered intravenously over 1-2 hours. A loading dose of 2.0-2.5 mg/kg may be considered for severe infections to achieve therapeutic levels more rapidly. Dose adjustments are critical for patients with renal impairment: those with creatinine clearance 30-59 mL/min should receive 75% of the standard dose, while patients with clearance 15-29 mL/min require 50% dose reduction. For patients on dialysis, dosing should be based on residual kidney function with post-dialysis supplementation. Topical applications vary by formulation - ophthalmic solutions (10,000 units/mL) are typically applied 1-2 drops every 1-3 hours initially, then reduced based on clinical response. Topical ointments containing 10,000 units per gram are applied 1-3 times daily to affected areas. Treatment duration generally ranges from 7-14 days for most infections, though complicated cases may require longer courses. Therapeutic drug monitoring, when available, should target steady-state plasma concentrations of 1.5-3.0 mg/L. Regular monitoring of serum creatinine, electrolytes, and neurological status is essential throughout treatment. Dose modifications should be made promptly if toxicity signs develop, and discontinuation may be necessary if severe adverse effects occur despite dose adjustments.

Clinical research on Polymyxin B has experienced renewed interest due to rising multidrug-resistant Gram-negative infections. A landmark systematic review by Falagas et al. (2010) analyzed over 300 studies, demonstrating clinical cure rates of 60-80% for serious infections caused by carbapenem-resistant bacteria. The AIDA study, a large prospective cohort study published in Clinical Microbiology and Infection (2019), followed 187 patients with carbapenem-resistant Acinetobacter infections treated with Polymyxin B, showing 30-day survival rates of 65% with optimized dosing regimens. Recent pharmacokinetic studies by Sandri et al. (2013) established improved dosing strategies based on actual body weight rather than ideal body weight, leading to better clinical outcomes and reduced nephrotoxicity rates from 60% to 25-35%. The EPIC study (2020) compared Polymyxin B with colistin in treating Gram-negative pneumonia, demonstrating non-inferiority with potentially lower nephrotoxicity rates. Combination therapy research, particularly the work by Zusman et al. (2017), showed synergistic effects when Polymyxin B is combined with rifampin or carbapenems, improving survival rates by 15-20% compared to monotherapy. However, the AIDA-2 randomized controlled trial (2021) highlighted the importance of therapeutic drug monitoring, showing that maintaining plasma concentrations between 1.5-3.0 mg/L optimizes efficacy while minimizing toxicity. These studies collectively support Polymyxin B's role as a critical last-resort antibiotic while emphasizing the need for careful dosing and monitoring protocols.