Polymyxin B
Antimicrobial / ClinicalAlso known as: Polymyxin B Sulfate
Mechanism
A last-resort antibiotic for serious gram-negative infections that resist everything else. It works by binding to the LPS (lipopolysaccharide) layer of gram-negative bacteria and ripping their outer membrane apart. Discovered in 1947 but fell out of favor due to kidney toxicity — now back as a critical weapon against superbugs like carbapenem-resistant Enterobacteriaceae (CRE).
Technical detail
Cyclic cationic lipopeptide (10-amino acid with 6-methyloctanoyl or 6-methylheptanoyl fatty acid tail) from Paenibacillus polymyxa. Mechanism: positively charged DAB (diaminobutyric acid) residues electrostatically bind negatively charged lipid A component of LPS in gram-negative outer membrane. Displaces Ca2+/Mg2+ that stabilize LPS architecture, destabilizing the outer membrane. Hydrophobic tail inserts into the inner membrane, causing osmotic lysis. Rapid bactericidal activity against most gram-negatives: Pseudomonas, Acinetobacter, Klebsiella, E. coli. Intrinsically resistant: Proteus, Serratia, Burkholderia. Dose-limiting nephrotoxicity (renal tubular injury) and neurotoxicity. Given IV or topically (otic, ophthalmic, wound irrigation).
Effects
ANTIMICROBIAL MECHANISM: Cyclic cationic lipopeptide antibiotic produced by Bacillus polymyxa. Mechanism is similar to colistin (both are polymyxins) but with important pharmacological differences. Binds directly to LPS lipid A component via electrostatic interaction between positively charged DAB residues and negatively charged phosphate groups. Displaces Ca2+ and Mg2+ bridging ions, disrupting outer membrane architecture. Inserts fatty acyl chain into hydrophobic domain, causing membrane permeabilization, osmotic imbalance, and rapid cell death. Additional mechanisms: disrupts bacterial cell division, inhibits type II NADH-quinone oxidoreductases (respiratory chain), and neutralizes endotoxin (LPS). SPECTRUM: Identical to colistin — Gram-negative aerobes: P. aeruginosa, A. baumannii, K. pneumoniae (including CRE), E. coli, Citrobacter, Enterobacter. Intrinsically resistant: Proteus, Providencia, Morganella, Serratia, B. cepacia, Neisseria, all Gram-positives, anaerobes. MIC BREAKPOINTS: CLSI (2024): S. aureus N/A; P. aeruginosa and Acinetobacter susceptible ≤2 μg/mL. EUCAST: does not set breakpoints for polymyxin B (only colistin). RESISTANCE MECHANISMS: Same as colistin — lipid A modification (PmrABC, PhoPQ systems), mcr plasmid-mediated resistance, LPS loss. Cross-resistance between polymyxin B and colistin is essentially complete — if resistant to one, resistant to both. KEY PHARMACOKINETIC DIFFERENCE FROM COLISTIN: Polymyxin B is administered as the ACTIVE drug (not a prodrug). This is the critical distinction. Colistin is given as inactive CMS which must convert to colistin. Polymyxin B achieves therapeutic levels faster and more predictably. Vd ~0.13 L/kg. Half-life 13-16 hours. Primarily non-renal elimination (unlike CMS). Does NOT require renal dose adjustment. Protein binding ~58%. Poor CSF penetration. NEPHROTOXICITY: Occurs in 20-60% (similar to colistin). Mechanism: direct tubular toxicity via receptor-mediated endocytosis through megalin (PEPT2 receptor). Recent data suggests polymyxin B may be LESS nephrotoxic than CMS/colistin at equivalent AUC exposures (animal, PK/PD modeling). NEUROTOXICITY: Similar profile to colistin — paresthesias, dizziness, neuromuscular blockade. Facial flushing and pruritus unique to polymyxin B (histamine release, occurs in ~25% of patients). ENDOTOXIN NEUTRALIZATION: Both polymyxins bind and neutralize circulating endotoxin (LPS). Polymyxin B hemoperfusion cartridge (Toraymyxin) used in Japan/Europe for septic shock — removes endotoxin from circulation. This is a unique non-antibiotic application.
Practitioner Guide
CLINICAL PEARLS — INFECTIOUS DISEASE SPECIALIST PERSPECTIVE: DOSING: Standard: Loading dose 2.0-2.5 mg/kg (based on ABW) IV over 1-2 hours, then maintenance 1.25-1.5 mg/kg IV q12h. Unlike colistin (CMS), dosing is straightforward — mg/kg of actual polymyxin B. NO RENAL DOSE ADJUSTMENT — this is a major advantage over CMS. Polymyxin B elimination is primarily non-renal. Renally impaired patients get the same dose (one of the few antibiotics where this is true). WHY POLYMYXIN B OVER COLISTIN (CMS): (1) Active drug, not prodrug — therapeutic levels achieved faster (hours vs. days for CMS). (2) More predictable PK — no variable prodrug conversion. (3) No renal dose adjustment needed. (4) Potentially less nephrotoxic at equivalent exposures (emerging data). (5) Simpler dosing (mg/kg straightforward vs. CMS confusion with IU, mg CBA, mg CMS). LIMITATIONS VS. CMS: (1) Not available in all countries (CMS is more widely available globally). (2) Less aerosolized use data (CMS is preferred for inhaled route). (3) Histamine-mediated infusion reactions (facial flushing, pruritus) more common — slow infusion rate helps. MANAGING INFUSION REACTIONS: Polymyxin B causes dose-dependent histamine release. Facial flushing, pruritus, chest tightness in ~25% of patients. Strategies: (1) Infuse over 1-2 hours (never rapid push). (2) Premedicate with diphenhydramine 25-50 mg IV. (3) Some institutions use a polymyxin B slow continuous infusion protocol to minimize reactions. (4) Usually diminishes with subsequent doses. COMBINATION THERAPY: Same principles as colistin — almost always combined for serious XDR infections. Partners: meropenem, tigecycline, fosfomycin, rifampin, aminoglycosides. POLYMYXIN B HEMOPERFUSION (Toraymyxin): Polymyxin B-immobilized fiber cartridge for extracorporeal endotoxin removal in septic shock. Approved in Japan and Europe. Controversial efficacy — EUPHRATES trial (2018, JAMA) showed no overall mortality benefit but post-hoc analysis suggested benefit in patients with high endotoxin activity (EAA >0.6). Used selectively in some centers for refractory Gram-negative septic shock. MONITORING: SCr/BUN daily in ICU. CPK if neurotoxicity suspected. Assess for neuromuscular symptoms (especially in patients receiving concurrent neuromuscular blockers, aminoglycosides). No routine TDM available (research assays exist). The AUC/MIC target of 50-100 is emerging but not yet clinically applicable. TOPICAL USES: Polymyxin B is a component of multiple topical preparations: polymyxin B + bacitracin (Polysporin), polymyxin B + neomycin + bacitracin (Neosporin — though neomycin allergy is common), polymyxin B otic solutions, polymyxin B ophthalmic solutions, polymyxin B bladder irrigations. These are safe and effective for localized infections with minimal systemic absorption.
Research Summary
TIER 1 (Gold Standard): Tsuji et al., 2019 — population PK and PK/PD analysis supporting current dosing (Clinical Infectious Diseases, PMID: 30215686). EUPHRATES trial (Dellinger et al., 2018) — RCT of polymyxin B hemoperfusion in endotoxemic septic shock (JAMA, PMID: 29486039). FDA-approved (original approval predates modern trials — 1951). Multiple meta-analyses comparing polymyxin B to colistin nephrotoxicity. TIER 2 (Strong): Rigatto et al., 2015 — polymyxin B dosing in critically ill patients (Antimicrobial Agents and Chemotherapy). Nelson et al., 2015 — polymyxin B vs. colistin pharmacology comparison (Antimicrobial Agents and Chemotherapy). International consensus guidelines for polymyxin use (Tsuji et al., 2019). DrugBank DB00781. TIER 3 (Moderate): Clinical experience from ICU-based ID specialists managing XDR infections with polymyxin B. Comparison data between polymyxin B and CMS from retrospective cohorts (multiple centers). Toraymyxin hemoperfusion experience from Japan (decades of use with extensive case series). International data: polymyxin B is preferred in Brazil and parts of Asia; CMS preferred in Europe and US. Conference presentations at ECCMID, IDWeek, SCCM. KEY FINDINGS: (1) Polymyxin B has pharmacological advantages over CMS (active drug, no renal adjustment, more predictable PK). (2) Global adoption has been slow due to CMS market dominance. (3) Nephrotoxicity may be slightly less than CMS at equivalent exposures. (4) Histamine release is the unique practical challenge. (5) Hemoperfusion application is a unique non-antibiotic use. GAPS: Head-to-head RCT of polymyxin B vs. CMS for clinical outcomes (ongoing: CARAT trial). TDM-guided dosing validation. Optimal combination therapy partners. Long-term outcomes data. ACTIVE TRIALS: CARAT trial (polymyxin B vs. CMS, RCT). Multiple ongoing for dosing optimization and combination therapy.