Polymyxins

Polymyxins - Cationic Critter Killers

• Mechanism: Act as cationic detergents. They bind to anionic lipopolysaccharide (LPS) on the outer membrane of Gram-negative bacteria, disrupting membrane integrity and causing leakage of intracellular contents.
• Spectrum: Narrow; primarily targets multidrug-resistant (MDR) Gram-negative rods (e.g., Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae).
  • No activity against Gram-positives, Proteus, or anaerobes.
• Toxicity: High risk of dose-dependent:
  • Nephrotoxicity (acute tubular necrosis)
  • Neurotoxicity (paresthesias, ataxia, neuromuscular blockade)

⭐ Reserved as a last-resort therapy for severe MDR Gram-negative infections due to significant toxicity.

Spectrum & Resistance - The Gram-Neg Gauntlet

• Spectrum: Concentration-dependent bactericidal activity exclusively against aerobic, Gram-negative bacteria.
  • Targets multi-drug resistant (MDR) pathogens, often as a last-resort agent.
  • Key targets: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae (including KPC), and Enterobacter spp.
• Intrinsic Resistance: Not active against:
  • Gram-positives (cell wall prevents access to membrane).
  • Proteus, Providencia, Morganella, Serratia, Burkholderia cepacia.
  • All anaerobes.
• Acquired Resistance:
  • Primary mechanism: Modification of the drug's target, Lipid A in the lipopolysaccharide (LPS) layer.
  • Covalent addition of cationic groups reduces the net negative charge of the outer membrane, repelling the positively charged polymyxin molecule.

⭐ The plasmid-mediated mcr-1 gene confers transferable colistin resistance, a major global health threat allowing resistance to spread rapidly between different bacterial species.

Clinical Use & PK - Last-Resort Lifesavers

• Primary Use: Salvage therapy for severe, multi-drug resistant (MDR) Gram-negative infections.
  • Key pathogens: Pseudomonas aeruginosa, Acinetobacter baumannii, and Carbapenem-resistant Enterobacteriaceae (CRE) like Klebsiella.
• Routes & Distribution:
  • Administered IV for systemic infections (e.g., VAP, bacteremia).
  • Topical use is common (skin, eye, ear drops). Inhaled for CF patients.
  • ⚠️ Poor distribution into CSF, lung parenchyma, and pleural fluid limits use in meningitis/pneumonia.
• Elimination:
  • Colistin (Polymyxin E): A prodrug (colistimethate sodium), cleared renally → requires dose adjustment.
  • Polymyxin B: Active drug, minimal renal excretion.

⭐ Due to significant nephrotoxicity and neurotoxicity (e.g., paresthesias, ataxia), therapeutic drug monitoring is crucial for IV therapy to balance efficacy and toxicity.

Adverse Effects - The Toxic Toll

Polymyxins exhibit significant dose-dependent toxicities, primarily targeting the kidneys and nervous system. Close monitoring is crucial.

• Nephrotoxicity (Most Common & Serious)

  • Direct damage to renal tubular epithelial cells → Acute Tubular Necrosis (ATN).
  • Manifests as ↑ BUN/Cr, proteinuria, and hematuria.
  • Usually reversible upon drug discontinuation.

• Neurotoxicity

  • Paresthesias (circumoral, stocking-glove), dizziness, vertigo, and ataxia.
  • ⚠️ Neuromuscular Blockade: Can lead to respiratory muscle paralysis, especially with high doses or in renal failure.

⭐ Polymyxin-induced neuromuscular blockade is potentiated by anesthetics and other neuromuscular blockers (e.g., succinylcholine), posing a high risk for post-operative respiratory depression.

High‑Yield Points - ⚡ Biggest Takeaways

• Act as cationic detergents, binding to LPS to disrupt the outer membrane of Gram-negative bacteria.
• Crucial for multidrug-resistant (MDR) Gram-negative pathogens like Pseudomonas, Acinetobacter, and Klebsiella.
• Major dose-limiting toxicities are severe nephrotoxicity (acute tubular necrosis) and neurotoxicity (paresthesias, weakness).
• Considered a last-resort therapy for severe infections due to its significant toxicity profile.
• Resistance emerges from modification of the LPS lipid A target site.
• Includes Polymyxin B and Polymyxin E (Colistin), requiring IV administration.