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Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity

Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity. Yumi Lee, Pharm.D. Pharmacy Practice Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical Instructor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy and Health Sciences of Long Island University

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Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity

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  1. Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity Yumi Lee, Pharm.D. Pharmacy Practice Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical Instructor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy and Health Sciences of Long Island University Brooklyn, New York

  2. Overview of Polymyxins • Polypeptide Antibiotics • Polymyxin A, B, C, D, E • Polymyxin B: Bacillus polymixa, 1947 • Polymyxin E (Colistin): Bacillus colistinus, 1950 Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

  3. Spectrum of Activity: Bactericidal • Gram-negative bacilli: broad spectrum • Escherichia coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, and Acinetobacter spp. • Resistant Pathogens • Proteus spp., Providencia spp., Serratia spp., Neisseria spp., Chromobacterium spp., Burkholderia spp. • Gram-positive organisms • Anaerobes Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

  4. Mechanism of Action • Mechanism of action: Bactericidal • Binds to bacterial outer membrane  disruption of membrane integrity • Displaces Mg2+ and Ca2+ bridges that stabilize lipopolysaccharide molecules of outer membrane  ↑ cell permeability  leakage of cell contents  death • Uses: • Infections caused by multi-drug resistant gram (-) bacteria • Pneumonia, bacteremia, UTI, surgical site infections, CNS, orthopedic infections, and endocarditis • Also used to enhance susceptibility of hydrophobic antimicrobials (e.g., erythromycin) Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

  5. Availability and Dosing • Polymyxin B sulfate • 10,000 U = 1 mg polymyxin B base • Available in 500,000 U (50 mg) vials • Dose: 15,000 - 25,000 U/kg/day divided Q12H • Colistimethate sodium • 30,000 U = 1 mg colistin base • Available in 150 mg vials • Dose: 2.5 - 5 mg/kg/day in 2 - 4 divided doses Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

  6. Adverse Effects of Polymyxins • Hypersensitivity • Electrolyte disturbance • Nephrotoxicity • Neurotoxicity • Neuromuscular blockade • Respiratory arrest Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

  7. Boxed Warnings • Nephrotoxicity • May cause nephrotoxicity; avoid concurrent or sequential use of other nephrotoxic drugs. • Neurotoxicity • May cause neurotoxicity, which can also result in respiratory paralysis from neuromuscular blockade especially when the drug is given soon after anesthesia or muscle relaxants. Avoid concurrent or sequential use of other neurotoxic drugs. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

  8. Clinical Manifestation of Nephrotoxicity • ↑SrCr • Proteinuria • Azotemia • Hematuria • Cylindruria • Oliguria • Acute tubular necrosis Frequency not defined Falagas ME et al. Critical Care 2006;10(1):1-13

  9. Paresthesia Ataxia Vertigo Headache Weakness Visual disturbances Confusion Seizures Neuromuscular blockade  respiratory muscle paralysis  respiratory failure Clinical Manifestation of Neurotoxicity Frequency not defined Falagas ME et al. Critical Care 2006;10(1):1-13

  10. Proposed Mechanisms of Toxicities • Nephrotoxicity • Increases renal tubular epithelial cell membrane permeability  increased transepithelial conductance of bladder • Neurotoxicity • Presynaptic action of polymyxins block release of acetylcholine to synaptic gap  neuromuscular blockade Dose-dependent and reversible Falagas ME et al. Critical Care 2006;10(1):1-13

  11. Incidence of Nephro/Neurotoxicity • Literature search on PubMed (1950-2008) • Search terms: colistin, polymyxin E, polymyxin B, adverse effects, toxicity, nephrotoxicity, and neurotoxicity • Early reports revealed high incidence of nephrotoxicity and neurotoxicity • Less occurrence of neurotoxicity than nephrotoxicity • Recent studies do not corroborate with older literature • No reports of neuromuscular blockade over past 15 years or more

  12. Initial Toxicity Reports

  13. Recent Toxicities Reports

  14. Prevention & Management of Toxicities • Renal dose adjustments • Avoid co-administration of potential nephrotoxic and neurotoxic agents • Prompt discontinuation • Quick diuresis by IV mannitol • Maintain fluid and electrolyte balance • Dialysis and respiratory support if necessary

  15. Polymyxins Dosage Adjustments • Polymyxin B • CrCl >50 mL/min: 15,000 – 25,000 units/kg/day divided Q12H • CrCl 20-50 mL/min: 75-100% of daily dose divided Q12H • CrCl 5 -20 mL/min: 50% of daily dose divided Q12H • CrCl <5 mL/min: 15% daily dose divided Q12H • Colistimethate • Scr <1.3 mg/dL: 2.5-5 mg/kg/day in 2-4 divided doses • Scr 1.3-1.5 mg/dL: 2.5-3.8 mg/kg/day Q12H • Scr 1.6-2.5 mg/dL: 2.5 mg/kg/day Q12H or Q24H • Scr 2.6-4 mg/dL: 1.5 mg/kg/day Q36H Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

  16. Conclusions • Polymyxins recently re-introduced into clinical practice for treatment of MDR-gram-negative infections • Nephrotoxicity and neurotoxicity represent major adverse effects of polymyxins • Data from recent literature suggest lower and less frequent incidence of toxicities • Caution and frequent monitoring is necessary when administering polymyxins

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