Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity

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Polymyxin B and the Risk of Nephrotoxicity/Neurot
oxicity

• 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

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Overview of Polymyxins

• Polypeptide Antibiotics
• Polymyxin A, B, C, D, E
• Polymyxin B Bacillus polymixa, 1947
• Polymyxin E (Colistin) Bacillus colistinus, 1950

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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

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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)

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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

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Adverse Effects of Polymyxins

• Hypersensitivity
• Electrolyte disturbance
• Nephrotoxicity
• Neurotoxicity
• Neuromuscular blockade
• Respiratory arrest

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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.

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Clinical Manifestation of Nephrotoxicity

• ?SrCr
• Proteinuria
• Azotemia
• Hematuria
• Cylindruria
• Oliguria
• Acute tubular necrosis

Frequency not defined
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Clinical Manifestation of Neurotoxicity

• Paresthesia
• Ataxia
• Vertigo
• Headache
• Weakness
• Visual disturbances

• Confusion
• Seizures
• Neuromuscular blockade ? respiratory muscle
  paralysis ? respiratory failure

Frequency not defined
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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
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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

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Initial Toxicity Reports
Study Drug Dose Nephrotoxicity Neurotoxicity
Fekety et al. Ann Intern Med 196257214-29. Colistimethate sulfate IM 17/48 (35.4) ?BUN 13/48 (27) parathesias 3/48 (6.2) ataxia
Tallgren et al. Acta Med Scand 1965177717-28. Colistimethate sulfate IM 9/25 (36) ?SCr (pre-existing renal impairment)
Olesen et al. Curr Ther Res Clin Exp 19679283-7. Colistimethate sulfate IV 6/23 (26) renal impairment 7/23 (30) albuminuria 1/23 (4.3) paresthesia
Koch-Weser et al. Ann Intern Med 197072857-68. Colistimethate sulfate IM 64/317 (20.1) (courses) 23/317 (7.2)
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Recent Toxicities Reports
Study Drug Dose Nephrotoxicity Neurotoxicity
Ouderkirk et al. Antimicrob Agents Chemother 2003472659-62. Polymyxin B IV 7/50 (14) doubling of SCr gt2 mg/dl
Sobieszczyk et al. J Antimicrob Chemother 200454566-9. Polymyxin B IV (21), INH (6), both (2) 3/29 (10) doubling of SCr 2/29 (7) new onset seizures and neuromuscular weakness
Kasiakou et al. Antimicrob Agents Chemother 2005493136-46. Colistimethate sulfate IV 4/50 (8) doubling of SCr gt1.3 mg/dl
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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

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Polymyxins Dosage Adjustments

• Polymyxin B
• CrCl gt50 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 lt5 mL/min 15 daily dose divided Q12H
• Colistimethate
• Scr lt1.3 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

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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