Download Polymyxin B

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
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
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
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
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.
Adverse Effects of Polymyxins

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Hypersensitivity
Electrolyte disturbance
Nephrotoxicity
Neurotoxicity
Neuromuscular blockade
Respiratory arrest
Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.
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.
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
Clinical Manifestation of Neurotoxicity





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Paresthesia
Ataxia
Vertigo
Headache
Weakness
Visual disturbances
Confusion
 Seizures
 Neuromuscular blockade
 respiratory muscle
paralysis  respiratory
failure

Frequency not defined
Falagas ME et al. Critical Care 2006;10(1):1-13
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
Incidence of Nephro/Neurotoxicity
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Literature search on PubMed (1950-2008)
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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
Initial Toxicity Reports
Study
Drug & Dose
Nephrotoxicity
Neurotoxicity
Fekety et al. Ann Intern
Med 1962;57:214-29.
Colistimethate
sulfate IM
17/48 (35.4%) ↑BUN
13/48 (27%)
parathesias; 3/48
(6.2%) ataxia
Tallgren et al. Acta Med
Scand 1965;177:717-28.
Colistimethate
sulfate IM
9/25 (36%) ↑SCr
(pre-existing renal impairment)
Olesen et al. Curr Ther
Colistimethate
Res Clin Exp 1967;9:283- sulfate IV
7.
6/23 (26%) renal
impairment; 7/23
(30%) albuminuria
1/23 (4.3%)
paresthesia
Koch-Weser et al. Ann
Intern Med 1970;72:85768.
64/317 (20.1%)
23/317 (7.2%)
Colistimethate
sulfate IM
(courses)
Recent Toxicities Reports
Study
Drug & Dose
Ouderkirk et al.
Polymyxin B IV
Antimicrob Agents
Chemother 2003;47:265962.
Sobieszczyk et al. J
Antimicrob Chemother
2004;54;566-9.
Nephrotoxicity
Neurotoxicity
7/50 (14%) doubling
of SCr >2 mg/dl
Polymyxin B IV
3/29 (10%) doubling 2/29 (7%) new onset
(21), INH (6), both of SCr
seizures and
(2)
neuromuscular
weakness
Kasiakou et al.
Colistimethate
Antimicrob Agents
sulfate IV
Chemother 2005;49:313646.
4/50 (8%) doubling
of SCr >1.3 mg/dl
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

Polymyxins Dosage Adjustments

Polymyxin B

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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



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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.
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
