Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity

Yumi Lee, Pharm.D.Pharmacy Practice Resident (PGY-1)

Kingsbrook Jewish Medical CenterClinical Instructor of Pharmacy Practice

Arnold & Marie Schwartz College of Pharmacy and Health Sciences of Long Island University

Brooklyn, New York

Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

Overview of PolymyxinsPolypeptide Antibiotics

Polymyxin A, B, C, D, EPolymyxin B: Bacillus polymixa, 1947Polymyxin E (Colistin): Bacillus colistinus, 1950

Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

Spectrum of Activity: BactericidalGram-negative bacilli: broad spectrum

Escherichia coli, Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, and Acinetobacter spp.

Resistant PathogensProteus spp., Providencia spp., Serratia spp., Neisseria

spp., Chromobacterium spp., Burkholderia spp. Gram-positive organismsAnaerobes

Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

Mechanism of ActionMechanism 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)

Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

Availability and DosingPolymyxin B sulfate

10,000 U = 1 mg polymyxin B baseAvailable in 500,000 U (50 mg) vialsDose: 15,000 - 25,000 U/kg/day divided Q12H

Colistimethate sodium30,000 U = 1 mg colistin baseAvailable 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 Hypersensitivity Electrolyte disturbance Nephrotoxicity Neurotoxicity Neuromuscular blockade Respiratory arrest

Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

Boxed WarningsNephrotoxicity

May cause nephrotoxicity; avoid concurrent or sequential use of other nephrotoxic drugs.

NeurotoxicityMay 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.

Falagas ME et al. Critical Care 2006;10(1):1-13

Clinical Manifestation of Nephrotoxicity

↑SrCrProteinuriaAzotemiaHematuriaCylindruriaOliguriaAcute tubular necrosis

Frequency not defined

Falagas ME et al. Critical Care 2006;10(1):1-13

Clinical Manifestation of Neurotoxicity

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

NeurotoxicityPresynaptic action of polymyxins block release of

acetylcholine to synaptic gap neuromuscular blockade

Dose-dependent and reversible

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

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 Res Clin Exp 1967;9:283-7.

Colistimethate sulfate IV

6/23 (26%) renal impairment; 7/23 (30%) albuminuria

1/23 (4.3%) paresthesia

Koch-Weser et al. Ann Intern Med 1970;72:857-68.

Colistimethate sulfate IM

64/317 (20.1%) (courses)

23/317 (7.2%)

Recent Toxicities Reports

Study Drug & Dose Nephrotoxicity Neurotoxicity

Ouderkirk et al. Antimicrob Agents Chemother 2003;47:2659-62.

Polymyxin B IV 7/50 (14%) doubling of SCr >2 mg/dl

Sobieszczyk et al. J Antimicrob Chemother 2004;54;566-9.

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 2005;49:3136-46.

Colistimethate sulfate IV

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 agentsPrompt discontinuationQuick diuresis by IV mannitolMaintain fluid and electrolyte balanceDialysis and respiratory support if necessary

Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.

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

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