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Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity Yumi Lee, Pharm.D. Pharmacy Practice Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical.

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Presentation on theme: "Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity Yumi Lee, Pharm.D. Pharmacy Practice Resident (PGY-1) Kingsbrook Jewish Medical Center Clinical."— Presentation transcript:

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

3 Landman et al. Clinical Microbiology Reviews 2008;21(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

4 Landman et al. Clinical Microbiology Reviews 2008;21(3): Mechanism of Action Mechanism of action: Bactericidal Binds to bacterial outer membrane  disruption of membrane integrity Displaces Mg 2+ and Ca 2+ 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)

5 Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 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 U/kg/day divided Q12H Colistimethate sodium 30,000 U = 1 mg colistin base Available in 150 mg vials Dose: mg/kg/day in divided doses

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

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

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

9 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

10 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

11 Incidence of Nephro/Neurotoxicity Literature search on PubMed ( ) 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 StudyDrug & DoseNephrotoxicityNeurotoxicity Fekety et al. Ann Intern Med 1962;57: Colistimethate sulfate IM 17/48 (35.4%) ↑BUN13/48 (27%) parathesias; 3/48 (6.2%) ataxia Tallgren et al. Acta Med Scand 1965;177: Colistimethate sulfate IM 9/25 (36%) ↑SCr ( pre-existing renal impairment) Olesen et al. Curr Ther Res Clin Exp 1967;9: 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: Colistimethate sulfate IM 64/317 (20.1%) (courses) 23/317 (7.2%)

13 Recent Toxicities Reports StudyDrug & DoseNephrotoxicityNeurotoxicity Ouderkirk et al. Antimicrob Agents Chemother 2003;47: Polymyxin B IV7/50 (14%) doubling of SCr >2 mg/dl Sobieszczyk et al. J Antimicrob Chemother 2004;54; 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: Colistimethate sulfate IV 4/50 (8%) doubling of SCr >1.3 mg/dl

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

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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