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 Polymyxins are a group of polypeptide antibiotics. They consist of 5 chemically different compounds (A-E) which were first discovered in the late 1940s. Polymyxin B and E (known as colistin) are the only agents available clinically because of their more favorable safety profile when compared with the other polymyxin compounds. The sole difference between colistin and polymyxin B is by a single amino acid change: D-phenylalanine in Polymyxin B in replaced with D-leucine in colistin. 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 The polymyxins exhibit bactericidal activity against most gram(-) aerobic bacilli, including Acinetobacter, Pseudomonas, Klebsiella, and Enterobacter species, which are all important nosocomial pathogens. However, several pathogens possess intrinsic resistance to the polymyxins including Proteus, Providencia, Serratia, Neisseria, Chromobacterium, and Burkholderia. Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65

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) Polymyxins are cationic agents that bind to the anionic bacterial outer member leading to a detergent effect that disrupts membrane integrity. In particular, polymyxins displace magnesium and calcium bridges that stabilize the bacterial outer member which leads to an increase in the permeability of the cell envelope, leakage of cell contents, and eventually death. Also used to enhance susceptibility of hydrophobic antimicrobials (e.g., erythromycin)  by disrupting the membrane 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 Polymyxins are renally cleared and needs to be renally adjusted. Colistin in commercially available as colistimethate sodium due to its less toxic profile. 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 Warnings Nephrotoxicity Neurotoxicity 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. With increased used, nephro and neurotoxicity due to the polymyxins became more apparent and as newer and safer antimicrobial agents were developed, the use of polymyxins gradually fell out of favor. However, with an increased incidence of gram(-) bacteria resistant to most classes of antibiotics, including the carbapenems, the polymyxins have resurfaced as a viable treatment options for infections because of these MDR-gram(-) organisms. 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 Azotemia includes decrease in GFR and increase serum creatinine and BUN Cylinduria- presence of renal casts in the urine 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 Neurotoxicity Presynaptic action of polymyxins block release of acetylcholine to synaptic gap  neuromuscular blockade Like its MOA… it increase tubular epithelial cell membrane permeability -- acute tubular necrosis Dose-dependent and reversible Falagas ME et al. Critical Care 2006;10(1):1-13

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. 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. 64/317 (20.1%) (courses) 23/317 (7.2%) Polymyxins fell out of favor due to these reports in the 1970s When doing literature search…. Found….

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 Most neurotox were case reports… Besides these 2 case reports, there are a hand full of other reports of neurotox possible due to poly Jimenez-Mejias et al. Eur J Clin Microbiol Infect Dis 2003;21:212-4. Colistimethate sulfate IV 5/21 (24%) doubling of SCr >2 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 Quick diuresis by IV mannitol to enhance renal clearance of drug

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.

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