Presentation on theme: "Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity"— Presentation transcript:
1 Polymyxin B and the Risk of Nephrotoxicity/Neurotoxicity Yumi Lee, Pharm.D.Pharmacy Practice Resident (PGY-1)Kingsbrook Jewish Medical CenterClinical Instructor of Pharmacy PracticeArnold & Marie Schwartz College of Pharmacyand Health Sciences of Long Island UniversityBrooklyn, New York
2 Overview of Polymyxins Polypeptide AntibioticsPolymyxin A, B, C, D, EPolymyxin B: Bacillus polymixa, 1947Polymyxin E (Colistin): Bacillus colistinus, 1950Polymyxins 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
3 Spectrum of Activity: Bactericidal Gram-negative bacilli: broad spectrumEscherichia 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 organismsAnaerobesThe 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
4 Landman et al. Clinical Microbiology Reviews 2008;21(3):449-65 Mechanism of ActionMechanism of action: BactericidalBinds to bacterial outer membrane disruption of membrane integrityDisplaces Mg2+ and Ca2+ bridges that stabilize lipopolysaccharide molecules of outer membrane ↑ cell permeability leakage of cell contents deathUses:Infections caused by multi-drug resistant gram (-) bacteriaPneumonia, bacteremia, UTI, surgical site infections, CNS, orthopedic infections, and endocarditisAlso 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 membraneLandman et al. Clinical Microbiology Reviews 2008;21(3):449-65
5 Availability and Dosing Polymyxin B sulfate10,000 U = 1 mg polymyxin B baseAvailable in 500,000 U (50 mg) vialsDose: 15, ,000 U/kg/day divided Q12HColistimethate sodium30,000 U = 1 mg colistin baseAvailable in 150 mg vialsDose: mg/kg/day in divided dosesPolymyxins 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.
6 Adverse Effects of Polymyxins HypersensitivityElectrolyte disturbanceNephrotoxicityNeurotoxicityNeuromuscular blockadeRespiratory arrestLexi-Comp Online. Hudson, OH: Lexi-Comp, Inc.; 2009; February 12, 2009.
7 Boxed Warnings Nephrotoxicity Neurotoxicity 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.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.
8 Clinical Manifestation of Nephrotoxicity ↑SrCrProteinuriaAzotemiaHematuriaCylindruriaOliguriaAcute tubular necrosisFrequency not definedAzotemia includes decrease in GFR and increase serum creatinine and BUNCylinduria- presence of renal casts in the urineFalagas ME et al. Critical Care 2006;10(1):1-13
9 Clinical Manifestation of Neurotoxicity ParesthesiaAtaxiaVertigoHeadacheWeaknessVisual disturbancesConfusionSeizuresNeuromuscular blockade respiratory muscle paralysis respiratory failureFrequency not definedFalagas ME et al. Critical Care 2006;10(1):1-13
10 Proposed Mechanisms of Toxicities NephrotoxicityIncreases renal tubular epithelial cell membrane permeability increased transepithelial conductance of bladderNeurotoxicityPresynaptic action of polymyxins block release of acetylcholine to synaptic gap neuromuscular blockadeLike its MOA… it increase tubular epithelial cell membrane permeability -- acute tubular necrosisDose-dependent and reversibleFalagas ME et al. Critical Care 2006;10(1):1-13
11 Incidence of Nephro/Neurotoxicity Literature search on PubMed ( )Search terms: colistin, polymyxin E, polymyxin B, adverse effects, toxicity, nephrotoxicity, and neurotoxicityEarly reports revealed high incidence of nephrotoxicity and neurotoxicityLess occurrence of neurotoxicity than nephrotoxicityRecent studies do not corroborate with older literatureNo reports of neuromuscular blockade over past 15 years or more
12 Initial Toxicity Reports StudyDrug & DoseNephrotoxicityNeurotoxicityFekety et al. Ann Intern Med 1962;57:Colistimethate sulfate IM17/48 (35.4%) ↑BUN13/48 (27%) parathesias; 3/48 (6.2%) ataxiaTallgren et al. Acta Med Scand 1965;177:9/25 (36%) ↑SCr(pre-existing renal impairment)Olesen et al. Curr Ther Res Clin Exp 1967;9:283-7.Colistimethate sulfate IV6/23 (26%) renal impairment; 7/23 (30%) albuminuria1/23 (4.3%) paresthesiaKoch-Weser et al. Ann Intern Med 1970;72:64/317 (20.1%) (courses)23/317 (7.2%)Polymyxins fell out of favor due to these reports in the 1970sWhen doing literature search…. Found….
13 Recent Toxicities Reports StudyDrug & DoseNephrotoxicityNeurotoxicityOuderkirk et al. Antimicrob Agents Chemother 2003;47:Polymyxin B IV7/50 (14%) doubling of SCr >2 mg/dlSobieszczyk et al. J Antimicrob Chemother 2004;54;566-9.Polymyxin B IV (21), INH (6), both (2)3/29 (10%) doubling of SCr2/29 (7%) new onset seizures and neuromuscular weaknessKasiakou et al. Antimicrob Agents Chemother 2005;49:Colistimethate sulfate IV4/50 (8%) doubling of SCr >1.3 mg/dlMost neurotox were case reports…Besides these 2 case reports, there are a hand full of other reports of neurotox possible due to polyJimenez-Mejias et al. Eur J Clin Microbiol Infect Dis 2003;21: Colistimethate sulfate IV 5/21 (24%) doubling of SCr>2 mg/dl
14 Prevention & Management of Toxicities Renal dose adjustmentsAvoid co-administration of potential nephrotoxic and neurotoxic agentsPrompt discontinuationQuick diuresis by IV mannitolMaintain fluid and electrolyte balanceDialysis and respiratory support if necessaryQuick diuresis by IV mannitol to enhance renal clearance of drug
16 ConclusionsPolymyxins recently re-introduced into clinical practice for treatment of MDR-gram-negative infectionsNephrotoxicity and neurotoxicity represent major adverse effects of polymyxinsData from recent literature suggest lower and less frequent incidence of toxicitiesCaution and frequent monitoring is necessary when administering polymyxins