Polymyxins

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Polymyxins, Clinical use of Polymyxins

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Polymyxins

  1. 1. Dr.T.V.Rao MD
  2. 2. IntroductionPolymyxin EFirst isolated in Japan 1949 & available for clinicaluse in 1959IM for gram (-) infectionFell out of favor after aminoglycosides usageAerosolized form for cystic fibrosisIV for pan resistant nosocomial infections(Pseudomonas & Acinetobacter spp.)
  3. 3. POLYMYXINSPolymyxins are antibiotics, with a general structureconsisting of a cyclic peptide with a long hydrophobictail. They disrupt the structure of the bacterial cellmembrane by interacting with its phospholipids. They areproduced by the Gram-positive bacterium Bacilluspolymyxa and are selectively toxic for Gram-negativebacteria due to their specificity for the lipopolysaccharidemolecule that exists within many Gram-negative outermembranes.
  4. 4. Structure of Polymyxin
  5. 5. Structure of PolymyxinsPolymyxin B Sulfate is one of agroup of basic polypeptideantibiotics derived from Bpolymyxa (B aero porous).Polymyxin B sulfate is thesulfate salt of Polymyxins B1and B2, which are produced bythe growth of Bacilluspolymyxa (Prazmowski)Migula (Fam. Bacillacea). It hasa potency of not less than 6000polymyxin B units per mg,calculated on the anhydrousbasis.
  6. 6. STRUCTURE OF POLYMYXIN
  7. 7. Mechanism of ActionBactericidalBind to lipopolysaccharides(LPS) & phospholipids inthe outer cell membrane of G(-) bacteriaNeutralize LPS & prevent pathophysiologic effects ofendotoxinResistance is uncommonDisk diffusion method cannot be used
  8. 8. Spectrum of ActivityPseudomonas & A. baumanniiE. coli, EnterobacterH. influenzaBordetella pertussisLegionella, Klebsiella spp.Salmonella spp., Shigella spp.Stenotrophomonas maltophilia
  9. 9. PharmacokineticsColistin sulfate, colistin methanesulfonateNot absorbed from GI tractHydrolized after IV administration to colistinHalf life 251 minutesExcreted in the urine, no biliary excretion
  10. 10. Clinical uses of PolymyxinsOnly polymyxins B and E are used clinically; the othersdamage the kidneys. Polymyxin B can also cause kidneydamage and therefore can only be applied topically totreat infections such as those of the eye, ear, skin, andurinary bladder. Polymyxin E, also known as colistin, isused frequently for diarrhea in children. The chieftherapeutic use of the polymyxins is treating infections ofgram-negative bacteria that are resistant to penicillin andother broad-spectrum antibiotics.
  11. 11. NEWER APPLICATIONSPolymyxins B and E (alsoknown as colistin) areused in the treatment ofGram-negative bacterialinfections. The globalproblem of advancingantimicrobial resistancehas led to a renewedinterest in their userecently.
  12. 12. Mechanism of actionAfter binding to lipopolysaccharide (LPS) in the outermembrane of Gram-negative bacteria, polymyxins disrupt boththe outer and inner membranes. The hydrophobic tail isimportant in causing membrane damage, suggesting adetergent-like mode of action.Removal of the hydrophobic tail of polymyxin B yieldspolymyxin nonapeptide, which still binds to LPS but no longerkills the bacterial cell. However, it still detectably increases thepermeability of the bacterial cell wall to other antibiotics,indicating that it still causes some degree of membranedisorganization
  13. 13. Clinical usesPolymyxins antibiotics are relatively neurotoxicand nephrotoxic[6] and are usually only used as alast resort if modern antibiotics are ineffective orare contraindicated. Typical uses are forinfections caused by strains of multi-drugresistant Pseudomonas aeruginosa orcarbapenemase-producing Enterobacteriaceae.
  14. 14. Colistin: the re-emerging antibiotic formultidrug-resistant Gram-negative bacterial infections. Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago
  15. 15. What is ColistinColistin (also called polymyxin E) belongs to the polymyxingroup of antibiotics [1]. It was first isolated in Japan in 1949from Bacillus polymyxa var. colistinus and became availablefor clinical use in 1959 [2,3]. Colistin was given as anintramuscular injection for the treatment of gram-negativeinfections, but fell out of favor after aminoglycosides becameavailable because of its significant side effects. It was later usedas topical therapy as part of selective digestive tractdecontamination and is still used in aerosolized form forpatients with cystic fibrosis.
  16. 16. Colistin – A PolymyxinColistin is a cationic polypeptide antibiotic from thepolymyxin family that was first introduced in 1962 butabandoned in the early 1970s because of initial reports ofsevere toxicities. However, a recent increase in theprevalence of multidrug resistant (MDR) Pseudomonasaeruginosa and the lack of novel agents in developmentcalls for a need to re-examine the role of colistin therapyin patients with cystic fibrosis.
  17. 17. How Colistin WorksColistin is a bactericidal drugthat binds tolipopolysaccharides andphospholipids in the outer cellmembrane of gram-negativebacteria. It competitivelydisplaces divalent cations fromthe phosphate groups ofmembrane lipids, which leadsto disruption of the outer cellmembrane, leakage ofintracellular contents, andbacterial death
  18. 18. How Polymyxins are DispensedPolymyxin B forInjection is in powder form suitable forpreparation of sterile solutions for intramuscular,intravenous drip, intrathecal, or ophthalmic use.In the medical literature, dosages have frequently beengiven in terms of equivalent weights of pure polymyxin Bbase.Each milligram of pure polymyxin B base isequivalent to 10,000 units of polymyxin B and eachmicrogram of pure polymyxin B base is equivalent to 10units of polymyxin B.
  19. 19. Experimental uses of PolymyxinsPolymyxins are used to neutralize or absorb LPScontaminating samples that are intended for use in e.g.immunological experiments. Minimization of LPScontamination can be important because LPS can evoke strongreactions from immune cells and therefore distort experimentalresults.By increasing permeability of the bacterial membrane system,polymyxin is also used to experimentally increase release ofsecreted toxins, such as Shiga toxin from Escherichia coli[7].
  20. 20. Colistin can neutralize Endotoxins In addition to its bactericidal effect, colistin can bind and neutralize lipopolysaccharide (LPS) and prevent the pathophysiologic effects of endotoxin in the circulation .
  21. 21. Dosing & Administration Optimal dose & dosing interval are unknownSystemic administration U.S. 2.5~5 mg/kg per day, in 2~4 doses U.K. 4~6 mg/kg per day, in 3 dosesInhaled administration Not FDA approved
  22. 22. Adverse ReactionNephrotoxicity Acute tubular necrosis 27% Normal renal function patient (mean inc. 0.9 mg/dL serum creatine) 58% impaired renal function patient (mean inc. 1.5 mg/dL serum creatine) Minimal data on long term use
  23. 23. Adverse ReactionNeurotoxicity 7% Facial & peripheral paresthesia Dizziness, weakness, vertigo, visual disturbance, confusion, ataxia, neuromuscular blockade Benign & reversible
  24. 24. Caution with PolymyxinsCaution: when this drug is given intramuscularly, intravenouslyand/or intrathecally, it should be given only to hospitalized patients,so as to provide constant supervision by a physician.Renal function should be carefully determined and patients withrenal damage and nitrogen retention should have reduced dosage.Patients with nephrotoxicity due to polymyxin b sulfate usually showalbuminuria, cellular casts, and azotemia. Diminishing urine outputand a rising bun are indications for discontinuing therapy with thisdrug..
  25. 25. Caution with PolymyxinsCaution: when this drug is given intramuscularly, intravenouslyand/or intrathecally, it should be given only to hospitalized patients,so as to provide constant supervision by a physician.Renal function should be carefully determined and patients withrenal damage and nitrogen retention should have reduced dosage.Patients with nephrotoxicity due to polymyxin b sulfate usually showalbuminuria, cellular casts, and azotemia. Diminishing urine outputand a rising bun are indications for discontinuing therapy with thisdrug..
  26. 26. SummaryBactericidal, binding to LPS & phospholipidsDisk diffusion method cannot be performedIV for pan resistant nosocomial infections(Pseudomonas & Acinetobacter spp.)Adverse effects (nephrotoxicity, neurotoxicity)
  27. 27. Polymyxins can Cause ToxicityNeurotoxic reactions may bemanifested by irritability,weakness, drowsiness,ataxia, perioral paresthesia,numbness of the extremities,and blurring of vision. Theseare usually associated withhigh serum levels found inpatients with impaired renalfunction and/ornephrotoxicity.
  28. 28. Summary – Colistin UseColistin is structurally and pharmacologically related topolymyxin B, the other commercially available drug from thepolymyxin class. Colistin is bactericidal in nearly all strains ofgram-negative bacilli. As with all antibiotics, resistance is ofparamount concern. Resistance to colistin has not beenfrequently documented. Colistin must be administeredparenterally, as it is not absorbed from the gastrointestinaltract, mucous membranes, or intact or denuded skin.Parenteral colistin has been replaced by less-toxic antibioticsand should be reserved for life-threatening infections causedby organisms resistant to preferred drugs
  29. 29. Polymyxins too Develop ResistanceThe gram-negativebacteria can developresistance to polymyxinsthrough variousmodifications of the LPSstructure that inhibit thebinding of polymyxins toLPS
  30. 30. Created by Dr.T.V.Rao MD for “e-learning” resources for Medical and ParamedicalStudents in Developing world Email doctortvrao@gmail.com

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