Polymyxins revisited

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Polymyxins revisited

  1. 1. Polymyxins RevistedNew indications for old antibiotics Dr Ashok Rattan, Chairman: Laboratory Medicine
  2. 2. PolymyxinsPolypeptide antibiotics first isolated from Bacillus polymyxa5 chemically different compounds (Polymyxin A – E) Polymyxin B Polymyxin E (Colistin)Polymyxin A, C and D too toxic for human use 2
  3. 3. ColistinCationic cyclic deca peptideLinked to a fatty acid chainThrough an α amide linkageAmino acid are: D leucine, L threonine, L α γ diamino butyric acidFatty acid could be 6 methyl octon oic acid (colistin A) 6 methyl eptanoic acid (colistin B) 3
  4. 4. Polymyxin E (Colistin)Colistin Methane Sulphonate, pentasodium colistimethanesulphate, colistin sulfonyl methate, CMS 4
  5. 5. Formulations:Colistin sulphate Colistimethate sodium (CMS)Oral, Tropical, inhalation use Parental, inhalation useActive drug, not absorbed Inactive prodrug, less toxic, orally hydrolysed in aqueous solution to active colistin Two formulations:International Unit is defined as minimal conc that inhibits A. colomycin: 500 k, 1 M, 2 M growth of E.coli 95 ISM in 1 international units ml broth at pH 7.2 B. Coly mycin: 150 mg colistin1 million IU = 80 mg of CMS active base/vial = 360 mg of CMS 5
  6. 6. Available formulations Colomycin injection Coly-Mycin M ParenteralManufacturer Dumex-Alpharma A/S, Parkedale Pharmaceuticals, Copenhagen, Denmark Rochester, MN, USALabelled content per vial 500 000, 1 000 000 or 150 mg colistin base activity 2 000 000 IU; about 12 500 units/mgMass of colistimethate 40 mg, 80 mg, or 160 mg About 400 mgsodium dry powder per vialAppearance Creamy-white powder White to slightly yellow lyophilised cakeRecommended dose* ≤60 kg bodyweight: 50 K 2.5– 5mg/kg per day colistin base IU– 75 K IU/kg per day in activity in two to four doses, = three divided doses, = about 6.67–13.3 mg/kg per day 4–6 mg/kg per day colistimethate sodium colistimethate sodium 6
  7. 7. Dose240 to 720 mg per day (3 to 9 million IU/day)In 2 – 4 divided doses CMS Colistin SulphateInactive prodrug Active drug International Unit is defined as minimal conc that inhibits growth of E.coli 95 ISM in 1 ml broth at pH 7.2 12 500 IU = 1 mg of CMS 2.67 mg of CMS = 1 mg colistin base activity 2 M IU of CMS = 160 mg of drug = 60 mg colistin base activity 7
  8. 8. Fell into disrepute in early 1970sRyan KJ et al. Colistimethate toxicity: report of a fatal case in a previously healthy child. JAMA 1969; 207 : 2099 - 101Brown JM et al. Acute renal failure due to overdosage of colistin. Med J Aust 1970; 2: 923 – 4Koch Weser J et al. Adverse effects of sodium colistimethate: manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med 1970; 72: 857 – 68. 8
  9. 9. Aminoglycosides, FQs & Penems became the antibiotic work horse in 1970s - 2000Gentamicin Amikacin Ciprofloxacin Meropenem 9
  10. 10. Emergence of MDR, XDR &courtesy Dr Chand Wattal Data PDRGram Negative Bacterial Infections 10
  11. 11. Bad bugs, no drugs: No ESKAPE CID 2009; 48: 1 - 12E nterococcus faeciumS taphylococcus aureusK lebseilla pneumoniaeA cinetobacter baumaniiP seudomonas aeruginosaE nterobacter species Clostridium difficile & E. coli 11
  12. 12. We have a basic problem We must make the best use of what we have 12
  13. 13. In vitro susceptibility of MDR bacteria Ana Gales et al: JCM 2001; 39 (1): 183 - 190 Tested MDR bacteria against: 12 antibiotics: Polymyxin B, Colistin, Ceftazidime, Cefepime, Imipenem, Meropenem, Ciprofloxacin, Levofloxacin, Amikacin, Tobramycin, Doxycycline, TMP-SMX ColistinOrganisms (number) MIC50 MIC90 % Susceptible (ug/ml) (ug/ml) < 2 ug/mlBurkholderia cepacia (12) > 128 > 128 0Stenotrophomonas maltophilia (23) < 1 32 73.9Morganella morganii (2) 64 > 128 0Proteus mirabilis (2) 64 > 128 0Acinetobacter baumannii (60) <1 2 96.7Pseudomonas aeruginosa (80) <1 <1 100Klebseilla pneumoniae (9) <1 <1 100Enterobacter spp. (5) <1 2 100 13
  14. 14. Anti Endotoxin ActivityInfection Immun 1996; 64: 4922 - 7 14
  15. 15. Colistin: Revival of Polymyxins for the management of MDR GNB Infections Falagas & Kasiakou CID 2005; 40: 1333 - 41Treatment of infections caused by MDR Acinetobacter baumannii Pseudomonas aeruginosa Klebsiella pneumoniaeCystic FibrosisVAPNosocomial pneumoniaBacteriemiaUTI 15Meningitis
  16. 16. Use of Colistin as salvage therapyColistin active against P. aeruginosa , Acinetobacter spp & Klebseilla spp.Can be used for Pneumonia, Bacteremia or UTI caused by these infectionsAcceptable toxicity & effectiveness 16
  17. 17. NephrotoxicityCMS at 160 mg x 3 has satisfactory safetyCMS maybe safer than aminoglycosidesCMS + AG have increased renal toxicityRIFLE (Risk, injury, failure,loss,end stage) 66 pt, 45% met criteria for nephrotoxicity 21% stopped CMS, reversible, toxicity 3.7 x > if dosed for more than 14 days 17
  18. 18. NeurotoxicityParasthesia, visual alteration, ataxia, neuromuscular blockadeReversible on stopping CMSCases are mild & infrequent (0 – 7%) 18
  19. 19. Spectrum of activitySusceptible Resistant Ps aeruginosa Gram Positive : All Acinetobacter spp Gram Negative Cocci Klebsiella spp Neisseria gonorrhoeae Esch coli N. meningitidis Enterobacter spp Gram Negative Bacilli Salmonella spp Proteus group Shigella spp Serratia spp Haemophilus influenzae Burkholderia spp Bordetella pertusis Brucella spp. 19 Anaerobic GNB
  20. 20. Variable activityStenotrophomonas maltophiliaAeromonas sppVibrio spp. 20
  21. 21. Colistin Susceptibility Break PointsOrganization Bacteria MIC Disk Diffusion S I R S I RCLSI Acinetobacter spp <2 >4 No Break Points Pseudomonas <2 4 >8 < 10 > 11 aeruginosa Enterobacteriaceae No Break PointsEUCAST Acinetobacter spp <2 >4 No Break Points Pseudomonas <2 >4 aeruginosa Enterobacteriaceae* <2 >4 Only E.coli, Klebsiella spp & Enterobacter spp. 21
  22. 22. PK PD correlationConcentration dependent killing 22
  23. 23. Excretion of Colistin 23
  24. 24. Recent Recommendations for Dose Calculation Anti Agents Chemother 2011: 55: 3284 - 3294Loading dose: 6 M IU desired target conc. X 2 X body wt = 300 mg CBA ( 1 mg CBA = 12 500 IU)Maintenance dose: desired target conc. X (1.5 X Cr Cl + 30) mg CBAUseful to add Melatonin or Vit C as nephroprotectantsNot likely to attain AUC/MIC values likely to be effective for MIC >0.5;Donot use as monotherapy 24
  25. 25. Mechanism of action1. Polymyxin have strong positive charge & a hydrophobic aryl chain2. Initial target is LPS component of Outer membrane3. Displaces divalent cations: Ca & Mg4. Causes disruption of cell membrane5. Increased permeability & leakage of cell contents & subsequent cell death6. Polymyxin binds to Lipid A portion of LPS exhibit anti endotoxin activity 25
  26. 26. Routes of administration of colistinColistin Methane Sulphonate (CMS) IV (IM) Inhalation Intrathecal IntraventricularColistin Sulphate Local application Oral (for Gut decontamination) 26
  27. 27. Colistin by aerosolised routeNaesens R et al. BMS Infect Dis 2011; 11: 31720 ICU pts with Ps aeruginosa pneumonia 6 received colistin by inhalation only 5 only by IV; 9 combined All received concomitent β lactamClinical response & no deaths in 6/63/9 of combined & 5/5 of IV group diedDose: 2 M IU/by aerosole TID 27
  28. 28. Clinical use of colistin in childrenFalagas ME et al: Int J Anti Agents 2009; 33: 503 e1 - 13326 children for treatment & 44 for prophylaxis271 of 311 children were available for evaluation 235 (86.7%) cured; 10 (3.7%) improved 6 (2.2%) deteriorated; 20 (7.4%) diedNo infection in 44 children who received prophylaxisNephrotoxicity in 10 childrenSystemic Colistin is an effective & acceptable option for MDR infectionsDose: 25 k IU/kg TID 28
  29. 29. Mechanism of resistanceHetroresistance: Presence of colistin resistant subpopulation within a microbial population that is susceptible based on MIC.1. LPS change or loss2. Efflux pump/potassium system3. Colistinase is produced by B. polymyxa that produces colistin, but has not yet been detected in clinical isolates 29
  30. 30. Mechanism of resistanceMoffatt JH et al: Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss ofLipopolysaccharide Production . AAC 2010; 54: 4971 - 7 LPS 30
  31. 31. Efflux Pump mediated Resistance to Colistin 31
  32. 32. Phenotype of resistance by two compartment systemRegulatory Contributing Mechanism or Gene EffectSystem Factors Site of ActionPmrA-PmrB PmrE PhoP-PhoQ Reduces negative Reduced binding PmrHFIJKLM activation charge of the affinity Mildly acidic pH bacterias lipid A High iron and LPS concentrations Low magnesium concentrationsPhoP-PhoQ OprH Exogenous OprH proteins reduce the polyamines occupy binding site for Low magnesium membrane colistin concentrations magnesium sites 32
  33. 33. Resistance in Clinical isolates: Acinetobacter baumanniiLocation FindingsAustralia 93.8% of 16 clinical isolates were heteroresistant to colistin.Spain 19.1% of 115 clinical isolates were resistant to colistin.Korea 27.9% of 214 isolates were resistant to colistin, with most of these resistant strains susceptible to conventional antibiotics.Western Pacific 3.3% of 30 isolates were resistant to colistin, 23% of the 30 isolates were colistin heteroresistant.United States Ventilator-associated pneumonia in a 55-year-old woman was initially susceptible to colistin (MIC 0.5 mg/L); after i.v. therapy, high-level colistin resistance developed (MIC > 1024 mg/L)Argentina 46.4% of 28 isolates from 28 different patients in an ICU showed colistin heteroresistance. A 22-year-old man initially susceptible to colistin developed resistance (MIC 32 mg/L) after receiving 33 intrathecal colistin for 48 hrs.
  34. 34. Resistance in Clinical isolates : Pseudomonas aeruginosaPlace FindingsAustralia 47.8% of 23 clinical isolates from patients with cystic fibrosis were resistant to colistin.Germany 34.9% of nonmucoid and 51.9% of mucoid strains were susceptible to colistin among 385 isolates obtained from patients with cystic fibrosis.United Colistin-resistant isolates were obtained from 6Kingdom children with cystic fibrosis over a 5-yr period; the children had previously received aerosolized colistin for a mean duration of 3.1 yrs. 34
  35. 35. Resistance in Clinical isolates : Klebsiella pneumoniaeLocation FindingsGreece 18 colistin-resistant isolates were identified in a tertiary hospital over a 16-mo period.Australia 27.27% of 22 Clinical isolates colistin resistant; Resistance in isolates were colistin heteroresistance was seen in 93.8% of the 16 colistin-susceptible isolatesSouth Korea 6.8% of 221 isolates were colistin resistant 35
  36. 36. Combination: FIC evaluation Synergy Additive AntagonismDoripenem 9/12 3/12 0Amikacin 7/11 4/11 0Teicoplanin 10/11 1/11 0Cwfwpime 9/12 3/12 0Rifampicin 9/12 3/12 0 36
  37. 37. Combination by Kill Kinetics & Population analysisPs aeruginosa: Imipenem or RifampicinAcinetobacter spp.: Doripenem or CefepimeKleb pneumoniae: Meropenem or AmikacinSulbactam was not tested. 37
  38. 38. Colistin + Teichoplanin against Acinetobacter 38
  39. 39. Synergistic activity of sulbactam combined with colistinagainst colistin-resistant Acinetobacter baumannii 39
  40. 40. Zhai B et al. JAC 2010; 65: 931 - 938 40
  41. 41. Take home messages1. Colistin has emerged as effective treatment for carbapenem resistant Gram Negative infections2. Colistin is associated with lower mortality than no effective treatment in these infections.3. Colistin is associated with higher mortality than beta lactam antibiotics in sensitive bacterial infections.4. Nephrotoxicity rates are not higher with colistin, colistin induced nephrotoxicity is reversible5. Emergence of colistin resistance has been described in high use settings6. Synergy with carbapenem, rifampicin & sulbactam has been reported 41
  42. 42. 42

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