Polimyksyna E – „nowy” stary antybiotyk

The Polymyxin E – „new” old antibiotic

Łukasz Hońdo

Krakowski Szpital Specjalistyczny im. Jana Pawła II

Łukasz Hońdo
Krakowski Szpital Specjalistyczny
im. Jana Pawła II
ul. Prądnicka 80, 31-202 Kraków
Tel.: 12 614 20 00

Wpłynęło: 12.03.2018
Zaakceptowano: 06.06.2018
Opublikowano on-line: 13.07.2018


Hońdo Ł. Polimyksyna E – „nowy” stary antybiotyk. Zakażenia XXI wieku 2018;1(3):129–134.
doi: 10.31350/zakazenia/2018/3/ZZ2018023


Stosowanie antybiotyków powoduje w dalszym ciągu lawinowo narastającą oporność. Mimo zwiększającej się świadomości oraz jasnych alarmujących komunikatów ze strony specjalistów o rozwagę nadal w lecznictwie stosuje się coraz więcej leków przeciwinfekcyjnych. W tej sytuacji, aby były skuteczne, zaistniała konieczność stosowania coraz większych dawek oraz połączenia antybiotyków, które do niedawna nie były objęte EBM (Evidence Based Medicine). Polimyksyny to grupa antybiotyków peptydowych o spektrum skierowanym na pałeczki Gram-ujemne. Mimo że to stare antybiotyki, a zastosowanie praktyczne ma tylko jeden z nich, wciąż w praktyce farmakologicznej pojawiają się problemy terapeutyczne.

Słowa kluczowe: antybiotykoterapia, kolistymetat sodowy, kolistyna E, polimyksyna, polimyksyny

The use of antibiotics continues to cause a rapidly growing resistance. Despite the increasing social awareness and clear alarming messages from specialists to approach this matter with caution, the number of anti-infective used is increasing. We are forced to use higher doses and combinations of antibiotics which until recently were not covered by EBM (Evidence Based Medicine). Polymyxins are a group of peptide antibiotics against Gram-negative pathogens. Although these are old antibiotics and only one of them is used in practice, there still occur therapeutic problems in pharmacological practice.

Key words: antibiotictherapy, co listimethate sodium, co listin, polimixin, polymyxin E

  1. Komura S, Kurahashi K. Partial purification and properties of L-2,4-diaminobutyric acid activating enzyme from a polymyxin E producing organism. J Biochem 1979;86(4):1013–1021.
  2. Hoeprich PD. The polymyxins. Med Clin North Am. 1970;54(5):1257–1265.
  3. Brown JM, Dorman DC, Roy LP. Acute renal failure due to overdosage of c olistin. Med J Aust 1970;2(20):923–924.
  4. Ryan KJ, Schainuck LI, Hickman RO, Striker GE. Co listimethate toxicity. Report of a fatal case in a previously healthy child. JAMA 1969;207(11):2099–2101.
  5. Conway SP, Pond MN, Watson A, Etherington C, Robey HL, Goldman MH. Intravenous c olistin sulphomethate in acute respiratory exacerbations in adult patients with cystic fibrosis. Thorax 1997;52(11):987–993.
  6. Katz E, Demain AL. The peptide antibiotics of Bacillus: chemistry, biogenesis, and possible functions. Bacteriol Rev 1977;41(2):449–474.
  7. Orwa JA, Govaerts C, Busson R, Roets E, Van Schepdael A, Hoogmartens J. Isolation and structural characterization of c olistin components. J Antibiot (Tokyo) 2001;54(7):595–599.
  8. Storm DR, Rosenthal KS, Swanson PE. Polymyxin and related peptide antibiotics. Annu Rev Biochem 1977;46:723–763 [doi: 10.1146/annurev.bi.46.070177.003451].
  9. McMillan FH, Pattison IC. Sodium co listimethate. I. Dissociations of aminomethanesulfonates in aqueous solution. J Pharm Sci 1969;58(6):730–737.
  10. Wallace SJ, Li J, Rayner CR, Coulthard K, Nation RL. Stability of co listin methanesulfonate in pharmaceutical products and solutions for administration to patients [published online ahead of print July 7, 2008]. Antimicrob Agents Chemother 2008;52(9):3047–3051 [doi: 10.1128/AAC.00103-08].
  11. Karta Charakterystyki Produktu Leczniczego Co listin TZF, data zatwierdzenia 10.03.2014.
  12. Sánchez MB. Antibiotic resistance in the opportunistic pathogen Stenotrophomonas maltophilia. Front Microbiol 2015;6:658 [doi: 10.3389/fmicb.2015.00658].
  13. Fosse T, Giraud-Morin C, Madinier I. Induced co listin resistance as an identifying marker for Aeromonas phenospecies groups. Lett Appl Microbiol 2003;36(1):25–29.
  14. Catchpole CR, Andrews JM, Brenwald N, Wise R. A reassessment of the in-vitro activity of co listin sulphomethate sodium. J Antimicrob Chemother 1997 Feb;39(2):255–260.
  15. Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J i wsp. Emergence of plasmid-mediated co listin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016;16(2):161–168 [doi: 10.1016/S1473-3099(15)00424-7].
  16. Hernández M, Iglesias MR, Rodríguez-Lázaro D, Gallardo A, Quijada N, Miguela-Villoldo P, Campos MJ, Píriz S, López-Orozco
  17. G, de Frutos C i wsp. Co-occurrence of co listin-resistance genes mcr-1 and mcr-3 among multidrug-resistant Escherichia coli isolated from cattle, Spain, September 2015. Euro Surveill 2017;22(31):pii=30586 [doi: 10.2807/1560-7917.ES.2017.22.31.30586].
  18. Pragasam AK, Shankar C, Veeraraghavan B, Biswas I, Nabarro LE, Inbanathan FY, George B, Verghese S, Molecular mechanisms of co listin resistance in Klebsiella pneumoniae causing bacteremia from India – a first report. Front Microbiol 2017;7:2135 [doi: 10.3389/fmicb.2016.02135].
  19. Davis SD, Iannetta A, Wedgwood RJ. Activity of co listin against Pseudomonas aeruginosa: inhibition by calcium. J Infect Dis 1971;(6):610–612.
  20. Schindler M, Osborn MJ. Interaction of divalent cations and polymyxin B with lipopolysaccharide. Biochemistry 1979;18(20):4425–4430.
  21. Warren HS, Kania SA, Siber GR. Binding and neutralization of bacterial lipopolysaccharide by c olistin nonapeptide. Antimicrob Agents and Chemiother 1985;28(1):107–112.
  22. Westwood M, Ramaekers B, Whiting P, Tomini F, Joore M, Armstrong N i wsp. Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis. J Health Technol Assess 2015;19(96):v-xxv, 1–236 [doi: 10.3310/hta19960].
  23. Nation RL, Garonzik SM, Li J i wsp. Updated US and European dose recommendations for intravenous co listin: how do they perform? Clin Infect Dis 2016;62:552–558.
  24. Li J, Nation RL, Turnidge JD. Defining the dosage units for co listin methanesulfonate: urgent need for international harmonization. Antimicrob Agents Chemother. 2006(12):4231-4232 [Doi: 10.1128/AAC.00756-06].
  25. Bergen PJ, Landersdorfer CB, Zhang J i wsp. Pharmacokinetics and pharmacodynamics of „old” polymyxins: what is new? Diagn Microbiol Infect Dis 2012;74(3):213–223 [doi: 10.1016/j.diagmicrobio.2012.07.010].
  26. Bergen PJ, Li J, Nation RL. Dosing of c olistin-back to basic PK/PD. Curr Opin Pharmacol 2011;11(5):464–469 [doi: 10.1016/j.coph.2011.07.004].
  27. Nation RL, Li J. Co listin in the 21st century. Curr Opin Infect Dis 2009;22(6):535–543 [doi: 10.1097/QCO.0b013e328332e672].
    1st International Conference on Polymyxins. Prato, Italy, 2–4 May, 2013. http://monash.edu/pharm/about/events/polymyxins (accessed March 12, 2018).
  28. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news_detail_002194.jsp&mid=WC0b01ac058004d5c1 (accessed March 12, 2018).
  29. Bakthavatchalam YD, Pragasam AK, Biswas I, Veeraraghavan BJ. Polymyxin susceptibility testing, interpretative breakpoints and resistance mechanisms: An update. J Glob Antimicrob Resist 2018;12:124–136 [doi: 10.1016/j.jgar.2017.09.011].
  30. Cheah SE, Wang J, Nguyen VT, Turnidge JD, Li J, Nation RL. New pharmacokinetic/pharmacodynamic studies of systemically administere d co listin against Pseudomonas aeruginosa and Acinetobacter baumannii in mouse thigh and lung infection models: smaller response in lung infection. J Antimicrob Chemother 2015;70(12):3291–3297 [doi: 10.1093/jac/dkv267].
  31. Dudhani RV, Turnidge JD, Nation RL, Li J. fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of co listin against Acinetobacter baumannii in murine thigh and lung infection models. J Antimicrob Chemother 2010 Sep;65(9):1984–1990.
  32. Khan DD, Friberg LE, Nielsen EI. A pharmacokinetic/pharmacodynamic (PK/PD) model based on in vitro time-kill data predicts the in vivo PK/PD index of co listin. J Antimicrob Chemother 2016;71(7):1881–1884 [doi: 10.1093/jac/dkw057].
  33. Sandri AM, Landersdorfer CB, Jacob J i wsp. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis 2013;57(4):524–531 [doi: 10.1093/cid/cit334].
  34. Nation RL, Garonzik SM, Thamlikitkul V, Giamarellos-Bourboulis EJ, Forrest A, Paterson DL, Li J, Silveira FP. Dosing guidance for intravenous colistin in critically-ill patients. Clin Infect Dis 2017;64(5):565–571 [doi: 10.1093/cid/ciw839].
  35. Couet W, Grégoire N, Marchand S, Mimoz O. C olistin pharmacokinetics: the fog is lifting. Clin Microbiol Infect. 2012;18(1):30–39 [doi: 10.1111/j.1469-0691.2011.03667.x].
  36. Nation RL, Garonzik SM, Thamlikitkul V i wsp. Dosing guidance for intravenous co listin in critically-ill patients. Clin Infect Dis. 2017;64(5):565–571 [doi: 10.1093/cid/ciw839].
  37. Tunkel AR, Hartman BJ, Kaplan SL i wsp. Practice guidelines for the nanagement of bacterial meningitis. Clin Infect Dis 2004;39(9): 1267–1284 [doi: 10.1086/425368].
  38. Lu Q, Luo R, Bodin L i wsp. Efficacy of high-dose nebulized co listin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, Anesthesiology 2012;117(6):1335–1347 [doi: 10.1097/ALN.0b013e31827515de].
  39. Valachis A, Samonis G, Kofteridis DP. The role of aerosolized co listin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med 2015;43(3):527-533 [doi: 10.1097/CCM.0000000000000771].
  40. Garonzik SM, Li J, Thamlikitkul V i wsp. Population pharmacokinetics of co listin methanesulfonate and formed co listin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011;55(7):3284–3294 [doi: 10.1128/AAC.01733-10].
  41. Li J, Rayner CR, Nation RL i wsp. Pharmacokinetics of co listin methanesulfonate and co listin in a critically ill patient receiving continuous venovenous hemodiafiltration, Antimicrob Agents Chemother 2005;49(11):4814–4815 [doi: 10.1128/AAC.49.11.4814-4815.2005].
  42. Heintz BH, Matzke GR, Dager WE, Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis, Pharmacotherapy 2009;29(5):562–577 [doi: 10.1592/phco.29.5.562].
  43. Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, Mouton JW, Paterson DL, Tam VH, Theuretzbacher U, Tsuji BT, Turnidge JD. Consistent global approach on reporting of co listin doses to promote safe and effective use. Clin Infect Dis 2014;58(1):139–141 [doi: 10.1093/cid/cit680].
  44. Liu X, Zhao M, Chen Y, Bian X, Li Y, Shi J, Zhang J. Synergistic killing by meropenem and co listin combination of carbapenem-resistant Acinetobacter baumannii isolates from Chinese patients in an in vitro pharmacokinetic/pharmacodynamic model. Int J Antimicrob Agents. 2016;48(5):559–563 [doi: 10.1016/j.ijantimicag.2016.07.018].
  45. Lenhard JR, Thamlikitkul V, Silveira FP, Garonzik SM, Tao X, Forrest A i wsp. Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity. J Antimicrob Chemother 2017;72(5):1415–1420 [doi: 10.1093/jac/dkx002].
  46. Timurkaynak F, Can F, Azap OK, Demirbilek M, Arslan H, Karaman SO. In vitro activities of non-traditional antimicrobials alone or in combination against multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii isolated from intensive care units. Int J Antimicrob Agents 2006;27(3):224–228 [doi: 10.1016/j.ijantimicag.2005.10.012].
  47. Deris ZZ, Yu HH, Davis K, Soon RL, Jacob J, Ku CK i wsp. The combination of co listin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses c olistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother 2012;56(10):5103–5112 [doi: 10.1128/AAC.01064-12].
  48. Bergen PJ, Bulman ZP, Saju S, Bulitta JB, Landersdorfer C, Forrest A i wsp. Polymyxin combinations: pharmacokinetics and pharmacodynamics for rationale use. Pharmacotherapy 2015;35(1):34–42 [doi: 10.1002/phar.1537].
  49. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD i wsp. Co listin alone versus c olistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis 2018;18(4):391–400 [doi: 10.1016/S1473-3099(18)30099-9].
  50. Karageorgopoulos DE, Falagas ME. Current control and treatment of multidrug-resistant Acinetobacter baumannii infections. Lancet Infect Dis 2008;8:751–762 [doi: 10.1016/S1473-3099(08)70279-2

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