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Polymyxins: An overview

Authors
Graeme MacLaren, MBBS, FCICM, FRACP, FCCM
Denis Spelman, MBBS, FRACP, FRCPA, MPH
Section Editor
David C Hooper, MD
Deputy Editor
Allyson Bloom, MD

INTRODUCTION

The polymyxins comprise a separate class of antibiotics and include a number of different compounds. However, only polymyxin B and polymyxin E (also known as colistin) are in clinical use [1]. They were isolated from Paenibacillus polymyxa and became available for clinical use in the 1950s [2,3]. Colistin was historically given as an intramuscular injection for the treatment of gram-negative bacterial infections, but fell out of favor after aminoglycosides became available because of its significant side effects, particularly nephrotoxicity.

More recently, intravenous polymyxin B and colistin have been used more frequently in the treatment of otherwise panresistant nosocomial infections, especially those due to Pseudomonas and Acinetobacter spp [4-8]. They are also used in aerosolized form for patients with cystic fibrosis. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

Polymyxin B and colistin have almost identical chemical structures and comparable mechanisms of action, resistance patterns, and spectra of activity. However, they have very different pharmacokinetics and pharmacodynamics [9]. These will all be reviewed here along with their adverse effects. The clinical settings in which the polymyxins may be used are discussed separately in the appropriate topic reviews.

MECHANISM OF ACTION

Polymyxins are bactericidal drugs that bind to lipopolysaccharides (LPS) and phospholipids in the outer cell membrane of gram-negative bacteria. They competitively displace divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death [3,10,11].

In addition to their bactericidal effect, the polymyxins can bind and neutralize LPS and may reduce the pathophysiologic effects of endotoxin in the circulation [12,13].

                    
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Literature review current through: Nov 2017. | This topic last updated: Nov 01, 2017.
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References
Top
  1. Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005; 40:1333.
  2. Kumazawa J, Yagisawa M. The history of antibiotics: the Japanese story. J Infect Chemother 2002; 8:125.
  3. Nation RL, Li J. Polymyxins. In: The Use of Antibiotics, 6th Ed, Kucers A (Ed), Heinemann, London 2010. p.955.
  4. Levin AS, Barone AA, Penço J, et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999; 28:1008.
  5. Garnacho-Montero J, Ortiz-Leyba C, Jiménez-Jiménez FJ, et al. Treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP) with intravenous colistin: a comparison with imipenem-susceptible VAP. Clin Infect Dis 2003; 36:1111.
  6. Markou N, Apostolakos H, Koumoudiou C, et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative bacilli in critically ill patients. Crit Care 2003; 7:R78.
  7. Linden PK, Kusne S, Coley K, et al. Use of parenteral colistin for the treatment of serious infection due to antimicrobial-resistant Pseudomonas aeruginosa. Clin Infect Dis 2003; 37:e154.
  8. Michalopoulos AS, Tsiodras S, Rellos K, et al. Colistin treatment in patients with ICU-acquired infections caused by multiresistant Gram-negative bacteria: the renaissance of an old antibiotic. Clin Microbiol Infect 2005; 11:115.
  9. Tran TB, Velkov T, Nation RL, et al. Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents 2016; 48:592.
  10. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacother 1999; 33:960.
  11. Li J, Turnidge J, Milne R, et al. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 2001; 45:781.
  12. Giacometti A, Cirioni O, Ghiselli R, et al. Antiendotoxin activity of antimicrobial peptides and glycopeptides. J Chemother 2003; 15:129.
  13. Warren HS, Kania SA, Siber GR. Binding and neutralization of bacterial lipopolysaccharide by colistin nonapeptide. Antimicrob Agents Chemother 1985; 28:107.
  14. Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol 2001; 39:183.
  15. Li J, Nation RL, Milne RW, et al. Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 2005; 25:11.
  16. Karabinis A, Paramythiotou E, Mylona-Petropoulou D, et al. Colistin for Klebsiella pneumoniae-associated sepsis. Clin Infect Dis 2004; 38:e7.
  17. Marchaim D, Chopra T, Pogue JM, et al. Outbreak of colistin-resistant, carbapenem-resistant Klebsiella pneumoniae in metropolitan Detroit, Michigan. Antimicrob Agents Chemother 2011; 55:593.
  18. Giani T, Arena F, Vaggelli G, et al. Large Nosocomial Outbreak of Colistin-Resistant, Carbapenemase-Producing Klebsiella pneumoniae Traced to Clonal Expansion of an mgrB Deletion Mutant. J Clin Microbiol 2015; 53:3341.
  19. Capone A, Giannella M, Fortini D, et al. High rate of colistin resistance among patients with carbapenem-resistant Klebsiella pneumoniae infection accounts for an excess of mortality. Clin Microbiol Infect 2013; 19:E23.
  20. Antoniadou A, Kontopidou F, Poulakou G, et al. Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. J Antimicrob Chemother 2007; 59:786.
  21. Baron S, Hadjadj L, Rolain JM, Olaitan AO. Molecular mechanisms of polymyxin resistance: knowns and unknowns. Int J Antimicrob Agents 2016; 48:583.
  22. Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2006; 50:2946.
  23. Owen RJ, Li J, Nation RL, Spelman D. In vitro pharmacodynamics of colistin against Acinetobacter baumannii clinical isolates. J Antimicrob Chemother 2007; 59:473.
  24. Liu YY, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16:161.
  25. McGann P, Snesrud E, Maybank R, et al. Escherichia coli Harboring mcr-1 and blaCTX-M on a Novel IncF Plasmid: First Report of mcr-1 in the United States. Antimicrob Agents Chemother 2016; 60:4420.
  26. Poirel L, Kieffer N, Brink A, et al. Genetic Features of MCR-1-Producing Colistin-Resistant Escherichia coli Isolates in South Africa. Antimicrob Agents Chemother 2016; 60:4394.
  27. Doumith M, Godbole G, Ashton P, et al. Detection of the plasmid-mediated mcr-1 gene conferring colistin resistance in human and food isolates of Salmonella enterica and Escherichia coli in England and Wales. J Antimicrob Chemother 2016; 71:2300.
  28. Levin AS. Treatment of Acinetobacter spp infections. Expert Opin Pharmacother 2003; 4:1289.
  29. Arroyo LA, García-Curiel A, Pachón-Ibañez ME, et al. Reliability of the E-test method for detection of colistin resistance in clinical isolates of Acinetobacter baumannii. J Clin Microbiol 2005; 43:903.
  30. Lo-Ten-Foe JR, de Smet AM, Diederen BM, et al. Comparative evaluation of the VITEK 2, disk diffusion, etest, broth microdilution, and agar dilution susceptibility testing methods for colistin in clinical isolates, including heteroresistant Enterobacter cloacae and Acinetobacter baumannii strains. Antimicrob Agents Chemother 2007; 51:3726.
  31. Tan TY, Ng LS, Poh K. Susceptibility testing of unconventional antibiotics against multiresistant Acinetobacter spp. by agar dilution and Vitek 2. Diagn Microbiol Infect Dis 2007; 58:357.
  32. Tan TY, Ng SY. Comparison of Etest, Vitek and agar dilution for susceptibility testing of colistin. Clin Microbiol Infect 2007; 13:541.
  33. https://clsi.org/media/1700/clsi-news-winter-2016.pdf.
  34. CDC Health Alert Network: Alert to U.S. Healthcare Facilities: First mcr-1 Gene in E. coli Bacteria found in a Human in the United States; June 13, 2016. https://emergency.cdc.gov/han/han00390.asp (Accessed on September 08, 2017).
  35. Chew KL, La MV, Lin RTP, Teo JWP. Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr-Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution. J Clin Microbiol 2017; 55:2609.
  36. Clinical and Laboratory Standards Institute (CLSI). 2017. Performance standards for antimicrobial susceptibility testing, 27th ed. CLSI document M100-S27. CLSI, Wayne, PA.
  37. Kunin CM, Bugg A. Binding of polymyxin antibiotics to tissues: the major determinant of distribution and persistence in the body. J Infect Dis 1971; 124:394.
  38. Reed MD, Stern RC, O'Riordan MA, Blumer JL. The pharmacokinetics of colistin in patients with cystic fibrosis. J Clin Pharmacol 2001; 41:645.
  39. Li J, Coulthard K, Milne R, et al. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother 2003; 52:987.
  40. Stein A, Raoult D. Colistin: an antimicrobial for the 21st century? Clin Infect Dis 2002; 35:901.
  41. Jiménez-Mejías ME, Pichardo-Guerrero C, Márquez-Rivas FJ, et al. Cerebrospinal fluid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis. Eur J Clin Microbiol Infect Dis 2002; 21:212.
  42. Markantonis SL, Markou N, Fousteri M, et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother 2009; 53:4907.
  43. Sandri AM, Landersdorfer CB, Jacob J, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens. Clin Infect Dis 2013; 57:524.
  44. Tam VH, Schilling AN, Vo G, et al. Pharmacodynamics of polymyxin B against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49:3624.
  45. Sandri AM, Landersdorfer CB, Jacob J, et al. Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis. J Antimicrob Chemother 2013; 68:674.
  46. Thamlikitkul V, Dubrovskaya Y, Manchandani P, et al. Dosing and Pharmacokinetics of Polymyxin B in Patients with Renal Insufficiency. Antimicrob Agents Chemother 2017; 61.
  47. http://www.medicines.org.uk/emc/medicine/1590 (Accessed on October 23, 2017).
  48. European Medicines Agency completes review of polymyxin-based medicines. December 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2014/10/WC500176334.pdf (Accessed on May 08, 2016).
  49. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2011; 53:879.
  50. Deryke CA, Crawford AJ, Uddin N, Wallace MR. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother 2010; 54:4503.
  51. Gauthier TP, Wolowich WR, Reddy A, et al. Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients. Antimicrob Agents Chemother 2012; 56:2392.
  52. Pogue JM, Ortwine JK, Kaye KS. Optimal Usage of Colistin: Are We Any Closer? Clin Infect Dis 2015; 61:1778.
  53. Nation RL, Garonzik SM, Li J, et al. Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform? Clin Infect Dis 2016; 62:552.
  54. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant gram-negative bacteremia. Clin Infect Dis 2013; 56:398.
  55. Nation RL, Garonzik SM, Thamlikitkul V, et al. Dosing guidance for intravenous colistin in critically-ill patients. Clin Infect Dis 2017; 64:565.
  56. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012; 54:1720.
  57. Trifi A, Abdellatif S, Daly F, et al. Efficacy and Toxicity of High-Dose Colistin in Multidrug-Resistant Gram-Negative Bacilli Infections: A Comparative Study of a Matched Series. Chemotherapy 2016; 61:190.
  58. Benattar YD, Omar M, Zusman O, et al. The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study. Clin Infect Dis 2016; 63:1605.
  59. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother 2009; 53:3430.
  60. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother 2011; 55:3284.
  61. Elefritz JL, Bauer KA, Jones C, et al. Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia. J Intensive Care Med 2017; 32:487.
  62. Dalfino L, Puntillo F, Ondok MJ, et al. Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study. Clin Infect Dis 2015; 61:1771.
  63. Solé-Lleonart C, Roberts JA, Chastre J, et al. Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines. Clin Microbiol Infect 2016; 22:359.
  64. FDA Drug Safety Podcasts — Colistimethate (marketed as Coly-Mycin M and generic products) http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm077907.htm (Accessed on December 06, 2011).
  65. Abdellatif S, Trifi A, Daly F, et al. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care 2016; 6:26.
  66. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 2010; 65:2645.
  67. Liu D, Zhang J, Liu HX, et al. Intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis. Int J Antimicrob Agents 2015; 46:603.
  68. Fernandez-Viladrich P, Corbella X, Corral L, et al. Successful treatment of ventriculitis due to carbapenem-resistant Acinetobacter baumannii with intraventricular colistin sulfomethate sodium. Clin Infect Dis 1999; 28:916.
  69. Vasen W, Desmery P, Ilutovich S, Di Martino A. Intrathecal use of colistin. J Clin Microbiol 2000; 38:3523.
  70. Berlana D, Llop JM, Fort E, et al. Use of colistin in the treatment of multiple-drug-resistant gram-negative infections. Am J Health Syst Pharm 2005; 62:39.
  71. Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis 2017.
  72. Kallel H, Hergafi L, Bahloul M, et al. Safety and efficacy of colistin compared with imipenem in the treatment of ventilator-associated pneumonia: a matched case-control study. Intensive Care Med 2007; 33:1162.
  73. Goverman J, Weber JM, Keaney TJ, Sheridan RL. Intravenous colistin for the treatment of multi-drug resistant, gram-negative infection in the pediatric burn population. J Burn Care Res 2007; 28:421.
  74. Linden PK, Paterson DL. Parenteral and inhaled colistin for treatment of ventilator-associated pneumonia. Clin Infect Dis 2006; 43 Suppl 2:S89.
  75. Hartzell JD, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009; 48:1724.
  76. Shields RK, Anand R, Clarke LG, et al. Defining the incidence and risk factors of colistin-induced acute kidney injury by KDIGO criteria. PLoS One 2017; 12:e0173286.
  77. Kubin CJ, Ellman TM, Phadke V, et al. Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy. J Infect 2012; 65:80.
  78. Justo JA, Bosso JA. Adverse reactions associated with systemic polymyxin therapy. Pharmacotherapy 2015; 35:28.
  79. Pogue JM, Ortwine JK, Kaye KS. Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins? Int J Antimicrob Agents 2016; 48:622.
  80. Akajagbor DS, Wilson SL, Shere-Wolfe KD, et al. Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center. Clin Infect Dis 2013; 57:1300.
  81. Phe K, Lee Y, McDaneld PM, et al. In vitro assessment and multicenter cohort study of comparative nephrotoxicity rates associated with colistimethate versus polymyxin B therapy. Antimicrob Agents Chemother 2014; 58:2740.
  82. Kim J, Lee KH, Yoo S, Pai H. Clinical characteristics and risk factors of colistin-induced nephrotoxicity. Int J Antimicrob Agents 2009; 34:434.
  83. Sirijatuphat R, Limmahakhun S, Sirivatanauksorn V, et al. Preliminary clinical study of the effect of ascorbic acid on colistin-associated nephrotoxicity. Antimicrob Agents Chemother 2015; 59:3224.
  84. Falagas ME, Rizos M, Bliziotis IA, et al. Toxicity after prolonged (more than four weeks) administration of intravenous colistin. BMC Infect Dis 2005; 5:1.
  85. Wolinsky E, Hines JD. Neurotoxic and nephrotoxic effects of colistin in patients with renal disease. N Engl J Med 1962; 266:759.
  86. Lindesmith LA, Baines RD Jr, Bigelow DB, Petty TL. Reversible respiratory paralysis associated with polymyxin therapy. Ann Intern Med 1968; 68:318.
  87. Koch-Weser J, Sidel VW, Federman EB, et al. Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med 1970; 72:857.
  88. Beringer P. The clinical use of colistin in patients with cystic fibrosis. Curr Opin Pulm Med 2001; 7:434.
  89. Mattos KPH, Cintra ML, Gouvêa IR, et al. Skin hyperpigmentation following intravenous polymyxin B treatment associated with melanocyte activation and inflammatory process. J Clin Pharm Ther 2017; 42:573.