Abstract
Polymyxins (polymyxin B and colistin) are bactericidal pentacationic cyclic lipodecapeptides that act specifically on Gram-negative bacteria. They were largely abandoned because of their toxicity to kidney proximal tubuli. Now they have been reinstated, in spite of their toxicity, in the therapy of severe infections caused by extremely multiresistant strains. Such strains are now rapidly emerging and spreading. The nephrotoxicity of polymyxins does complicate the therapy, may even require its discontinuation, and must be weighed against the beneficial effects on patient survival. Furthermore, in the recent years it has become increasingly clear that the current dosage regimens are suboptimal in critically ill patients. Clinicians are advised to use larger doses, but this further increases nephrotoxicity. Since there is notably synergy between polymyxins and several other antibiotics, combination therapies may be useful, and clinical evidence for their advantages is currently accumulating. Novel, less nephrotoxic compounds that have strong antibacterial activity would be very welcome. The nephrotoxicity of polymyxins might be related to their very highly cationic nature. In contrast to the old polymyxins, which carry five positive charges, NAB739 carries three positive charges only. The activity of NAB739 against Escherichia coli and Klebsiella pneumoniae is quite close to that of polymyxin B. Pieces of indirect evidence suggest that NAB739 might be less nephrotoxic than the old polymyxins. Ongoing studies compare the efficacy and nephrotoxicity of NAB739 and polymyxin B in animal models. Useful compounds might also include NAB7061 and NAB741, both carrying three positive charges. They lack potent direct action but sensitize Gram-negative bacteria to other antibiotics by facilitating their entry inside the cell.
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Ali FE, Cao G, Poydal A, Vaara T, Nation RL, Vaara M, Li J (2009) Pharmacokinetics of novel antimicrobial cationic peptides NAB7061 and NAB739 in rats following intravenous administration. J Antimicrob Chemother 64:1067–1070
Arhin FF, Sarmiento I, Belley A, McKay GA, Draghi DC, Grover P, Sahm DF, Parr TR Jr, Moeck G (2008) Effect of polysorbate 80 on oritavancin binding to plastic surfaces: implications for susceptibility testing. Antimicrob Agents Chemother 52:1597–1603
Arya A, Li T, Zhang S, Chuong L, Kang C, Zhang X, Mortin LI (2010) Efficacy of CB-182,804, a novel polymyxin analog, in rat and mouse models of Gram-negative bacterial infections. Abstr 50th Intersci Conf Antimicrob. Agents Chemother, Boston, abstr F1-1627
Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, Dhanji H, Chart H, Bou G, Livermore DM, Woodford N (2011) Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother 55:3370–3379
Bergen PJ, Li J, Nation RL (2011) Dosing of colistin-back to basic PK/PD. Curr Opin Pharmacol 11:464–469
Bogdanovich T, Adams-Haduch JM, Tian GB, Nguyen MH, Kwak EJ, Muto CA, Doi Y (2011) Colistin-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the international epidemic clone ST258. Clin Infect Dis 53:373–376
Brown MRW, Winsley BE (1971) Synergism between polymyxin and Polysorbate 80 against Pseudomonas aeruginosa. J Gen Microbiol 68:367–373
CLSI (2012) M07–A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 9th edn. Clinical and Laboratory Standards Institute, Wayne
Coleman S, Deats T, Pawliuk R, Chavan A, Oleson FB Jr (2010) CB-182,804 is less nephrotoxic as compared to polymyxin B in monkeys following seven days of repeated intravenous dosing. Abstr 50th Intersci Conf Antimicrob Agents Chemother, Boston, abstr F1-1630
Couet W, Grégoire N, Marchand S, Mimoz O (2012) Colistin pharmacokinetics: the fog is lifting. Clin Microbiol Infect 18:30–39
Das D, Buyk J, Van Bambeke F, Lorent J, Mingeot-Leclercq MP, Gobin P, Couet W, Tulkens PM (2011) Abstr 51th Intersci Conf Antimicrob Agents Chemother, abstr F2-170. Comparative assessment of antibacterial and ccytotoxic effects of colistin (CST) colistin methanesulfonate (CMS) and polymyxin B (PMB) using Pseudomonas aeruginosa, macrophages and renal cells, and liposomes
Davies B, Cohen J (2011) Endotoxin removal devices for the treatment of sepsis and septic shock. Lancet Infect Dis 11:65–71
Falagas ME, Kasiakou SK (2006) Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care 10:R27
Falagas ME, Rafailidis PI (2009) Nephrotoxicity of colistin: new insight into an old antibiotic. Clin Infect Dis 48:1729–1731
Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, Kapaskelis A, Nikita D, Michalopoulos A (2010) Colistin therapy for microbiologically documented multidrug-resistant Gram-negative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 35:194–199
Fernández-Reyes M, Rodriguez-Falcón M, Chiva C, Pachón J, Andreu D, Rivas L (2009) The cost of resistance to colistin in Acinetobacter baumannii: a proteomic perspective. Proteonomics 9:1632–1645
Froelich JM, Tran K (2006) Wall D (2006) A pmrA constitutive mutant sensitizes Escherichia coli to deoxycholic acid. J Bacteriol 188:1180–1183
Gales AC, Reis AO, Jones RN (2001) Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol 39:183–190
Gales AC, Jones RN, Sader HS (2010) Contemporary activity of colistin and polymyxin B against a worldwide collection of gram-negative pathogens: results from the SENTRY antimicrobial surveillance program (2006–09). J Antimicrob Chemother 66:2070–2074
Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silveira FP, Forrest A, Nation RL (2011) 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 55:3284–3294
Gunn JS (2008) The Salmonella PmrAB regulon: lipopolysaccharide modifications, antimicrobial peptide resistance and more. Trends Microbiol 16:284–290
Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, Vishnepolsky M, Weintraub A, Wortmann G (2009) Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 48:1724–1728
Karvanen M, Malmberg C, Mohamed A, Lagerbäck M, Friberg LE, Cars O (2011) Colistin is extensively lost during normal experimental conditions. Abstr 51th Intersci Conf Antimicrob Agents Chemother, Chicago, abstr D-690.
Katsuma N, Sato Y, Ohki K, Okimura K, Ohnishi K, Sakura N (2009) Development of des-fatty acyl-polymyxin B decapeptide analogs with Pseudomonas aeruginosa-specific antimicrobial activity. Chem Pharm Bull 57:332–336
Keith DD, Borders D, Curran WV, Leese RA, Mahamoon A, Jarolman H, Francis ND, Zhang Y, Arya A, Cotroneo N, Mortin LI, Silverman J, Brian P (2010) Synthesis and activity of CB-182,804: a novel polymyxin analog active against clinically relevant Gram-negative bacteria. Abstr 50th Intersci Conf Antimicrob Agents Chemother, Boston, abstr F1-1619.
Kwa AL, Lim TP, Low JG, Hou J, Kurup A, Prince RA, Tam VH (2008) Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections. Diagn Microbiol Infect Dis 60:163–167
Kwa AL, Abdelraouf K, Low JG, Tam VH (2011) Pharmacokinetics of polymyxin B in a patient with renal insufficiency: a case report. Clin Infect Dis 52:1280–1281
Landman D, Georgescu C, Martin DA, Quale J (2008) Polymyxins revisited. Clin Microbiol Rev 21:449–465
Landman D, Urban C, Bäcker M, Kelly P, Shah N, Babu E, Bratu S, Quale J (2010) Susceptibility profiles, molecular epidemiology, and detection of KPC-producing Escherichia coli isolates from the New York City vicinity. J Clin Microbiol 48:4604–4607
Lee J, Patel G, Huprikar S, Calfee DP, Jenkins SG (2009) Decreased susceptibility to polymyxin B during treatment for carbapenem-resistant Klebsiella pneumoniae infection. Antimicrob Agents Chemother 47:1611–1612
Li J, Nation RL, Owen RJ, Wong S, Spelman D, Franklin C (2007) Antibiograms of multidrug-resistant clinical Acinetobacter baumannii: promising therapeutic options for treatment of infection with colistin-resistant strains. Clin Infect Dis 45:594–598
Li J, Velkov T, Nation RL, Thompson PE (2010) Patent application WO2010/130007 A1
Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A, Forrest A, Bulitta J, Tsuji BT (2010) Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacother 30:1279–1291
López-Rojas R, Domínguez-Herrera J, McConnell MJ, Docobo-Peréz F, Smani Y, Fernández-Reyes M, Rivas L, Pachón J (2011) Impaired virulence and in vivo fitness of colistin-resistant Acinetobacter baumannii. J Infect Dis 203:545–548
Lo-Ten-Foe JR, de Smet AM, Diederen BMW, Kluytmans JAJ, van Keulen PHJ (2007) 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 51:3726–3730
Markou N, Markantonis SL, Dimitrakis E, Panidis D, Boutzouka E, Karatzas S, Rafailidis P, Apostolakos H, Baltopoulos G (2008) Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther 30:143–151
Meyers E, Parker WL, Brown WE (1974) EM49: a new polypeptide antibiotic active against cell membranes. Ann NY Acad Sci 234:493–501
Michalopoulos AS, Falagas ME (2011) Colistin: recent data on pharmacodynamics properties and clinical efficacy in critically ill patients. Ann Intensive Care 1:30
Mingeot-Leclercq MP, Tulkens PM, Denamur S, Vaara T, Vaara M (2012) Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells. Peptides 35:248–252
Moffatt JH, Harper M, Harrison P, Hale JD, Vinogradov E, Seemann T, Henry R, Crane B, St Michael F, Cox AD, Adler B, Nation RL, Li J, Boyce JD (2010) Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother 54:4971–4977
Murata T, Tseng W, Guina T, Miller SI, Nikaido H (2007) PhoPQ-mediated regulation produces a more robust permeability barrier in the outer membrane of Salmonella enterica Serovar typhimurium. J Bacteriol 189:7213–7222
Nation RL, Li J (2009) Colistin in the 21st century. Curr Opin Infect Dis 22:535–543
Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656
Oliveira MS, Prado GVB, Costa SF, Grinbaum RS, Levin AS (2009) Polymyxin B and colistimethate are comparable as to efficacy and renal toxicity. Diagn Microbiol Infect Dis 65:431–434
Pastewski AA, Caruso P, Parris AR, Dizon R, Kopec R, Sharma S, Mayer S, Ghitan M, Chapnick EK (2008) Parenteral polymyxin B use in patients with multidrug-resistant Gram-negative bacteremia and urinary tract infections: a retrospective case series. Ann Pharmacother 42:1177–1187
Pogue JM, Lee J, Marchaim D, Yee V, Zhao JJ, Chopra T, Lephart P, Kaye KS (2011) Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 53:879–884
Quale J, Shah N, Kelly P, Babu E, Bäcker M, Rosas-Garcia G, Salamera J, George A, Bratu S, Landman D (2012) Activity of polymyxin B and the novel polymyxin analogue CB-182,804 against contemporary Gram-negative pathogens in New York City. Microb Drug Resist 13:574–581
Raetz CRH, Reynolds CM, Trent MS, Bishop RE (2007) Lipid A modification systems in Gram-negative bacteria. Annu Rev Biochem 76:295–329
Rennie RP, Koeth L, Jones RN, Fritsche TR, Knapp CC, Killian SB, Goldstein BP (2007) Factors influencing broth microdilution antimicrobial susceptibility test results for dalbavancin, a new glycopeptide agent. J Clin Microbiol 45:3151–3154
Rolain JM, Roch A, Castanier M, Papazian L, Raoult D (2011) Acinetobacter baumannii resistant to colistin with impaired virulence: a case report from France. J Infect Dis 204:1146–1147
Sader HS, Farrell DJ, Jones RN (2011) Susceptibility of Klebsiella spp. to colistin and polymyxin B: results from the SENTRY Antimicrobial Surveillance Program (2006–2009). Int J Antimicrob Agents 37:174–175
Sato Y, Shindo M, Sakura N, Uchida Y, Kato I (2011) Novel des-fatty acyl-polymyxin B derivatives with Pseudomonas aeruginosa-specific antimicrobial activity. Chem Pharm Bull 59:597–602
Servais H, Jossin Y, Van Bambeke F, Tulkens PM, Mingeot-Leclercq M-P (2006) Gentamicin causes apoptosis at low concentrations in renal LLC-PK1 cells subjected to electroporation. Antimicrob Agents Chemother 50:1213–1221
Simner PJ, Zhanel GG, Pitout J, Tailor F, McCracken M, Mulvey MR, Lagacé-Wiens PR, Adam HJ, Hoban DJ, Canadian Antimicrobial Resistance Alliance (CARA) (2011) Prevalence and characterization of extended-spectrum β-lactamase- and AmpC β-lactamase-producing Escherichia coli: results of the CANWARD 2007-2009 study. Diagn Microbiol Infect Dis 69:326–334
Tam VH, Cao H, Ledesma KR, Hu M (2011) In vitro potency of various polymyxin B components. Antimicrob Agents Chemother 55:4490
Tsubery H, Ofek I, Cohen S, Fridkin M (2000) The functional association of polymyxin B with bacterial lipopolysaccharide is stereospecific: studies on polymyxin B nonapeptide. Biochemistry 39:11838–11844
Tsubery H, Ofek I, Cohen S, Fridkin M (2001) N-terminal modifications of polymyxin nonapeptide and their effect on antibacterial activity. Peptides 22:1675–1681
Vaara M (1981) Increased outer membrane resistance to ethylenediamine tetraacetate and cations in novel lipid a mutants. J Bacteriol 48:426–434
Vaara M (1992) Agents that increase the permeability of the outer membrane. Microbiol Rev 56:395–411
Vaara M (2010) Polymyxins and their novel derivatives. Curr Opin Microbiol 13:574–581
Vaara M, Vaara T (1983) Sensitization of Gram-negative bacteria to antibiotics and complement by a non-toxic oligopeptide. Nature (London) 303:526–528
Vaara M, Vaara T (1994) Ability of cecropin B to penetrate the enterobacterial outer membrane. Antimicrob Agents Chemother 38:2498–2501
Vaara M, Vaara T, Sarvas M (1979) Decreased binding of polymyxin by polymyxin-resistant mutants of Salmonella typhimurium. J Bacteriol 139:664–667
Vaara M, Vaara T, Jensen M, Helander I, Nurminen M, Rietschel E, Mäkelä P (1981) Characterization of the lipopolysaccharide from the polymyxin-resistant pmrA mutants of Salmonella typhimurium. FEBS Lett 129:145–149
Vaara M, Viljanen P, Vaara T, Mäkelä PH (1984) An outer membrane-disorganizing peptide PMBN sensitizes E. coli strains to serum bactericidal action. J Immunol 132:2582–2589
Vaara M, Fox J, Loidl G, Siikanen O, Apajalahti J, Hansen F, Frimodt-Moeller N, Nagai J, Takano M, Vaara T (2008) Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. Antimicrob Agents Chemother 52:3229–3236
Vaara M, Siikanen O, Apajalahti J, Fox J, Frimodt-Moeller J, He H, Poydyal A, Li J, Nation RL, Vaara T (2010a) A novel polymyxin derivative that lacks the fatty acid tail and carries only three positive charges has strong synergism with agents excluded by the intact outer membrane. Antimicrob Agents Chemother 54:3341–3346
Vaara M, Siikanen O, Apajalahti J, Frimodt-Møller N, Vaara T (2010b) Susceptibility of carbapenemase-producing strains of Klebsiella pneumoniae and Escherichia coli to the direct antibacterial activity of NAB739 and to the synergistic activity of NAB7061 with rifampin and clarithromycin. J Antimicrob Chemother 65:942–994
Van den Bosshe L, Van Schedael A, Chopra S, Hoogmartens J, Adams E (2011) Identification of impurities in polymyxin B and colistin bulk sample using liquid chromatography coupled to mass spectrometry. Talanta 83:1521–1529
Vingsbo Lundberg C, Vaara T, Frimodt-Møller N, Vaara M (2010) Novel polymyxin derivatives are effective in treating experimental E. coli peritoneal infection in mice. J Antimicrob Chemother 65:981–985
Walkty A, DeCorby M, Nichol K, Karlowsky JA, Hoban DJ, Zhanel GG (2009) In vitro activity of colistin (polymyxin E) against 3,480 isolates of Gram-negative bacilli obtained from patients in Canadian hospitals in the CANWARD study, 2007–2008. Antimicrob Agents Chemother 53:4924–4926
Yahav D, Farbman L, Leibovici L, Paul M (2011) Colistin: new lessons on an old antibiotic. Clin Microbiol Infect 18:18–29
Zawascki AP, Goldani LZ, Li J, Nation RL (2007) Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. J Antibiot Chemother 60:1206–1215
Zawascki AP, Goldani LZ, Cao G, Superti SC, Lutz L, Barth AL, Ramos F, Boniatti MM, Nation RL, Li J (2008) Pharmacokinetics of intravenous polymyxin B in critically ill patients. Clin Infect Dis 47:1298–1304
Zhanel GG, Adam HJ, Low DE, Blondeau J, Decorby M, Karlowsky JA, Weshnoweski B, Vashisht R, Wierzbowski A, Hoban DJ, Canadian Antimicrobial Resistance Alliance (CARA) (2011) Antimicrobial susceptibility of 15,644 pathogens from Canadian hospitals: results of the CANWARD 2007-2009 study. Diagn Microbiol Infect Dis 69:291–306
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Vaara, M. (2014). Old and Novel Polymyxins Against Serious Gram-Negative Infections. In: Marinelli, F., Genilloud, O. (eds) Antimicrobials. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-39968-8_8
Download citation
DOI: https://doi.org/10.1007/978-3-642-39968-8_8
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-39967-1
Online ISBN: 978-3-642-39968-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)