Elsevier

Drug Resistance Updates

Volume 13, Issues 4–5, August–October 2010, Pages 132-138
Drug Resistance Updates

Resistance to polymyxins: Mechanisms, frequency and treatment options

https://doi.org/10.1016/j.drup.2010.05.002Get rights and content

Abstract

Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disintegrating the bacterial membranes. The most important mechanism of resistance includes modifications of the bacterial outer membrane structure, including lipopolysaccharide. Lipopolysaccharide modification is mostly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. These mechanisms exist with some differences in many gram-negative bacterial species. Resistance to polymyxins is generally less than 10%. In specific regions, such as the Mediterranean basin, Korea and Singapore, they tend to be higher. Heteroresistance to polymyxins is associated with exposure to polymyxins and especially suboptimal therapeutic dosage. Polymyxin combination regimens, tigecycline and fosfomycin may be useful options for the treatment of polymyxin-resistant gram-negative infections.

Introduction

Polymyxins include polymyxin B and colistin (polymyxin E), and are derivatives of the Bacillus polymyxa subspecies colistinus. They belong to a diverse group of natural antimicrobials found in eucariotic cells called cationic antimicrobial peptides. Structurally, they are decapeptides bound to a fatty acid chain. They consist of a seven-member cyclic ring of aminoacids with a tripeptide side chain. The side chain links to the lipidic part of the molecule. The heptapeptide ring is the same between the two polymyxins with the exception of a single aminoacid, which is phenylalalanine in polymyxin B and leucine in colistin (Kwa et al., 2007).

Polymyxins were discovered in the late 1940's and were widely used until the mid-1980's when they were forsaken due to the reported adverse events, namely nephrotoxicity. They remained in clinical practice for the management of pseudomonal lung infections in patients with cystic fibrosis and in topical solutions with other antimicrobials for the treatment of ear or eye infections. They reappeared as an option for the management of gram-negative infections (administration by the intravenous, and/or nebulized or intrathecal route) for non-cystic fibrosis patients after the emergence of multidrug-resistant pathogens and the subsequent restriction of possible alternatives (Falagas and Kasiakou, 2005). Despite their relatively recent reintegration in clinical practice, resistance to polymyxins constitutes already an issue of significance.

Polymyxins are active against gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp., Escherichia coli and other enterobacteriaceae. However, there are species possessing intrinsic resistance, such as Providencia spp., Neisseria spp., Proteus spp., Serratia marcescens and Burkholderia cepacia. Polymyxins are not active against gram-positive bacteria nor against anaerobes.

Section snippets

Mechanism of action

Lipopolysaccharide (LPS) is a structural component of the bacterial outer membrane consisting of O antigen, a core polysaccharide and lipid A, which anchors in the outer membrane (Raetz and Whitfield, 2002). It bears negative charge and confers to the integrity and stability of the bacterial outer membrane. Polymyxins, having positive charge, displace Mg2+ or Ca2+ and bind on lipid A component resulting in the destabilization and disruption of the outer and inner membranes (Brown and Tsang, 1978

Mechanisms of resistance

Gram-negative bacteria may develop resistance through mechanisms that are common for colistin and polymyxin B. The most important mechanism involves modifications of the bacterial outer membrane, mainly through the alteration of the LPS moiety (Kline et al., 2008, Raetz and Whitfield, 2002). However, further modifications of the bacterial outer membrane may confer to polymyxin resistance (Campos et al., 2004, Moore et al., 1984). Another mechanism includes the development of an efflux

Worldwide antimicrobial susceptibility rates

Resistance to polymyxins varies in different parts of the world and in different settings. Typical settings in which polymyxins are widely used include patients with cystic fibrosis and patients admitted in the intensive care unit (ICU). The last two decades there have been numerous reports regarding polymyxin resistance rates. We concentrate on reports presenting relevant data for K. pneumoniae, P. aeruginosa, and A. baumannii, excluding those presenting no resistance at all (Table 2). Reports

Heteroresistance

Heteroresistance may be defined as the emergence of resistance to a specific antibiotic by a subpopulation of an otherwise susceptible population to this antibiotic according to susceptibility testing (Falagas et al., 2008a). Heteroresistance to polymyxins was not reported until recently. Topical reports present data of heteroresistant A. baumannii strains from patients admitted to the ICU (Hernan et al., 2009, Li et al., 2006). Colistin use is known to be a risk factor for the isolation of

Treatment options for polymyxin-resistant gram-negative bacilli

The lack of options for the treatment of infections due to polymyxin-resistant gram-negative pathogens necessitates the pursuit of other solutions. Combination therapy of polymyxins with other antibiotics may be a feasible alternative. There are studies reporting encouraging data regarding the outcomes of patients with such infections after treatment with various combinations of colistin with other antibiotics (Falagas et al., 2005, Falagas et al., 2008b). The most frequently used colistin

Conclusion

Polymyxins are old antibiotics that returned to clinical practice due to the lack of options for the treatment of multidrug-resistant gram-negative infections. They act by disrupting the bacterial membranes resulting in cellular death. The main mechanism of resistance is the modification of the bacterial outer membrane, which is mainly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. Resistance to polymyxins is generally less than 10%, but is higher in the Mediterranean and

References (97)

  • A.C. Gales et al.

    Global assessment of the antimicrobial activity of polymyxin B against 54 731 clinical isolates of Gram-negative bacilli: report from the SENTRY antimicrobial surveillance programme (2001–2004)

    Clin. Microbiol. Infect.

    (2006)
  • P.Z. Gatzeva-Topalova et al.

    Structure and mechanism of ArnA: conformational change implies ordered dehydrogenase mechanism in key enzyme for polymyxin resistance

    Structure

    (2005)
  • R.C. Hernan et al.

    Selection of colistin-resistant Acinetobacter baumannii isolates in postneurosurgical meningitis in an intensive care unit with high presence of heteroresistance to colistin

    Diagn. Microbiol. Infect. Dis.

    (2009)
  • R.N. Jones et al.

    Antipseudomonal activity of piperacillin/tazobactam: more than a decade of experience from the SENTRY Antimicrobial Surveillance Program (1997–2007)

    Diagn. Microbiol. Infect. Dis.

    (2009)
  • T. Kline et al.

    Synthesis of and evaluation of lipid A modification by 4-substituted 4-deoxy arabinose analogs as potential inhibitors of bacterial polymyxin resistance

    Bioorg. Med. Chem. Lett.

    (2008)
  • Y.T. Lee et al.

    Differences in phenotypic and genotypic characteristics among imipenem-non-susceptible Acinetobacter isolates belonging to different genomic species in Taiwan

    Int. J. Antimicrob. Agents

    (2009)
  • F.M. MacKenzie et al.

    Antibiograms of resistant Gram-negative bacteria from Scottish CF patients

    J. Cyst. Fibros.

    (2004)
  • A. Michalopoulos et al.

    Intravenous fosfomycin for the treatment of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae in critically ill patients: a prospective evaluation

    Clin. Microbiol. Infect.

    (2010)
  • P.R. Reeves et al.

    Bacterial polysaccharide synthesis and gene nomenclature

    Trends Microbiol.

    (1996)
  • N. Roussos et al.

    Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

    Int. J. Antimicrob. Agents

    (2009)
  • A. Walkty et al.

    Antimicrobial susceptibility of Pseudomonas aeruginosa isolates obtained from patients in Canadian intensive care units as part of the Canadian National Intensive Care Unit study

    Diagn. Microbiol. Infect. Dis.

    (2008)
  • M.D. Winfield et al.

    Transcriptional regulation of the 4-amino-4-deoxy-L-arabinose biosynthetic genes in Yersinia pestis

    J. Biol. Chem.

    (2005)
  • A. Yan et al.

    An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli

    J. Biol. Chem.

    (2007)
  • W. Yau et al.

    Colistin hetero-resistance in multidrug-resistant Acinetobacter baumannii clinical isolates from the Western Pacific region in the SENTRY antimicrobial surveillance programme

    J. Infect.

    (2009)
  • M.D. Adams et al.

    Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system

    Antimicrob. Agents Chemother.

    (2009)
  • K.B. Anthony et al.

    Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline

    Clin. Infect Dis.

    (2008)
  • A. Bell et al.

    Outer membrane protein H1 of Pseudomonas aeruginosa: purification of the protein and cloning and nucleotide sequence of the gene

    J. Bacteriol.

    (1989)
  • J.A. Bengoechea et al.

    Temperature-regulated efflux pump/potassium antiporter system mediates resistance to cationic antimicrobial peptides in Yersinia

    Mol. Microbiol.

    (2000)
  • S. Bratu et al.

    Emergence of KPC-possessing Klebsiella pneumoniae in Brooklyn, New York: epidemiology and recommendations for detection

    Antimicrob. Agents Chemother.

    (2005)
  • S. Bratu et al.

    Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents

    J. Antimicrob. Chemother.

    (2005)
  • D.A. Brown et al.

    Chemical and electrophoretic changes induced by polymyxin B on outer membrane components from Serratia marcescens

    J. Antibiot (Tokyo)

    (1978)
  • M.A. Campos et al.

    Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides

    Infect Immun.

    (2004)
  • M. Castanheira et al.

    Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase- and metallo-beta-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program

    Antimicrob. Agents Chemother.

    (2008)
  • Castanheira, M., Sader, H.S., Jones, R.N., Antimicrobial susceptibility patterns of KPC-producing or CTX-M-producing...
  • A. Clausell et al.

    Gram-negative outer and inner membrane models: insertion of cyclic cationic lipopeptides

    J. Phys. Chem. B

    (2007)
  • S.D. Davis et al.

    Activity of colistin against Pseudomonas aeruginosa: inhibition by calcium

    J. Infect. Dis.

    (1971)
  • O.K. Eser et al.

    Antimicrobial resistance and existence of metallo-beta-lactamase in Acinetobacter species isolated from adult patients

    Mikrobiyol Bul.

    (2009)
  • M.E. Falagas et al.

    Outcome of infections due to pandrug-resistant (PDR) Gram-negative bacteria

    BMC Infect. Dis.

    (2005)
  • M.E. Falagas et al.

    Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections

    Clin. Infect. Dis.

    (2005)
  • M.E. Falagas et al.

    Fosfomycin: use beyond urinary tract and gastrointestinal infections

    Clin. Infect. Dis.

    (2008)
  • C.A. Fica et al.

    Intravenous colistin in the treatment of infections due to pan-resistant Gram negative bacilli

    Rev. Chilena Infectol.

    (2007)
  • A.C. Gales et al.

    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)
  • E. Garcia-Penuela et al.

    Susceptibility pattern of Acinetobacter baumannii clinical isolates in Madrid vs. Hong Kong

    Rev. Esp Quimioter.

    (2006)
  • P.Z. Gatzeva-Topalova et al.

    Crystal structure and mechanism of the Escherichia coli ArnA (PmrI) transformylase domain. An enzyme for lipid A modification with 4-amino-4-deoxy-l-arabinose and polymyxin resistance

    Biochemistry

    (2005)
  • P.Z. Gatzeva-Topalova et al.

    Crystal structure of Escherichia coli ArnA (PmrI) decarboxylase domain. A key enzyme for lipid A modification with 4-amino-4-deoxy-L-arabinose and polymyxin resistance

    Biochemistry

    (2004)
  • J.L. Gomez-Garces et al.

    Susceptibility of 228 non-fermenting gram-negative rods to tigecycline and six other antimicrobial drugs

    J. Chemother.

    (2009)
  • J.S. Gunn et al.

    PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella typhimurium antimicrobial peptide resistance

    J. Bacteriol.

    (1996)
  • J.S. Hawley et al.

    Susceptibility of acinetobacter strains isolated from deployed U.S. military personnel

    Antimicrob. Agents Chemother.

    (2007)
  • Cited by (206)

    • Types and applications of potential antibiotics produced by fungi

      2023, Fungal Secondary Metabolites: Synthesis and Applications in Agroecosystem
    View all citing articles on Scopus
    View full text