Drug Resistance Updates 13 (2010) 132–138 Contents lists available at ScienceDirect Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup Resistance to polymyxins: Mechanisms, frequency and treatment options Matthew E. Falagas a,b,c,* , Petros I. Rafailidis a,b , Dimitrios K. Matthaiou a,d a Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece b Department of Medicine, Henry Dunant Hospital, Athens, Greece c Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA d Department of Medicine, “G. Gennimatas” General Hospital, Thessaloniki, Greece article info Article history: Received 27 April 2010 Received in revised form 24 May 2010 Accepted 24 May 2010 Keywords: Colistin Multidrug-resistance Polymyxin Pandrug-resistance Fosfomycin Tigecycline abstract Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disinte- grating 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 mecha- nisms 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. © 2010 Elsevier Ltd. All rights reserved. 1. 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 infec- tions 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 * Corresponding author at: Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 15 123, Marousi, Greece. Tel.: +30 694 611 0000; fax: +30 210 683 9605. E-mail address: m.falagas@aibs.gr (M.E. Falagas). restriction of possible alternatives (Falagas and Kasiakou, 2005). Despite their relatively recent reintegration in clinical practice, resistance to polymyxins constitutes already an issue of signifi- cance. Polymyxins are active against gram-negative pathogens includ- ing 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. 2. Mechanism of action Lipopolysaccharide (LPS) is a structural component of the bacte- rial 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. Polymyx- ins, having positive charge, displace Mg 2+ or Ca 2+ and bind on lipid A component resulting in the destabilization and disruption of the outer and inner membranes (Brown and Tsang, 1978; Clausell et al., 2007; Davis et al., 1971; Newton, 1956; Schindler and Osborn, 1979). The most potent part of the polymyxin molecule is the hydrophobic lipid tail. Polymyxin nonapeptide, which is the acyl part remaining after the removal of the lipidic component, exerts antimicrobial properties though to a lesser extent. It has lesser affinity than the hydrophobic tail, but sensitizes bacteria to the 1368-7646/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.drup.2010.05.002