Resistance to polymyxins: Mechanisms, frequency and treatment options
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
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