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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EExtensively drug resistant Gram-negative superbugs Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae present a global medical challenge due to their resistance to almost all current antibiotics, and no new antibiotics will be available for many years to come. Frequently, the only active antibiotics currently in use are colistin (polymyxin E) and polymyxin B. This article presents an overview of how polymyxins kill Gram-negative superbugs and how resistance develops.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EExtensively drug resistant (XDR) Gram-negative superbugs \u003Cem\u003EPseudomonas aeruginosa, Acinetobacter baumannii\u003C\/em\u003E, and \u003Cem\u003EKlebsiella pneumoniae\u003C\/em\u003E present a global medical challenge due to their resistance to almost all current antibiotics, and no new antibiotics will be available for many years to come. Frequently, the only active antibiotics currently in use are colistin (polymyxin E) and polymyxin B. Jian Li, PhD, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia, presented an overview of how polymyxins kill Gram-negative superbugs and how resistance develops.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EPolymyxins became available for clinical use more than 50 years ago but they were abandoned in the 1970s due to \u201chigh\u201d rates of nephrotoxicity and neurotoxicity, and the availability of other new antibiotics. However, antibiotic resistance in Gram-negative superbugs has refocused attention on these agents over the last decade. Significant progress has been made recently in understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of polymyxins. Polymyxins have a narrow spectrum and are active mostly against Gram-negative bacterial pathogens. They demonstrate rapid initial killing (but with the potential for regrowth) and negligible postantibiotic effect [Li J et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2001, 2006; Dudhani RV et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2010, \u003Cem\u003EJ Antimicrob Chemother\u003C\/em\u003E 2010]. Although the detailed mechanism of antibacterial activity of the polymyxins remains unclear, there is evidence that they rapidly permeabilize bacterial outer membrane by interacting with lipopolysaccharide (LPS) molecules [Hancock RE, Chappel DS. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 1999]. \u003Cem\u003EIn vitro\u003C\/em\u003E studies have shown that polymyxins can induce intermembrane molecular contacts. For example, in \u003Cem\u003EEscherichia coli\u003C\/em\u003E metabolic changes leading to cell death are triggered when polymyxins induce phospholipid exchange between the outer membrane and cytoplasmic membrane, which forms envelope-crossing pores [Daugelavicius R et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2000; Liechty A et al. \u003Cem\u003EBiochim Biophys Acta\u003C\/em\u003E 2000]. A recent biochemical study suggests that polymyxins induce rapid killing of Gram-negative bacteria through hydroxyl radical production [Sampson TR et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EPathogenic organisms have developed countermeasures to resist polymyxins. One study has shown that \u003Cem\u003EK. pneumoniae\u003C\/em\u003E increased the production of capsule polysaccharide (CPS) when grown in the presence of polymyxin B. This suggests that CPS protects bacteria by limiting the interaction of antimicrobial peptides with bacterial surface [Campos MA et al. \u003Cem\u003EInfect Immun\u003C\/em\u003E 2004]. Polymyxin resistance in \u003Cem\u003EA. baumannii\u003C\/em\u003E can result from mutational inactivation of genes essential for lipid A biosynthesis [Moffatt JH et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2010]. Strains harboring these mutations have been unable to produce LPS. In response to total LPS loss, \u003Cem\u003EA. baumannii\u003C\/em\u003E alters the expression of critical transport and biosynthesis systems associated with modulating the composition and structure of the outer membrane [Henry R et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2012]. In Gram-negative bacteria, the most common mechanism of polymyxin resistance is associated with modifications of lipid A of the LPS, thereby diminishing the initial polar interaction between positively charged polymyxins and negatively charged LPS [Moskowitz SM et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2012; Arroyo LA et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2011; Beceiro A et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EDr. Li concluded by pointing out that understanding the mechanisms of activity and resistance of polymyxins will greatly help in the design of novel lipopeptides that are active against polymyxin-resistant MDR isolates.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EKeith Kaye, MD, MPH, Wayne State University, Detroit, Michigan, USA, hypothesized that polymyxin combination therapy offers significant advantages for treating XDR Gram-negative bacilli; however, controlled data comparing combination therapy to monotherapy are sparse. He noted that combination therapy might prevent the emergence of resistance. Yet, clinical evidence for these advantages is very limited and collaborative investigator-initiated, multicenter trials are urgently needed [Paul M, Leibovici L. \u003Cem\u003EInfect Dis Clin North Am\u003C\/em\u003E 2009].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EColistin is increasingly returning to use because its spectrum of activity focuses on Gram-negative organisms and it has no cross resistance with other classes of antibacterials. However, there are problems with colistin. It never underwent the rigorous development procedures that are required of modern antibiotics; therefore, there is a lack of conformity in dosing and the currently recommended dosing regimens are based on inaccurate PK data. Clinical experience with colistin varies greatly, making interpretation difficult. In addition, recent studies report dose-dependent nephrotoxicity in about 40% of all subjects [DeRyke CA et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2010; Hartzell JD et al. \u003Cem\u003EClin Infect Dis\u003C\/em\u003E 2009; Pogue JM et al. \u003Cem\u003EClin Infect Dis\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ECombination therapy with colistin is being considered for several reasons: colistin has shown synergistic effects with a variety of other agents \u003Cem\u003Ein vitro\u003C\/em\u003E, dose-related toxicity may limit colistin use in some situations, and, most importantly, the results of a study show treatment failure with colistin monotherapy in isolates that demonstrate heteroresistance to colistin [Rodriguez CH et al. \u003Cem\u003EDiagn Microbiol Infect Dis\u003C\/em\u003E 2009]. Combination therapy might also prevent emergence of polymyxin resistance. Combinations of colistin plus rifampin, aminoglycosides, tigecycline, fosfomycin or carbapenems have been suggested and, so far, data have been encouraging. Several trials are underway with colistin combinations with rifampin, carbapenem, or fosfomycin. The role of lower dose colistin in combination therapy remains unclear.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003ENebulization of colistin methanesulfonate (CMS), an inactive prodrug of colistin, is more efficient than intravenous administration of colistin to rapidly reach high efficient colistin concentrations within the lung, especially in intubated critical care patients with pulmonary infection, said William Couet, PhD, Universit\u00e9 de Poitiers, Poitiers, France.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EPlasma colistin concentrations at steady-state have been shown to be hardly higher than 2 \u00b5g\/mL, which may be insufficient at treating some bacterial infections [Plachouras D et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2009]; however, patients with ventilator-associated tracheobronchitis due to Gram-negative bacteria achieved relatively higher levels of colistin in the epithelial lining fluid (ELF) and favorable microbiological response using inhaled CMS [Athanassa ZE et al. \u003Cem\u003EIntensive Care Med\u003C\/em\u003E 2012]. In a recent study with rats, two thirds of CMS was absorbed directly and one third was converted to colistin in the ELF following nebulization. CMS and formed colistin concentrations in the ELF after the inhalation of CMS (15 mg\/kg in rats) are shown in \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E. Although lower in relative terms, colistin concentrations in the ELF could be high enough to show activity against microorganisms following CMS nebulization [Marchand S et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/14\/21\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022CMS and Colistin Concentrations in ELF.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2145673816\u0022 data-figure-caption=\u0022CMS and Colistin Concentrations in ELF.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/14\/21\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/14\/21\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/14\/21\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12897\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ECMS and Colistin Concentrations in ELF.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from the American Society for Microbiology. Marchand S et al. Aerosol therapy with colistin methanesulfonate: A biopharmaceutical issue illustrated in rats. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E. 2010;54(9):3702\u20137.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EKey characteristics of antibiotics for nebulization are low membrane permeability and, to a lower extent, efflux transport.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/14\/21.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzn9nd\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn9nd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}