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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\u003EIn the 1980s, antimicrobial resistance among gram-negative (Gm) pathogens seemed to be under control. Much has since changed, and physicians are now facing unprecedented clinical challenges due to the growing proliferation of multidrug-resistant Gm pathogens. This article describes current epidemiological, mechanistic, and demographic trends that are related to this worldwide epidemic.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EEmerging Therapies\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EIn the 1980s, antimicrobial resistance among gram-negative (Gm) pathogens seemed to be under control, with the availability of a growing anti-Gm armamentarium, including oxyimino-cephalosporins, fluoroquinolones, and carbapenems. Multiple treatment options were available in most infections and, while resistance to older antibiotics was common, it was caused by a relatively few stable mechanisms\u2014TEM-1 \u03b2-lactamase, for example, accounted for over 90% of ampicillin resistance in \u003Cem\u003EE. coli.\u003C\/em\u003E What is more, the residents of India and China\u2014a third of the world\u0027s population\u2014had yet to experience large-scale exposure to modern medicine, modern antibiotics, and their consequences.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EMuch has since changed, and physicians are now facing unprecedented clinical challenges due to the growing proliferation of multidrug-resistant Gm pathogens. David Livermore, PhD, Antibiotic Resistance Monitoring and Reference Laboratory, London, United Kingdom (UK), described current epidemiological, mechanistic, and demographic trends that are related to this worldwide epidemic.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003E\n         \u003Cem\u003EE. coli\u003C\/em\u003E is a crucially important Gm pathogen, causing 80% of urinary tract infections, and is the most frequent Gm agent of bacteremia. For 20 years, \u003Cem\u003EE. coli\u003C\/em\u003E was among the most susceptible Gm bacteria to modern antibiotics, but, over the past decade it has joined \u003Cem\u003EEnterobacter, Klebsiella\u003C\/em\u003E, and \u003Cem\u003EPseudomonas.\u003C\/em\u003E According to recent data from the European Antimicrobial Resistance Surveillance Network (EARS-net), increasing proportions of \u003Cem\u003EE. coli\u003C\/em\u003E bloodstream isolates are nonsusceptible to fluoroquinolones and cephalosporins. In Italy, for example, rates of fluoroquinolone resistance among \u003Cem\u003EE. coli\u003C\/em\u003E bloodstream isolates jumped from between 1% and 5% to between 25% and 50% from 2001 to 2009 [\u003Ca href=\u0022http:\/\/www.ecdc.europa.eu\u0022\u003Ehttp:\/\/www.ecdc.europa.eu\u003C\/a\u003E]. These Southern European resistance rates pale in comparison to those observed in South and East Asia. According to a 2007 survey, \u003Cem\u003EE. coli\u003C\/em\u003E isolates from intraabdominal infections in China and India, 50% and 80% respectively, carried extended-spectrum \u03b2-lactamases (ESBLs), rendering them resistant to modern oxyimino-generation cephalosporins [Hawser SP et al. \u003Cem\u003EAAC\u003C\/em\u003E 2009]. It is striking that resistance to third-generation cephalosporins among \u003Cem\u003EE. coli\u003C\/em\u003E in India and China is now more prevalent than ampicillin resistance in \u003Cem\u003EE. coli\u003C\/em\u003E in Sweden or Norway\u2014countries that are known for their low antibiotic use and resistance.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EThe accumulation of resistance to fluoroquinolones and cephalosporins in \u003Cem\u003EE. coli\u003C\/em\u003E and related species is clinically important, and is dramatically supported by a 2007 meta-analysis by Schwaber and Carmeli [\u003Cem\u003EJAC\u003C\/em\u003E 2007], who found that patients with bacteremia due to ESBL-containing pathogens had increased mortality rates compared with those with non-ESBL strains (pooled RR, 1.85; 95% CI, 1.39 to 2.47; p\u0026lt;0.001). The difference was attributed to delayed effective treatment, with many of the ESBL-producing strains resistant to the physician\u0027s choice of empiric therapy. Early use of carbapenems, which are stable to ESBLs, might seem a logical solution to this problem; however, diverse carbapenemases are starting to emerge among Gms [Patel G et al. \u003Cem\u003EExpert Rev Anti Infect Ther\u003C\/em\u003E 2011]. These include the VIM and NDM metallo and the KPC and OXA-48 nonmetallo types.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EEARS-net data reveal that although most European countries still have very low rates of carbapenem nonsusceptibility (\u0026lt;1% in \u003Cem\u003EKlebsiella\u003C\/em\u003E bacteremia isolates across the continent), resistance is widespread in Greece, where rates among \u003Cem\u003EKlebsiella\u003C\/em\u003E species reached 40% in 2005 and 50% by 2009. A major shift in carbapenemase type also occurred in Greece. The initial problem was the spread of plasmids that encoded VIM metallo-\u03b2-lactamases among \u003Cem\u003EKlebsiella\u003C\/em\u003E strains, but this has now been supplanted by the problem of a single \u003Cem\u003EKlebsiella\u003C\/em\u003E strain with a nonmetallo \u2018KPC\u2019 carbapenemase that is spreading nationally [\u003Ca href=\u0022http:\/\/www.ecdc.europa.eu\u0022\u003Ehttp:\/\/www.ecdc.europa.eu\u003C\/a\u003E; Vatopoulos A \u003Cem\u003EEurosurv\u003C\/em\u003E 2008; Giakkoupi P et al. \u003Cem\u003EEurosurv\u003C\/em\u003E 2009]. Outbreaks of \u003Cem\u003EKlebsiella\u003C\/em\u003E that produce the KPC carbapenemase were first noted in the United States (US) in 2005, but in addition to dissemination in the US, Israel and Greece, there are now growing clusters elsewhere in Europe, South America, and East Asia [Bratu S et al. \u003Cem\u003EArch Int Med\u003C\/em\u003E 2005; Nordmann P et al. \u003Cem\u003ELancet ID\u003C\/em\u003E 2009].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EPathogens that produce another carbapenemase, OXA-48, are resistant to carbapenems but are susceptible to cephalosporins (unless they also have ESBLs), a pattern that is not always recognized by automated systems and therefore often missed. OXA-48 carbapenemase has spread from Turkey, where it has been recorded since 2000, into North Africa and Europe, while similar enzymes have been recorded in India and South America [Benouda et al. \u003Cem\u003EAnn Trop Med Para\u003C\/em\u003E 2010; Moquet et al. \u003Cem\u003EEID\u003C\/em\u003E 2011; Cuzon et al. \u003Cem\u003EIJAA\u003C\/em\u003E 2010; Cuzon et al. \u003Cem\u003EAAC\u003C\/em\u003E 2008; Cuzon et al. \u003Cem\u003EAAC\u003C\/em\u003E 2011; Goern et al. \u003Cem\u003EIJAA\u003C\/em\u003E 2011; Matar et al. \u003Cem\u003ECMI\u003C\/em\u003E 2008; Carrer et al. \u003Cem\u003EAAC\u003C\/em\u003E 2010; Carrer et al. \u003Cem\u003EAAC\u003C\/em\u003E 2008; Poirel et al. \u003Cem\u003EAAC\u003C\/em\u003E 2011; Castanheira et al. \u003Cem\u003EAAC\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ENDM-1 carbapenemase is prevalent in India and Pakistan and has repeatedly been exported to Europe, North America, and Asia by people who have had contact with medical facilities in the Indian subcontinent [Kumarasamy KK et al. \u003Cem\u003ELancet ID\u003C\/em\u003E 2010]. NDM-1 is often coded by plasmids that can spread readily among bacteria and is commonly produced together with rRNA methylases that confer aminoglycoside resistance. Some Gm pathogens with NDM enzymes have near-complete resistance\u2014susceptible only to colistin, with or without moderate susceptibility to fosfomycin and tigecycline [Kumarasamy KK et al. \u003Cem\u003ELancet ID\u003C\/em\u003E 2010]. The dissemination of NDM-1 in parts of India is striking, with one survey revealing a 5% to 7% prevalence among \u003Cem\u003EEnterobacteriaceae\u003C\/em\u003E species in Mumbai [Deshpande P et al. \u003Cem\u003EClin Infect Dis\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EMultiresistant bacteria carriage rates among healthy individuals is facilitating the spread and repeated introduction into hospitals, and is a critical subject of international interest. Separate studies have shown gastrointestinal tract colonization by ESBL \u003Cem\u003EE. coli\u003C\/em\u003E in 13% of job applicants in Saudi Arabia [Kadar et al. \u003Cem\u003EICHE\u003C\/em\u003E 2007] and in nursing home residents in Northern Ireland (40%) and Italy (64%) [Rooney PJ et al. \u003Cem\u003EJAC\u003C\/em\u003E 2009; March A et al. \u003Cem\u003ECMI\u003C\/em\u003E 2010]. A prospective study in Sweden revealed that one quarter of previously uncolonized individuals became colonized with ESBL \u003Cem\u003EE. coli\u003C\/em\u003E during travel, with the highest rates of colonization associated with travel to East Asia (29%) and India (88%) [Tangden T et al. \u003Cem\u003EAAC\u003C\/em\u003E 2010]. NDM-carrying bacteria were shown to inhabit the gut of 27% of inpatients and 14% of outpatients in military hospitals in Pakistan [Perry et al. \u003Cem\u003EJAC\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EThe molecular basis of proliferating resistance among Gm bacteria is more complex than previously thought. Potent bacterial strains, such as sequence type (ST) 131 \u003Cem\u003EE. coli\u003C\/em\u003E serotype 025 [Uchida et al. \u003Cem\u003EIJAA\u003C\/em\u003E 2010; Guenther S et al. \u003Cem\u003EJAC\u003C\/em\u003E 2010] and ST258 \u003Cem\u003EK. pneumoniae\u003C\/em\u003E [Woodford N et al. \u003Cem\u003EFEMS Micro Revs\u003C\/em\u003E 2011], play a pivotal role. \u003Cem\u003EE. coli\u003C\/em\u003E ST131 commonly hosts plasmids that encode CTX-M-15 ESBL and has been instrumental in their international dissemination, while ST258 \u003Cem\u003EK. pneumoniae\u003C\/em\u003E is playing a similar role in the spread of KPC carbapenemases. However, ST131 \u003Cem\u003EE. coli\u003C\/em\u003E may also carry other ESBL types, including CTX-M-3 (Belfast) and CTX-M-14 (Far East), or may have no ESBL.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EDeeper analysis shows that the plasmids that carry \u03b2-lactamase genes are remarkably dynamic and are constantly in flux. The dominant \u003Cem\u003EE. coli\u003C\/em\u003E ST131 variant in the UK (\u2018Strain A\u2019) typically contains a complex CTX-M-15 plasmid, EK499, which is a fusion between two parent plasmids, one of which (pEK516) resembles, but is not identical to those that commonly host CTX-M-15 internationally [Woodford N et al. \u003Cem\u003EAAC\u003C\/em\u003E 2009]. Moreover, although CTX-M-3\u2014prevalent in \u003Cem\u003EE. coli\u003C\/em\u003E ST131 from Belfast\u2014differs from CTX-M-15 by only 1 amino acid, the plasmids that encode CTX-M-3 and CTX-M-15 are completely different. In the case of NDM, the encoding gene has transferred swiftly among plasmids that belong to diverse incompatibility groups, though the mechanism of transfer is unclear. Prof. Livermore suggests that this genetic fluidity among bacteria is perhaps \u201cthe finest but most disturbing evidence of evolution we shall ever see.\u201d\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThe emergence of carbapenem resistance is beginning to drive the use of nonconventional antibiotics, such as colistin, tigecycline, and fosfomycin, but none of these is ideal, and some resistance is beginning to emerge, even to colistin [Kontopoulou K et al. \u003Cem\u003EJHI\u003C\/em\u003E 2010]. In addition, current pipeline agents represent incomplete solutions. Avibactam, a new \u03b2-lactamase inhibitor, inhibits KPC but not metallo-\u03b2-lactamases, and while CXA-201 (cephalosporin CXA101+tazobactam) evades ESBLs and has very good anti-\u003Cem\u003EPseudomonas\u003C\/em\u003E activity, it lacks activity against carbapenemase producers [Livermore DM et al. \u003Cem\u003EAAC\u003C\/em\u003E 2011; Livermore DM. \u003Cem\u003EJAC\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EAging populations, shifting world economies, and inadequate sanitation add to an already complex problem of emerging resistance. The elderly, who form a growing percentage of the population, are more vulnerable to infections, and economic growth in India and China is greatly increasing access to sophisticated medicine and modern antibiotics, often in settings where infection control and regulation of antibiotic use are weak. These are the perfect conditions to drive the selection of resistance, illustrated by the ESBL rates. In India, the lack of public health infrastructure is a tremendous concern. A recent study by the Health Board of the Delhi Municipal Council found that 18% of tap water samples were contaminated with fecal bacteria and that hundreds of millions lack access to a flush toilet [UN News Center 2010]. Improving sanitation here to prevent the spread of resistant bacteria is as important as it was in the US in the early twentieth-century in preventing the spread of classical infectious diseases.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EDevelopment of new anti-Gm antibiotics is urgently needed and hinges on overcoming three challenges. First, discovery of agents that are capable of permeating the Gm cell wall and evading efflux is a key scientific challenge. Second, the regulatory pathway needs to confirm efficacy and safety, but has become too complex and often fails to test antibiotics in the types of patients or settings where they are most likely to be used. The third, and key economic challenge, is the likely return of antibiotic development. Short-term agents for acute infection do not generate the long-term income. These and other challenges must be confronted in order to effectively halt the spread of resistant Gm pathogens.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\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\/11\/12\/6.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_openurl.js?nzmx21\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}