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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.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\u003Cp id=\u0022p-1\u0022\u003EUrinary tract infections occur at least once in up to 60% of women, with about a third of those experiencing recurrent infections. Prophylaxis with current antibiotics is effective, but can cause side effects and promote drug resistance. Novel approaches are under development that show promise in preventing and treating urinary tract infections.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eurinary tract infection\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EUTI\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003E\n               \u003Cem\u003EE coli\u003C\/em\u003E\n            \u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ebacterial infections\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Einfectious diseases clinical trials\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Evaccinations\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003EUp to 60% of women experience at least 1 urinary tract infection (UTI), and about one-third of those will suffer from recurrent infections. The majority of UTIs are caused by \u003Cem\u003EEscherichia coli\u003C\/em\u003E, which can be sourced from multiple reservoirs, explained Marc Stegger, MSc, Statens Serum Institute, Copenhagen, Denmark.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe \u003Cem\u003EE coli\u003C\/em\u003E clones found to cause most UTIs are also found in gut and fecal flora, which is related to the routes of transmission of \u003Cem\u003EE coli\u003C\/em\u003E such as food animals, meat, healthy and infected people, pets, waste water, and care providers. Indeed, within the household, children, pets, and sexual partners can transmit \u003Cem\u003EE coli\u003C\/em\u003E [Johnson JR et al. \u003Cem\u003EJ Clin Microbiol\u003C\/em\u003E. 2008].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EAlthough food sources like meat have been previously implicated as an important reservoir for \u003Cem\u003EE coli\u003C\/em\u003E\u2013associated UTIs [Overdevest I et al. \u003Cem\u003EEmerg Infect Dis\u003C\/em\u003E. 2011], more recent data from the Netherlands using whole genome sequencing have demonstrated that such transmission occurs with less frequency than originally believed [de Been M et al. \u003Cem\u003EPLoS Genet\u003C\/em\u003E. 2014]. However, the US setting is different, as modern farming is predominated by concentrated animal feeding operations, which represents an ideal environment for the selection of drug-resistant bacteria. Organic farming is not immune to selection of resistant bacteria, as organic criteria allow the injection of chicken eggs with gentamicin. The question then becomes how much overlap is there between UTIs and extraintestinal pathogenic \u003Cem\u003EE coli\u003C\/em\u003E (ExPEC).\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ETo answer this question, researchers collected meat from local grocery stores in Flagstaff, Arizona (population 66\u2005000), and \u003Cem\u003EE coli\u003C\/em\u003E was sampled from bladder and kidney infections from Flagstaff Medical Center. The initial analyses using Illumina sequencing demonstrated that \u003Cem\u003EE coli\u003C\/em\u003E concentrations ranged from 60% to 90% of pork, chicken, and turkey samples, whereas ExPEC levels ranged from \u0026lt;\u200510% in pork, almost 20% in chicken, and \u0026gt;\u200530% in turkey. Furthermore, antibiotic-resistant \u003Cem\u003EE coli\u003C\/em\u003E was found in up to 75% of meat samples, particularly in turkey samples. Further analysis of the UTI isolates suggested that UTIs associated with \u003Cem\u003EE coli\u003C\/em\u003E strain ST131 may be sourced from food; however, there was little evidence of isolate \u003Cem\u003EH\u003C\/em\u003E30Rx transmission via food.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EUnderstanding the route of transmission and potential reservoirs for \u003Cem\u003EE coli\u003C\/em\u003E is important to help prevent infection or reduce practices that promote \u003Cem\u003EE coli\u003C\/em\u003E habitation. In addition, Florian M.E. Wagenlehner, MD, PhD, Justus-Liebig-University, Gie\u03b2en, Germany, discussed the use of antibiotics and immunostimulation as prophylaxis for recurrent UTIs, noting that much of the relevant data is from older studies.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003ELow-dose antibiotics are effective in preventing recurrent UTIs in nonpregnant women. As a result of supportive evidence, the 2015 European Association of Urology guidelines recommend prophylaxis daily or after intercourse with nitrofurantoin, trimethoprim, trimethoprim-sulfamethoxazole, or fosfomycin trometamol for nonpregnant women with recurrent UTIs, and cephalexin during pregnancy [Grabe M et al. \u003Cem\u003EEur Urol\u003C\/em\u003E. 2015]. However, antibiotic prophylaxis is associated with side effects and could promote antibiotic resistance, thus contributing to future treatment failure. In a study from 2000, prophylaxis with 500 mg of ciprofloxacin was significantly associated with ciprofloxacin resistance after treatment. Therefore, Prof Wagenlehner suggested that prophylaxis be used only after behavioral modification has failed [Lichtenberger P, Hooton TM. \u003Cem\u003EInt J Antimicrob Agents\u003C\/em\u003E. 2011].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EAn alternative to antibiotic prophylaxis is immunostimulation, such as with the oral bacterial lysate immunostimulant OM-89. Multiple placebo-controlled studies have demonstrated that the number of UTIs was substantially decreased in patients who received OM-89 compared with placebo. Indeed, a meta-analysis of 5 randomized, placebo-controlled trials of OM-89 for the prevention of UTI found that a significantly greater number of patients were free from UTIs compared with placebo (\u003Cem\u003EP\u003C\/em\u003E\u2005=\u2005.001) [Naber KG et al. \u003Cem\u003EInt J Antimicrob Agents\u003C\/em\u003E. 2009].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EAnother mechanism of prophylaxis is through vaccination against the \u003Cem\u003EE coli\u003C\/em\u003E that commonly cause UTIs. Harry Mobley, PhD, University of Michigan Medical School, Ann Arbor, Michigan, USA, discussed the status of \u003Cem\u003EE coli\u003C\/em\u003E vaccines. Multiple vaccine candidates have been tested [Brumbaugh AR, Mobley HL. \u003Cem\u003EExpert Rev Vaccines\u003C\/em\u003E. 2012]; however, the difficulty is determining factors that differ among humans and \u003Cem\u003EE coli\u003C\/em\u003E, yet are recognized by the immune system and targetable by a vaccine.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EAs a result of these stringent criteria, Dr Mobley stated that there are currently just 6 vaccine candidates, with outer membrane iron acquisition systems a potential target. Differential gel electrophoresis studies have demonstrated that iron receptor proteins are upregulated in the urine of patients with UTIs. Although the urinary tract is typically iron-limiting [Alteri CJ, Mobley HL. \u003Cem\u003EInfect Immun\u003C\/em\u003E. 2007], iron acquisition genes appear to be induced by \u003Cem\u003EE coli\u003C\/em\u003E in the host. Studies in mouse models have demonstrated that vaccines targeting heme receptors Hma and ChuA, siderophore receptor IreA, aerobactin receptor lutA [Alteri CJ et al. \u003Cem\u003EPLoS Pathog\u003C\/em\u003E. 2009], and yersiniabactin receptor FyuA, as well as siderophores themselves, have reduced bacterial loads and induced an immune response when used for intranasal vaccination.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EIn addition, understanding how different strains of \u003Cem\u003EE coli\u003C\/em\u003E adhere to the urothelial cells of the urinary tract is an important step to develop novel agents to treat UTIs. Beat Ernst, PhD, Pharmacenter University of Basel, Basel, Switzerland, discussed the pharmacokinetic requirements of such agents. Adhesion to urothelial cells is facilitated by FimH that causes pili formation, which has different affinity states depending on the bladder environment. Several antagonists to the low- and high-affinity states of pili have been in development [Kleeb S et al. \u003Cem\u003EJ Med Chem\u003C\/em\u003E. 2015; Scharenberg M et al. \u003Cem\u003EAssays Drug Dev Technol\u003C\/em\u003E. 2011].\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EAccording to Prof Ernst, antagonists of pili must be selective, undergo renal excretion, have metabolic stability, be soluble, and have oral bioavailability. A recent study in a mouse model evaluated the efficacy of FimH antagonist UT189, which demonstrated decreased \u003Cem\u003EE coli\u003C\/em\u003E concentration in the bladder after oral dosing and in the kidney after subcutaneous dosing (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Kleeb S et al. \u003Cem\u003EJ Med Chem\u003C\/em\u003E. 2015].\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\/15\/48\/28\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effect of FimH Antagonist on Escherichia coli Concentration in MiceCFU, colony forming units; CIP, ciprofloxacin; PO, orally; SC, subcutaneous.Adapted with permission from Kleeb S et al, FimH Antagonists: Bioisosteres to Improve the in Vitro and in Vivo PK\/PD Profile, J Med Chem, 2015, Vol 58, Pages 2221-2239. Copyright 2015 American Chemical Society.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1848696850\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Effect of FimH Antagonist on \u0026amp;lt;em\u0026amp;gt;Escherichia coli\u0026amp;lt;\/em\u0026amp;gt; Concentration in MiceCFU, colony forming units; CIP, ciprofloxacin; PO, orally; SC, subcutaneous.Adapted with permission from Kleeb S et al, FimH Antagonists: Bioisosteres to Improve the in Vitro and in Vivo PK\/PD Profile, \u0026amp;lt;em\u0026amp;gt;J Med Chem\u0026amp;lt;\/em\u0026amp;gt;, 2015, Vol 58, Pages 2221-2239. Copyright 2015 American Chemical Society.\u0026amp;lt;\/div\u0026amp;gt;\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\/15\/48\/28\/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\/15\/48\/28\/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\/15\/48\/28\/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\/16627\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\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003EEffect of FimH Antagonist on \u003Cem\u003EEscherichia coli\u003C\/em\u003E Concentration in Mice\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ECFU, colony forming units; CIP, ciprofloxacin; PO, orally; SC, subcutaneous.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EAdapted with permission from Kleeb S et al, FimH Antagonists: Bioisosteres to Improve the in Vitro and in Vivo PK\/PD Profile, \u003Cem\u003EJ Med Chem\u003C\/em\u003E, 2015, Vol 58, Pages 2221-2239. Copyright 2015 American Chemical Society.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-16\u0022\u003EIn conclusion, recurrent UTIs remain a tremendous public health problem, with a large proportion of women experiencing recurrent infections. Although prophylaxis is effective for most patients with current antibiotics, this practice can lead to side effects and promotion of antibiotic resistance. Therefore, novel approaches are being developed to prevent and treat UTIs, including immunostimulation, vaccines, and targeting bacterial adhesion.\u003C\/p\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 SAGE Publications\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\/15\/48\/28.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?nzlme2\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?nzlme2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}