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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\u003EUntreated septic shock is usually fatal within 24 to 36 hours. Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that the pathogenesis of sepsis is primarily driven by excessive proinflammatory activity of the cytokine network even though the triggering infection may have been eliminated by appropriate antimicrobial therapy [van der Poll T, van Deventer SJ. \u003Cem\u003EInfect Dis Clin North Am\u003C\/em\u003E 1999]. It has been suggested that the failure of these trials to show clinical benefit, in conjunction with recent experimental data, raises doubt about the validity of this assumption.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EPneumonia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EBacterial Infections\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EViral Infections\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EUntreated septic shock is usually fatal within 24 to 36 hours. Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that the pathogenesis of sepsis is primarily driven by excessive proinflammatory activity of the cytokine network even though the triggering infection may have been eliminated by appropriate antimicrobial therapy [van der Poll T, van Deventer SJ. \u003Cem\u003EInfect Dis Clin North Am\u003C\/em\u003E 1999]. Anand Kumar, MD, University of Manitoba, Winnipeg, Canada, suggested that the failure of these trials to show clinical benefit, in conjunction with recent experimental data, raises doubt about the validity of this assumption.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EIn patients with pneumococcal pneumonia, bacterial load is associated with the likelihood of death and the risk of septic shock [Rello J et al. \u003Cem\u003EChest\u003C\/em\u003E 2009]. As the log PCR copies of the organism go up, so does the probability of septic shock and death (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Many studies have shown that time to antimicrobial therapy is a critical determinant of survival in meningococcal sepsis. However, when the relative impact of blood bacterial load and time to antimicrobial therapy on mortality in patients with meningococcal sepsis is considered, the critical factor is blood bacterial load. This suggests that delays in antimicrobial treatment simply mark the development of a greater bacterial load with delays in therapy and that bacterial load is the key driver of sepsis [Lala HM et al. \u003Cem\u003EJ Infect\u003C\/em\u003E 2007]. Prof. Kumar suggested that the speed of clearance of the microbial pathogen is the critical determinant of outcome in septic shock.\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\/33\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Pneumococcal Pneumonia and Risk of Septic Shock.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1902860851\u0022 data-figure-caption=\u0022Pneumococcal Pneumonia and Risk of Septic Shock.\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\/33\/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\/33\/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\/33\/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\/12907\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-4\u0022 class=\u0022first-child\u0022\u003EPneumococcal Pneumonia and Risk of Septic Shock.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReprinted with permission from the American College of Chest Physicians. Rello J. Severity of pneumococal pneumonia associated with genomil bacteria load. \u003Cem\u003EChest\u003C\/em\u003E 2009; 136(3): 832.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-5\u0022\u003EWhat then is the best approach for treatment? Prof. Kumar believes that early appropriate antimicrobial therapy is the simplest effective approach and has shown that early therapy is associated with significant improvement in mortality rates across a variety of clinical infections and microbes [Kumar A et al. \u003Cem\u003ECrit Care Med\u003C\/em\u003E 2006]. \u201cBut what can you do if you miss the early window of opportunity?\u201d asked Prof. Kumar. One option is to increase the intensity of the therapy by using a cidal versus static drug or increasing the dose to speed elimination of the pathogen. Another possible approach might be combination therapy (with drugs from different antiobiotic classes to which a pathogen is known to be sensitive), but monotherapy versus combination therapy studies show mixed results (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Safdar N et al. \u003Cem\u003ELancet Infect Dis\u003C\/em\u003E 2004; Micek S et al. \u003Cem\u003EAntimicrob Agents Chemother\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cdiv id=\u0022F2\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\/33\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Monotherapy Versus Combination Therapy in Severe Bacteremic Pneumococcal Pneumonia.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1902860851\u0022 data-figure-caption=\u0022Monotherapy Versus Combination Therapy in Severe Bacteremic Pneumococcal Pneumonia.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/14\/33\/F2.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\/33\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\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\/33\/F2.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\/12908\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 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EMonotherapy Versus Combination Therapy in Severe Bacteremic Pneumococcal Pneumonia.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReprinted with permission from A. Kumar, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003EAmong critically ill patients (but not less ill patients) with pneumococcal bacteremia, combination antibiotic therapy was associated with lower 14-day mortality (23.4% vs 55.3%; p=0.0015) [Baddour LM et al. \u003Cem\u003EAm J Respir Crit Care Med\u003C\/em\u003E 2004]. Patients with community-acquired pneumonia with shock receiving combination therapy do better than those receiving monotherapy, but no difference is seen in patients not in shock [Rodr\u00edguez A et al. \u003Cem\u003ECrit Care Med\u003C\/em\u003E 2007]. Prof. Kumar said that a meta-analysis study showed that combination antibiotic therapy yielded improved survival and clinical response of high-risk, life-threatening infections, particularly those associated with septic shock, but was detrimental to survival in low-risk patients [Kumar A et al. \u003Cem\u003ECrit Care Med\u003C\/em\u003E 2010]. In another propensity-matched study of septic shock, the percentage of patients surviving at 28 days was greater for combination therapy compared with monotherapy (p=0.0002) across a broad range of clinical syndromes and pathogens [Kumar A et al. \u003Cem\u003ECrit Care Med\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EProf. Kumar noted that there appears to be an underlying principle that explains divergent results in combination therapy, which implies that the benefits of combination therapy are primarily restricted to the critically ill, particularly those with shock, and that combination therapy is only required for short periods. In addition, combination therapy likely only makes sense when the combination of local antibiotic use patterns and local resistance\/frequency distribution of pathogens results in suboptimal cidality with monotherapy.\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\/33.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?nzn9vp\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?nzn9vp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}