gram - negative ( gn ) bacteria have often been implicated in the pathogenesis of severe sepsis and septic shock , although the exact mechanism is uncertain . there is evidence to support two different theories on how gn bacteria induce harmful systemic responses . the intravascular stimulus hypothesis posits that bacteria invade through a normal or damaged epithelium and enter the bloodstream , inducing systemic inflammatory responses ( for example , increased vascular permeability , leukocyte - endothelial adhesion , and activation of complement and clotting pathways ) and resulting in multiorgan failure . a second theory suggests that the multiorgan dysfunction and shock result from neuroendocrine dysregulation and mediators released into the bloodstream from the infected tissues ; circulating bacteria or endotoxin are not needed as direct stimuli for intravascular inflammation . previous studies have shown that proinflammatory cytokines ( tnf , il-1 , il-6 , and il-8 ) are elevated in patients with acute respiratory distress syndrome and septic shock . measuring blood levels of these cytokines may help in evaluating the severity and predicting the outcome in patients with sepsis . il-6 is induced by tnf , and appears in the circulation after the initial tnf response , making it a good surrogate marker of localized tnf activity . il-6 has a longer half - life than tnf and its blood levels remain elevated in the presence of various diseases . c - reactive protein ( crp ) , an acute - phase protein , has been used as a sepsis marker , although blood levels may be elevated in response to non - infectious conditions ( trauma , ischemia , and burns ) . some authors have reported that elevated crp plasma levels correlate with an increased risk of organ failure and death while persistently high crp concentrations have been associated with a poor outcome . procalcitonin is another sepsis marker with kinetic characteristics that may allow anticipation of diagnosis of sepsis 24 to 28 hours before the crp level . abe and colleagues investigate the relationship between the type of bacteremia and its relationship to pathophysiology and potential clinical outcomes . the study participants were adults admitted to the intensive care unit of a university hospital in japan over an 8-year period . eligible patients ( n = 259 ) had at least one blood culture drawn during hospitalization , met the criteria for sepsis , and had a white cell count , a crp level and an il-6 level drawn . participants were evaluated according to severity of sepsis ( sepsis , severe sepsis and septic shock ) and according to the type of bacteremia ( gram - positive ( gp ) , gn , and mixed ( gp / gn ) ) . the white cell count , crp level , il-6 blood level and mortality were compared among the different pathogenic bacterial species and patient groups . the rate of gn bacteremia was significantly higher in patients with septic shock than in patients with severe sepsis or with sepsis ( 43.0% vs. 22.7% vs. 22% , respectively ) . patients with severe sepsis also had higher rates of mixed bacteremia than patients with severe sepsis or with sepsis ( 12.3% vs. 5.3% vs. 3.1% , respectively ) . by contrast , the rate of gp bacteremia was greater in patients with sepsis and with severe sepsis than in those with septic shock ( 72.4% vs. 68% vs. 43.9% , respectively ) . corresponding to these findings , crp and il-6 levels and mortality were significantly higher in patients with septic shock when compared with either sepsis patients or severe sepsis patients . mortality was not significantly higher in patients with gn ( 40% ) when compared with gp ( 28% ) and with mixed bacteremia ( 33.3% ) . the authors demonstrated statistically significant higher levels of crp and il-6 in patients with gn bacteremia than in patients with gp bacteremia . comparison of crp and il-6 between the gn and gp bacteremias is important , although the appearance of these cytokines in the circulation is not as predictable as in experimental models of sepsis . interfering therapeutic agents , compromised response mechanisms and a variable temporal relationship to the onset of infection make the interpretation of both the frequency and magnitude of these cytokines difficult . the study could be strengthened by further evaluating responses of individual pathogens , resistance patterns and trends , and their possible associations with comorbidities , source of bacteremia , length of stay , and mortality . abe and colleagues discuss the danger signals that alert the immune system and trigger defensive immune responses . these inflammatory responses may be generated in response to exogenous pathogen - associated molecular patterns and to endogenous signals of tissue and cell injury ( alarmins ) . among the alarmins , high mobility group box 1 has been described as a mediator of sepsis that could potentially be a target for anti - inflammatory therapy . these observations support a distinct immunopathophysiologic behavior of sepsis in patients with gn bacteremia that may influence clinical outcomes . the results of the study are limited by its retrospective nature , which can introduce selection bias . for instance , sepsis patients were statistically significantly younger ( 54.7 years ) than severe sepsis patients ( 61.7 years ) . addition ally , the study is limited by observations from just one hospital in japan . nonetheless , differences in the virulence mechanisms between gn bacteria and gp bacteria identified in abe and colleagues ' study could be further explored and characterized at the molecular level . better understanding of these processes will make sepsis less alarmin(g ) and its clinical course and outcome more predictable [ 11 - 14 ] . crp : c - reactive protein ; gn : gram - negative ; gp : gram - positive ; il : interleukin ; tnf : tumor necrosis factor .
gram - negative bacteremia has been associated with severe sepsis , although the exact mechanism and pathophysiological differences among bacterial species are not well understood . in the previous issue of critical care , abe and 
 colleagues report results of a retrospective study that show a significantly higher incidence of gram - negative bacteremia among adult intensive care unit patients with septic shock than in those with sepsis or severe sepsis . in this study , c - reactive protein and il-6 levels were significantly higher in gram - negative bacteremia than in gram - positive bacteremia . 
 these observations suggest a distinct immunopathophysiologic behavior of sepsis in patients with gram - negative bacteremia that may influence clinical outcomes . 
 future research exploring new biomarkers and danger signals and further characterizing differences in the virulence mechanisms between gram - negative and gram - positive bacteria appears promising and could lead to new therapeutics and to improved clinical outcomes .