Gram-negative versus Gram-positive bacteremia: what is more alarmin(g)?

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.


Abstract
Gram-negative bacteremia has been associated with severe sepsis, although the exact mechanism and pathophysiological diff erences 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 signifi cantly 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 signifi cantly higher in Gram-negative bacteremia than in Grampositive bacteremia. These observations suggest a distinct immunopathophysiologic behavior of sepsis in patients with Gram-negative bacteremia that may infl uence clinical outcomes. Future research exploring new biomarkers and danger signals and further characterizing diff erences in the virulence mechanisms between Gram-negative and Gram-positive bacteria appears promising and could lead to new therapeutics and to improved clinical outcomes.
Th e rate of GN bacteremia was signifi cantly 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 fi ndings, CRP and IL-6 levels and mortality were signifi cantly higher in patients with septic shock when compared with either sepsis patients or severe sepsis patients. Mortality was not signifi cantly higher in patients with GN (40%) when compared with GP (28%) and with mixed bacteremia (33.3%). Th e point estimates do diff er, however, suggesting that the sample was underpowered. Th e authors demonstrated statis tically signifi cant higher levels of CRP and IL-6 in patients with GN bacteremia than in patients with GP bacteremia.
Th e authors chose IL-6 and CRP as biomarkers. Both have been challenged as markers of infection considering that they are relatively nonspecifi c. Newer sepsis markers such as procalcitonin might be more appealing. 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 diffi cult. Th e 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 [1]. Th ese infl ammatory responses may be generated in response to exogenous pathogen-associated molecu lar 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-infl am matory therapy.
Th ese observations support a distinct immunopathophysiologic behavior of sepsis in patients with GN bacteremia that may infl uence clinical outcomes. Th e results of the study are limited by its retrospective nature, which can introduce selection bias. For instance, sepsis patients were statistically signifi cantly 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, diff erences in the virulence mechanisms between GN bacteria and GP bacteria identifi ed in Abe and colleagues' study could be further explored and charac terized at the molecular level. Better understanding of these processes will make sepsis less alarmin(g) and its clinical course and outcome more predictable [11][12][13][14].