Gram-positive Sepsis


Sep 10, 2014
Not Uganda
- GRAM-POSITIVE SEPSIS: Mechanisms and Differences from Gram-Negative Sepsis

"This article [reviews] the mechanisms by which gram-positive bacteria lead to septic shock, with regard to bacterial structure and toxicology and the host responses elicited both in animal models and in the clinical setting. Gram-positive organisms are better suited to invade host tissues and elicit, in general, a brisker phagocytic response than gram-negative organisms. The lack of endotoxin in the outer cell wall is compensated for by the presence of exposed peptidoglycan and a range of other toxic secreted products. It appears that cell wall components of gram-positive bacteria may signal via the same receptor as gram-negative endotoxin, although the type of signal and coreceptor may differ. Both animal and clinical data suggest that, unlike endotoxin-mediated shock, gram-positive infection produces a modest TNF response only and does not respond well to anti-TNF therapies. This leads one to conclude that the mechanisms leading to shock in gram-positive infection may be multifactorial and perhaps more difficult to treat."

"In modern intensive care settings, gram-positive bacteria account for up to 50% of severe sepsis or septic shock cases, yet the pathogenesis of gram-positive shock is poorly understood.[36,45] This contrasts with the well-researched field of gram-negative sepsis, where the role.of bacterial endotoxin is known to be central to development of septic shock."

"Gram-positive infections often arise from infected foci at, or just under, the body surface (e.g., skin infections, wound infections, muscle). Infection is often associated with an influx of host neutrophils, and the bacteria have an array of tools that allow, first, invasion of the outer host layers and, second, evasion of neutrophil-mediated phagocytosis. The processes of invasion and killing of phagocytes contribute to the inflammatory cascade leading to septic shock. In contrast, gram-negative infection often arises from within the host (e.g., gastrointestinal tract, biliary tract, urinary tract) and may be controlled by antibody and complement alone. Invasiveness and neutrophil-derived proinflammatory damage are more prominent features in gram-positive infection."

"Peptidoglycan comprises up to 40% of gram-positive cell mass and is exposed on the bacterial cell wall surface, whereas gram-negative peptidoglycan lies within the confines of the bacterial outer membrane. Recent data suggest that, like endotoxin, peptidoglycan is released by bacteria during infection and can reach the systemic circulation.[38] Peptidoglycan from a variety of gram-positive bacteria can demonstrate proinflammatory activity in a number of ex vivo assays.[28,29,33,50,90]"

"Others have injected purified staphylococcal or streptococcal peptidoglycan into animal models and detected changes ranging from development of immune-mediated arthritis or isolated contact system activation to shock with multiorgan failure.[12,13,41,59] Such striking differences may be related to the use of peptidoglycan from different strains, purity of injected reagents, contaminating endotoxin, or different dosing regimens."

"The mechanism by which peptidoglycan activates host cells is clearly of importance; previous studies suggested that endotoxin and peptidoglycan may share a 70-kd coreceptor on human mononuclear cells, although this unfortunately turned out to be cell-bound albumin.[16,65] Recent studies confirm that the proinflammatory actions of peptidoglycan are largely serum-dependent and, like endotoxin, are mediated by the cell surface molecule CD14.[28,64] Indeed, lipid A partial structures can block some of the biologic actions of peptidoglycan, implying that the two molecules may compete for similar binding sites on CD14.[95] In most biologic assays tested, the potency of peptidoglycan is demonstrably less than that of endotoxin. The signal transduction pathways triggered following ligation of CD14 may differ significantly between peptidoglycan and endotoxin.[25]"

"Lipoteichoic acids (LTAs) are covalently linked to molecules of peptidoglycan in the gram-positive cell wall and are unique to this group of bacteria. Purified LTA is proinflammatoryin cell culture, and, like peptidoglycan and endotoxin-induced bioactivity, many of its actions appear to be serum- and CD14-dependent.* The ex vivo and in vivo biologic activities attributed to LTAs are summarized in Table 2."


"Nearly all gram-positive pathogens have a hydrophilic capsule of some kind; the function can be merely antigenic, antiphagocytic, or even invasive. Gram-negative pathogens also produce capsules, yielding a mucoid colony appearance on solid media. The capsule of Streptococcus pyogenes is composed of hyaluronic acid and is an essential virulence factor in invasive infection.[3,32,73] Molecular techniques have shown that the capsule augments resistance to phagocytosis and internalization by other host cells and assists in attachment to epithelial cells.[10,72]"

"Gram-positive bacteria can produce specific toxins that are known to cause defined clinical syndromes in the absence of disseminated sepsis; examples include botulism, anthrax, and diphtheria. The role of gram-positive toxins in the pathogenesis of septic shock is less well defined. Endotoxin can dissociate from the bacterial membrane and freely circulate in sepsis; there is clear evidence that this can occur in both animal models and clinical sepsis and that endotoxemia is associated with features of septic shock.[7,17,47] In contrast, there is scant evidence that gram-positive toxins can be detected systemically during clinical sepsis.[79] Evidence of pathophysiologic disturbance following administration of gram-positive toxins is currently limited to certain semitized animal models of systemic inflammation."

"Gram-positive pathogens produce a number of enzymes that are postulated to act as spreading agents or invasins. Although gram-negative bacteria also produce proteolytic enzymes, their need to invade and spread in host tissues is normally not as great. Cleavage of host structural proteins may lead to proinflammatory changes in the host, disruption of normal tissue function, and multiorgan failure. Clostridial phospholipase C directly damages the cell membranes of a wide range of host cells. Staphylococcal lipase and nuclease are believed to underlie dissemination of S. aureus during invasive sepsis, and pneumococcal neuraminidase may have a similar role. S. pyogenes produces a cysteine protease, streptococcal pyrogenic exotoxin B (SPEB), which can cleave human fibronectin, degrade vitmnectin, and activate human matrix metalloproteinases. [35,57]"


"The key elements of the primary host response to endotoxin are listed in Table 4. These elements are believed to underlie development of hypotension, shock, and, ultimately, multiorgan failure.[15,24,56,61,77] It isn't clear from the discussion above that gram-positive bacteria possess the machinery capable of activating the same elements as endotoxin. Indeed, the activation of certain components such as neutrophils and T lymphocytes may be more prominent in gram-positive than in gram-negative infection."


- Clinical Gram-positive sepsis: Does it fundamentally differ from Gram-negative bacterial sepsis?
- Gram-positive and gram-negative bacterial toxins in sepsis
- How gram-positive organisms cause sepsis
- Gram-negative versus Gram-positive bacteremia: what is more alarmin(g)?
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