The significance of endotoxin release in experimental and clinical sepsis in surgical patients — Evidence for antibiotic-induced endotoxin release?

Abstract

Sepsis and peritonitis remain a serious challenge for surgical patients, despite improvement in surgical therapy and intensive care and the introduction of new powerful antibiotics. Recent in vitro studies revealed the potential of certain antibiotics, e.g. penicillin-binding protein (PBP) 3-specific antibiotics, to cause antibiotic-induced endotoxin release. Other types of antibiotics, e.g., PBP 2-specific antibiotics, were associated with no or less endotoxin release. Further in vitro experiments and investigations in animals support the hypothesis of antibiotic-induced endotoxin release, but there is little clinical evidence. The clinical significance of endotoxin is subject of open dispute with many pro's and contra's. Endotoxin, although an important trigger, may not be the only factor to induce cytokine release, e.g., peptidoglycans were able to stimulate cells to release cytokines. Gram-positive pathogens have gained more importance in clinical sepsis and may not be sufficiently reflected in current clinical studies. The hypothesis that neutralization of endotoxin and pro-inflammatory cytokines is beneficial in sepsis was seriously challenged by the results of recent clinical and experimental studies. The better understanding of mechanisms in endotoxin-induced cell activation and cell, cell-receptor and soluble receptor interactions led to new treatment options. Recent reports on the complex pathogenesis of peritonitis and the detection of pathogen-related factors with intraperitoneal immune response may have implications on clinical studies investigating the potential of new compounds and the effect of antibiotics on endotoxin release. However, only few reports are available on the clinical significance of antibiotic-induced endotoxin release, and association of endotoxin release with pathogens, mortality or alteration of physiological parameters were not observed. With regard to the particulars of these studies, e.g., a small study population or low mortality rate, mortality may not be an ideal outcome parameter for these studies. There is clinical evidence for antibiotic-induced endotoxin release. However, the need for well-designed and performed studies using newly developed monitoring devices in intensive care therapy is obvious.

Comparative Effects of Ciprofloxacin and Ceftazidime on Cytokine Production in Patients with Severe Sepsis Caused by Gram-Negative Bacteria

“…Ampicillin-sulbactam and cefamandole seem to induce gamma interferon production, clindamycin seems to induce TNF-␣ and IL-6 release, lincomycin induces IL-4 release, and teicoplanin induces TNF-␣, IL-1␣, and IL-6 release (10,12,28). Conversely, erythromycin, roxithromycin, and vancomycin have been shown to down-regulate TNF-␣ production (13). In a recent study, conducted with patients with infections caused by gram-negative bacteria, antibiotic-induced endotoxemia was detectable in 9 of 27 patients, while both ceftazidime-and imipenem-treated individuals showed increases in TNF-␣ and IL-6 levels (4).…”

“…While in vitro studies on the effect of ciprofloxacin on endotoxin release are conflicting (13), such studies have clearly demonstrated that the fluoroquinolones exhibit several immunomodulatory actions, mainly affecting cellular and humoral immunity by attenuating cytokine response. In general, although they seem to induce in vitro IL-2 synthesis, they inhibit the synthesis of IL-1, IL-6, TNF-␣, and IL-12 and significantly enhance the synthesis of IL-10 and colony-stimulating factors.…”

“…Pathogen-associated microbial patterns, such as endotoxin in gram-negative bacteria and lipoteichoic acid in gram-positive bacteria, have been recognized as major contributors to the pathogenesis of sepsis syndrome, and their clinical significance has been investigated in clinical studies for more than 20 years (13,20). Endotoxin (lipopolysaccharide [LPS]) is a component of the outer membrane of gram-negative bacteria that stimulates macrophages to secrete a wide array of proinflammatory cytokines, such as TNF-␣, IL-1␤, IL-6, and IL-8 (5).…”

Effect of Ceftazidime on Systemic Cytokine Concentrations in Rats

“…Although antimicrobials are the primary treatment options for sepsis, they also have the potential to worsen the inflammatory state in some patients (5,7). This has been attributed to the release of large amounts of endotoxin (i.e., lipopolysaccharide) as the result of bacterial killing by bactericidal and cell wall-active antimicrobials (4,6,9). Endotoxin is known to enhance the expression of proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-␣], interleukin-1 [IL-1], and IL-6) that have been implicated in the pathogenesis of sepsis and multiple-organ-dysfunction syndrome (1,3).…”

Yersinia enterocolitica

“…At this time, however, the multiplication of the infused pathogenic organisms (which are generally not yet identified) must be prevented through broad-spectrum antibiotic cover. The extent to which the decomposing bacteria may release further endotoxins has not yet been discussed in detail in the literature [27]. In order to identify the pathogen, a blood culture should be prepared before the antibiotics are administered (as in any transfusion incident, in general).…”