Antibiotic induced endotoxin release and clinical sepsis: a review

Sepsis and peritonitis have not lost much of their danger for patients. The mortality rate in peritonitis has only marginally decreased during the last 30 years despite aggressive surgical and sophisticated intensive care treatment. In intra-abdominal infection and peritonitis source control remains the mainstay of treatment, although general principles and denominators of successful source control need to be established. Endotoxin has been recognized as a major player in the pathogenesis of sepsis and its significance in clinical disease has been investigated in clinical studies for more than 20 years. Since the Sixties there is a growing interest in the effect of antibiotics and other compounds on the release of endotoxin. The effect of antibiotics on the release of endotoxin and inflammatory parameters, e.g., cytokines, remains to be clarified despite a growing body of in-vitro studies, animal studies and a few clinical studies. The purpose of this review is to evaluate the evidence of endotoxin release in clinical studies and the effect that antibiotic treatment may have in-vitro, in-vivo and in clinical studies on endotoxin and cytokine release. In-vitro antibiotic-induced endotoxin release may depend on antibiotic class, presence of serum, type of organism, site of antibiotic action and Gram-stain. Endotoxin release may be different in late or early lysis, proportional to the number of killed pathogens. Morphology of bacteria may have an impact on endotoxin release and phagocytosis. Antibiotic-treated animals may show higher endotoxin levels with a higher survival rate than untreated animals. Plasma endotoxin may increase despite decreasing bacteremia. There may be a similar killing rate by different antibiotics but a difference in endotoxin release. Intestinal endotoxin does not necessarily correlate to the level of gram-negative bacteria. However, the alteration of the gut content by pretreatment may be associated with reduced endotoxemia and increased survival. Antibiotic-induced endotoxin release may be different depending on the type of infection, the location of infection, the virulence of strains, Gram-stain, mode of application and dosage of antibiotic. Different antibiotics may induce the release of different forms of endotoxin which may be lethal for sensitized animals. The combination of antibiotics with inhibitors of endotoxin or the pro-inflammatory response may be responsible for increased survival by decrease of endotoxin release. The clinical significance of antibiotic-induced endotoxin release is documented only in a few clinical disorders, e.g., meningitis, urosepsis. The difference in endotoxin release by PBP 2-specific antibiotics, e.g., imipenem, and PBP 3-specific antibiotics, e.g., ceftazidime, may not be visible in each study. Patients with increased multi-organ failure (MOF) scores may profit from treatment with antibiotics known to decrease endotoxin. In conclusion, the clinical significance of antibiotic-induced endotoxin release remains to be clarified. Type of pathogen and its virulence may be more important than recently suggested. gram-positive pathogens were just recently recognized as an important factor for the development of the host response. In case of fever of unknown origin in intensive care patients either failure of treatment, e.g., failure of source control in intra-abdominal infection, or a side effect of antibiotic treatment, e.g., endotoxin release, should be considered as a cause of the fever.