Comparison of Endotoxin Release by Different Antimicrobial Agents and the Effect on Inflammation in Experimental Escherichia coli Meningitis

Abstract

In a rabbit Escherichia coli meningitis model, endotoxin liberation and concentrations of leukocytes, tumor necrosis factor (TNF), and lactate were compared after a single intravenous dose of cefotaxime, cefpirome, meropenem, chloramphenicol, or gentamicin. These antibiotics caused a 2- to 10-fold increase in cerebrospinal fluid concentrations of free (filterable) endotoxin within 2 h of starting treatment. By contrast, free endotoxin concentrations increased almost 100-fold in untreated animals 4 h later as bacteria continued to multiply. An initial enhancement of inflammation in the central nervous system occurred in all treatment groups compared with untreated controls. No significant differences were observed between treatment groups except for lower TNF concentrations in chloramphenicol-treated animals. Antibiotic therapy in E. coli meningitis, irrespective of the agent used, may result in an increase in free endotoxin and enhancement of inflammation, but the amount of endotoxin liberated is considerably smaller than that shed by untreated bacteria.

Update on Meningococcal Disease with Emphasis on Pathogenesis and Clinical Management

“…Some studies show even a transitory worsening of the inflammation after antibiotic administration, possibly due to the enhancement of endotoxin release (153,324). This finding contrasts with studies of sepsis, where antibiotic-induced endotoxin release has never been observed (see "Pathophysiology of shock," above, and "Antibiotic treatment" below).…”

“…Some investigators have suggested that antibiotics exacerbate meningeal inflammation by stimulating endotoxin release (11,324), and have therefore suggested postponing antibiotic treatment until after dexamethasone was given (405). However, these recommendations are dangerous, since proliferating bacteria shed more endotoxin than those exposed to antibiotics and delay in sterilization of CSF worsens the prognosis (153,273).…”

Clinical relevance of antibiotic-induced endotoxin release

“…In general, such studies showed a decrease in bacterial counts concurrent with an increase in endotoxin levels in antibiotic-treated animals or a larger increase in endotoxin levels in treated than in untreated animals. This was demonstrated in experimental E. coli sepsis in rabbits (65,69) and pigs (63), H. influenzae sepsis in rats (79), meningococcal sepsis in mice (20), and E. coli (35,73) Parallel with a higher increase in endotoxin levels in antibiotic-treated animals, some studies reported higher TNF levels (35,54,57), but a correlation between a rise in endotoxin level and interleukin 6 levels could not be demonstrated (23). Although corticosteroids appear to have no influence on the process of antibiotic-induced endotoxin release (31,57), the TNF response of the host could be attenuated by dexamethasone (54,57).…”

Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis

“…The release of bacterial cell wall fragments giving rise to the brain production of IL-1, IL-6, and TNF-␣ will not only exacerbate inflammation, but also further damage the blood-brain barrier (4 -7). However, in recent studies of experimental Escherichia coli meningitis, the amount of bacterial endotoxin ultimately released as a consequence of bacteriolysis was much lower than that released by bacteria not being exposed to antibiotics (8). This finding led us to hypothesize whether there might be another virulence factor for exacerbating inflammation as a consequence of antibiotic treatment.…”