Effects of Different Types and Combinations of Antimicrobial Agents on Endotoxin Release from Gram-negative Bacteria: An In-Vitro and In-Vivo Study

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Abstract
Total and free endotoxin release in time from cultures of Escherichia coli by different antibiotics was studied in vitro for 4 h in relation to the antibiotic effect on viable counts and morphological features of the test cultures. The most rapid fall in viable counts was seen after treatment with imipenem or the combination of imipenem with tobramycin, accompanied by an early, but minimal increase (1.8-fold) of the total (free plus cell-bound) endotoxin level at 1 h. Total endotoxin levels increased approximately 5-fold upon incubation with ceftazidime, tobramycin or the combination of tobramycin with cefuroxime, whereas incubation with cefuroxime or aztreonam alone caused a late 22-and 49-fold increase in total endotoxin, respectively, at 4 h. In chloramphenicol treated cultures there was still an increase in viable counts during therapy, resulting in an ultimately 78-fold increase of mean levels of total endotoxin. Free endotoxin levels increased approximately 6-fold within 1 h upon treatment with imipenem, alone or in combination with tobramycin, or ceftazidime as the result of rapid lysis of bacteria. Treatment with cefuroxime or aztreonam induced a relatively late but much higher release of free endotoxin (118-and 222-fold, respectively), which was due to the formation of long filamentous structures during the first 2 h of incubation and eventually cell lysis. Both tobramycin and the combination of tobramycin with cefuroxime caused a more gradual rise in free endotoxin, with a ± 15-fold increase in free endotoxin at 4 h. In chloramphenicol treated cultures, as in the control cultures, the level of free endotoxin remained proportional to the amount of viable organisms. We also studied plasma endotoxin levels in 20 patients with septic shock. 10 out of these 20 patients had a detectable endotoxemia (>5 ng/l) on admission. We describe the patterns of plasma endotoxin in these patients during the first 24 h of antibiotic treatment. We conclude that, in the in-vitro study, values of total endotoxin, free endotoxin, and the rate of release of endotoxin varies with the antibiotic used. We also demonstrate that in patients under treatment for septic shock endotoxin release can be related to the administration of antibiotics.