KINETICS OF ENDOTOXIN AND INTERLEUKIN-6 FOLLOWING MULTIPLE DOSES OF ANTIBIOTICS FOR EXPERIMENTAL GRAM-NEGATIVE BACTERIAL SEPSIS

The comparative data on antibiotic-mediated endotoxin release in exper imental sepsis are limited to single dose administration. The relative concentration versus time profiles of antibiotic-mediated free endoto xin and interleukin 6 (IL-6) release were characterized during the fir st three dosing intervals of ceftazidime (200 mg/kg), aztreonam (200 m g/kg), imipenem (100 mg/kg), ciprofloxacin (25 mg/kg) and gentamicin ( 25 mg/kg) for the treatment of experimental Klebsiella pneumoniae (ser otype K2) murine sepsis following thermal injury. To a 12-15% total bo dy surface area nonlethal burn, similar to 10(3) cfu were given subcut aneously to infect the burn site, resulting in sepsis by day 3 and 100 % mortality by day 6. Three intraperitoneal doses of each antibiotic o r saline were begun at 72 h post burn and infection, when mice were se ptic with organ dysfunction. Following first dose administration, ceft azidime resulted in significantly higher free median endotoxin (1190 E U/ml, 15.2-fold increase) and IL-6 concentrations (28385 pg/ml, 5.20-f old increase) compared to all other agents (P < 0.05). Maximum endotox in and IL-6 levels following the first doses of imipenem (533 EU/ml, 1 2152 pg/ml) and aztreonam (480 EU/ml, 14997 pg/ml) were also higher th an gentamicin (97 EU/ml, 5392 pg/ml) and saline (110 EU/ml, 5754 pg/ml ) controls (P < 0.05). Ciprofloxacin (218 EU/ml, 4653 pg/ml) resulted in intermediate endotoxin release. Despite a continued increase in end otoxin levels over the three dosing intervals, IL-6 levels were only t ransiently elevated after the first dose with a significant 88-98% red uction by dose 3 for all antibiotics. While there remained a significa nt association between concentrations of free endotoxin and IL-6 for a ll three doses of most antibiotics, the slope of the relationship decl ined with each subsequent dose administration, suggesting either the d evelopment of tolerance to endotoxin or a dependence on total endotoxi n concentrations (or other factors) for IL-6 production. We conclude t hat the in vivo administration of antibiotics results in differential production of free endotoxin and IL-6 concentrations with the greatest increases occurring following first-dose administration of ceftazidim e. Aztreonam and imipenem also resulted in a relatively large increase in endotoxin levels compared to ciprofloxacin and gentamicin. In addi tion, the rapid and persistent decline in IL-6 concentrations followin g multiple doses of all antibiotics, despite increasing free endotoxin levels, may suggest the development of antibiotic-induced tolerance t o endotoxin. Further study of the clinical significance of antibiotic- induced endotoxin release and the role that antibiotics may play in th e development of tolerance is warranted.