ANTIBIOTIC-INDUCED ENDOTOXIN RELEASE IS ORGANISM-DEPENDENT IN EXPERIMENTAL GRAM-NEGATIVE SEPSIS

The majority of in vitro and animal experiments that have been perform ed to assess antibiotic-induced endotoxin release (AIER) have employed a single test isolate, usually Escherichia coli. To determine the inf luence of microorganism type on AIER and interleukin-6 (IL-6) response , CF-I mice were made septic following a 12-15% total body surface are a nonlethal burn and subeschar challenge (LD90) with Klebsiella pneumo niae K2 (similar to 10(3) cfu), Proteus mirabilis 4552 (similar to 10( 1) cfu) and Pseudomonas aeruginosa SBI-N (similar to 10(2) cfu). Three intraperitoneal (i.p.) doses, given every 4 h, of ceftazidime (TAZ, 2 00 mg/kg), imipenem (IMI, 100 mg/kg), ciprofloxacin (CIP, 25 mg/kg) an d gentamicin (GEN, 25 mg/kg) were administered post burn and infection beginning when mice were septic with organ dysfunction. Free endotoxi n concentrations were significantly (P < 0.001) higher following all a ntibiotics for treatment of K. pneumoniae as compared to Ps. aeruginos a (intermediate) and P. mirabilis infections. Differential AIER was hi ghest for TAZ and IMI, intermediate for CIP and lowest for GEN, for th e treatment of K. pneumoniae and Ps. aeruginosa infections. There was a strong positive correlation between endotoxin release and IL-6 produ ction for K. pneumoniae treated animals, however increased endotoxin l evels for Pseudomonas were accompanied by decreases in IL-6 levels. Fo r P. mirabilis infection endotoxin levels were comparatively low, but highest for GEN and IMI. However, corresponding IL-6 levels increased only 3.2-fold for IMI and actually decreased by 50% for GEN following the first dose. Interestingly, CIP resulted in only modest endotoxin r elease and TAZ caused no appreciable release, however IL-6 concentrati ons dramatically increased 39.9-fold (TAZ) and 32.6-fold (CIP). This s uggests that other pro-inflammatory mediators released from the bacter ium, and not endotoxin, were more important determinants in the overal l host response to antibiotic exposure. In conclusion, these data prov ide supportive evidence that absolute and differential AIER and produc tion of IL-6 is organism-dependent in experimental Gram-negative sepsi s. As a result, general conclusions concerning differential AIER for i nfection caused by E. coli or K. pneumoniae cannot necessarily be extr apolated to other species of Gram-negative bacilli. Furthermore, these study results strongly indicate that the microorganism and other pert inent pro-inflammatory factors (i.e. exotoxins, proteases), must be ta ken into account in the study design and data analysis of any experime ntal or clinical trial that is conducted to determine the significance of differential AIER.