CORRELATION OF ANTIBIOTIC-INDUCED ENDOTOXIN RELEASE AND CYTOKINE PRODUCTION IN ESCHERICHIA COLI-INOCULATED MOUSE WHOLE-BLOOD EX-VIVO

Escherichia coli were incubated in mouse whole blood ex vivo supplemen ted with p-lactam antibiotics that possessed preferential affinities f or penicillin-binding proteins (PBPs). After 4 h, viable bacteria were undetectable in the presence of any of the 3 antibiotics tested, wher eas significant increases in colony-forming units were detected in sam ples not treated with antibiotics. Differential levels of endotoxin in platelet-rich plasma were detected using the limulus amebocyte lysate assay, according to differential antibiotic affinities for the variou s PBPs. Levels of tumor necrosis factor-alpha (TNF-alpha) and interleu kin-6 (IL-6) in antibiotic treated cultures after 8 h of incubation co rrelated well with the levels of endotoxin at 4 h (r = .96, P < .0001 for TNF-alpha; r = .91, P = .0002 for IL-6). These data indicate that differential affinities of beta-lactam antibiotics for PBPs affect bot h endotoxin and cytokine responses ex vivo in mouse blood and correlat e with in vivo protective efficacy of these antibiotics in gram-negati ve experimental models.