RELEASE OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-6 DURING ANTIBIOTIC KILLING OF ESCHERICHIA-COLI IN WHOLE-BLOOD - INFLUENCE OF ANTIBIOTIC CLASS, ANTIBIOTIC CONCENTRATION, AND PRESENCE OF SEPTIC SERUM

The concentration and accessibility of endotoxin can increase followin g antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin lev els in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and inter leukin-6 production in whole blood ex vivo after exposure of log-phase Escherichia coil to antibiotics belonging to different classes, in a final concentration of 0.5, 5, or 50 times the MIC. After 4 h of incub ation at 50 times the MIC, ceftazidime and ciprofloxacin treatment res ulted in levels of endotoxin, TNF-alpha, and interleukin-6 significant ly higher than those of imipenem and gentamicin (P < 0.001). Similar d ifferences in cytokine induction were measured after 8 h of incubation . At 0.5 times the MIG, the differences between the antibiotics in mea sured endotoxin and cytokine levels were small, with levels comparable to the levels in untreated cultures. Polymyxin B and, to a lesser deg ree, recombinant bactericidal/permeability-increasing protein 21 (rBPI -21) were found to be potent inhibitors of TNF-alpha release, supporti ng the concept that the differences between the antibiotics in cytokin e production were indeed due to differences in amounts of biologically active endotoxin. The presence of serum from patients suffering from untreated sepsis decreased TNF-alpha production significantly, in a co ncentration dependent manner.