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 supplemented with beta-lactam antibiotics that possessed preferential affinities for penicillin-binding proteins (PBPs). After 4 h, viable bacteria were undetectable in the presence of any of the 3 antibiotics tested, whereas significant increases in colony-forming units were detected in samples 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 various PBPs. Levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in antibiotic-treated cultures after 8 h of incubation correlated 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 both endotoxin and cytokine responses ex vivo in mouse blood and correlate with in vivo protective efficacy of these antibiotics in gram-negative experimental models.
Norimatsu
M
M
Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
Morrison
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DC
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D015377:Cilastatin / Q000494:pharmacology; D000077728:Cilastatin, Imipenem Drug Combination; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004338:Drug Combinations; D004359:Drug Therapy, Combination / Q000494:pharmacology; D004731:Endotoxins / Q000096:biosynthesis*; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology; D005260:Female; D015378:Imipenem / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D016018:Least-Squares Analysis; D000077731:Meropenem; D051379:Mice; D012044:Regression Analysis; D013845:Thienamycins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004338:Drug Combinations; D004731:Endotoxins; D015850:Interleukin-6; D013845:Thienamycins; D014409:Tumor Necrosis Factor-alpha; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination; D002442:Ceftazidime; D000077731:Meropenem