• Paul Skorup, Lisa Maudsdotter, Eva Tano, Miklós Lipcsey, Markus Castegren, Anders Larsson, and Jan Sjölin.
• Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
• Crit. Care Med. 2018 Jul 1; 46 (7): e634-e641.

ObjectivesTo investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses.DesignProspective, placebo-controlled interventional experimental study.SettingUniversity research unit.SubjectsThirty-six healthy pigs administered Escherichia coli as a 3-hour infusion.InterventionsAfter 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline.Measurements And Main ResultsPlasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation.ConclusionsTreatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model.

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