Human ex vivo comparison of Escherichia coli and Pseudomonas aeruginosa lipopolysaccharide–induced immune responses and cefiderocol effects in whole blood

Immune dysregulation is central in bacterial sepsis with lipopolysaccharide (LPS) of gram-negative bacteria acting as a key component in innate immune activation. Modulation of the host response by potential immunomodulatory agents may confer benefits. This ex vivo study compared cytokine responses induced by E. coli and P. aeruginosa LPS and evaluated the impact of cefiderocol on LPS-induced immune activation in human whole blood. Whole blood from ten healthy volunteers was stimulated ex vivo with E. coli or P. aeruginosa LPS in the presence or absence of cefiderocol and incubated for 4 h at 37 °C. Plasma concentrations of TNF-α, IL-1β, IL-6, IL-10, IFN-α, IFN-γ, and IL-8 were quantified at 0 h, 2 h, and 4 h using a multiplex immunoassay. Cytokine release was significantly higher after E. coli LPS stimulation than with P. aeruginosa LPS across all analytes. Mean TNF-α area under the curve (AUC₀-₄) was 2379 pg*h/mL with cefiderocol vs 1936 pg*h/mL without (percent difference 18.2% [95% CI, 5.9-31.4]) after E. coli LPS stimulation, and 278 pg/mL vs 242 pg*h/mL (12.9% [4.3-21.5]) after P. aeruginosa LPS stimulation. For IL-6, cefiderocol slightly increased AUC₀-₄ following E. coli LPS stimulation (4584 vs 3635 pg*h/mL; 20.7% [8.3-33.0]) but not with P. aeruginosa LPS (184 vs 201 pg*h/mL; - 9.3% [- 53.7-35.2]). IL-1β, IL-10, IFN-α, IFN-γ, and IL-8 levels were mostly unaffected by cefiderocol. Cefiderocol did not suppress cytokine release in human whole blood. In this study, E. coli LPS elicited a stronger immune response than P. aeruginosa LPS.