Beta-lactam antibiotics have immunomodulatory effects in vitro, including changes consistent with sepsis-induced immunosuppression

Abstract

Abstract Introduction Sepsis is associated with immunosuppression, predisposing patients to secondary infections. Many treatments routinely used for infections have immunomodulatory effects, including antibiotics. We therefore assessed the immunomodulatory effects of beta-lactam antibiotics on monocyte and lymphocyte immunophenotype. Methods Peripheral blood mononuclear cells isolated from Emergency Department patients with bacterial infection were incubated with narrow-spectrum (amoxicillin and cefuroxime) or broad-spectrum (piperacillin-Tazobactam and meropenem) beta-lactam antibiotics at low and high concentrations. We compared the effects of antibiotics with and without an additional stimulus, LPS for 24 h or anti-CD3/CD28 beads for 72 h to evaluate the effect on monocyte and lymphocyte phenotype respectively. Using spectral flow cytometry, we evaluated functional markers associated with immune activation and reproducible phenotypes consistent with sepsis-induced immunosuppression. Results Beta-lactams, at higher-dose, were associated with increased monocyte CCR2 and decreased CD14 expression. Cefuroxime, meropenem and piperacillin had additional effects, causing a reduced monocyte HLA-DR, NOX-2, CLIP, and NF-κB expression with increased CD80. Beta-lactam exposure was associated with increased CD4 + lymphocyte viability, whilst amoxicillin had additional effects including reduced PD-1 expression and proliferation, and increased IL-7R expression. Changes to immune cell phenotype were minimal in CD8 + lymphocytes, at lower antibiotic doses, or in unstimulated cells. Conclusion Beta-lactam antibiotics have immunomodulatory effects in vitro, including changes consistent with sepsis-induced immunosuppression at clinically relevant doses. Further work is required to determine the mechanisms underpinning these observations and clinical implications, which may have significant clinical implications on the type and duration of antibiotics administered, and highlight the need for therapeutic antibiotic monitoring.