Snow, Timothy Arthur Chandos; (2025) Antibiotics exacerbate features of sepsis-induced immunosuppression. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Critical illness is associated with an immunocompromised state, characterised by functional impairments in monocytes and lymphocytes, predisposing to subsequent infections. Critically ill patients represent the highest per capita users of antibiotics. Understanding the effect of antibiotics on immune (dys)function in critically ill patients is therefore imperative, particularly as antibiotic levels are extremely variable due to impaired pharmacokinetics. I hypothesised that antibiotics exacerbate features of critical illness-induced immunosuppression in patients with sepsis, surgery and COVID-19. I conducted a cohort study of patients admitted to Critical Care. Using cell culture, spectral flow cytometry, and ELISA, I characterised patient immunophenotype followed by ex vivo experiments to evaluate the effect of antibiotics on monocyte and lymphocyte function. Compared to mild infection, septic patients had lower monocyte HLA-DR expression and lymphopenia which were associated with mortality. Multiple other functional pathways were also impaired. Beta-lactam antibiotics (amoxicillin, cefuroxime, meropenem, and piperacillin) exacerbated these features, particular monocyte antigen presentation. Many of the effects were dose-dependent. I demonstrate commonality between the immunophenotype of patients undergoing elective major surgery with sepsis. Additional effects were identified in monocytes on chemokine receptor expression and T-cell suppression following a secondary stimulus in vitro. Contrary to my hypothesis, cefuroxime (but not amoxicillin or metronidazole) ameliorated the effect of surgery on lymphocyte function. Finally, I characterised serum levels of multiple biomarkers that were targets for immunomodulators in clinical trials for COVID-19. Only seven biomarkers, including IL-6 and neutralising antibodies differentiated between mild and severe disease. Many of the immunomodulatory drugs trialled during COVID targeted biomarkers which did not differentiate between disease severity, which may explain their lack of benefit in clinical trials. Clarithromycin then demonstrated an immunomodulatory effect on spike-protein stimulated cytokine release from volunteer lymphocytes. My work supports ongoing antimicrobial stewardship attempts to reduce inappropriate use of antibiotics.

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