IMMUNE EXPRESSION PROFILES IN PATIENTS WITH SEPTIC SHOCK: EFFECTS OF MICROBES AND ANTIBIOTIC THERAPY

BACKGROUND Septic shock is a life-threatening condition characterized by circulatory, cellular and metabolic alterations caused by a dysregulated host response to infection. Antibiotic therapy is a cornerstone of treatment, but several antibiotics may also exert immunomodulatory effects beyond their antimicrobial activity. This study aimed to evaluate whether pathogen characteristics and empirical antibiotic selection were associated with different immune-inflammatory trajectories and clinical outcomes in patients with septic shock. METHODS This retrospective observational study included adult patients admitted to the Intensive Care Unit of the University Hospital of Modena between 2014 and 2024 with septic shock. Clinical characteristics, infection site, microbiological profile, treatments, outcomes and immune- inflammatory biomarkers were collected. Biomarkers were evaluated at baseline, day 3 and 7. The analyses focused on Gram-positive versus Gram-negative infections, MDR versus non-MDR Gram- negative infections, Gram-positive versus Gram-negative pulmonary infections, and linezolid versus vancomycin-teicoplanin-daptomycin (VTD) in Gram-positive infections. Longitudinal biomarker changes were assessed using linear mixed models. RESULTS The study population included 564 patients. Gram-negative bacteria were the most frequent pathogens and bloodstream was the most common infection site. In the overall cohort, Gram-positive and Gram-negative infections showed different inflammatory profiles, particularly regarding procalcitonin kinetics, but no significant differences in major clinical outcomes. Among Gram-negative infections, MDR pathogens were associated with lower appropriateness of empirical antibiotic therapy and higher ICU and hospital mortality. However, immune trajectory differences were mainly observed after restriction to pulmonary infections. In this subgroup, CD4+ trajectory differed between MDR and non-MDR infections. Among pulmonary infections, Gram-positive and Gram-negative pathogens showed comparable baseline characteristics and outcomes, but significant differences emerged in the temporal trajectories of CD3+, CD8+, CD16+ and CD19+ cells. In Gram-positive infections, VTD was associated with a faster decline in procalcitonin, more rapid SOFA score improvement, and a more favorable CD19+ B-cell trajectory compared with Linezolid. These associations were confirmed after adjustment for baseline differences, including clinical severity, dialysis, SARS-CoV-2 infection, surgical status and infection site. CONCLUSION In patients with septic shock, pathogen characteristics, infection site, antimicrobial resistance and empirical antibiotic therapy may influence immune-inflammatory trajectories during the first week. Although major clinical outcomes were not always different between groups, longitudinal immune markers revealed distinct patterns of immune recovery. VTD was associated with a more favorable inflammatory, clinical and humoral immune trajectory compared with Linezolid in Gram-positive infections, even after adjustment for relevant baseline differences. These findings suggest that empirical antibiotic therapy may not be immunologically neutral in septic shock. However, given the retrospective observational design, the results should be interpreted as associative and hypothesis-generating. Further prospective studies are needed to clarify the relationship between antibiotic selection and immune recovery in septic shock.