To Örebro University

Sepsis remains a major cause of morbidity and mortality despite advances in antimicrobial therapy and critical care. Early recognition,timely initiation of effective antimicrobial treatment, and appropriate dose optimization are central to improving outcomes but are challenged by patient heterogeneity, dynamic organ dysfunction, and limitations of conventional diagnostics. The aim of this thesis was to investigate key aspects of early sepsis management in adults with community-acquired bloodstream infections, focusing on early recognition, antimicrobial strategies, pharmacokinetics, and molecular diagnostics. Papers I and II were based on a retrospective cohort of adults with blood culture–positive infections. Paper I evaluated the association between early antimicrobial strategy and outcome and found lower 28-day mortality among patients receiving β-lactam therapy combined with a single-dose aminoglycoside compared with β-lactam monotherapy, without an increased risk of acute kidney injury. Paper II assessed early recognition using clinical severity scores and demonstrated that a NEWS2 score ≥5 had high sensitivity for identifying Sepsis-3–defined sepsis and identified most fatal cases, although discrimination between bacterial etiologies was limited. Papers III and IV were based on the prospective SIVA study of critically ill patients with severe sepsis or septic shock. Substantial inter- and intraindividual variability in β-lactam exposure was observed during the first 48 hours despite standard dosing. Full-length 16S rRNA sequencing revealed frequent bacterial DNAemia, sometimes persisting despite adequate antimicrobial exposure and clearance of viable bacteria from blood cultures. Overall, the findings highlight the dynamic nature of early sepsis and support an integrated and individualized approach to early sepsis management.