Sepsis in end-stage liver disease and acute-on-chronic liver failure: pathophysiology, diagnostic challenges, and pharmacological management.

Background: Sepsis represents a leading cause of acute decompensation, acute-on-chronic liver failure (ACLF), and short-term mortality in patients with end-stage liver disease (ESLD). Its clinical course is shaped by the coexistence of profound systemic inflammation, cirrhosis-associated immune dysfunction (CAID), and early multiorgan failure, which together complicate diagnosis, antimicrobial management, and supportive care. Methods: This narrative review synthesizes current evidence on the epidemiology, immunopathophysiology, microbiology, diagnostic strategies, and therapeutic management of sepsis in patients with ESLD and ACLF, with a specific focus on pharmacological considerations, antimicrobial resistance, biomarker-guided diagnosis, and emerging immunomodulatory and extracorporeal therapies. Results: Patients with ESLD and ACLF exhibit a dynamic immune phenotype characterized by impaired innate and adaptive immune responses alongside persistent systemic inflammation, predisposing them to severe infections and sepsis. Multidrug-resistant bacterial pathogens and invasive fungal infections are increasingly prevalent and significantly worsen outcomes. Although rapid molecular diagnostics and selected biomarkers improve early pathogen identification and risk stratification, their diagnostic accuracy remains limited by baseline inflammation and hepatic dysfunction. Empirical antimicrobial therapy must balance early broad-spectrum coverage with antimicrobial stewardship, accounting for altered pharmacokinetics and pharmacodynamics. Supportive strategies-including optimized fluid resuscitation, vasopressor therapy, renal replacement techniques, and extracorporeal blood purification-remain central, whereas immune-modulating therapies such as granulocyte colony-stimulating factor, interleukin-1 blockade, and intravenous immunoglobulins are biologically plausible but not yet supported by robust clinical evidence. Conclusion: Sepsis in ESLD and ACLF is a complex, high-risk condition requiring an integrated, multidisciplinary approach that combines early diagnosis, individualized pharmacological strategies, and tailored organ support. Despite advances in diagnostics and supportive care, outcomes remain poor, underscoring the urgent need for disease-specific clinical trials to refine antimicrobial strategies and evaluate targeted immunomodulatory interventions in this vulnerable population.