Background/Objectives: Acute-on-chronic liver failure (ACLF) is a life-threatening complication of cirrhosis, characterized by organ failures and high short-term mortality. Alcohol-related cirrhosis is one of the most frequent underlying etiologies of ACLF in Europe. Infections, particularly those leading to sepsis are recognized triggers; however, their relative contribution, clinical features, and prognostic impact in critically ill patients with alcohol-related cirrhosis remain incompletely defined. This study aimed to systematically identify and characterize precipitating events of ACLF in this population and to compare outcomes between sepsis- and non-sepsis-related cases. Methods: We conducted a retrospective cohort study including 188 ICU patients with alcohol-related cirrhosis who were treated for ACLF at a tertiary university medical center. ACLF was defined and graded according to the European Association for the Study of the Liver—Chronic Liver Failure Consortium (EASL-CLIF) criteria, and sepsis was diagnosed according to Sepsis-3 definitions. Clinical data, precipitating events, microbiological evidence, organ support requirements, and in-hospital outcomes were systematically analyzed. Results: Sepsis was the most frequent precipitating event, identified in 118 patients (62.8%), while 70 patients (37.2%) developed ACLF due to non-septic triggers such as gastrointestinal bleeding. Patients with sepsis-associated ACLF presented with more advanced disease (ACLF grade 2–3 in 80.5% vs. 57.1%, p = 0.004), higher Chronic Liver Failure Consortium—Acute-on-Chronic Liver Failure Score (CLIF-C ACLF) scores (median 55 vs. 50, p = 0.04), longer ICU stays (median 11 vs. 4.5 days, p < 0.001), and markedly higher in-hospital mortality (60.2% vs. 20.0%, p < 0.001) compared to patients without sepsis. Pneumonia (48.3%), urinary infections (17.8%) and spontaneous bacterial peritonitis (16.1%) were the leading infectious foci triggering sepsis. Microbiological evidence was obtained in 82.2% of sepsis cases, with frequent polymicrobial infections and opportunistic pathogens including Enterococcus faecium and Candida albicans. Conclusions: In critically ill patients with alcohol-related cirrhosis, infections leading to sepsis are the predominant precipitating event of ACLF and the strongest determinant of short-term prognosis. Compared with non-sepsis triggers, sepsis-associated ACLF is characterized by more severe disease, greater need for organ support, longer ICU stays, and substantially higher mortality. These findings highlight the urgent need for early recognition, rapid diagnostic strategies, and optimized infection management to improve outcomes in this high-risk population.

Background: Acute-on-chronic liver failure (ACLF) is a severe, rapidly progressing syndrome in patients with liver cirrhosis, often triggered by bacterial infections. Piperacillin/Tazobactam is a key antibiotic in this setting, and therapeutic drug monitoring (TDM) helps optimize its dosing. This study evaluates the impact of an interprofessional TDM strategy for Piperacillin/Tazobactam in ACLF patients in the ICU. Methods: This retrospective ICU study evaluated an interprofessional TDM approach for optimizing Piperacillin/Tazobactam dosing in critically ill ACLF patients. The team, consisting of physicians, clinical pharmacists, and staff nurses, engaged in shared decision making, collaboratively interpreting TDM results and adjusting the dosing accordingly. This study included 26 patients with ACLF who underwent initial TDM and 7 who received follow-up TDM. Piperacillin/Tazobactam dosing was modified based on TDM recommendations, with serum concentrations measured weekly. Adherence to and the implementation of interprofessional dosing recommendations were systematically analyzed to assess the impact of this approach. Results: The initial TDM showed that 30.8% of patients had Piperacillin/Tazobactam levels within the target range, while 53.8% were above and 15.4% below. The interprofessional team recommended dose reductions in seven patients, increases in three, and no change in eleven, with five requiring antibiotic modifications. At the first follow-up TDM, 20.0% reached target levels, while 80.0% remained above, with no subtherapeutic cases. The team recommended one further dose reduction and maintained dosing in four patients. All recommendations were fully implemented, demonstrating strong adherence to the collaborative protocol. Conclusions: The interprofessional TDM strategy optimized Piperacillin/Tazobactam dosing in ACLF patients with full adherence to the recommendations. This collaborative approach improves outcomes and supports global efforts to curb antibiotic resistance.