Antibiotic Exposure and the Emergence of Multidrug-Resistant Bacteria in Patients With Liver Cirrhosis: A Prospective Cohort Study

BACKGROUND: Infections caused by multidrug-resistant organisms (MDROs) are a growing concern in patients with advanced chronic liver disease and acute-on-chronic liver failure, worsening clinical outcomes. Although prior antibiotic exposure is associated with resistance, prospectively defined, clinically actionable exposure thresholds in this population are lacking. We aimed to quantify cumulative-exposure thresholds for de novo MDRO acquisition and assess the prognostic impact of MDRO emergence on survival. METHODS: We prospectively enrolled 256 consecutive adults with advanced chronic liver disease at the University Hospital Frankfurt (2020-2023). Antibiotic exposure was quantified using defined daily doses (DDD) and antibiotic use density (AUD); MDRO colonisation and infection were captured by systematic microbiological surveillance. Time-to-death was analysed in a competing-risk framework with liver transplantation as competing event. RESULTS: Among 246 patients without MDRO at the first admission swab, de novo acquisition of vancomycin-resistant enterococci (VRE) or Gram-negative MDR was strongly associated with cumulative antibiotic exposure (p<0.001). The 20% probability threshold for VRE was reached at 9.6 cumulative DDDs of any antibiotic, with substantially lower thresholds for β-lactam/β-lactamase inhibitor combinations, carbapenems, and glycopeptides. De novo MDRO detection during follow-up, but not at baseline, was independently associated with increased 180-day mortality (HR 2.15, 95% CI 1.27-3.64; p=0.004). CONCLUSIONS: In advanced cirrhosis, MDRO emergence is associated with cumulative antibiotic exposure beyond distinct, class-specific thresholds and carries excess mortality. These prospective findings identify cumulative antibiotic burden as a modifiable risk factor and support an exposure-aware approach to antimicrobial stewardship in this population.