Drug-resistant bacterial infections in end-stage liver disease: immune imbalance and intervention advances.

Patients with end-stage liver disease (ESLD) face a markedly elevated risk of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. This vulnerability worsens prognosis and severely limits therapeutic options. The underlying mechanisms extend beyond hepatic synthetic and detoxification failure to encompass a complex and multifaceted state of immune dysfunction. In this review, we synthesize current evidence on how ESLD-associated immune defects drive susceptibility to drug-resistant infections. We examine key abnormalities across multiple interconnected domains: depletion and dysfunction of Kupffer cells, complement deficiency, T-cell exhaustion with regulatory T-cell expansion, disruption of the gut-liver axis, immunometabolic reprogramming driven by hyperammonemia and lactate accumulation, and upregulation of immune checkpoint molecules such as PD-1/PD-L1. These pathways collectively promote colonization, persistence, and therapeutic refractoriness of MDR pathogens. We also evaluate emerging therapeutic strategies targeting these immune defects, including checkpoint inhibitors, cytokine and cellular therapies, microbiome modulation, and metabolic interventions, while acknowledging the challenges that limit their clinical translation. By proposing an integrated framework that links distinct immune defects to MDR infection pathogenesis, we aim to guide the development of biomarker-driven, personalized immunomodulatory approaches that complement antimicrobial therapy and ultimately improve outcomes in this high-risk population.