Understanding Daptomycin Resistance Mechanisms and Treatment Challenges in Enterococcus faecium Infection: A Case Series

Daptomycin-resistant <i>Enterococcus faecium</i> (DRE) poses an increasing therapeutic challenge, particularly in immunocompromised patients and solid organ transplant recipients. Surveillance data from the Centers for Disease Control and Prevention indicate that approximately 6.5% of <i>E. faecium</i> isolates are daptomycin-resistant, underscoring the need for heightened clinical vigilance, particularly for prompt identification and treatment. In this case series, three patients with advanced liver disease, including two status post orthotopic liver transplantation, are described who developed DRE during treatment for bloodstream infection. These cases illustrate the dynamic nature of antimicrobial susceptibility under daptomycin exposure and highlight the contributions of persistent source control issues, intravascular infection, and altered host factors to treatment failure. All patients were successfully managed by escalating to combination therapy with high-dose daptomycin and ceftaroline, alongside appropriate source control. This series emphasizes the importance of periodic susceptibility reassessment during daptomycin therapy and cautions clinicians against assuming sustained susceptibility in patients with prolonged bacteremia or complex infections. Early recognition of evolving resistance and timely therapeutic adjustment may improve outcomes in this high-risk population.