Vancomycin-Resistant E. faecium: Addressing Global and Clinical Challenges

Abstract

Antimicrobial resistance (AMR) poses a profound threat to modern healthcare, with vancomycin-resistant Enterococcus faecium (VREfm) emerging as a particularly resilient and clinically significant pathogen. This mini-review examines the biological mechanisms underpinning VREfm resistance, including biofilm formation, stress tolerance, and the acquisition of resistance genes such as vanA and vanB. It also explores the behavioural, social, and healthcare system factors that facilitate VREfm transmission, highlighting disparities in burden across vulnerable populations and low-resource settings. Prevention strategies are mapped across the disease pathway, spanning primary, secondary, and tertiary levels, with a particular focus on the role and evolving challenges of antimicrobial stewardship programmes (ASP). We highlight emerging threats, such as rifaximin-induced cross-resistance to daptomycin, which challenge conventional stewardship paradigms. Finally, we propose future directions to enhance global surveillance, promote equitable stewardship interventions, and accelerate the development of innovative therapies. Addressing VREfm requires a coordinated, multidisciplinary effort to safeguard the efficacy of existing antimicrobials and protect at-risk patient populations.

Keywords: antimicrobial resistance; antimicrobial stewardship; vancomycin-resistant Enterococcus faecium.

Figure 1

Mechanism of vancomycin resistance in Enterococcus faecium. This schematic illustrates the induction and effect of vancomycin resistance mediated by the vanA or vanB operon. On the left, vancomycin binds to the D-Ala–D-Ala terminus of the peptidoglycan precursor, preventing cross-linking and inhibiting cell wall synthesis. Detection of vancomycin by the membrane-bound sensor kinase VanS leads to autophosphorylation and phosphate transfer to the cytoplasmic response regulator VanR, which activates transcription of the vanHAX operon. On the right, the enzymatic products of this operon are shown: (1) VanH reduces pyruvate to D-lactate (D-Lac); (2) VanA ligates D-Ala to D-Lac, producing the D-Ala–D-Lac dipeptide; and (3) VanX cleaves residual D-Ala–D-Ala, ensuring exclusive incorporation of the resistant precursor. Vancomycin is unable to bind to D-Ala–D-Lac, thus permitting normal peptidoglycan cross-linking and conferring high-level resistance. Created with BioRender.com.

Figure 2

Conceptual framework linking determinants, levels of prevention, and targeted interventions for VREfm control. This schematic integrates the key biological, behavioural, and systemic determinants driving the emergence and spread of vancomycin-resistant Enterococcus faecium (VREfm). These determinants are mapped onto three levels of prevention: primary (limiting emergence and transmission), secondary (facilitating early detection and containment), and tertiary (reducing clinical impact and complications). Corresponding evidence-based interventions are aligned to each level, including: antimicrobial stewardship programmes, strategic de-escalation of high-risk antibiotic use in clinical and agricultural settings, enhanced surveillance in low- and middle-income countries (LMICs), and the development of novel and combination treatment strategies. This framework highlights the importance of integrated, multidisciplinary responses to effectively contain VREfm at local, national, and global levels.