Enterococcus faecium, historically a commensal species, has undergone a marked ecological and clinical shift to become a leading multidrug resistant (MDR) hospital-acquired pathogen. This transformation carries serious global public health implications because therapeutic choices are increasingly limited and patient morbidity and mortality have risen as effective drug targets have diminished.
The review frames this shift as an outcome of long-term evolutionary processes interacting with contemporary selective pressures, especially widespread antibiotic use in both clinical and non-clinical environments.
A central theme is the species’ exceptional genomic plasticity, which enables rapid adaptation to changing environments. Genome flexibility in E. faecium facilitates acquisition and rearrangement of genetic material and underpins its capacity to develop and disseminate resistance traits. This plasticity operates in concert with selection imposed by intensive antibiotic exposure.
The authors emphasize that genetic flexibility is not a single mechanism but a collection of processes that include the gain and loss of genomic islands, plasmids, insertion sequences, and other rearrangements that alter phenotype and fitness.
Comparative genomic analyses, as reviewed, distinguish between different clades of E. faecium—broadly categorized as community-acquired and hospital-acquired lineages. Hospital-associated clones, particularly the well-recognized clonal complex 17, are characterized by an enrichment of antibiotic resistance determinants, mobile genetic elements and virulence-associated features.
This clade-specific structure helps explain why certain lineages are overrepresented in healthcare-associated infections: their genomes harbor combinations of traits that promote survival and spread in the hospital environment under antimicrobial pressure.
The review identifies horizontal gene transfer and mobile genetic elements as major drivers of resistance evolution in E. faecium. Plasmids, transposons, insertion sequences and other mobile elements facilitate the movement of resistance genes between strains and across ecological niches. These processes accelerate the emergence of MDR phenotypes and promote dissemination within and between clades.
Because many resistance determinants are located on mobile elements, the potential for rapid, clade-independent spread is significant, particularly where antibiotic selection favors maintenance and transmission of these elements.
Clinical consequences of E. faecium’s evolution are manifest in resistance to multiple frontline agents. The review highlights loss of efficacy for several key therapies, including penicillin, vancomycin, linezolid, and daptomycin. Resistance across these drug classes has substantially narrowed therapeutic options, complicating treatment of Gram-positive infections and contributing to worse clinical outcomes.
The authors underscore that the combination of limited drug targets and expanding resistance mechanisms elevates the risk for difficult-to-treat infections in healthcare settings.
The review situates MDR E. faecium within a one health framework, noting that humans, animals and the environment act as integrated reservoirs. Non-clinical antibiotic application and environmental contamination create opportunities for selection and exchange of resistance determinants, linking community and hospital ecologies.
This interconnectedness implies that control strategies must extend beyond hospitals to consider agricultural practices, environmental pathways and cross-sectoral transmission dynamics.
To address the challenge posed by MDR E. faecium, the authors call for several coordinated actions:
Implementation of integrated genomic surveillance to monitor clade dynamics, track mobile elements and detect emerging resistance trends.
Development of novel therapeutic approaches to replenish limited treatment options and target resistant strains or their mobile elements.
Strengthening of antimicrobial stewardship programs aligned with World Health Organization priorities to reduce selective pressure that drives resistance emergence and spread.
These measures are presented as complementary: surveillance informs stewardship and therapeutic development, while stewardship reduces the selection that enables resistant clones to dominate.
The authors declare no competing interests. Ethical approval is not applicable for this review. Publication identifiers reported include PMID 42579153 and DOI 10.1007/s00203-026-05077-0. The article appears in Archives of Microbiology (2026).