The worldwide ratio of E. faecalis-to-E. faecium infections in clinical settings has changed dramatically in favor of E. faecium CC17 after acquiring high resistance to multiple antimicrobials. In addition, the latter species is naturally resistant to cephalosporins and aminoglycosides at low levels, and the CC17 lineage is nearly always resistant to ampicillin (13). More importantly, vancomycin-resistant E. faecium CC17 has spread globally in the past few decades (14). As such, a better understanding of the resistance mechanisms of this pathogen is needed for the prediction and prevention of its dissemination.
Resistance to ampicillin is a primary trait of E. faecium CC17. In the United States, nosocomial infections caused by ampicillin-resistant E. faecium CC17 increased in the 1980s, followed by the emergence of vancomycin-resistant E. faecium CC17 in the 1990s. In Europe, vancomycin-resistant E. faecium CC17 prevalence rates have been increasing since the 2000s. These findings strongly suggest that the emergence and spread of ampicillin-resistant E. faecium CC17 in hospitals has preceded the dramatic emergence of vancomycin-resistant E. faecium CC17. Hence, efforts for preventing the further spread of this epidemical pathogen should focus on the early disclosure of ampicillin-resistant E. faecium CC17 strains.
Ampicillin resistance in E. faecium CC17 is due to 1) alterations caused by mutations in penicillin-binding protein (PBP5), resulting in lower affinity; and 2) overproduction of PBP5 (5). E. faecium isolates of hospitals acquired selective advantage after obtaining ampicillin resistance and some virulence genes. After successfully exploiting the hospital environment, the adaptive isolates increased in frequency to become the dominant clones. By the “genetic capitalism” strategy, the dominant isolates acquired additional adaptive mechanisms more easily, such as vancomycin resistance, thereby fully adapting as a nosocomial pathogen that spread globally (15). Several studies have reported that the nucleotide difference of the PBP5 gene between ampicillin-resistant and -sensitive E. faecium isolates was 5%. The mutation of the PBP5 gene may be the reason for the ampicillin resistance phenotype (6).
The van genes, especially vanA, vanB, and vanM, carry greater clinical significance, as they can confer intermediate-to-high levels of resistance to vancomycin and are encoded on MGEs. In some European countries, 30% to 50% of E. faecium CC17 isolates showed vancomycin resistance, and this was considered the greatest threat to successful clinical treatment. In China, the prevalence of vancomycin-resistant E. faecium (VREfm) has been considered as low as 3.6% according to the report from 2010 China Antimicrobial Surveillance Network (CHINET). However, a monitoring data covering 45 tertiary hospitals indicated that the incidence of VREfm had increased to 14.3% in 2013 (16). Due to the conjugative transposons and plasmids, the dissemination of vancomycin resistance was expanded among enterococcal strains, species, and even genera such as Staphylococcus aureus. Consequently, VREfm are already the second most common nosocomial pathogen in the United States after heavy use of vancomycin in clinical settings (4).
Similarly in Europe, VREfm colonization and infection dramatically increased over a short period of time. However, unlike in the United States, VREfm colonization was limited in hospitals, and large community spreading was thought to be one reason for the sudden increase in VREfm colonization and infection. In the late 1980s, farmers in Europe began adding to animal feed avoparcin, a glycopeptide antimicrobial-like vancomycin. After this, VREfm colonization was soon observed in farm animals as well as in the community. The use of avoparcin in the animal industry was subsequently banned in Europe in 1996. However, persistent VREfm colonization in poultry has been reported up to eight years after the ban (17).
The optimal therapy for VRE infections in clinical settings remains uncertain. The new antibiotics daptomycin and linezolid are the most utilized last-line antibiotics. However, mutations in any one of the three genes, liaF, liaS, and liaR, have been linked to daptomycin resistance, while mutations in 23S rRNA, the Cfr rRNA methyltransferase gene, or optrA have been reported to cause linezolid resistance. Although plasmid-mediated linezolid resistance can lead to sporadic outbreaks, resistance to last-line antibiotics remains uncommon (8).
Transferable resistance poses a great threat, as it can produce a much greater threat due to its wide and rapid dissemination. Several reports have suggested that the acquisition of insertion sequence (IS) elements can facilitate the niche adaptation of E. faecium CC17 by increasing its genome plasticity. These findings indicate that the global emergence of E. faecium CC17, as observed since 1990, represents the evolution of the CC17 lineage with better adaptation (AMR) than other E. faecium lineages to the constraints of hospital environments (10).