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Antibiotic resistance in Enterococcus faecium clinical isolates Expert Rev. Anti Infect. Ther. 12(2), 239–248 (2014)

Vincent Cattoir*1,2 and Jean-Christophe Giard2 1 CHU de Caen, Service de Microbiologie & Centre National de Re´fe´rence sur la Re´sistance aux Antibiotiques (Laboratoire Associe´ Ente´rocoques), F-14033 Caen, France 2 Universite´ de Caen Basse-Normandie, EA 4655 U2RM, F-14032 Caen, France *Author for correspondence: Tel.: +33 231 064 572 Fax: +33 231 064 573 [email protected]

The worldwide ratio of Enterococcus faecalis-Enterococcus faecium infections is currently changing in favor of E. faecium. Intrinsic and acquired antimicrobial resistance traits of this latter species can explain this evolution as well as the diffusion of hospital-adapted strains belonging to the clonal complex CC17. Like other enterococci, E. faecium is naturally resistant to cephalosporins and aminoglycosides (at low level). Because of its high genome plasticity, it can also acquire numerous other resistances. It is noteworthy that most modern isolates of E. faecium are highly resistant to ampicillin while a non-negligible proportion of them (depending on geographical locations) are resistant to glycopeptides (especially in the USA). Even if resistance to newer antimicrobial agents (linezolid, daptomycin, tigecycline) is still uncommon, some clinical isolates with reduced susceptibility or resistance have already been reported and better understanding of resistance mechanisms is needed for prediction and prevention of their dissemination. KEYWORDS: antimicrobial resistance • CC17 • E. faecium • glycopeptide resistance • VREF

Although they are part of the normal intestinal flora of humans, enterococci are a leading cause of hospital-acquired infections with the emergence of multidrug-resistant (MDR) isolates, especially vancomycin-resistant enterococci (VRE) [1]. The spread of VRE isolates has been associated with significant increases in mortality, length of hospital stay and healthcare costs [2]. Due to the development of MDR isolates and the paucity of newer antimicrobial agents, therapeutic options for the treatment of enterococcal infections has become challenging. Approximately 80% of enterococcal infections are caused by Enterococcus faecalis while ca. 20% are due to Enterococcus faecium, which is increasingly reported [3]. Notably, E. faecium is part of the ‘no ESKAPE’ pathogens besides Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., which comprise major MDR opportunistic organisms [4]. In addition, there has been since the end of the 1980s, the worldwide dissemination of a subpopulation of E. faecium highly resistant to ampicillin and fluoroquinolones that acquired, at a later stage, resistance to vancomycin, commonly referred to as vancomycin-resistant E. faecium (VREF). These

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10.1586/14787210.2014.870886

hospital-adapted isolates belong to the so-called clonal complex CC17, and are responsible for numerous hospital outbreaks due to their important colonization and persistence capacities [5]. Beside its selective advantage provided by intrinsic and acquired antibiotic resistance traits (TABLE 1), E. faecium is well equipped with many virulence factors such as adhesion and secreted proteins that are involved in their epidemiological success in hospital settings [3]. The aim of this review is to update the knowledge on mechanistic and epidemiological traits of resistance recently published for E. faecium. The text is mainly focused on the most recent findings, particularly on new antimicrobial agents and emerging resistance mechanisms. b-lactams

b-lactam antibiotics inhibit the last steps of the peptidoglycan synthesis by binding to the high-molecular-weight penicillin-binding proteins (PBPs) [6]. Enterococci are intrinsically resistant to cephalosporins by production of low-affinity PBPs. By contrast, penicillins (especially ampicillin) alone or combined with an aminoglycoside represent the drugs of choice for the treatment of enterococcal

 2014 Informa UK Ltd

ISSN 1478-7210

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Table 1. Main mechanisms of antimicrobial resistance in Enterococcus faecium. Antibiotics

Mechanism of resistance

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Intrinsic resistance Cephalosporins

Low-affinity PBP

Aminoglycosides (low level)

Low-level uptake

Tobramycin (moderate level)

Enzymatic inactivation (AAC[6´]-Ii) Ribosomal methylation (EfmM)

Acquired resistance Ampicillin (high level)

Overproduction/alterations of PBP5

Gentamicin (high level)

Enzymatic inactivation (AAC[6´]-Ie-APH[2´´]-Ia)

Streptomycin (high level)

Alterations of S12 ribosomal protein

Glycopeptides

Precursor modification (VanA, VanB)

Fluoroquinolones

Alterations in DNA gyrase and topoisomerase IV

Macrolides

Ribosomal methylation (Erm)

Linezolid

Ribosomal mutations (23S rRNA)

Daptomycin

Complex changes in cell envelope

PBP: Penicillin-binding protein.

infections. However, ampicillin resistance, which is exceptional in E. faecalis, has become very frequent in E. faecium, representing 95–100% and 70–95% of VREF and E. faecium clinical isolates, respectively [7–14]. In this latter species, the resistance is mainly due to overexpression and/or mutations of a gene coding for the low-affinity PBP5 [15–17]. An alternate mechanism of high-level ampicillin resistance has been selected in vitro, being due to the production of b-lactamresistant L,D-transpeptidase and D,D-carboxypeptidase bypassing the D,D-transpeptidase activity of the PBPs [18]. As opposed to PBP5-mediated ampicillin resistance, this L,Dtranspeptidase is inhibited by imipenem [19]. Fortunately, this novel mechanism of resistance has not yet been reported in clinical isolates. Finally, other resistance determinants have been recently identified using genome-wide analysis, especially ddcP coding for a low-molecular-weight PBP with D, D-carboxypeptidase activity [20]. Aminoglycosides

Aminoglycosides are fast-acting bactericidal antimicrobial agents inhibiting the protein biosynthesis through the binding to the conserved A-site of 16S rRNA on the 30S small subunit of the bacterial ribosome [21]. Although enterococci present a lowlevel resistance to these antibiotics, the combination of cell 240

wall-active agents (e.g., penicillins, glycopeptides) and aminoglycosides results in a significant bactericidal synergy. Indeed, the alteration of the parietal structure allows a better penetration of aminoglycosides [22]. Moreover, it has been proposed that the synergistic effect is likely due to the formation of reactive oxygen species contributing to cell death [23]. The intrinsic resistance of enterococci (MICs from 4 to 256 mg/l) is due to a limited drug uptake [24]. In addition, acquired high-level resistance to aminoglycosides (usually MICs ‡2000 mg/l) is commonly found among enterococcal clinical isolates [24,25]. The main mechanism of resistance is the production of aminoglycoside-modifying enzymes (AMEs): aminoglycoside acetyltransferases (AACs), aminoglycoside phosphotransferases (APHs) and aminoglycoside nucleotidyltransferases (ANTs) [21]. Noteworthy, E. faecium is intrinsically resistant to tobramycin and kanamycin (preventing their combination with penicillins or glycopeptides) by production of two chromosomal enzymes: AAC(6´)-Ii and EfmM, a 16S rRNA methyltransferase [26,27]. Therefore, gentamicin and streptomycin constitute the drugs of choice for the treatment of severe infections caused by E. faecium, and testing for high-level resistance to these compounds should be performed [24]. High-level resistance to streptomycin results from single-step mutations in the S12 ribosomal protein or the acquisition of genes encoding ANT(3´´)-Ia or ANT(6´)-Ia enzymes [25]. High-level gentamicin resistance is usually due to the acquisition of a transposon harboring the bifunctional enzyme AAC(6´)-Ie-APH(2´´)-Ia, responsible for cross-resistance to all clinically available aminoglycosides, except streptomycin [25]. Also, several other determinants have been occasionally described in high-level gentamicin resistance, such as APH(2´´)-Ib, APH(2´´)-Ic or APH(2´´)-Id [25]. Finally, two other AMEs, APH(3´)-IIIa and ANT(4´´)-Ia, have been identified in E. faecium, responsible for the low-level resistance to kanamycin and to tobramycin-kanamycin-amikacin, respectively [25]. Around 50–60% of recent E. faecium clinical isolates are highly resistant to streptomycin whereas high-level resistance to gentamicin ranges from 20 to 80% depending on the country [7–9,28] Glycopeptides

Although E. faecalis has caused almost all enterococcal infections since the early 1990s, E. faecium is the most difficult species to treat due to its multidrug resistance. Furthermore, E. faecium slowly but progressively replaces E. faecalis in human infections [29]. The epidemiological success of E. faecium can be partially explained by its great genomic plasticity, which enables it to cope with numerous environmental stresses including antimicrobial pressure. Recently, the comparative analysis of the genomic sequence of 51 E. faecium strains reveals that the epidemic hospital-adapted lineage emerged approximately 75 years ago, which coincides with the beginning of antibiotics area [30]. This illustrates the spectacular ability of E. faecium to remodel its genome contents. For proof, the clonal complex CC17 (based on multilocus sequence typing – MLST – scheme), Expert Rev. Anti Infect. Ther. 12(2), (2014)

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Antibiotic resistance in Enterococcus faecium

has been well characterized as a subpopulation of E. faecium particularly well hospital-adapted, highly pathogenic and resistant to ampicillin and fluoroquinolones but not always to vancomycin [5]. Moreover, it has been reported that between 2002 and 2006, the increased number of infections caused by enterococci in Danish hospitals was mainly due to E. faecium isolates belonging to the CC17 [31]. The CC17 strains belong to the hospital-associated clade that is genetically distant from the community-associated clade. They harbor the insertion sequence 16 (IS16) and are highly resistant to ampicillin and fluoroquinolones [32–34]. The first VREF has been isolated in 1986 in Europe (after 30 years of glycopeptide use) and since were disseminated worldwide especially in hospital environments [1,30,35–37]. Data on enterococcal infections collected from several US hospitals (84,050 isolates) between 2010 and 2012 revealed that 20.6% of the isolates were resistant to vancomycin. While E. faecium correspond to 24% of the isolates, one-third are vancomycin resistant that represents 75% of the glycopeptide-resistant enterococci strains [38]. This is in accordance with a previous study showing that up to 80% of E. faecium clinical isolates recovered from US hospitals are vancomycin resistant [39]. In Europe, the prevalence of vancomycin resistance among E. faecium isolates highly diverges according to the country and ranged from more than 30% (i.e., Ireland, Greece) to less than 1% (Nordic countries) [37]. Vancomycin and teicoplanin are the two glycopeptidic antibiotics used to treat serious human infections due to Grampositive bacteria. These high-molecular-weight molecules do not enter into the cytoplasm but interact with the D-Ala-D-Ala terminus of the pentapeptide precursors of the peptidoglycan [40]. The formation of a stable complex involving five hydrogen bonds leads to the blockage of the transglycosylation and transpeptidation reactions in cell wall synthesis. Consequently, the precursors accumulate inside the cell, the cell wall loses its integrity and the bacteria die. Like with penicillins, glycopeptides are usually combined with an aminoglycoside because of the bactericidal synergistic effect. The very sophisticated mechanism of resistance to glycopeptides is based on the presence of operons encoding enzymes that synthesize new precursors with low affinity (where the last D-Ala is changed by D-Lac or D-Ser) (ligases), and that eliminate or prevent the formation of the native precursor with high affinity (D,D-dipeptidases and carboxypeptidases). Precursors with the D-Ala-D-Lac terminus have 1000-fold less affinity to vancomycin than those ending in D-Ala-D-Ala resulting in a high level of resistance (MIC >16 mg/l). On the other hand, the precursors ending with D-Ala-D-Ser, those are sevenfold less affine to vancomycin leads to a low level of resistance (MIC of 8–16 mg/l) [41]. Eight different operons involved in the acquired resistance to glycopeptides (vanA, B, D, E, G, L, M, N) and an intrinsic one (vanC1/C2/C3/C4) have been characterized in enterococci. Among them, only vanA, B, D, M and N were found in E. faecium (TABLE 2) [1,42,43]. Of note, the vanN is the www.expert-reviews.com

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sole operon leading to the synthesis of D-Ala-D-Ser ending precursors in E. faecium and may be specific for this strain [44,45]. VanA and VanB types are the most frequently retrieved in VREF and are both borne by transposons (Tn1546 and Tn1547, respectively) [41]. VanA isolates are inducible resistant to high level of vancomycin and teicoplanin (MIC >64 mg/l). The expression of genes of the operon is controlled by a two-component regulatory system vanRS. On the other hand, VanB-resistant strains of E. faecium exhibit various levels of vancomycin resistance (MIC from 4 to 1000 mg/l) but remain susceptible to teicoplanin that does not induce the vanB operon. It is also worth noting that ampicillin-resistant mutants producing an L,D-transpeptidase activity also appears to be resistant to glycopeptides [46]. Fluoroquinolones

Fluoroquinolones are bactericidal agents acting against a large panel of Gram-negative and Gram-positive bacteria. However, they show a limited antimicrobial activity against enterococci, although newer compounds (i.e., levofloxacin and moxifloxacin) are more active. High-level acquired resistance results from point mutations in gyrA and parC genes encoding subunits A of DNA gyrase and topoisomerase IV, respectively [47]. Interestingly, high-level fluoroquinolone resistance appears to be increasingly distributed among hospital-adapted E. faecium clinical isolates, especially those belonging to the clonal lineage CC17 [48,49]. Indeed, around 80% of E. faecium and 95% of VREF (all belonging to the CC17) were resistant to levofloxacin [7–14]. Moreover, some findings strongly suggest that a NorA-like efflux pump exists in E. faecium, which may be involved in resistance to hydrophilic fluoroquinolones [50]. Quinupristin–dalfopristin

Quinupristin–dalfopristin is an injectable streptogramin that was the first drug approved by the US FDA (1999) for the treatment of VRE infections. It actually consists of two semisynthetic compounds combined in a 30:70 ratio (w/w): quinupristin (streptogramin B) and dalfopristin (streptogramin A) [51]. Individually, these compounds are bacteriostatic against most Gram-positive bacteria, but they synergistically become bactericidal when combined [52]. Streptogramins A and B act by interfering with bacterial protein synthesis by binding to adjacent regions within the P site of 23S rRNA of the 50S ribosomal subunit [53]. A variety of mechanisms confer resistance to streptogramins A or B, including modifying enzymes, drug efflux and modification of the ribosomal target [54]. The methylation of the 23S rRNA is the most common resistance mechanism to streptogramins, which is due to methylases encoded by erm genes (especially erm[B]), leading to cross-resistance to macrolides–lincosamides–streptogramins B (MLSB phenotype). This latter phenotype is frequently found in E. faecium [55,56], and around 95% of VREF clinical isolates have been found to be resistant to erythromycin and clindamycin in France [9]. As opposed to E. faecalis that is intrinsically resistant to lincosamides and streptogramins A (LSA phenotype) due to the 241

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Table 2. Types of resistance to glycopeptides described in Enterococcus faecium. Type of resistance VanA

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VanM

VanB

VanD

VanN

Level of resistance

High

High

Variable

Moderate

Low

MIC (mg/l) Vancomycin

64–1000

>256

4–1000

64–128

16

Teicoplanin

16–512

48–128

0.5–1

4–64

1

Expression

Ind.

?

Ind.

Const.

Const.

Location

Plasmid (chromosome)

Plasmid (chromosome)

Chromosome (plasmid)

Chromosome (plasmid)

Chromosome

Conjugative transfer

+

+

+

-

+

Precursors end

D-Ala-D-Lac

D-Ala-D-Lac

D-Ala-D-Lac

D-Ala-D-Lac

D-Ala-D-Ser

Prevalence

Very high

Very low

High

Low

Very low

Const.: Constitutive; Ind.: Inducible. Data taken from [1,36].

synthesis of the ABC protein Lsa(A), E. faecium is naturally susceptible. However, LSA-resistant E. faecium can be selected in vitro and in vivo, bringing into play a unique point mutation in the domestic gene eat(A) coding for an ABC protein related to Lsa(A) [57]. Interestingly, this novel resistance phenotype seems nonetheless common in VREF, since it has been detected among 23% of the 60 VREF clinical isolates collected in France [57]. Streptogramins B can also be enzymatically inactivated by lyases encoded by the vgb(A) gene while acetyltransferases [encoded by vat(D), vat(E), and vat(H) genes] degrade streptogramins A [56]. Note that vat(D) and vat(E) genes have also been detected in animals due to the use of the growth promoter virginiamycin [58]. Finally, a putative efflux mechanism, mediated by the ABC protein VgaD, has been detected in some E. faecium clinical isolates [25]. Linezolid

Linezolid, first oxazolidinone launched since April 2000, is indicated in the treatment of infections caused by Grampositive bacteria, including VRE (600 mg b.i.d.). Linezolid alters protein synthesis by binding to the 23S RNA and preventing the assembly of the functional 70S initiation complex [59]. Like macrolides, lincosamides, tetracyclines and chloramphenicol, oxazolidinones are essentially bacteriostatic, and they exhibit a ca. 2-h post-antibiotic effect. Notably, linezolid is equally active against vancomycin-susceptible and resistant E. faecium isolates [60], with MIC50 and MIC90 both at 1–2 and 2–4 mg/l, respectively [7,10,11,13,61–65]. Despite the difficulty of in vitro selection (frequency ~10-9), linezolid resistance can emerge during therapy [66], especially but not exclusively after a prolonged therapy [67,68]. In enterococci, it is generally associated with a point mutation (G2576T) in the central loop of domain V of the 23S rRNA, also described in linezolid-resistant staphylococci [64,69–73]. Interestingly, the level of resistance is correlated with the proportion of mutated 23S rDNA alleles. E. faecium harbors 242

6 copies, and linezolid MIC is 2, 8–16, 32 and 64 mg/l in the presence of 0, 1, 2 or 3, and 4 or 5 mutated copies, respectively [74]. Another mutation (G2505A) was also identified in an in vitro selected resistant E. faecium mutant [75]. MICs of resistant enterococcal strains range from 8 to 128 mg/l, the CLSI susceptibility breakpoint being £4 mg/l [67,70,71,76]. In staphylococci, other point mutations in domain V of 23S rRNA have also been described as well as mutations in ribosomal proteins L3 and L4, but they have not been yet reported in enterococci [77–82]. More recently, another mechanism of resistance has been described, which is due to the production of the chloramphenicol florfenicol resistance (Cfr) protein that specifically methylates the 23S rRNA at the A2503 residue [83]. Initially identified in staphylococcal isolates from animal sources, it has since been detected in some human S. aureus and one E. faecalis clinical isolates, but not in E. faecium so far [84–86]. Interestingly, Cfr causes cross-resistance to five different antibiotic families: phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramins A (the so-called PhLOPSA phenotype) [87]. Except for Cfr, none of the mechanisms of resistance to other protein synthesis inhibitors confers cross-resistance to linezolid [88]. A large majority of E. faecium clinical isolates remain susceptible to linezolid with a prevalence of resistance usually lower than 2% irrespective of the resistance phenotype to vancomycin [7,8,10–14,62,64,89]. However, some hospitals have reported notable rates of resistance (5–10%) among VRE isolates, particularly in the USA [11,62], while hospital outbreaks caused by linezolidresistant VREF have been also reported [69]. Daptomycin

Daptomycin is a cyclic lipopeptide antibiotic that exerts a potent and rapid bactericidal activity against Gram-positive bacteria, including MDR E. faecium isolates [90]. It has been available in the USA since September 2003 and it is commonly employed for the treatment of VRE infections, even if it does Expert Rev. Anti Infect. Ther. 12(2), (2014)

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Antibiotic resistance in Enterococcus faecium

not have FDA approval in this indication [8]. This off-label use is supported by retrospective studies that have shown similar outcomes for patients with severe enterococcal infections treated by daptomycin (median dosage at 6 mg/kg/day intravenously) or linezolid [91–94]. Daptomycin irreversibly interacts with the bacterial cell membrane in a calcium-dependent manner, leading to the disruption in its integrity with an efflux of potassium ions and the dissipation of the ion concentration gradient. Cell death occurs as a result in DNA, RNA and protein synthesis [59]. The development of resistance to daptomycin remains uncommon in enterococci, with spontaneous in vitro resistance frequencies ~10-9 [95]. However, several failures of daptomycin therapy for E. faecium bacteremia have been reported with the emergence of high-level resistance (MIC >32 mg/l) [96–98]. This resistance can rapidly emerge (after less than 10 days of exposure), especially in patients with disorders of calcium homeostasis, low doses of daptomycin or end-stage renal failure [98]. Note that daptomycin activity against E. faecium is independent of the presence of van operons or linezolid resistance [93]. As previously described in E. faecalis, some chromosomal mutations in genes involved in the structure of the cell envelope and biophysical properties of the cell membrane are responsible for resistance in E. faecium [99,100]. Notably, several in-frame deletions have been identified either in genes coding for enzymes involved in phospholipid metabolism, such as GdpD (glycerophosphoryl diester phosphodiesterase) and Cls (cardiolipin synthetase) or in a gene coding for a putative membrane protein named LiaF, which is part of the three-component system LiaFSR (lipide-II interacting antibiotics) known to regulate the response of the cell envelope to antimicrobial agents in Bacillus subtilis [101,102]. Other mutations have been identified in other genes putatively involved in daptomycin resistance, but their role need to be confirmed [103,104]. Particularly, amino acid changes were found in the essential two-component system YycFG (analogous to LiaSFR) that regulates cell envelope homeostasis and cell division [104]. Daptomycin-resistant enterococcal isolates have marked ultrastructural changes in the cell envelope with cell wall thickening, increased net positive surface charge and decreased cell membrane fluidity as well as significant reduction in the ability of daptomycin to depolarize and permeabilize the cell membrane [99,105]. These modifications are associated with biochemical and biophysical alterations in cell membrane lipid metabolism, particularly in phospholipid content [105]. It is worth noting that some therapy failures have been reported in patients suffering from bacteremia caused by E. faecium isolates exhibiting MICs (3–4 mg/l) close to the CLSI susceptibility breakpoint (£4 mg/l) [106,107]. Interestingly, there is a strong association between elevated daptomycin MICs and the presence of mutations in the liaFSR locus. These mutations are a prerequisite for high-level resistance in combination with subsequent mutations in gdpD and/or cls genes [99,100]. Therefore, a daptomycin MIC of 3–4 mg/l may be an indicator of possible treatment failure, corresponding to a first-step mutant predisposed to develop in vivo high-level resistance. www.expert-reviews.com

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All surveillance studies conducted in Europe and North America have shown daptomycin susceptibility rates close to 100% in E. faecium with MIC50 and MIC90 around 1 and 2 mg/l, respectively, regardless of the resistance to vancomycin [64,65,89,93]. For instance, in a recent study conducted in France, 100% of 60 epidemiologically unrelated VREF clinical isolates were categorized as susceptible to daptomycin with a range of MICs from 0.25 to 4 mg/l [65]. Tigecycline

Tigecycline is the first representative of the novel glycylcycline class, which exhibit a potent activity against a broad spectrum of Gram-positive and Gram-negative bacteria, including VRE isolates [108]. It is currently approved by the FDA for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections (June 2005) as well as community-acquired bacterial pneumonia (May 2009). Tigecycline must be administered parentally at the dosage of 50 mg/ kg every 12 h after an initial dose of 100 mg/kg [108]. This bacteriostatic antibiotic acts through binding to the bacterial 30S ribosomal subunit and blocking entry of the amino-acyl tRNAs into the A site of the ribosome, leading to the inhibition of protein biosynthesis [59]. Interestingly, tigecycline is not affected by the two major mechanisms of tetracycline resistance, that is, active efflux (e.g., tet[K] in enterococci) and ribosomal protection (e.g., tet[M] in enterococci) [109]. Also, common mechanisms of resistance to other antibiotic classes do not affect tigecycline activity. Resistance is difficult to select in vitro (frequency ~10-9) mainly related to overexpression of efflux pump systems in Gram-negatives whereas acquired resistance remains very uncommon in Gram-positives [110]. Indeed, enterococcal clinical isolates with MIC values above the EUCAST susceptible breakpoint (£0.25 mg/l) are exceptional, while high-level resistant strains (MIC >1 mg/l) have not been reported yet. All TEST (Tigecycline Evaluation and Surveillance Trial) international studies have reported tigecycline susceptibility rates close to 100% in E. faecium with MIC50 and MIC90 of 0.06–0.12 and 0.12–0.25 mg/l, respectively, regardless of the resistance to vancomycin [10–13,62,63,111]. In a recent French study, only 2 of 60 epidemiologically unrelated VREF clinical isolates were categorized as non-susceptible to tigecycline with an MIC at 0.5 mg/l [65]. However, molecular mechanism of this reduced susceptibility phenotype remains unknown. Expert commentary & five-year view

Over the years, E. faecium has demonstrated its potential to acquire a variety of resistance determinants and to adapt to different hostile environments, leading to its emergence and diffusion in the hospital settings. This is particularly true for ampicillin- and vancomycin-resistant isolates belonging to the CC17. Toward new antimicrobial agents (such as linezolid and daptomycin), acquired resistance is also emerging in E. faecium, mainly due to mutations in chromosomal genes. In addition, there is a potential risk of emergence of plasmid-mediated 243

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linezolid resistance, since the cfr gene has been identified several times in E. faecalis [112]. Several new anti-Gram-positive antibiotics have been very recently commercialized. For instance, ceftaroline is a novel cephalosporin with activity against methicillin-resistant S. aureus and penicillin-resistant pneumococci, but enterococci remain resistant (MIC >32 mg/l) to this drug [113]. Some other drugs (e.g., lipoglycopeptides) are going into development as potential options for the VREF treatment but their number is limited and their activity is variable [114]. Plazomicin is a next-generation aminoglycoside that retains activity against both Gram-negative and Gram-positive bacterial strains expressing AMEs, but its activity against enterococci does not seem to be clinically relevant [115]. Besides classical antimicrobial therapies, other alternative therapeutic options are promising and should be encouraged, such as immunotherapy and bacteriophage therapy [116,117]. To conclude, large efforts

must be pursued in order to prevent development and spread of antibiotic resistance in E. faecium through infection control policies and antibiotic stewardship programs. Acknowledgement

The authors warmly thank A Hartke for critical reading of the manuscript and insightful comments. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Enterococcus faecium is becoming one of the leading causes of hospital-acquired infections. There is currently a shift in clinical significance from Enterococcus faecalis to this species. • The high genome plasticity of E. faecium is one of the major characteristics that may explain why it successfully adapt to harsh conditions such as the hospital environment and how it can cope with antibiotic and antiseptic stresses. • Its inherent resistance to antimicrobial agents such as cephalosporins and aminoglycosides (low level) as well as to its ability to acquire and share new antibiotic resistance traits (especially against ampicillin, gentamicin [high level] and vancomycin), causes more and more therapeutic problems. • For the treatment of infections caused by vancomycin-resistant E. faecium (VREF) isolates, a limited arsenal is currently available but some molecules (e.g., linezolid, daptomycin or tigecycline) can be alternative options. However, acquired resistance to these novel drugs is possible and has been already detected in vitro and in vivo. • It is necessary to maintain the vigilance face to the dissemination of well hospital-adapted E. faecium strains (in particular, VREF belonging to the clonal complex CC17) and to have rigorous policies of hygiene and antimicrobial use.

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