ANALYSIS OF SELECTED GENETIC TRAITS, PHENOTYPES, AND THE EPIDEMIOLOGICAL THREAT OF ENTEROCOCCUS BACTERIA RESISTANT TO VANCOMYCIN

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VOLUME 58 , ISSUE 1 (June 2019) > List of articles

ANALYSIS OF SELECTED GENETIC TRAITS, PHENOTYPES, AND THE EPIDEMIOLOGICAL THREAT OF ENTEROCOCCUS BACTERIA RESISTANT TO VANCOMYCIN

Wojciech Rogóż / Daniel Sypniewski * / Ilona Bednarek

Keywords : antimicrobial resistance, Enterococcus, vancomycin, VRE

Citation Information : Postępy Mikrobiologii - Advancements of Microbiology. Volume 58, Issue 1, Pages 35-48, DOI: https://doi.org/10.21307/PM-2019.58.1.035

License : (CC-BY-NC-ND 4.0)

Published Online: 10-June-2019

ARTICLE

ABSTRACT

Enterococci are Gram-positive bacteria that belong to facultative anaerobic cocci. Species belonging to the Enterococcus genus generally display little infectious potential, although they can cause serious nosocomial infections. The groups at high risk include patients with proliferative diseases, chronic liver diseases, and graft recipients. Since 1980s infections with enterococci resistant to numerous antibiotics have been observed with increasing frequency. There are two independent ways of developing resistance to vancomycin, connected with the common use of vancomycin for MRSA treatment and the non-medical use of this antibiotic. Nine phenotypes of vancomycin-resistant enterococcal strains can be distinguished: VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM, VanN. These phenotypes differ at the molecular level to a different extent. Current treatments of enterococcal infections usually include drugs such as linezolid, quinupristin/dalfopristin, daptomycin, tigecycline, and chloramphenicol. Data available from Europe and other parts of the world indicate a constant increase in the number of emerging VRE isolates, as well as strains resistant to antibiotics other than vancomycin.

1. Introduction. 2. Infections with enterococci. 3. Treatment of enterococcal infections and antimicrobial resistance. 4. Development of VRE phenomenon. 5. Drugs used to control infections with VRE strains. 6. Routes of VRE spread. 7. VRE phenotypes. 8. Molecular characteristics of VRE phenotypes. 9. Epidemiological situation in the world. 10. Epidemiological situation in Poland. 11. Epidemiological situation in Europe. 12. Summary

Translated

Streszczenie: Enterokoki to bakterie Gram-dodatnie, należące do względnie beztlenowych ziarniaków. Gatunki należące do rodzaju Enterococcus na ogół mają niewielki potencjał infekcyjny, jednak mogą wywoływać groźne zakażenia szpitalne. Do grupy podwyższonego ryzyka zalicza się pacjentów z chorobami rozrostowymi, z przewlekłymi chorobami wątroby oraz po przeszczepach. Od lat osiemdziesiątych XX w. obserwuje się pojawiające się coraz częściej zakażenia enterokokami opornymi na liczne antybiotyki. Istnieją dwie, niezależne od siebie drogi rozwoju oporności na wankomycynę, związane z powszechnym leczeniem MRSA przy pomocy wankomycyny oraz jej zastosowaniem pozamedycznym. Wśród opornych na wankomycynę szczepów enterokoków można wyróżnić 9 fenotypów: VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM, VanN. Wszystkie te fenotypy różnią się między sobą w większym lub mniejszym stopniu na poziomie molekularnym. Obecnie stosowanymi w leczeniu infekcji wywołanych enterokokami są m. in. linezolid, chinuprystyna/dalfoprystyna, daptomycyna, tigecyklina i chloramfenikol. Posiadane obecnie dane, zarówno z terenu Europy, jak i całego świata wskazują na stały wzrost ilości pojawiających się izolatów VRE, jak również opornych na antybiotyki inne niż wankomycyna.

1. Wprowadzenie. 2. Zakażenia enterokokami. 3. Leczenie zakażeń enterokokami i antybiotykooporność. 4. Rozwój zjawiska oporności na wankomycynę. 5. Leki stosowane w zwalczaniu zakażeń szczepami opornymi na wankomycynę. 6. Drogi powstawania oporności na wankomycynę. 7. Fenotypy szczepów opornych na wankomycynę. 8. Charakterystyka molekularna fenotypów szczepów opornych na wankomycynę. 9. Sytuacja epidemiologiczna na świecie. 10. Sytuacja epidemiologiczna w Polsce. 11. Sytuacja epidemiologiczna w Europie. 12. Podsumowanie

Graphical ABSTRACT

1. Introduction

Enterococci are Gram-positive bacteria which belong to facultatively anaerobic cocci. They occur mainly in the intestines, where they constitute natural microflora, protecting against pathogens. They generally have the form of diplococci or short chains. The genus Enterococcus is comprised of 38 species, but only some of them are clinically relevant – these include Enterococcus faecalis, E. faecium, E. gallinarum and E. casseliflavus [1, 2]. The first species is very often isolated from the digestive system, especially of the large intestine, and the genitourinary system (approx. 39–95% of clinical trials), just like E. faecium, which, however, can be isolated much less frequently (in approx. 3–47% of clinical trials) [1]. Both of these species can be human pathogens. The other two, E. gallinarum and E. casseliflavus, despite exhibiting natural resistance to vancomycin, appear sporadically (in about 5% of clinical samples in total) and are generally not pathogenic [3, 4].

Enterococci, in laboratory conditions, can be grown on widely available, non-selective enriched media, such as chocolate agar or blood agar. They also grow in the conditions of high concentrations of sodium chloride and bile salts. They are characterized by high temperature tolerance – they can grow in the range of 10–45°C. Around the colonies of enterococci on agar with sheep blood, haemolysis areas can be observed. In microscopic analysis, it is practically impossible to distinguish them from pneumococci (Streptococcus pneumoniae), therefore it is necessary to use biochemical tests. They show resistance to optochin, which is active against pneumococci and, moreover, they are not soluble in bile salts, and the PYR test result (presence of L-pyrrolidonyl arylamidase) is positive [4].

Despite generally small infectious potential, the species belonging to the genus Enterococcus may be the cause of dangerous nosocomial infections [4]. In the United States, they are one of the most frequently isolated micro-organisms from the gastrointestinal tract and wounds [3]. They do not form strong bacterial toxins, but possess many other virulence factors, which include:

  1. surface adhesins, such as: a) ESP protein (enterococcal surface protein), whose task is to bind collagen to the surface of a bacterial cell. It occurs in E. faecalis and E. raffinosus. In the former species it is composed of 1972 amino acids and in the latter of 2311; it is encoded by esp gene [1, 46]. It is also a potential virulence factor in E. faecium [1]; b) polysaccharide glycocalyx, which mediates binding to host cells, such as epithelial cells lining the surface of the vagina or intestine [4]; c) the aggregating substance (AS) present in the cell membrane. It enables bacterial cells to aggregate, bind to host cells, and also contributes to the rizontal transfer of plasmid DNA [4]. It is encoded by, for example, the agg gene or the asa1 gene [7, 8].

  2. extracellular proteins such as: a) gelatinase and serine protease, which exhibit proteolytic activity against gelatine, haemoglobin, collagen and other proteins [4]; b) cytolysin exhibiting haemolytic activity and inhibiting the growth of Gram-positive bacteria; it may also contribute to local tissue damage [4]; it is composed of larger and smaller subunits, encoded by cyl-L and cyl-S genes [7] respectively; c) hyaluronidase, secreted by E. faecium strains from the CC17 clonal complex, occurring all over the world (including Poland); it is encoded by the gen hylEfm [1];

The virulence factors characteristic of E. faecalis are: cytolysin, gelatinase, hyaluronidase, suboxides, aggregating substance and surface adhesins, such as the Esp protein [9]. In the genome of E. faecalis asa1 and gelE genes occur much more often than in E. faecinum. E. faecalis produces particles enabling biofilm formation much more often than E. faecium [8].

2. Infections with enterococci

The high probability of infection with these pathogens is primarily associated with the usage of antibiotics with a broad spectrum of action [4]. The group of elevated risk includes patients with proliferative diseases, chronic liver diseases and recipients of transplanted organs. Due to the high resistance of enterococci to disinfectants and antiseptics, these bacteria are most often transported on the surface of the hands of medical personnel in hospitals [1]. Of great significance is the fact that Enterococcus bacteria can survive on hands for even up to 60 minutes [10]. The transfer of bacteria carrying genes which are resistant to vancomycin between animals and humans is possible. This phenomenon has been documented in the case of E. faecium and E. faecalis strains [11]. Under specific circumstances, enterococci may develop in other locations in the organism than their typical locations, for example in the respiratory system [4].

Bacteria of the genus Enterococcus are etiological factors of diseases such as endocarditis, sepsis, peritonitis, intra-abdominal abscesses, cholangitis or burn wounds [1]. Bacteria of the genus Enterococcus, which show presence of significant virulence factors, enabling the induction of infections difficult to treat (mainly in hospitals), can be classified as representatives of completely different clonal complexes. The clonal complex (CC – Clonal Complexes) is a group of bacterial clones whose representatives originate from a common ancestor and show mutual similarity at the molecular level, and sometimes also in terms of certain phenotypic traits, e.g. possession of virulence factors [12]. Clonal complexes are distinguished by means of the MLST molecular technique (MultiLocus Sequence Typing), in which the sequences of several gene alleles, encoding primary metabolism proteins, are analysed. These genes are expressed in all representatives of a given species at a similar level – for this reason they are called constitutive genes. In the E. faecium analysis carried out by Homan et al. [13], the following genes were considered: adk (gene encoding adenylate kinase), atpA (ATP alpha synthase gene coding), ddl (gene coding for D-alanine:D-alanine ligase), gyd (gene coding for 3-phosphoglyceric aldehyde dehydrogenase), gdh (gene encoding glucose-6-phosphate dehydrogenase), pstS (gene encoding ABC family transporter) and gene encoding the phosphoribosylaminoimidazole ATPase subunit [10, 12, 13].

The basic clonal complex of the species E. faecium is CC-17 popular in Europe and worldwide. Representatives of the CC-17 complex in the majority of cases show resistance to vancomycin (VER – Vancomycin-Resistant Enterococcus) [10]. The strains of this complex show presence of Esp protein and ability to produce hyaluronidase and the collagen-binding Acm protein. They are also resistant not only to vancomycin, but also to ampicillin and quinolones, such as ciprofloxacin [14, 15]. Due to the prevalence of CC-17, they are a significant problem both in Poland, in the USA and globally. The analysis carried out by Top et al. [16] shows that out of 217 VR E. faecium isolates, 97% (i.e. 211 isolates) were representatives of this clonal complex. CC-5, being popular in Europe, belongs to other clonal complexes of the species E. faecium and in the case of E. faecalis these are CC-2 and CC-9 [11, 17]. A team of researchers led by M. Kawalec, studying cloning complexes of isolates obtained from Polish hospitals until 2007, determined that in addition to the worldwide known CC-2 and CC-9, there have also occurred new groups of clones: CC-87 and CC-21. The first of them was responsible for the creation of four VRE foci, three of which were associated with the VanA phenotype, and one with VanB. The strains belonging to this clone demonstrated the ability to conduct a haemolysis process, but were not able to produce gelatinase [17].

3. Treatment of enterococcal infections and antimicrobial resistance

Standard treatment of enterococcal infections involves applying a combination of aminoglycoside with vancomycin or ampicillin [4]. The main problem in the treatment of enterococcal infections, however, is the high resistance of these bacteria to antibiotics [18]. It can be both innate and acquired. E. faecium exhibits natural resistance to cephalosporins, lincosamides (e.g. clindamycin), trimethoprim with sulfamethoxazole, as well as to low concentrations of aminoglycosides [1, 4, 18]. The reason for this phenomenon is the low level of penetration of aminoglycosides into cells. This is the reason for combining the representatives of this group of antibiotics with drugs inhibiting cell wall synthesis – mainly ampicillin [19]. In addition, enterococci have naturally increased resistance to penicillins – in comparison to streptococci, they are from 10 to even 100 times less sensitive to β-lactam antibiotics (E. faecalis), while E. faecium is 4–16 times less sensitive than E. faecalis [1, 4, 19]. This is associated with the overexpression of PBP5 proteins (penicillin binding proteins), very often found in E. faecium, and much less frequently in the case of E. faecalis, and, to a much lesser extent, with the production of β-lactamases – this mechanism (conditioned by the plasmid gene) occurs, on the other hand, in enterococci very rarely [19]. Currently, it is assumed that 25% of enterococci strains, both E. faecium and E. faecalis, are resistant to high concentrations of aminoglycosides – such strains are called HLAR (High Level Aminoglicoside Resistance) [1, 4]. Resistance to gentamycin was first observed in the United States in 1979, in both E. faecium and E. faecalis, as well as gentamycin, tobramycin, amikacin, kanamycin and streptomycin in 1983 [20, 21]. The reason of this resistance may stem either from the enzymatic modification or degradation of the antibiotic (in the course of research on the mentioned samples from 1983, numerous enzymes have been detected, for example 3’-phosphotransferase, 2’-phosphotransferase or 6’-acetyltransferase [18, 21]), or from changing the structure of the site of antibiotic attachment to ribosomes [17]. The vast majority of E. faecium strains are resistant to ampicillin [4, 18].

4. Development of VRE phenomenon

The first reports on the emergence of vancomycin resistance in infections with the bacteria of the genus Enterococcus, i.e. occurrence of VRE strains, appeared in Europe, in Great Britain in 1988 (E. faecalis and E. faecium), and a year later in the United States [1, 22]. Very important from the epidemiological point of view was also the year 2002, during which the first case was recorded, when, through the horizontal transfer of genomes, the translocation of the vanA operon occurred between a representative of the genus Enterococcus with VanA phenotype and the bacterium Staphylococcus aureus, resistant to methicillin, i.e. between VRE and MRSA strains, resulting in the formation of methicillin-resistant Staphylococcus aureus, insensitive to both methicillin and teicoplanin, i.e. the VRSA strain [1]. It is important that the strains classified as VRE are classified as XDR (eXtensively Drug Resistant). Belonging to this group means that the bacterium is currently only sensitive to one antibiotic from one or two groups which are intended to fight the representatives of its species [23].

5. Drugs used to control infections with VRE strains

In order to be able to cure the cases of VRE, it is necessary to use the latest antibacterial drugs, which unfortunately are not free of defects. The basic medicines used to treat VRE include linezolid. This antibiotic is one of the oxazolidinone derivatives. The FDA recommends its use in case of infection with VRE E. faecium, but also for the control of MRSA (Methicyllin-Resistant Staphylococcus aureus) or penicillin-sensitive strains of S. pneumoniae. The mechanism of action of linezolid consists in inhibiting protein synthesis by interacting with the mRNA-tRNA complex and ribosome. This disrupts the formation of the initiation complex by binding the ribosomal 50S subunit and preventing the attachment of tRNA [4]. This antibiotic is effective mainly against Gram-positive aerobic and anaerobic bacteria [24]. Resistance to linezolid may be quite rare, but among the VRE it is perceivable. The first cases were reported in 2001 in 5 patients treated with linezolid [25]. Also in 2001, the first cases of resistance to the mentioned antibiotic were recorded in Great Britain (two isolates of E. faecium and one of E. faecalis) [26]. A point mutation was detected in the 23S rDNA encoding gene (G2576T mutation in nucleotide 2576), whose occurrence is correlated with the ineffectiveness of therapy, and thus may constitute one of the markers of linezolid resistance to linezolid with unknown mechanism [27].

Another medication treated as the so-called “last resort” drug is a mixture of quinupristin/dalfopristin. It is, however, ineffective in the case of E. faecalis infections. Fluoroquinolones inhibiting the synthesis of nucleic acids are also used, but unfortunately, are not very active in relation to vancomycin-resistant strains [4]. According to Leavis et al., the parC, gyrA, parB and GyrE genes are responsible for the resistance of VRE to fluoroquinolones, such as ciprofloxacin. Especially the mutations in the first two genes make the bacteria highly resistant to ciprofloxacin [28]. Next, it is worth paying attention to daptomycin. It is a cyclic peptide antibiotic used in therapy in the USA since 2003 [29]. However, as early as in 2005, the first report appeared on the occurrence of infection with a VRE strain of E. faecium, which was also insensitive to this antibiotic. Only replacing it with the combined administration of linezolid and doxycycline led to curing the patient [2930].

Another example of the medication used to treat VRE is tigecycline. This semi-synthetic antibiotic, included in the glycylcycline group, exhibits bacteriostatic activity by disrupting the binding of aminoacyl-tRNA to the A site of the bacterial ribosome as a result of binding to the 30S subunit. Although this is a highly modified tetracycline derivative, tigecycline is also active against non-resistant strains [31]. Tigecycline is also generally effective in the control of both MRSA, VRE and many Enterobacteriaceae that produce carbapenemase [32]. It is used in accordance with the recommendation of KORLD (Polish acronym for: National Reference Centre for Antimicrobial Susceptibility), for the treatment of severe skin infections, subcutaneous tissues and abdominal cavity [33]. As with all available drugs, resistance thereto has also been developed. In 2008, a patient was reported from an intensive care unit from a hospital in Germany, from whom a tigecycline-resistant E. faecalis strain was isolated [31].

Other sources suggest that chloramphenicol may be used to combat infections with VRE [34]. This drug induces inhibition of transpeptidation on bacterial ribosomes as a result of binding to their 50S subunit. Its spectrum of activity includes aerobic and anaerobic Gram-positive and Gram-negative bacteria, as well as rickettsiae. In general, it exhibits bacteriostatic activity. It is recommended that it should be used only in the most severe cases, due to numerous strong side effects. It causes strong suppression of the bone marrow, and can contribute to the occurrence of the grey syndrome in new-borns. It also adversely affects normal intestinal microflora [35]. During the years 2006–2007, VRE resistant to this drug strain was isolated from three patients in the University Hospital in Bydgoszcz [36].

6. Routes of VRE spread

Two different and independent patterns can be distinguished, according to which resistance to vancomycin was formed among the bacteria of the genus Enterococcus. One of the schemes took place in the USA, where vancomycin was an antibiotic commonly used during the treatment of methicillin-resistant Staphylococcus aureus (MRSA), as well as during the treatment of antibiotic diarrhoea induced by Clostridium difficile. The second scheme was observed in Europe, where, as a result of feeding farmed animals with feed enriched with the glycopeptide avoparcin, there occurred a transfer of VRE between animals and humans [1]. The US and Canada were the only major countries that had not introduced avoparcin in agricultural applications. Most probably, this is the reason for the fact that until 2008, the VRE strain was not isolated from any analysed sample from livestock in these countries. In Europe, however, in the 1990s, the presence of vancomycin-resistant Enterococcus in the intestinal microbiota of farm animals was common. The use of this antibiotic as a growth stimulant began in 1975. It was most often administered to pigs, turkeys and calves. The scale of the phenomenon is best illustrated by the fact that in 1994, in Denmark alone, about 24 kg of vancomycin was used in human therapy, and about 24.000 kg of avoparcin was used as a growth stimulant in agriculture. The first country to forbid the use of the aforementioned antibiotic was Sweden. This resulted in an avalanche of similar decisions, ended with EU Directive 97/6/EC, prohibiting the use of avoparcin in agriculture [14]. Unfortunately, such accidents did not end with the avoparcin incident. Still in 2000, it was reported that antibiotics, identical to those used in clinical therapy, were commonly used in agriculture in Russia. Antibiotics are still used in a completely uncontrolled way in many countries around the world. The best example is shrimp farming in Asia [37]. Noteworthy is the phenomenon called the “the Swedish paradox”. It is manifested by the fact that despite a very short (especially compared to other European countries) duration of avoparcin application in this country – for less than 10 years, until 1984 – the incidence of VRE was very high there. It continued for just as long after the end of its application, although in other countries the number of isolated VREs decreased [14]. There were other VRE reservoirs on both continents. In the United States, these were hospitals and no strains outside the hospital environment were observed, while in Europe, animals were the reservoir [1].

7. VRE phenotypes

Among the strains of vancomycin-resistant enterococci, nine phenotypes can be distinguished. These are: VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM, VanN [1]. One of them, VanC, is an example of natural (species-specific) resistance. It is a feature of species that do not pose a significant clinical threat: E. gallinarum (vanC1), E. casseliflavus (vanC2 and vanC4) and E. flavescens (vanC3). It is generally associated with a constitutive mechanism of resistance. Bacteria of the VanC phenotype exhibit low resistance to vancomycin and are at the same time sensitive to teicoplanin. The genes determining this phenotype are localised in the chromosomal DNA of bacteria and never undergo horizontal transfer [3840]. Other phenotypes are an example of acquired resistance to glycopeptides [1]. The VanA, VanB, VanD and VanM phenotypes are characterised by the modified structure of the murein precursor in which the D-Ala-D-Ala sequence in the final pentapeptide is replaced by the D-Ala-D-Lac depsipeptide [40]. In other phenotypes, i.e. VanC, VanE, VanG, VanL and VanN, the terminal sequence of the pentapeptide takes the form of: D-Ala-D-Ser [40]. Due to the fact that gene clusters conditioning the VanA and VanB phenotypes are located on mobile genome elements, such as transposons and plasmids, they are of greatest clinical significance. The most noticeable difference between these phenotypes is that VanA strains are resistant to both vancomycin and teicoplanin, and VanB only to vancomycin. There are three subtypes – VanB1, VanB2 and VanB3 – identified by the genetic differences between them. On the other hand, only a few E. faecalis strains, in which VanG and VanE phenotypes have been described, have shown full sensitivity to teicoplanin and resistance to vancomycin only at low concentrations [38]. In most countries around the world, especially in Europe, USA and South Korea, the VanA phenotype dominates, while VanB is more popular in Australia and Singapore [10]. In Poland, no phenotypes other than VanA, VanB and VanC have been detected, and the most frequently isolated strains have exhibited the VanA phenotype [1, 10]. Table I presents a summary of the most important features that differentiate the phenotypes of vancomycin-resistant enterococci.

Table I

Characterization of vancomycin-resistant Enterococcus phenotypes

10.21307_PM-2019.58.1.035-tbl1.jpg

8. Molecular characteristics of VRE phenotypes

There exists a set of genes which determine the VanA phenotype. They include vanY, vanZ, ORF1, ORF2 (the latter two are not related to resistance, but enable the transposition to occur) and genes forming the van operon: vanH, vanA, vanX, vanR and vanS [3, 41]. They occur in the transposon Tn1546, located in plasmids pIP816. The genes associated with the VanA phenotype can also be found on numerous other plasmids, for example on pRUM, pS177, pWZ909, pLG1, Inc18, pSL1, pSL2, pIP816 [4246]. The vanY and vanZ genes are not necessary for resistance, but they either increase its level (vanY) or impact the resistance to low concentrations of teicoplanin (vanZ). The van operon, in turn, is created by the structural genes (vanH, vanA and vanX – called the VanHAX protein genes) and the regulatory genes (vanR and vanS). The vanA gene encodes a D-dipeptide ligase that catalyses the formation of the D-Ala-D-Lac dipeptide. It is later integrated into the murein precursors in the cytoplasm instead of D-Ala-D-Ala. However, this will require generating D-lactate (D-Lac) – this is enabled by the dehydrogenase of the D-hydroxy acid, encoded by the vanH gene. In order for D-Ala-D-Ala moiety not to be formed parallel to D-Ala-D-Lac in the cell, the hydrolysis of the amide bond present therein is necessary. This reaction is catalysed by the DD-dipeptidase encoded by the vanX gene [3, 41, 47]. Regulatory genes, present in the operon, are in charge of initiating the transcription of the VanHAX protein complex, according to an induced mechanism. The appearance of vancomycin or teicoplanin in the environment stimulates autophosphorylation of the histidine kinase (phosphorylation of the His164 residue), which is a cell membrane protein, which in turn is a product of the expression of the vanS gene [48]. This enzyme, after autophosphorylation, catalyses the phosphorylation of Asp53 in the second element of the regulation system, i.e. the VanR protein. It is a transcription factor present in the cytoplasm, which as a result binds to the van operon promoter in a phosphorylated form, activating its transcription [3, 48]. Figure 1 shows the pattern of the gene structure forming the VanA, VanB, VanD, VabG and VanM operons.

Fig. 1.

The scheme of the gene cluster structure determining phenotypes VanA, VanB, VanD, VanG i VanM (based on [41, 47, 49, 52]).

10.21307_PM-2019.58.1.035-f001.jpg

The strains belonging to the VanB phenotype have a set of genes with functions analogous to those of VanA. Therefore, the operon structure genes have been described as vanB and vanXB, and regulatory genes have been described as vanRB and vanSB. There are also vanYB and vanW genes – the latter is the only one that has no equivalent in the case of the VanA phenotype [47]. The genes affecting the VanB phenotype can be located in transposons Tn1549, Tn1547 and Tn5382 (the latter also contains a gene encoding an enzyme called Ant(3”)-la, affecting the resistance to aminoglycosides in enterococci). Their movement between bacterial chromosomes may occur [38].

The VanC and VanE phenotypes are genetically very similar. They contain operons formed from vanC or vanE (encoding the D-dipeptide ligase, which forms D-Ala-D-Ser) and vanXY (encoding D,D-dipeptidase-D,D-carboxypeptidase), vanT (encoding serine racemase, which enables the conversion of the L-serine available in the cell to D-serine) vanR and vanS encoding the operon regulatory protein and histidine kinase, respectively. The VanD phenotype is associated with an average level of resistance to vancomycin and teicoplanin. The genes affecting this phenotype occur in chromosomal DNA and so far there have been no reports stating that they can undergo transfer [38]. In the operon of this phenotype, there are also genes analogous to the those mentioned above: vanRD, vanSD, vanYD, vanHD, vanD and vanXD. It has been confirmed that the genes affecting the VanD phenotype may be located, among others, on the Tn1546 transposon [4950].

There are some differences in the operon of the VanG phenotype, where the whole structure is preceded by a three-element regulatory sequence (vanU). Next there are vanRG, vanSG (encoding the proteins mentioned above), vanYG (encoding D,D-carboxypeptidase), vanW (of unknown function), followed by vanG, vanXYG and vanTG [51].

Recently described in more detail, the VanL phenotype has many features in common with the VanC and VanE phenotypes, but its serine racemase is encoded by two genes: vanTmL and vanTrL. Their similarity with vanT in the VanC phenotype is 51% and 49%, respectively. The VanN phenotype, like the two above, exhibits susceptibility to low concentrations of vancomycin and sensitivity to teicoplanin. There occurs an operon therein, containing the vanN gene, characteristic of it, which encodes the ligase and the vanXYN, vanTN, vanRN and vanSN genes with analogous functions as in the VanC and VanE phenotypes [50]. The VanM phenotype, discovered in E. faecium in 2010, is particularly interesting [52]. Characteristic of this phenotype is the occurrence of VanM ligase composed of 343 amino acids and conditioning resistance to vancomycin and teicoplanin. The similarity of the protein product of the vanM gene to the products of the expression of the genes vanA, vanB, vanD and vanF is on the following level, respectively: 79.9; 70.8; 66.3 and 78.8%. Secondarily, the operon is created by vanRM, vanSM, vanYM, vanHM, vanM and vanXM genes. In general, the structure of the operon is the most similar to that found in the VanD phenotype [52].

9. Epidemiological situation in the world

In 2003, researchers from Texas led by J.H. Jorgensen undertook research into the effectiveness of other antibiotics used in the fight against VRE. 156 isolates were collected from 7 different facilities. Among them were 126 E. faecium isolates (VanA and VanB phenotypes numbering 109 and 17, respectively), 5 E. faecalis isolates (3 vanA and 2 vanV), 2 E. avium isolates (vanA), 1 E. durans isolate ( vanA), 10 isolates of E. gallinarum (vanC1) and 12 isolates of E. casseliflavus (vanC2) [53]. The results of the team’s research are summarized in Table II.

Table II

Resistance to the selected antibiotics of VRE isolates collected from 7 different hospitals

10.21307_PM-2019.58.1.035-tbl2.jpg

As presented in Table II, among the tested VRE strains with clinically significant phenotypes, the most samples showed resistance to ampicillin and doxycycline, with the lowest number to quinupristin/dalfopristin and linezolid. For these drugs, also the MIC50% and MIC90% figures were the lowest. Among the less clinically relevant VRE strains, the level of resistance is significantly lower. Interestingly, in the course of the analysis of the effect of daptomycin on VRE, it was established that the occurrence of the VanA or VanB phenotype does not significantly affect the effectiveness of the antibiotic [53].

Simner et al. analysed 2927 isolates of enterococci collected in Canada over the course of 6 years, until 2013. Only 4.2% showed resistance to vancomycin. All examined VREs belonged to E. faecium, and 90% of them displayed the VanA phenotype. During the analysed period, the incidence of VRE infections in hospitals had tripled [54]. In general, in the United States, the level of resistance to vancomycin among enterococci is much higher (approx. 33% of the tested Enterococcus isolates do not exhibit susceptibility to vancomycin) than in Canada (where VREs are below 10%) [55].

It is also worth paying attention to the epidemiological situation in other regions of the world. D. Ravi’s team analysed the isolates of Enterococcus obtained from a hospital in Chennai, India between February 2013 and January 2014, from patients from different departments and age groups [56]. Out of the 200 samples included, the majority were representatives of E. faecalis (55%). The vast minority were other species: E. faecium, E. avium, E. hirae, E. casseliflavus, E. durans and E. gallinarum, representing, successively 29%; 10.5%; 3%; 1%; 1% and 0.5%. Only 2.5% of the isolates showed resistance to vancomycin. The same number was resistant to teicoplanin. Surprisingly, as many as 5% of enterococci strains were resistant to linezolid. Definitely the most of them were resistant to tetracycline and ciprofloxacin (47% of strains) and erythromycin (73% of strains) [56].

Japan is a country where VREs constitute a very small percentage of all enterococci. According to Suzuki et al., only 20 cases of VREs appeared in the Tokyo University hospital within 20 years until 2010. However, between 2011 and 2012, as many as nine isolates were detected in this facility, all of which exhibited the phenotype of VanB. The presence of the transposon Tn 5382, containing the genes determining this phenotype, was found in the analysed material [57].

The results of the analysis of spring and mineral water pollution, which was carried out between January 2013 and February 2014 in China, are interesting. 314 samples taken from 101 bottled water factories from ten different provinces of the Middle Kingdom were tested. 48 of them were contaminated with E. faecalis, but none of the detected strains were resistant to vancomycin nor to any of the other 11 antibiotics that were considered. On the other hand, several virulence genes were detected in the analysed bacteria: asa1 (79.3% of strains, encoding a factor allowing attachment to eukaryotic cells), ace (39.3% of strains, encoding an adhesive protein which binds collagen, whereby it may limit the effectiveness of the immune system), or gelE, which was possessed by all the tested strains [58]. According to a study by Sun et al., in China the dominant VRE species is E. faecium and the phenotype VanA. Out of the 101 samples analysed, coming from 12 different hospitals, E. faecium constituted as many as 96 with the remaining 5 being E. faecalis. Almost all isolates (except for individual cases) exhibited the VanA phenotype. Among E. faecium, the vast majority was the clonal complex CC17, while in the case of E. faecalis it was CC4 [59]. Lai et al. demonstrated that there is a close, positive correlation between using teicoplanin and tigecycline to the incidence of VRE related infections related to healthcare in Taiwan [60].

Researchers from Brazil examined 93 VRE isolates (E. faecium) originating from 13 different hospitals. All strains were identified as having the VanA phenotype, due to the detected vanA gene. Only 6.5% of the isolates displayed the ability to form biofilms [61]. In another study conducted in the same country at Londrina University Hospital, the presence of four potential virulence genes, present in isolated VRE strains, was verified. 40 isolates were tested for the presence of the following genes: esp (gene encoding the Esp protein), gelE, efaA and cylA. All the strains were resistant to vancomycin and teicoplanin. In each of the strains, at least one of the virulence genes mentioned above was confirmed. The presence of the esp gene (87.5% of strains) and the efaA gene (82.5% of strains) was established with the greatest frequency; gelE (70% of strains) and cylA (65% of strains) gens were less frequently detected. In 32.5% of isolates, all 4 genes were found to be present. Interesting is the fact that whenever the presence of the efaA gene was detected in the strain, it also had the esp gene [62].

Considering the participation of livestock in the transmission of drug-resistant microbial strains, alarming reports are coming from South Africa. In 2014, 400 samples of cows faeces from two remote farms were analysed there. Noteworthy is the fact that all animals had frequent contact with antibiotics from the group of penicillins (ampicillin, penicillin G), macrolides (tylosin: a commonly used antibiotic for the treatment of chickens and cattle, also available in Poland), as well as with quinolones (danofloxacin, used in agriculture to treat cattle as Advocin [63]). In 341 samples, strains of the genus Enterococcus were detected. Most of them were E. faecium (52.94% of isolates) and E. durans (23.53% of isolates). The remaining species were in definite minority. All the detected strains of enterococci were resistant to vancomycin (VRE) and cloxacillin. For other antibiotics: amikacin, cefalotin, streptomycin, penicillin G, clindamycin, neomycin and erythromycin, the percentage of resistant strains was 74%, 88%, 94%, 91%, 97%, 91% and 99% respectively. Antibiotics with the lowest resistance were successively: ciprofloxacin (12% strains), amoxicillin/clavulanic acid (8% strains) and imipenem (0.6% strains). No strain sensitive to all antibiotics was found, while two of the isolates were resistant to all 12 tested drugs, and other 7 strains were susceptible to only one of them. Molecular analysis showed the presence of the following virulence genes: gelE (97% of strains), asa1 (94.11% of strains) and esp (79.4% of strains). At the same time, it was found that 65.29% of strains showed the presence of vanC genes, and 19.7% of strains displayed the presence of vanB genes. The presence of the vanA gene was not detected [64].

The next region covered by the VRE research was the Caribbean. Akpaka et al. collected 45 VRE samples from hospitals in Trinidad and Tobago. All the isolates were derived from patients after prolonged hospitalization with nosocomial infections. 84% of the strains were E. faecum containing the vanA gene, and the remaining 16% were E. faecalis, in whose DNA the presence of the vanB gene was detected. All strains were sensitive to linezolid, but at the same time 100% E. faecalis were resistant to levofloxacin, ciprofloxacin, erythromycin and quinupristin/dalfopristin. Similarly, all E. faecium strains were resistant to levofloxacin, ciprofloxacin and erythromycin, but as many as 82% of the strains of this species were sensitive to quinupristin/dalfopristine. The analysed virulence factors in the bacteria under test were the genes: esp, detected in all isolates, which is often present in bacteria isolated from healthy carriers, and the hyl gene encoding hyaluronidase, the presence of which significantly increases the invasiveness of enterococci [65].

However, from the studies by Somily et al. investigating the incidence of VRE in Saudi Arabia, it appears that out of the 378 isolates of enterococci, only 17 showed resistance to vancomycin. 76% of them were members of the E. faecium species and the remaining 24% belonged to E. gallinarum. The VanA phenotype was exhibited by all VREs from the species E. gallinarum and most of the E. faecium [66].

10. Epidemiological situation in Poland

As can be seen in the graph shown in Fig. 2 in Poland over the years 2010–2015 there is a disturbing growth trend in both the number of E. faecium and E. faecalis strains resistant to vancomycin, isolated from the blood of patients (data from KORLD [67]). The percentage of the resistant strains of E. faecium is definitely higher (in 2014 they accounted for almost 20% of all isolates of this species) than vancomycin-resistant E. faecalis, whose largest percentage share occurred in 2015 (2.8%) [67]. Summing up the above data, it can be concluded that despite the much less frequent occurrence of E. faecium in the population as compared to E. faecalis, E. faecium is a key problem due to its frequently occurring vancomycin-resistant strains [1, 67].

Fig. 2.

Vancomycin resistance among E. faecium and E. faecalis strains isolated from blood samples of the Polish patients between 2010 and 2015 [67].

10.21307_PM-2019.58.1.035-f002.jpg

Talaga et al. analyzed 154 samples of enterococci from 4 different hospitals from the Lesser Poland region, collected over one year. The team’s research points to the conclusion that vancomycin-resistant Enterococcus strains hold a small share in the total pool of bacteria tested. All of the E. faecalis strains showed sensitivity to the analysed antibiotics, including vancomycin. It was established that despite the general tendency of the VanA phenotype to dominate, in the Lesser Poland, E. faecium with the VanB phenotype has a larger percentage share in the VRE population than E. faecium with the VanA phenotype. All of the E. faecium isolates, including VREs, were sensitive to quinupristin/dalfopristin [68].

For the first time in Poland, VRE strains appeared in Gdańsk in 1999. It was E. faecium of the VanA phenotype. In the same year, for the first time, there also appeared a VRE isolate with the VanB phenotype (in Warsaw). Since then, isolated cases of local outbreaks have been reported every year. Among all the alarming factors reported in Polish hospitals, the percentage of VREs is relatively low – over the years 2012–2014 it fluctuated around 1–2% [1]. Although there are VREs in Poland both with the VanA and VanB phenotypes, VanA cases are much more common [1, 7, 66, 67]. Research in this field was conducted by, among others, the teams of Grzybowska et al., from the Transplantation Institute [69], and by Talaga-Ćwiertnia et al. [70]. As presented in Table III, the cases of VRE are relatively few compared to other alarming factors. Their number in successive years gradually increases. At the same time in 2014 it was noted that three groups of alarming factors were responsible for infections of surgery sites in hospitals only in 4.5%: MRSA, VRE and ESBL [71].

Table III

The specification of VRE isolates number and the percentages of all alarming factors at 195 Polish hospitals between 2012 and 2016 (data according to [71])

10.21307_PM-2019.58.1.035-tbl3.jpg

Despite the dominance of the bacteria of the VanA phenotype, pathogens with the VanB phenotype may become a considerable threat. Sadowy et al. analysed 278 VRE isolates with the VanB phenotype, collected over 11 years (1999–2010) in 22 Polish cities. It was found that the genes conditioning this phenotype are most often located in the Tn1549 transposon – within the bacterial chromosome (81.65%) or in a plasmid (18%). Only in one case was it observed that the plasmid containing Tn1549 was integrated into the bacterial chromosome. By 2006, the genes determining the VanB phenotype had been localized in plasmids, and in subsequent years they were found mainly in the bacterial chromosome [72]. Interesting research was carried out on samples classified as VRE, obtained from patients of the University Hospital in Bydgoszcz in 2005–2009. Kożuszko et al. analysed the species composition of VREs and the effectiveness of various antibiotics in combating them. It was found that for 159 vancomycin-resistant strains, 133 belonged to E. faecium and only 26 to E. faecalis. In each consecutive year, the number of such isolates was greater. None of the isolates exhibited resistance to linezolid, only a very small number to chloramphenicol (3) and quinupristin/dalfopristine (1). Almost all the strains showed resistance to rifampicin and ciprofloxacin, and the level of resistance to gentamycin, ampicillin and penicillin was also very high (in none of the cases was it lower than 74%). The number of strains resistant to streptomycin in subsequent years decreased, reaching 25.8% in 2009, and the ones resistant to tetracycline oscillated between 20–30%. In the following years, the level of resistance to teicoplanin increased strongly (by 20% over 4 years), which indicates a steady increase in the share of strains with the VanA phenotype in the VRE population [36].

Relevant data on the genetic features of VRE E. faecalis are provided by the work of Łysakowska’s team [7]. The authors investigated the presence of virulence genes among 161 strains from surgical wards of two hospitals in Lódź during the years 2005–2006. The affiliation of the strains to the analysed species was confirmed by detecting the D-alanine-D-alanyl ligase gene in the PCR reaction. The virulence genes being the object of search were: agg, cyl-L and cyl-S, esp, gelE and sprE gene. Only three strains did not show the presence of the analysed virulence genes. The cyl-L gene was identified in 52.2% of strains, the agg gene in 62.73% and the esp gene in 71.2% of E. faecalis strains. Over 80% of the strains possessed gelE and sprE genes (85.1% and 82.6% respectively). These were genes from the pool under test, most often present in the analysed strains. It is extremely important that the strains which were resistant to ampicillin (only 6.8%) possessed minimum three virulence genes at the same time. As many as 99 strains (or 61.49%) had four or more virulence genes [7].

The aim of the research conducted by Młynarczyk et al. was to examine the level of genetic similarity of 20 VRE strains isolated in 2005–2008 from samples of patients from three wards of the Infant Jesus Clinical Hospital in Warsaw. The phenotype of the tested VRE strains E. faecium was determined by means of a PCR reaction in which primers complementary to the DNA of the genes encoding D-dipeptide ligase were used: vanA, vanB, vanD, vanE and vanG. Their presence confirms the occurrence of an appropriate phenotype (VanA, VanB, VanD, VanE and VanG). It was observed that all E. faecium isolates had the vanA ligase gene, and none of them had other searched-for genes. This confirmed that all VRE strains exhibited the VanA phenotype. The analysed strains exhibited a high diversity at the genome level. 12 of them came from patients treated in the same Intensive Care Unit [40]. At the same hospital, the number of VRE infections was analysed over the years 1998–2005, which marks the very beginning of the history of VRE presence in Poland. Over the years, the number of Enterococcus-type infections steadily grew (from 293 isolates in 1998 to 1185 isolates in 2005), but cases of VRE began to appear from 2003, when 11 isolates were obtained. In the following year there were 13, and in 2005 as many as 64 isolates. This means a steady upward trend [40, 73].

Additionally, 195 isolates of the bacteria of the genus Enterococcus bacteria originating from industrial pig farms in the Kuyavian-Pomeranian Province were tested. Skowron et al. established that the dominant species was E. hirae (68%), while the remaining species had a significantly smaller share in the population (E. faecalis 21%, E. faecium 3%). Only 2 isolates, with the VanC phenotype [74], exhibited resistance to vancomycin.

11. Epidemiological situation in Europe

The study by Orsi et al. points to the conclusion that there is a great diversity in the frequency of VRE occurrence in Europe. VREs are definitely more common in the south of Europe than in the north [75]. Schouten et al. carried out an analysis of VRE cases in Europe. Thanks to the cooperation of 49 laboratories from 27 European countries, 4208 isolates of Enterococcus were collected from clinical trials. It was found that among them there were 18 VRE cases with the VanA phenotype and 5 with the VanB phenotype. In turn, there were 71 isolates featuring the VanC phenotype. The VanA phenotype was most frequently found in the tests from Great Britain (2.7%), and VanB in isolates from Slovenia (2%). The VanC phenotype was most prevalent in the isolates from Latvia (14.3%) and Turkey (11.7%). Among these samples, E. gallinarum dominated over E. casseliflavus. Based on these data, it can be concluded that in Europe the occurrence frequency of VREs possessing the most dangerous phenotypes is relatively low [76]. When analysing the level of threat from antibiotic resistant strains of bacteria in the Old Continent, it is advisable to pay attention to EARS-Net network reports. According to these reports, in all countries except Greece, VRE E. faecalis infections are not a clinically significant problem, as opposed to VRE E. faecium. Until 2009, Poland looked very favourable, compared to other European countries, as infections with the aetiology of E. faecium VRE represented no more than 5% of all those caused by this bacterium. Unfortunately, in 2012, Poland was included in the group, where this figure is between 5 and 10%, and in 2015 it was moved to the group in which this parameter fluctuates between 10 and 25% [1, 77].

The reason for these alarming changes may be the fact that Poland shares its borders with countries where this ratio had been higher much earlier (Czech Republic, Germany, Lithuania). The level of this ratio in the countries which Poles deem interesting as holiday resorts (Greece, Italy), or as the destination of their economic emigration (Ireland, Great Britain) is of considerable significance too [77]. One of the reasons for the observed distribution of VREs in Europe may be different guidelines on the use of antibiotics, or information campaigns and the education level of the public. Animals can also be a vector for enterococci, e.g. dogs. Kubašová et al. analysed 160 samples of enterococci derived from 105 animals in eastern Slovakia. E. faecium was found in 57.5% of them, E. faecalis in 21.9%, E. hirae in 17.5%, and the remaining species were few. As many as 71.9% of the strains showed resistance to teicoplanin. However, what is most puzzling is the fact that 9 strains of E. faecium had a marker specific to nosocomial infections [78].

According to the analysis of Remschmidt et al., in Germany the threat from the VRE is on the rise. The percentage of VREs among enterococci varies widely between individual federal states: the highest one is in central Germany (Berlin, North Rhine-Westphalia, Hesse, Saarland, Saxony-Anhalt, Saxony and Thuringia), where VREs are above 10% of all enterococci, and the lowest one occurs in the north. This tendency did not change over the years 2007–2016. 12.659 isolates of enterococci from hospital samples were recorded, and 833 of them showed resistance to vancomycin [79]. In turn, Gastmeier et al. demonstrated that in Germany, over the period of 2007–2012, the rate of VRE infections increased from 0.87% to 4.58% in the case of postoperative wounds and from 4.91% to 12.99% in the case of blood infections [80].

An interesting analysis of VRE strains from the E. faecium species was carried out by researchers from Turkey. They tested 55 isolates containing vancomycin-resistant bacteria. All the strains were resistant to penicillin G, ampicillin and gentamycin. At the same time, they were sensitive to linezolid and quinupristin/dalfopristine. 22 isolates that were obtained from patients showing symptoms of infection were considered invasive, and the remaining 33, which came from the colonized rectum of patients without symptoms of bacterial infection, were considered non-invasive. In all the strains the presence of the vanA gene was demonstrated. No virulence genes were detected in 14 isolates. One such gene, esp, was present in 39 isolates, two genes in one isolate (esp and ebpA; the latter encoding the peptide A subunit associated with biofilm formation in endocarditis [81]) – as well as 5 additional genes: esp; ebpA; asa1; gelE and cpd. There was a noticeable tendency whereby among the invasive strains, the presence of virulence genes was low [82].

Pinholt et al. analysed 495 VRE E. faecium samples from several hospitals in Denmark over the years 2012–2014. It was established that at the beginning of the study, the majority of the VRE population consisted of four large groups of bacteria with close phylogenetic relationships within the groups. As time passed, there was a steady increase in the diversity of microorganisms; new, less numerous groups were formed. Some of them caused the epidemic and disappeared, while others were present in several different locations throughout the duration of the study [83].

Table IV

Percentages of vancomycin-resistant Enterococcus faecium isolates in the European countries between 2012 and 2015 (data according to [77])

10.21307_PM-2019.58.1.035-tbl4.jpg

12. Summary

Antibiotic resistance among the bacteria which are representatives of the genus Enterococcus is becoming an increasingly important problem for modern health care. Years of negligence associated with the reckless use of antibiotics have resulted in a growing number of strains resistant not only to standard pharmacological agents intended for their control, but also to the “last resort” drugs. Understanding the molecular determinants of resistance mechanisms may be one of the ways to reduce the threat posed by antibiotic-resistant enterococci.

Acknowledgements

The article was translated by EURO-ALPHABET from Polish into English under agreement 659/P-DUN/2018 and funded by the Ministry of Science and Higher Education.

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XML PDF Share

FIGURES & TABLES

Fig. 1.

The scheme of the gene cluster structure determining phenotypes VanA, VanB, VanD, VanG i VanM (based on [41, 47, 49, 52]).

Full Size   |   Slide (.pptx)

Fig. 2.

Vancomycin resistance among E. faecium and E. faecalis strains isolated from blood samples of the Polish patients between 2010 and 2015 [67].

Full Size   |   Slide (.pptx)

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