Enterococci Acquire New Kinds of Resistance

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1 S80 Enterococci Acquire New Kinds of Resistance Roland Leclercq From the Service de Bacteriologie-Virologie-Hygiene, HOpital Henri Mondor, Universite Paris XII, Creteil, France In recent years, enterococci have become increasingly resistant to a broad range of antimicrobial agents. The development of high-level resistance to aminoglycosides, penicillins, and glycopeptides singly and in combination has important clinical implications. Strains of Enterococcus faecium that are resistant to every useful available antibiotic have been described. Resistance to penicillin can be due to overproduction of penicillin-binding protein (which has low affinity for penicillins) or to production of 13-lactamase. High-level resistance of enterococci to gentamicin is due to the synthesis of a modifying enzyme. In this case, the synergistic activity of the combination of penicillin with any aminoglycoside (except for streptomycin) is totally abolished. Acquired resistance to glycopeptides is often plasmid-mediated and is associated with a major epidemic potential since certain plasmids are self-transferable from E. faecium to a variety of gram-positive organisms, including Staphylococcus aureus. Historically, enterococci have been considered rather feeble pathogens. However, this optimistic view is being challenged by the increasing number of nosocomial infections caused by these organisms [1]. Moreover, in recent years, enterococci have become increasingly resistant to a broad range of antimicrobial agents. For these reasons, increased attention has been focused on the enterococcus by the scientific and medical community [2]. The increase in incidence of nosocomial infections caused by enterococci in particular, Enterococcus faecium is at least partly due to the wide variety of intrinsic and acquired resistances characteristic of these species. Consequently, enterococci are well suited to survive in hospital settings, where antibiotic selective pressure is heavy. The development of highlevel resistance to aminoglycosides, penicillins, and glycopeptides (vancomycin and teicoplanin) singly and in combination has important clinical implications. In this article the described major mechanisms of antimicrobial resistance in enterococci are reviewed. Intrinsic Resistance in Enterococci The limited choice of antibiotics and the poor results of single-agent antimicrobial therapy in the treatment of serious enterococcal infections are mostly related to the intrinsic resistance of the organism. Intrinsic resistance is an inherent property of a bacterial genus or species. Enterococci are intrinsically resistant to 0-lactam antibiotics, aminoglycosides, and sulfonamides. Additional intrinsic resistance traits are characteristic of specific enterococcal species. Reprints or correspondence: Dr. R. Leclercq, Service de Bacteriologie-Virologie-Hygiêne, HOpital Henri Mondor, University Paris XII, 51, Avenue Marechal de Lattre de Tassigny, Crêteil Cedex, France. Clinical Infectious Diseases 1997; 24(Suppl 1):S by The University of Chicago. All rights reserved /97/ $ lactam agents and aminoglycosides. The MICs of penicillin G, ampicillin, amoxicillin, piperacillin, and imipenem against enterococci are times greater than those against streptococci. The increased resistance of enterococci has been associated with the presence of penicillin-binding proteins (PBPs) with decreased affinity for /3-lactams [3, 4]. In addition, even 0-lactam agents that have activity are not bactericidal against the majority of strains. Poor bactericidal activity is also observed with other cell-wall-active agents such as glycopeptides. Resistance to cephalosporins is still more pronounced and renders these drugs ineffective in vivo. Combinations of 0-lactams or glycopeptides with aminoglycosides achieve bactericidal synergy, although the MICs of the aminoglycosides generally range from 8 mg/l to 64 mg/l. This low-level resistance to aminoglycosides is also an intrinsic property of enterococci. Since aminoglycoside uptake by bacteria requires oxidatively generated energy [5], intrinsic resistance probably reflects inefficient active transport of aminoglycoside due to poor membrane energization. The mechanism by which a cell-wall-synthesis inhibitor/aminoglycoside combination achieves synergy is explained by the facilitation of aminoglycoside uptake that results from disruption of the cell wall by the cell-wall-active agent [6]. Sulfonamides and trimethoprim. When tested in vitro in appropriate conditions i.e., in media devoided of thymidine, which reverses the action of co-trimoxazole enterococci appear susceptible to this antibiotic combination. However, under certain circumstances, enterococci can use exogenous folates, present in the urine, for instance. They could thereby escape inhibition by antifolate agents and could be resistant in vivo to these antimicrobials. This point is controversial since it has been demonstrated for E. faecium but not clearly for Enterococcus faecalis [7]. However, co-trimoxazole was not efficacious in treatment of experimental endocarditis due to E. faecalis in a rabbit model [8]. Intrinsic resistance of specific enterococcal species. All strains of E. faecium produce an aminoglycoside 6'-acetyltrans-

2 CID 1997;24 (Suppl 1) Enterococcal Resistance to Antibiotics S81 ferase, encoded by the chromosomal gene aac(6')-ii, which modifies most commercially available aminoglycosides [9]. Production of this enzyme abolishes the bactericidal activity of a penicillin or a glycopeptide with an aminoglycoside, except with aminoglycosides that are not substrates for the enzyme, such as streptomycin and gentamicin. It is surprising that the synergy of amikacin combined with a penicillin is also retained, although this aminoglycoside is a substrate for the enzyme [10]. Vancomycin has low intrinsic activity (MIC, 2-32 mg/l) against some rarely isolated enterococcal species such as Enterococcus gallinarum, Enterococcus casseliflavus, and Enterococcus flavescens. The lower MIC breakpoint of vancomycin (4 mg/l) divides the bacterial population into two unequal parts, with certain isolates categorized as susceptible [11]. The glycopeptide resistance genes vanc] for E. gallinarum and vanc2 for E. casseliflavus and E. flavescens are specific for these species [12, 13]. Intrinsic resistance of E. faecalis to clindamycin is helpful in bacterial identification. E. faecalis is also resistant to streptogramin A type antibiotics [14]. Except for Enterococcus durans and E. faecium, most enterococcal species display both resistances. Acquired Resistance /3-Lactam antibiotics. Acquired resistance to 0-lactam antibiotics can be due to synthesis of /3-lactamase or to modification of the PBP target. Although both mechanisms can be present in E. faecalis and in E. faecium, they are not represented equally. /3-Lactamase-producing strains of E. faecalis were first isolated in 1981 in the United States and subsequently in Argentina and Lebanon [15]. Resistance due to such synthesis is rare in E. faecium. Resistance due to f3-lactamase production is generally plasmid-mediated and is often linked with highlevel resistance to gentamicin [15]. The /3-lactamase is a penicillinase that is highly homologous to that encoded by the blaz gene of Staphylococcus aureus [16]. However, unlike that of S. aureus, the penicillinase of E. faecalis is constitutively produced, possibly due to the absence of a repressor protein [17]. Although clonal spread of /3-lactamase-producing enterococci has been reported [18], for the most part this type of resistance remains confined to specific hospitals and does not account for the reported overall increase in resistance of enterococci to penicillin. This increase is mostly due to the spread of penicillinresistant E. faecium strains that do not produce /3-lactamase. Resistance in these strains is due to modification of PBPs, particularly overproduction of a preexisting PBP that has low affinity for /3-lactam drugs. This mechanism was first studied in Enterococcus hirae. In laboratory isolated mutants, the amount of low-affinity PBP5 correlated to the level of penicillin resistance; the MIC of penicillin was approximately equal to that of /3-lactam drug necessary to saturate PBP5 [19]. These strains grew normally in the presence of penicillin concentrations that saturated all PBPs, except PBP5, which suggests that when PBP5 is overproduced, it can substitute for the functions of all the other PBPs of the cell. Overproduction of this protein may be due to a deletion in an upstream regulatory region of the E. hirae PBP5 gene pbp5 [20]. It is interesting that the aminoacid sequence of E. hirae PBP5 is 33% homologous to PBP2a, which confers methicillin resistance in staphylococci [21]. Penicillin-resistant mutants can be readily selected in vitro among other enterococcal species, including E. faecalis [22]. However, penicillin-resistant clinical isolates of only a limited number of species have been reported, including E. faecium and, to a lesser extent, Enterococcus raffinosus. Clinical isolates of E. faecium display various levels of penicillin resistance, with MICs of penicillin ranging from 8 mg/l to >512 mg/l. Among moderately resistant strains of E. faecium, the mechanism of penicillin resistance is also attributed to overproduction of PBP5 of this species. Further modifications in the primary structure of PBP5, leading to additional decreases in penicillin-binding capacity, appear responsible for a high level of penicillin resistance [23]. Aminoglycosides. Enterococci acquire resistance to aminoglycosides by three distinct mechanisms: alteration of the ribosomal target site, interference with antibiotic transport, and enzymic detoxification of the antibiotic. The first two mechanisms are due to chromosomal mutations, whereas the third mechanism is generally mediated by plasmids [24]. In clinical enterococcal isolates, high-level resistance (MIC, >1,000 mg/l) is usually mediated by aminoglycoside-modifying enzymes. However, in certain strains of E. faecalis, high-level resistance to streptomycin can also be due to ribosomal mutations [25]. As is the case for gram-negative bacteria, the enzymes can be divided into any of three classes, depending upon the reaction catalyzed (phosphorylation or nucleotydilation of a hydroxyl group; acetylation of an amino group), and are named according to the site modified. The enzymes vary in their substrate ranges, which are often very broad. Identical aminoglycosidemodifying enzymes cause high-level resistance to aminoglycosides and/or resistance to synergism with penicillins in enterococci and staphylococci [26]. Numerous enzymes have been described, including streptomycin adenylyltransferase, 3 '-phosphotransferase, 4'-nucleotidyltransferase (rare in enterococci), and a bifunctional 6'-acetyltransferase 2" phosphotransferase (AAC[6']-APH[2"]). The latter enzyme is a fusion protein that has dual enzymic activity, conferring high-level resistance to gentamicin and to most commercially available aminoglycosides [27]. The presence of an enzyme confers to the host high-level resistance toward the antibiotics that are modified in vitro. As expected, the synergistic activity of the combination of a penicillin with an aminoglycoside is abolished. It is surprising that this suppression also occurs when the aminoglycoside is a poor substrate for the enzyme and when,

3 S82 Leclercq CID 1997;24 (Suppl 1) consequently, its bacteriostatic activity is not significantly affected. For instance, the rate of modification of amikacin and netilmicin by AAC(6')-APH(2") is not sufficient to confer highlevel resistance to the host (MICs, only between 64 mg/l and 256 mg/l) but can prevent the synergism between these antibiotics and penicillins or glycopeptides. In fact, synergism of the combination of penicillin with any aminoglycoside (except streptomycin) is suppressed [27]. A high incidence (>20%) of high-level gentamicin resistance in E. faecalis, including blood isolates, has been reported from various countries [28]. However, the incidence varies, depending on the particular hospital and ward. Glycopeptides. Acquired vancomycin resistance was first detected in 1986 [29, 30]. Two phenotypes, VANA and VANB, can be distinguished phenotypically on the basis of the antibacterial and inducing activity of glycopeptides. Inducible resistance to high levels of vancomycin (MIC, 64 mg/l) and teicoplanin (MIC, 16 mg/l) defines the VANA phenotype [30]. This class of resistance is usually mediated by self-transferable plasmids. VANB-type strains are inducibly resistant to various levels of vancomycin (MICs, 4 mg/l to 1,000 mg/l) and are susceptible to teicoplanin [31]. This dissociated phenotype is due to the fact that vancomycin acts as an inducer, whereas teicoplanin does not. Low- and high-level VANB-type resistance is transferable by conjugation in certain strains [31, 32]. Transfer of resistance is associated with mobilization of large genetic elements ( kb) from chromosome to chromosome [32]. Analyses of the nucleotide sequence of the resistance genes and of the functions of the corresponding proteins in the VANA-type strain E. faecium BM4147 have provided insights into the mechanism of resistance (for a review, see [33]). The resistance genes are carried by the 10.8-kb transposon named Tn1546 [34]. Tn1546 encodes nine polypeptides, two involved in transposition functions (ORF1 and ORFII) and seven cooperating to confer vancomycin resistance [33]. The seven polypeptides involved in the expression of VANA can be assigned to three functional groups: regulation of vancomycin resistance genes (VanR and VanS), resistance to glycopeptides by production of a modified target (VanH, VanA, and VanX), and accessory proteins that are not essential for the expression of glycopeptide resistance (VanY and VanZ). Glycopeptides are inhibitors of the cell-wall synthesis. They are large molecules that form complexes with the peptidyl-dalanyl-d-alanine termini of peptidoglycan precursors at the cell surface. The presence of these large complexes at the surface of the cytoplasmic membrane prevents cell-wall synthesis by hindering the transfer of cytoplasmic precursors to the growing peptidoglycan chain and by blocking formation of interpeptidic bonds [35]. The VanA and VanH proteins are a ligase of broad substrate specificity and a dehydrogenase, respectively, that act together to synthesize the depsipeptide D-alanyl-D-lactate, which replaces the D-alanyl-D-alanine terminus of peptidoglycan precursors [36]. Although the modified precursors can be incorporated normally into the cell wall by enzymes encoded by the host chromosome, the substitution results in a dramatic decrease in affinity for vancomycin. Hence, such strains are resistant, since vancomycin can no longer inhibit cell-wall synthesis. However, in addition to VanH and VanA, the VanX protein is also necessary for expression of glycopeptide resistance. VanX is a D,D dipeptidase that hydrolyzes the dipeptide D-alanyl-D-alanine, which should otherwise compete with D-alanyl-D-lactate [37]. The distal portion of Tn1546 encodes two proteins, VanY and VanZ, which are not required for glycopeptide resistance. VanY is a D,D carboxypeptidase that could contribute to resistance by cleaving the terminal D-alanine from precursors resulting from incorporation of D-alanyl-D-alanine that escape hydrolysis by VanX [38]. VanZ, which is not significantly related in structure to other proteins, appears to confer lowlevel resistance to teicoplanin by an unknown mechanism [39]. The vana, vanh and vanx resistance genes are regulated at the transcriptional level by the VanR-VanS two-component regulatory system, which is encoded upstream of vanh [40]. The two regulatory proteins are probably involved in transmitting a signal in response to the presence of vancomycin at the surface of the cell. Spread of VANA-type resistance in clinical isolates appears to be due to dissemination of Tn1546 or related elements in self-transferable plasmids rather than by spread of a bacterial clone or a single plasmid [34, 41]. Thus far, the van genes have been naturally detected only in enterococci. However, enterococci are known to be capable of exchanging gentamicin or macrolide resistance with other species of gram-positive organisms via transfer of conjugative plasmids [42]. Therefore, it is not surprising that some glycopeptide resistance plasmids have broad host ranges and can readily transfer in vitro to a variety of gram-positive organisms, including streptococci, Lactococcus lactis, Listeria monocytogenes, and (of most concern) S. aureus [41, 43]. In addition, VANA-type enterococci are widely spread in nature and have been isolated from the stools of healthy carriers, from farm animals, and from wastewater treatment plants [44]. These observations lead one to anticipate the future dissemination of glycopeptide resistance genes to more virulent pathogens. Multidrug Resistance Although the antibiotic resistances mentioned above can exist independently, they can be combined in a single strain and thus present more cause for concern. In particular, penicillin resistance due to overproduction of PBP5 or synthesis of 0- lactamase can be associated with glycopeptide resistance and high-level resistance to gentamicin. This accumulation of resistance traits has been observed mostly in E. faecium strains. The emergence of multidrug resistance also concerns alternative antimicrobials that are in development.

4 CID 1997; 24 (Suppl 1) Enterococcal Resistance to Antibiotics S83 For instance, a combination of streptogramin A and B antibiotics (quinupristin/dalfopristin) has been used for treatment of severe infections due to multidrug-resistant strains of E. faecium. Unfortunately, a strain that produces an acetyltransferase modifying the streptogramin A component of the combination has already been described [45]. The facility of enterococci at acquiring new resistance determinants is extended to antibiotics that are not used to treat enterococcal infections because of their weak activity against these organisms. Most strains are also resistant to tetracyclines (via tetk, tetl, tetm, and teto genes), macrolides (via erm genes), and chloramphenicol (via cat genes). In addition, numerous strains of E. faecalis highly resistant to gentamicin are resistant to ciprofloxacin. Although of slight clinical significance, these resistances are not harmless, since resistant enterococci might be selected by antibiotics not used against these bacteria. Conclusion Evolution of enterococci toward resistance to multiple antimicrobials is a major cause of concern. The fact that these organisms are less virulent than others is not reassuring, since acquisition by the bacteria of virulence genes is possible. Enterococci constitute a large reservoir of resistance genes, and because they are ubiquitous, the spread of high-level vancomycin resistance in methicillin-resistant staphylococci is to be feared. References 1. Schaberg DR, Culver DH, Gaynes RP. Major trends in the microbial etiology of nosocomial infection. Am J Med 1991; 91(suppl 3B): 72S-5S. 2. Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990; 3: Fontana R, Cerini R, Longoni P, Grossato A, Canepari P. 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