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Intrinsic and acquired resistance mechanisms in enterococcus

Intrinsic and acquired resistance mechanisms in enterococcus REVIEW Virulence 3:5, 421–433; August 15, 2012; 2012 Landes Bioscience Intrinsic and acquired resistance mechanisms in enterococcus Brian L. Hollenbeck and Louis B. Rice* Department of Medicine; Lifespan/Rhode Island Hospital and Alpert Medical School of Brown University; Providence, RI USA Keywords: enterococcus, antibiotic resistance, review, treatment established. Along with increasing antimicrobial resistance, the Enterococci have the potential for resistance to virtually all acquisition of virulence factors and the ability of enterococcus to clinically useful antibiotics. Their emergence as important form biofilms have also contributed to the rise in nosocomial nosocomial pathogens has coincided with increased prevalence. expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in This paper reviews the mechanisms underlying antibiotic enterococci may be intrinsic to the species or acquired resistance in enterococci, both intrinsic (universally found within through mutation of intrinsic genes or horizontal exchange the genome of the species) and acquired (through acquisition of of genetic material encoding resistance determinants. This new genetic material or through sporadic mutations to intrinsic paper reviews the antibiotic resistance mechanisms in genes). Interspecies differences will be addressed as they arise Enterococcus faecium and Enterococcus faecalis and discusses throughout the paper. This paper will additionally provide an treatment options. overview of current treatment strategies for enterococcal infec- tions. Focus will be on Enterococcus faecalis and E. faecium,as these two species account for the overwhelming majority of human enterococcal infections (Table 1). Introduction Intrinsic Resistance Enterococci are Gram-positive, facultative anaerobic organisms characterized by their ability to grow at 6.5% NaCl concentra- β-lactams and cephalosporins. Growth of most bacteria depends tions and at high pH and to hydrolyze bile-esculin and L- upon enzymatic linkage of pentapeptide precursor molecules into pyrrolidonyl-B-naphthylamide (PYR). Formerly considered mem- a peptidoglycan cell wall. The enzymes responsible for these cross- bers of Lancefield group D streptococcus, DNA homology studies linking reactions are referred to as penicillin binding proteins suggested that they are a distinct genus. Enterococci were (PBPs) because β-lactams (structural analogs of pentapeptide previously considered commensal organisms of little clinical precursors) bind covalently and disrupt normal cell wall growth. importance, but have emerged as serious nosocomial pathogens Attachment of β-lactam agents to PBPs results in impaired cell responsible for endocarditis and infections of the urinary tract, wall synthesis and, in most cases, programmed cell death via bloodstream, meninges, wounds and the biliary tract, among creation of reactive oxygen species. Enterococci express low- others. Recent surveillance data indicate that the enterococcus is affinity PBPs (PBP5 in E. faecium, PBP4 in E. faecalis) that bind the third most commonly isolated nosocomial pathogen (12% of weakly to β-lactam antibiotics. As a result, minimum inhibitory all hospital infections), behind only coagulase-negative staphylo- concentrations (MICs) for penicillins are typically 2–8 mg/ml for 2 7 coccus and Staphylococcus aureus. The rise in prevalence of E. faecalis and 8–16 mg/ml for E. faecium, much higher than enterococcal infections in humans is influenced to some degree by MICs for streptococci and related Gram-positive organisms that the ability of enterococci to escape the action of our most do not contain chromosomally-encoded low-affinity PBP genes. commonly used antibiotics. The influence of antibiotics is most At the population level, enterococcal MICs have increased over 9,10 11 directly seen on the extent to which enterococci colonize the time. Galloway-Pena et al. demonstrated two distinct clades gastrointestinal tract. Animal data have clearly shown the of E. faecium. These clades have PBP5 enzymes that vary in relationship between exposure to parenteral antibiotics, especially affinity, a result of differences in amino acid sequence and extended-spectrum cephalosporins and agents with potent activity transcriptional regulation. Overproduction of non-mutated low- against anaerobic bacteria, and high level gastrointestinal affinity PBPs represents a relatively rare mechanism by which 3 7,12 colonization by ampicillin-resistant Enterococcus faecium. The enterococci express low-level resistance to penicillins. relationship between colonization and subsequent infection is also Early studies by Jawetz et al. indicated that enterococci were not killed by penicillin when exposed to drug concentrations in the range of the MIC (a phenomenon known as tolerance). *Correspondence to: Louis B. Rice; Email: lrice@lifespan.org Tolerance in E. faecalis has been attributed to removal of reactive Submitted: 04/16/12; Revised: 06/25/12; Accepted: 06/26/12 http://dx.doi.org/10.4161/viru.21282 oxygen species by the enzyme superoxide dismutase. In other www.landesbioscience.com Virulence 421 Table 1. Mechanisms of resistance to E. faecium and E. faecalis Antibiotic Mechanism Associated Phenotype Intrinsic, Host range References resistance of resistance enzyme sporadic or associated MGE Aminoglycosides Low cell wall - Low-level aminoglycoside resistance, Intrinsic E. faecalis 8–10 permeability synergy preserved Ribosome mutation - High-level aminoglycoside resistance Sporadic E. faecalis 42 with MIC . 128,000 mg/ml E. faecium Aminoglycoside- Aac(6’)-Ii Low-level tobramycin and kanamycin Intrinsic E. faecium 11 modifying enzyme resistance (AME) AME Aph(3’)-IIIa Low-level kanamycin resistance pJH1 E. faecium 43 AME Ant(4’’)-Ia Low-level resistance to kanamycin, plP810 E. faecium 44 tobramycin, amikacin and neomycin AME Aph(2’’)-Ia-Aac(6’)Ie High-level gentamicin resistance Tn5281 E. faecalis 34 E. faecium AME Aph(2’’)-Ib High-level gentamicin resistance Unknown E. faecium 136 AME Aph(2’’)-Ic High-level gentamicin resistance pYN134 E. faecalis 38 E. faecium AME Aph(2’’)-Id High-level gentamicin resistance Unknown E. faecium 40 AME Ant(6’)-Ia High-level streptomycin resistance Tn1546, Inc.18, E. faecalis 37, 137, 138 Tn5382 E. faecium AME Ant(3’’)-Ia High-level streptomycin resistance pR538–1 E. faecium 37, 41 Ribosome-modifying EfmM Tobramycin and kanamycin resistance Intrinsic E. faecium 12 methyltransferase b-lactams and cephalosporins PBP4/5 production - Low-level penicillin resistance; moderate Intrinsic E. faecalis 3 to high-level cephalosporin resistance E. faecium PBP4/5 point mutation - High-level ampicillin and imipenem Sporadic E. faecalis 25–27 resistance E. faecium Altered cell wall L,D-transpeptidase b-lactam resistance Intrinsic E .faecium 139, 140 Destruction of b-lactamase b-lactam resistance Tn552 and others E. faecalis 4 b-lactam ring on bla genes E. faecium Glycopeptides Synthesis of VanA, VanH, VanY, Resistance to vancomycin +/2 Tn1546, Inc.18 E. faecalis 47 alternative cell wall VanX, VanR, VanS teicoplanin depending on the E. faecium phenotype Lincosamides ABC-efflux pump Lsa Resistance to clindamycin, Intrinsic E. faecalis 14 streptogrammin A and B ABC-efflux pump MsrC Low-level resistance to streptogramin B Intrinsic E. faecium 16 compounds ABC-efflux pump VgaD Streptogramin A resistance Putative E. faecium 83 transposon Acetyltransferase VatD (SatA) Streptogramin A resistance Putative E. faecium 77 transposon Acetyltransferase VatH Streptogramin A resistance Putative E. faecium 83 transposon Acetyltransferase VgbA Streptogramin B resistance Unknown E. faecium 79 Acetyltransferase VatE (SatG) Streptogramin A resistance Unknown E. faecium 78, 141 Altered ribosome ErmA MLS phenotype Tn554 E. faecalis 142 E. faecium Altered ribosome ErmB MLS phenotype Tn917,Tn1545 E. faecalis 16, 20 E. faecium 422 Virulence Volume 3 Issue 5 Table 1. Mechanisms of resistance to E. faecium and E. faecalis (continued) Antibiotic Mechanism Associated Phenotype Intrinsic, Host range References resistance of resistance enzyme sporadic or associated MGE Linezolid rRNA point G2576T, G2505A, Linezolid resistance Sporadic E. faecalis 89–91 mutations L4(F101L) E. faecium Methylated rRNA Cfr Linezolid, lincosamides, pEF-01 E. faecalis 94 streptogramin A resistance E. faecium Daptomycin Altered membrane- Cardiolipin Contributes to Daptomycin resistance Sporadic E. faecalis 104, 105 bound protein sythetase through an unknown mechanism E. faecium Altered membrane- GdpD Daptomycin resistance, effect is Sporadic E. faecalis 105 bound protein amplified in combination liaF mutation E. faecium Altered membrane- LiaF Daptomycin resistance when combined Sporadic E. faecalis 105 bound protein with gdpD mutation E. faecium Gram-positive species, downregulation or absence of a two- activity conferred by expression of the lsa gene. lsa is related component signal transduction VncR/S autolytic system also structurally to ATP-binding cassette (ABC)-efflux pumps, suggest- 15 24 contributes to penicillin tolerance, but this mechanism has not ing drug efflux as a possible mechanism, and was found in 180/ been demonstrated in enterococcus. Tolerance may be induced 180 strains of E. faecalis and 0/189 other enterococcus species, when penicillin is administered by pulsed-dosing. As such, suggesting the gene is intrinsic to E. faecalis. In general, for clinical penicillin-naive enterococcal strains may appear susceptible in resistance to quinupristin-dalfopristin to occur, the bacteria must be 16,17 vitro but develop tolerance after exposure to the drug. resistant to both streptogramin A and streptogramin B. E. faecium Aminoglycosides. Both E. faecium and E. faecalis are harbors a different putative ABC-efflux pump encoded by the intrinsically resistant to clinically achievable concentrations of intrinsic msrC gene. This gene, a close relative of msrA and msrB aminoglycosides. In E. faecalis, MICs vary for the aminoglyco- in staphylococci, confers low-level resistance (MIC 1–2 mg/ml) to sides, with the greatest degree of resistance seen to streptomycin streptogramin B compounds, explaining the elevated quinupristin- (MIC up to 500 mg/ml). Intrinsic resistance in E. faecalis is dalfopristin MICs seen when E. faecium acquires a separate attributed to an inability of the aminoglycoside to enter the cell determinant that confers streptogramin A resistance alone. (where they act by inhibiting ribosomal protein synthesis), as Trimethoprim-sulfamethoxazole. Most bacteria lack the ability demonstrated in experiments by Moellering and colleagues in the to absorb folate from the environment and as such require de 18,19 early 1970s. When enterococci were exposed to radiolabeled novo folate synthesis in order to produce nucleic acids. The aminoglycoside with or without penicillin, higher intracellular antibiotic combination trimethoprim-sulfamethoxazole inhibits aminoglycoside concentrations were achieved in the presence of two sequential steps in the tetrahydrofolate synthesis pathway, the cell wall synthesis inhibitor. The combination of cell wall thereby inhibiting folate synthesis and synergistically killing a active agents and aminoglycosides also resulted in bactericidal broad spectrum of bacterial species. Enterococci are unusual in activity (bactericidal synergism). These studies provide physiologic that they can absorb folic acid from the environment, bypassing context to the long-standing observations of improved clinical the effects of trimethoprim-sulfamethoxazole. Therefore, in vitro outcomes with aminoglycoside-penicillin combination therapy. testing of enterococcal susceptibility to trimethoprim-sulfa- Some enterococci also express chromosomally-encoded methoxazole in a media devoid of folate will yield a susceptible enzymes that increase the MIC of aminoglycosides and prevent result. Despite this apparent in vitro susceptibility, trimetho- synergism. Ubiquitous among E. faecium, the aminoglycoside 6' prim-sulfamethoxazole is ineffective in treating serious entero- 28,29 acetyltransferase [AAC(6')-Ii] confers resistance to tobramycin coccus infections. with MICs as high as 1000 mg/ml and to kanamycin. Additionally, an efmM-encoded m C methyltransferase in Acquired Resistance E. faecium confers low-level resistance to dibekacin, tobramycin and kanamycin. EfmM methylates the 16S rRNA resulting in a Acquired resistance in enterococci (that which is not intrinsic to sterically-hindered ribosome target site. the species) can occur through sporadic mutations or through Intrinsic enzyme-mediated high-level resistance to neither acquisition of foreign genetic material. Horizontal gene exchange gentamicin nor streptomycin has been described in enterococci. among enterococci occurs through the transfer of pheromone- As such, these drugs retain synergistic activity in enterococci and sensitive or broad host range plasmids, or through the movement have consequently emerged as the drugs of choice to achieve of transposons. With few exceptions, multiple plasmids and synergism in severe infections caused by either E. faecium or transposons can be identified in clinical strains. These elements E. faecalis. may interact with each other and with the bacterial chromosome Lincosamides and streptogramins. E. faecalis are intrinsically to form composite mobile elements. For recent reviews of the resistant to clindamycin (a lincosamide), quinupristin (streptogra- plasmids and transposons in enterococci, refer to Palmer and min B class) and dalfopristin (streptogramin A class) through Hagstead, respectively. www.landesbioscience.com Virulence 423 Pheromone-responsive plasmids are found predominantly in an MIC of 32 mg/ml). Ceftobiprole shows good in vitro activity 41,42 E. faecalis. Chromosomally encoded lipoprotein fragments against E. faecalis with no reports of resistance to date, but is (“pheromones”) released by recipient cells are sensed by nearby ineffective against penicillin-resistant clinical strains of E. 43,44 donor cells and stimulate production of aggregation substance faecium. (Asa1, PrgB and others), encoded by the plasmid. Aggregation Aminoglycosides. While intrinsic mechanisms result in low- substance interacts with enterococcal binding substance (EBS) on level aminoglycoside resistance, acquisition of mobile genetic the surface of the recipient cell and stimulates recipient-donor elements typically underlies high-level aminoglycoside resistance contact that promotes conjugation. These plasmids transmit in both E. faecium and E. faecalis. Ensuing MICs range from genetic information in a highly efficient manner between 2,000 mg/ml to as high as 128,000 mg/ml. Among the genes that E. faecalis strains (10 /donor cell during 4 h of mating), but encode high-level resistance, the most concerning are those that are largely restricted to this species. pRUM plasmids in E. faecium result in gentamicin and streptomycin resistance because these are similar to pheromone-responsive plasmids in E. faecalis in that antibiotics are used for synergistic therapy of serious enterococcal they transfer at a high frequency but exhibit a narrow host range. infections. In contrast, broad host range plasmids are capable of High-level gentamicin resistance most frequently occurs through transferring genetic information to other gram-positive and even acquisition of a bifunctional gene encoding APH(2'')-Ia-AAC(6')- 30 27 45 gram-negative species, but at a lower frequency (10 /donor cell Ie. These enzymes inactivate gentamicin (and structurally related during 4 h of mating) than pheromone-responsive plasmids. aminoglycosides) by phosphorylation at the 2'hydroxy position of Transfer of these plasmids requires close contact between cells. gentamicin and simultaneous acetylation of the 6'hydroxy position 46,47 Inc.18-type plasmids are well-known broad host range plasmids of the other aminoglycosides. The modified antibiotic is no that have been implicated in the transfer of vancomycin resistance longer capable of binding to its target on the 30S ribosomal subunit determinants to S. aureus in recent years. and thereby loses antibacterial activity. Strains that contain aph(2'')- Three types of transposons are responsible for most gene Ia-aac(6')-Ie are clinically resistant to all aminoglycosides except for mobility in enterococci, Tn3 family transposons, composite streptomycin. The aph(2'')-Ia-aac(6')-Ie gene is most commonly transposons, and conjugative transposons. The prototypical Tn3 flanked by IS256 in a composite transposon designated Tn4001 in family transposons are Tn917 [conferring macrolide, lincosamide S. aureus and Tn5281 in E. faecalis. and streptogramin resistance (MLS )] and Tn1546 (conferring Several other genes have been identified that confer gentamicin B B 49–51 glycopeptide resistance), whereas the prototypical conjugative resistance, including aph(2'')-Ic, aph(2'')-Id and aph(2'')-Ib. In transposon is Tn916, which confers resistance to minocycline and comparison with aph(2'')-Ia-aac(6')-1e, these genes are minor tetracycline. Composite transposons can readily be formed by contributors to gentamicin resistance in enterococci. Their the interaction of related IS elements that are liberally sprinkled prevalence varies by geographical region. Importantly, MICs for throughout the genome of most clinical enterococcal strains. The enterococci harboring aph(2'')-Ic may be as low as 256 mg/ml, an movement of these IS elements not only confers mobility to MIC which would be interpreted as gentamicin-susceptible by resistance genes, but it promotes cointegration of plasmids with labs that use an MIC of 500 mg/ml as a cut-off to determine high- other plasmids and with the bacterial chromosome. level gentamicin resistance. Despite the lower MIC, bacteria β-lactams. Enterococci may develop increased resistance to expressing these enzymes are resistant to the synergistic activity of penicillins through acquisition of β-lactamases or PBP4/5 cell wall active agents and gentamicin. Thus, in geographical mutations. Plasmid-mediated bla genes (encoding β-lactamases) area where aph(2'')-Ic is present, laboratories should be alerted to were first described in E. faecalis in 1983. Since that time, lower the threshold MIC for gentamicin to enhance detection of enterococcal β-lactamase production has been rare and described enterococci that would be resistant to synergy. predominantly in E. faecalis. The bla genes in enterococcus are High-level resistance to streptomycin occurs most commonly identical to those in S. aureus and are often encoded by remnants through enzymatic modification of the antibiotic or by single of staphylococcal β-lactamase transposon Tn552. point mutations to the ribosome. Two well-described adenylyl- High-level penicillin resistance in E. faecium is most commonly transferases, Ant(6')-Ia and Ant(3'')-Ia, are capable of inactivating 48,52 associated with accumulation of point mutations in the penicillin streptomycin (and structurally related aminoglycosides). binding region of PBP5. A variety of point mutations have been Enterococci can also develop ribosomal mutations that result in 36,37 38 described in both E. faecium and E. faecalis. Although these streptomycin resistance. Whereas resistance caused by aminogly- point mutations likely originated de novo in individual bacteria coside-modifying enzymes (AME) will typically have MICs in the under selective pressure from antibiotics, chromosome-to-chro- 4,000 to 16,000 mg/ml range, ribosomal mutations result in mosome transfer of low affinity pbp5 genes has been documented MICs of 128,000 mg/ml. in vitro and likely contributes to the dissemination of high-level Other acquired AMEs have been identified in enterococci, penicillin resistance in E. faecium. including Aph(3')-IIIa, an aminoglycoside phosphotransferase Ceftaroline and ceftobiprole, fifth generation cephalosporins, that confers resistance to kanamycin and Ant(4'')-Ia, a have activity against enterococcus, but may be prone to emergence nucleotidyltransferase that confers resistance to tobramycin, 40 55 of resistance with increased clinical use. Clark et al. subjected amikacin, neomycin and kanamycin. As these enzymes do not E. faecalis to serial passages of ceftaroline and identified two confer gentamicin or streptomycin resistance, they are of less resistant isolates (one with an MIC of 8 mg/ml and the other with clinical significance. 424 Virulence Volume 3 Issue 5 Glycopeptides. The acquisition of glycopeptide resistance by to D-lac. Host enzymes ligate D-ala-D-lac to the tripeptide enterococci has been an epidemiological and antimicrobial precursor, yielding the low affinity pentapeptide precursor. Full dilemma for the past 25 years. First described in 1988, resistance to glycopeptides, however, requires not only construc- glycopeptide-resistant enterococci (GRE) have since emerged as tion of the altered precursor, but also elimination of normal 33,57,58 a major cause of nosocomial infections. The majority of GRE precursors. VanX hydrolyzes D-ala-D-ala to its constituent infections are attributed to E. faecium, although glycopeptide amino acids, which allows D-ala-D-lac to be the sole substrate for resistance occurs in E. faecalis and other enterococcus species as cell wall synthesis. VanY hydrolyzes the terminal D-ala from any well. Currently in the United States, an estimated 30% of clinical normal pentapeptide precursor, rendering it useless for normal cell 56 60 enterococcus isolates are resistant to glycopeptides. wall construction. The mechanism by which VanZ augments Vancomycin acts by binding to the D-ala-D-ala terminus of the resistance is unknown, but when present it confers decreased pentapeptide precursor, thereby inhibiting cell wall synthesis. susceptibility to teicoplanin. Additional open reading frames Glycopeptide-resistant organisms modify these pentapeptide VanW and VanV have been described on the VanB operon; their precursors, replacing the terminal D-ala with D-lac or D-ser. functions also are not yet known. These modified cell wall precursors bind glycopeptides with Expression of the genes for VanA, H, X, Y and Z are all 1,000-fold lower affinity than do normal precursors. To create the regulated by VanR and VanS, a two-component sensor-transducer modified precursors at least seven enzymes are required. Using the system that is part of the VanA operon within Tn1546. While the VanA cassette as a model, these enzymes are VanA, H, X, Y, Z, R specific regulatory factors are not known, the presence of and S (Fig. 1). Initially, cellular pyruvate is converted to d-lactate glycopeptides in the environment results in activation of VanS by the VanH dehydrogenase. The VanA ligase then ligates D-ala through autophosphorylation. Activated VanS then phosphorylates Figure 1. An illustration of the VanA resistance mechanism as it relates to normal cell wall synthesis. The top pathway denotes normal cell wall synthesis, and the mechanisms by which VanX and VanY disrupt this pathway. The shaded pathway denotes construction of a modified cell wall that is resistant to vancomycin. Adapted from Gold et al. www.landesbioscience.com Virulence 425 VanR. Phosphorylated VanR increases VanH, A, X, Y and Z The complex enzymatic pathways that confer glycopeptide transcription through interaction with specific promoter regions. resistance predate the emergence of GRE in the late 1980s. VanR also interacts with its own promoter region, augmenting E. gallinarum and E. casseliflavus exhibit innate low-level resistance 63 75 VanR and VanS transcription. Clinical strains that harbor the through a chromosomally-encoded VanC operon and have been VanA operon but contain deletions in VanR and VanS genes have implicated as a source of the genes seen in other Van 76,77 been isolated and are susceptible to both vancomycin and phenotypes. Additionally, a number of soil and bowel teicoplanin. This suggests that VanR activity is required for the organisms have been identified as harboring VanB genes and 64,65 full expression of the VanA operon. may have played a role in the transfer of glycopeptide-resistance 78-82 VanA and VanB operons are by far the most prevalent in genes to E. faecium. Enterococci are increasingly recognized as human GRE infections. In the VanA phenotype, the enterococcus belonging to two distinct clades, one that predominates in the is resistant to both vancomycin and teicoplanin. In the VanB hospital environment and another within the community. These phenotype, vancomycin but not teicoplanin induces resistance clades differ genetically, and may have diverged between 300,000 resulting in a vancomycin resistant, teicoplanin-susceptible to a million years ago. The nosocomial clade has acquired phenotype; however, constitutive expression (which may be virulence and resistance determinants that confer a selective selected by teicoplanin exposure) results in resistance to both advantage in this setting. Acquisition of the VanA cassette in the compounds. VanC resistance is intrinsic to E. gallinarum and late 1980s likely conferred further advantage that contributed to E. casseliflavus. A total of nine resistance operons have been the observed increase in prevalence of infections due to E. faecium. described. They may be grouped by their ligase activity. Operons Streptogramins. The streptogramin B/A combination quinu- that encode D-lac ligases result in high-level resistance with MICs pristin-dalfopristin is one of two antibiotics approved by the FDA . 256 mg/ml (VanA, VanB, VanD and VanM) while operons for treatment of infections caused by vancomycin-resistant that encode D-ser ligases result in low-level resistance with MICs E. faecium. Because E. faecalis are intrinsically resistance to 31,66–69 8–16 mg/ml (VanC, VanE, VanG, VanL and VanN). Of streptogramins, the majority of genes that confer horizontally- the low-level resistance phenotypes, only VanN has been shown transferable resistance have been isolated from E. faecium. to be transferable. Between 1 to 12% of E. faecium isolates are resistant to 84,85 Horizontal transfer of the Van genes occurs through a variety of streptogramins. There are three mechanisms by which mechanisms. VanA is mobilized on Tn3-family transposon acquired genetic elements cause streptogramin resistance: acetyla- Tn1546.Tn1546 is found on both non-conjugative and tion of the antibiotic, efflux of the antibiotic, and dimethylation conjugative plasmids. Inc.18 plasmids are broad host range of the 23S rRNA target site. To date, 12 genes that cause plasmids that have been implicated in the transfer of the VanA streptogramin resistance have been described in enterococci, operon to methicillin-resistant S. aureus. Vancomycin-resistant although additional genes have been described in staphylococci S. aureus (VRSA) has been found in clinical settings in a handful and streptococci. of cases. Werner et al. demonstrated in vitro that interspecies The widespread use of virginamycin, a veterinary streptogramin transfer of Tn1546 is relatively uncommon compared with A compound, was associated with extensive resistance among intraspecies transfer. It appears that while broad host-range enterococci isolated from farm animals and agricultural sewage. plasmids can transfer between species, their stability within Consequently, quinupristin-dalfopristin resistance is most com- different species varies. As such, broad host range plasmids mon in environmental samples, although the prevalence in containing an intact copy of Tn1546 may transfer resistance to nosocomial infections with resistance is increasing. Enzymatic staphylococci more stably, since the transposon can transfer to acetylation of streptogramin A compounds was the first resistance replicons within the staphylococcal strain that are stable. mechanism described in the class. Virginamycin acetyltransferase Staphylococcal variants that have acquired broad host range genes vatD, vatE and vatH are among the streptogramin resistance plasmids with Tn1546 variants that have lost their ability to genes with probable veterinary origins. vatD and vatE (formerly transfer through deletion of or insertion into the transposition called satG) have been isolated from plasmids alongside erm and genes will exhibit an unstable phenotype due to the instability of vgbA genes (described below) that reduce susceptibility to the plasmid in the staphylococcal milieu. Additionally, in vitro streptogramin B—thus providing full resistance to quinupristin- 86–89 studies demonstrating transfer of Tn1546 from enterococcus to dalfopristin. One plasmid has been identified with both vatD 72,73 90 S. aureus have occurred in E. faecalis. Sequence homology has and the VanA operon, resulting in resistance to both been observed between plasmids found in VRSA isolates and vancomycin and quinupristin (but not dalfopristin) when GRE isolates taken from VRSA infected patients, with the most expressed in recipient cells in vitro. VatH may be seen in overlap occurring with E. faecalis isolates. Compared with conjunction with another streptogramin acetyltransferase, VgbA, E. faecium, VanA-containing E. faecalis are relatively uncommon the only known acetyltransferase with activity against strepto- in the clinical setting. If E. faecalis is a more effective (but less gramin B in enterococci. All of the above acetyltransferase genes common) donor than E. faecium, then this may help to explain have been isolated exclusively from E. faecium, with the exception why VanA in staphylococci is rare. VanB is most often carried on of vatE which has been isolated from E. faecium and from a carried on Tn5382/1549 or related conjugative transposons. E. faecalis in a veterinary setting. VanB carrying transposons have been identified in pheromone- The ABC-efflux channel VgaD also plays a role in acquired 30,31 sensitive and conjugative plasmids. streptogramin resistance, independent of the intrinsic ABC-efflux 426 Virulence Volume 3 Issue 5 channels encoded by lsa genes in E. faecalis and msrC gene in was the first enterococcus harboring cfr to be reported in the E. faecium (described above). VgaD has been described only in literature, although human isolates of E. faecalis and E. faecium E. faecium. vgaD was found on a plasmid with vatH, both of with cfr were reported in a 2010 abstract. Overall, linezolid which confer only streptogramin A resistance. To date, no other resistance remains rare in enterococci. acquired streptogramin efflux pumps have been described. Daptomycin. Daptomycin is a lipoprotein with bactericidal Perhaps the best understood mechanism of streptogramin activity against enterococci. While not FDA approved for resistance is dimethylation of the 23S rRNA. This resistance treatment of GRE, it is often used by clinicians for this 104-106 mechanism, which confers the MLS or MLS phenotype occurs purpose. The epidemiology of daptomycin resistance in A B through acquisition of either the ermA or ermB genes on broad enterococcus (defined as MIC . 4 mg/ml) was recently reviewed host range plasmids such as pAMβ1. If these plasmids also contain by Kelesidis et al. Rates of daptomycin resistance in this study vatE or vatD genes, then they confer resistance to quinupristin- were approximately 0.6% (111 daptomycin resistant isolates/ dalfopristin when acquired by a recipient cell. 17,084 enterococcus isolates total). In general, E. faecium is more Linezolid. Prior to FDA approval in 2000, reports of linezolid likely than E. faecalis to express daptomycin resistance, although resistance in enterococci existed but were rare. The emergence of resistance has been reported in both species. The increased linezolid resistance occurred slowly and only in sporadic cases prevalence of daptomyicin resistance in E. faecium may reflect associated with prolonged exposure. The industry-sponsored increased use of daptomycin with this species compared with LEADER trial has monitored linezolid efficacy from 2004 to E. faecalis, which is usually susceptible to penicillins. Daptomycin 2009 and has found yearly resistance rates between 0.49 and resistance appears to be less common in North America than in 56 94 107 1.83%. In contrast, Pogue et al. found linezolid resistance in Asia or Europe. 20% of GRE samples from the University of Pittsburgh Medical Daptomycin incorporates itself into the cell membrane of Center. Only 25% of isolates in their study were associated with Gram-positive organisms in the presence of physiologic calcium prior linezolid exposure, suggesting clonal spread. concentrations and promotes leakage of intracellular potassium Linezolid is a first-in-class oxazolidinone, an entirely synthetic into the extracellular space, resulting in cell death by destruction 108-110 class of antibiotics that binds to the initiation complex and of the transcellular potassium gradient. Normal cell inhibits protein synthesis. Most bacteria, including the enter- membrane polarity is required for daptomycin intercalation. In ococci, have multiple copies of the genes encoding 23S rRNA. staphylococci, alteration of the cell membrane charge by virtue of E. faecalis have four copies of the gene and E. faecium six modification of cell membrane lipoproteins has been associated 96 111 copies. with reduced daptomycin susceptibility. In theory, the presence of multiple gene copies makes A number of genes resistance from sporadic mutations less likely because the have been described in staphylococci that contribute to unaffected gene copies would mask the effect of the mutated daptomycin resistance, none of which have been identified in gene. However, recombination between susceptible and resistant enterococcus to date. While the mechanism of daptomycin copies (referred to as “gene conversion”) will yield strains with resistance in enterococcus remains unresolved, several reports have multiple mutated copies under persistent linezolid selective elucidated gene mutations associated with enterococcus dapto- 113,114 pressure. In clinical isolates, a mutation in one E. faecium mycin resistance. rRNA gene conferred an MIC of 8–16 mg/ml. The same mutation Palmer et al. created three daptomycin-resistant strains by in . 3 rRNA genes conferred an MIC between 64–128 mg/ml. exposing E. faecalis to increasing daptomycin concentrations until A variety of point mutations that confer linezolid resistance have stable resistance was identified. They then performed complete been identified, the most common of which is G2576T. In the genome sequencing of the strains before and after emergence of most recent LEADER study results (2009), the G2576T daptomycin resistance and identified seven gene mutations. Of mutation was identified in all eight of the linezolid-resistant the seven mutations observed in this study, only EF1797 and enterococci strains isolated in the United States. Four of the eight EF0631 gene mutations were identified in all three resistant strains found in this study were isolated in Louisville, KY and strains. EF1797 encodes a putative membrane protein that may 56,97 appeared clonally related. Other sporadic point mutations be involved in phosphatidylserine and sphingolipid synthesis, but have been associated with linezolid resistance, including G2505A its function has yet to be determined. EF0631 encodes a putative 98-100 and L4 (F101L). cardiolipin sythetase (cls), a transphosphatidylase involved in the In 2006, the transferable cfr gene was identified in S. aureus as synthesis of the cell membrane protein cardiolipin. One specific the source of resistance to linezolid, lincosamides and strepto- mutation in this gene, R218Q, was found in two of the resistant gramin A compounds, among others. Cfr encodes an rRNA strains and occurs in the presumed active domain of the EF0631 methyltransferase that modifies an adenosine in the linezolid- enzyme. Through comparison with a DNA sequence database, binding region on the 23S rRNA, preventing antibiotic binding. the authors identified one other E. faecalis strain with an EF0631 It is hypothesized that the cfr gene emerged from animal strains of frameshift mutation, but this isolate had a daptomycin-susceptible bacteria that were exposed to natural compounds with an rRNA phenotype. 101,102 114 binding site similar to linezolid. In 2011, cfr was identified In a similar study, Arias et al. compared the nucleotide in an E. faecalis strain (designated EF-01) from a cattle farm in sequence and cell membrane proteins of E. faecalis isolates before China. In this strain, the gene was located on a plasmid and after the development of daptomycin resistance in a patient (pEF-01) and flanked by IS1216, suggesting transposability. This with enterococcus bacteremia. Genome sequencing of the www.landesbioscience.com Virulence 427 resistant strain revealed three mutated genes: cls, gdpD and liaF.A In uncomplicated, fully susceptible E. faecalis and E. faecium cardiolipin synthetase mutation was identified but when the infections, ampicillin remains the preferred therapy. In the mutant gene was placed in daptomycin-sensitive enterococcus uncommon presence of β-lactamase, combination with a strain the MIC did not change. The same cls mutation was β-lactamase inhibitor such as sulbactam may improve outcomes. observed in other E. faecalis and E. faecium strains resistant to When complicated infections such as endocarditis occur in daptomycin. The other two gene mutations, gdpD (glyceropho- susceptible enterococcal infections, an aminoglycoside should be sphoryl diester phosphodiesterase) and liaF (lipid II cycle- added to a cell wall active agent for synergistic killing, as has been interfering antibiotic protein), did have an impact on MICs the standard for almost 60 years. Among aminoglycosides, only when reconstituted in the daptomycin-susceptible strain. The liaF gentamicin and streptomycin should be considered for synergistic mutation increased the MIC from 1 to 4 mg/ml. The gdpD therapy. Historically, twice-daily or three times daily aminoglyco- mutation did not increase the MIC, but the combination of both side dosing regimens have been used. In streptococcus infections, proteins increased the MIC to 12 mg/ml. Mutations in both gdpD once-daily aminoglycoside dosing was shown to be effective in and liaF were also identified in other resistant strains of E. faecalis humans. For enterococcal endocarditis, though, once-daily and E. faecium, but were not demonstrated in the Palmer study. aminoglycoside dosing has only been studied in animal models 122–124 125,126 Thus, cardiolipin synthetase, GdpD and LiaF are cell membrane with evidence for and against its use. Differences proteins associated with daptomycin resistance. Given that a between these studies likely reflect the pharmacodynamic and number of different membrane-associated proteins have been pharmacokinetic differences between the animal models. In linked to reduced daptomycin susceptibility in staphylococci, it humans, the efficacy of once-daily aminoglycoside dosing has seems likely that more genes conferring enterococcal resistance to not been established for enterococcus infections. As such, daptomycin will be identified in the future. guidelines continue to recommend three times daily dosing for Tigecycline. Tigecycline, a novel glycylcycline antibiotic, gained gentamicin and twice-daily dosing for streptomycin. In the FDA approval in 2005 for complicated intra-abdominal infections, presence of high-level penicillin resistance, synergy has been skin and soft tissue infections, and community-acquired pneu- observed in animal models with the combination of aminoglyco- monia. It has been used off-label to successfully treat MRSA and sides and other cell wall active antibiotics including vancomycin 115 128 GRE infections. Typical tigecycline MICs for enterococcus range or daptomycin. from 0.125 mg/ml to 0.25 mg/ml, while MICs . 0.5 mg/ml are In the instance of complicated enterococcal infections resistant considered resistant. Early surveillance studies of tigecycline showed to high-levels of gentamicin and streptomycin, an alternative no cases of resistant enterococcus, agent must be used for synergistic activity. Despite relative although two case reports of E. faecalis strains with MICs of 2 mg/ml and 6 mg/ml, respectively, resistance to both agents, the combination of ceftriaxone and 117,118 129 have been described. A more recent study from Taiwan ampicillin has been shown to be efficacious in animals. In case reviewed antimicrobial resistance among 219 VRE isolates and reports and prospective case-series, 56 patients have been treated 130-132 found two isolates with a tigecycline MIC of 0.5, and one isolate with this combination with success rate of 71.4% (40/56); with an MIC of 1, with a trend toward increasing tigecycline MIC although these numbers may reflect publication bias. The over time. The mechanism of tigecycline resistance in presumed benefit of ceftriaxone-ampicillin combination therapy enterococcus is unknown. In staphylococcus, tigecycline resistance is attributed to full saturation of PBPs 2–4, which cannot be is mediated by a novel family of efflux pumps, but these genes achieved with either agent alone. By inhibiting all PBPs, the have not been demonstrated in enterococcus. bacteria have no alternative enzyme with which to build a cell Other antibiotics. Resistance occurs to other antibiotics wall. In in vitro and animal model studies, similar synergistic including macrolides, tetracyclines, chloramphenicol, fosfomycin, bactericidal activity has been shown with other cell wall active rifampin and quinolones. These resistance mechanisms will not be combination therapies, including ceftriaxone-fosfomycin and 134 135 described in this review, as resistance to these antimicrobial agents ampicillin-imipenem, but not with ampicillin-ertapenem. is so common that they are seldom involved in treatment of Treatment of glycopeptide-resistant enterococcus. Vancomycin- enterococcus infections. resistant enterococci pose particular problems for treatment because the strains which harbor VanA and VanB resistance are also typically Management resistant to other classes of antibiotics. While only linezolid and quinupristin-dalfopristin have FDA approval for treatment of GRE Because of the differences in resistance patterns between infections, other antimicrobial agents including daptomycin, E. faecium and E. faecalis, it is imperative to differentiate the tigecycline, fosfomycin, quinolones, tetracyclines and new fifth pathogen to the species level and perform susceptibility testing on generation cephalosporins exhibit in vitro activity and have been strains isolated from patients with clinical infections. Treatment of used with success in individual cases. In uncomplicated cases, enterococcal infections depends upon (1) the species, (2) the monotherapy based upon the antibiotic susceptibility profile is resistance patterns present in the clinical isolate and (3) the appropriate. In complicated cases such as endocarditis, the ideal location and severity of the infection. Uncomplicated enterococcal therapy for GRE has not been determined. infections may be adequately treated with monotherapy, whereas Both linezolid and quinupristin-dalfopristin have been shown severe infections such as endocarditis benefit from a synergistic to be efficacious in treatment of complicated GRE infections and 56,136 regimen. are FDA approved for this indication. Linezolid has been 428 Virulence Volume 3 Issue 5 used for GRE endocarditis in both E. faecalis and E. faecium, both other empirical regimens, there were significantly more adverse with and without additional agents. To date, it has not been events and a non-significant trend toward higher mortality. As shown that combination therapy is more efficacious than such, tigecycline monotherapy should not be considered as first monotherapy in this setting. Because linezolid is not bactericidal, line for treatment of GRE infections. Tigecycline demonstrates in treatment of GRE endocarditis with linezolid remains controver- vitro synergism with a number of other agents, including rifampin sial. Quinupristin-dalfopristin can be efficacious against and daptomycin, although these combinations have not been E. faecium, but should not be used to treat E. faecalis due to evaluated beyond small case series in humans. the intrinsic presence of lsa-mediated resistance (described above). When using quinupristin-dalfopristin for treatment of severe or Future Directions complicated GRE infections, combination therapy may be necessary although the optimal choice and dose of adjunct Over the years enterococci have demonstrated the potential to antibiotic has yet to be determined. Several studies have compared harbor and transfer resistance genes and as such have become an linezolid to quinupristin-dalfopristin. In a small, single-center important clinical pathogen. A better understanding of resistance study, Chong et al. found increased resistance and increased mechanisms to daptomycin and tigecycline is needed and will aid number of days of bacteremia in patients treated with in the prediction and prevention of epidemiologic spread. Several quinupristin-dalfopristin. Several other studies also reported more new drugs are emerging as potential options for GRE treatment. 56,138 resistance to quinupristin-dalfopristin than linezolid, suggest- Ceftaroline has been shown to be more efficacious than linezolid ing that of the two linezolid may be superior for GRE treatment. in animals and may play a larger role in the future. Use of daptomycin for GRE infections, particularly endocard- Additionally, arbekacin, which is not currently available in the itis, is appealing because of its bactericidal activity against United States, has demonstrated synergistic killing in combina- enterococci. While monotherapy may be adequate in many tion with penicillins even in the presence of high-level gentamicin 106,139 146 GRE infections, daptomycin failure has been reported. Arias and streptomycin resistance. A number of antibiotic combina- et al. reported subsequent response to the combination of tions, including those mentioned in the management section, daptomycin/gentamicin/ampicillin after failing daptomycin have shown in vitro synergistic activity and are promising as monotherapy, which may be explained by a synergistic effect of potential treatment modalities for complicated GRE infections, the triple therapy. Daptomycin synergy has been described in but must first be evaluated more rigorously in humans. The novel vitro with ampicillin, cephalosporins, imipenem, rifampin and glycopeptide oritavancin is currently under investigation and 140-143 gentamicin. shows promise in treating GRE infections. In addition, non- As with quinupristin-dalfopristin, there may be a role for adjunct antibiotics to achieve a synergistic effect, antimicrobial pharmacotherapy targeted at specific virulence although appropriate agents and dosing regimens have not been factors (such as anti-adhesions) may play a preventative or adequately evaluated in humans. therapeutic role in the management of enterococcal infections. Tigecycline has also been used off-label for treatment of GRE. Future directions of research must focus on development of new Cai et al. performed a meta-analysis of randomized trials to antimicrobial agents. Finally, efforts must continue to prevent evaluate the use of tigecycline for GRE infections. 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In-vitro synergistic activity of the com- 22122863; http://dx.doi.org/10.1159/000330458 RP. Antimicrobial activities of daptomycin, vancomy- bination of ampicillin and arbekacin against vancomy- 134. Brandt CM, Rouse MS, Laue NW, Stratton CW, cin, and oxacillin in human monocytes and of cin-and high-level gentamicin-resistant Enterococcus Wilson WR, Steckelberg JM. Effective treatment of daptomycin in combination with gentamicin and/or faecium with the aph(2'')-Id gene. Diagn Microbiol multidrug-resistant enterococcal experimental endo- rifampin in human monocytes and in broth against Infect Dis 2000; 37:297-9; PMID:10974585; http:// carditis with combinations of cell wall-active agents. J Staphylococcus aureus. Antimicrob Agents Chemother dx.doi.org/10.1016/S0732-8893(00)00155-3 Infect Dis 1996; 173:909-13; PMID:8603970; http:// 2007; 51:1559-62; PMID:17283190; http://dx.doi. dx.doi.org/10.1093/infdis/173.4.909 org/10.1128/AAC.00973-06 135. Pasticci MB, Mencacci A, Moretti A, Palladino N, 141. Cilli F, Aydemir S, Tunger A. In vitro activity of Maria Lapalorcia L, Bistoni F, et al. In vitro daptomycin alone and in combination with various Antimicrobial Activity of Ampicillin-Ceftriaxone and antimicrobials against Gram-positive cocci. J Ampicillin-Ertapenem Combinations Against Clinical Chemother 2006; 18:27-32; PMID:16572890 Isolates of Enterococcus faecalis with High Levels of Aminoglycoside Resistance. Open Microbiol J 2008; 2:79-84; PMID:19088915; http://dx.doi.org/10. 2174/1874285800802010079 www.landesbioscience.com Virulence 433 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Virulence Taylor & Francis

Intrinsic and acquired resistance mechanisms in enterococcus

Virulence , Volume 3 (5): 149 – Aug 15, 2012

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Copyright © 2012 Landes Bioscience
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10.4161/viru.21282
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Abstract

REVIEW Virulence 3:5, 421–433; August 15, 2012; 2012 Landes Bioscience Intrinsic and acquired resistance mechanisms in enterococcus Brian L. Hollenbeck and Louis B. Rice* Department of Medicine; Lifespan/Rhode Island Hospital and Alpert Medical School of Brown University; Providence, RI USA Keywords: enterococcus, antibiotic resistance, review, treatment established. Along with increasing antimicrobial resistance, the Enterococci have the potential for resistance to virtually all acquisition of virulence factors and the ability of enterococcus to clinically useful antibiotics. Their emergence as important form biofilms have also contributed to the rise in nosocomial nosocomial pathogens has coincided with increased prevalence. expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in This paper reviews the mechanisms underlying antibiotic enterococci may be intrinsic to the species or acquired resistance in enterococci, both intrinsic (universally found within through mutation of intrinsic genes or horizontal exchange the genome of the species) and acquired (through acquisition of of genetic material encoding resistance determinants. This new genetic material or through sporadic mutations to intrinsic paper reviews the antibiotic resistance mechanisms in genes). Interspecies differences will be addressed as they arise Enterococcus faecium and Enterococcus faecalis and discusses throughout the paper. This paper will additionally provide an treatment options. overview of current treatment strategies for enterococcal infec- tions. Focus will be on Enterococcus faecalis and E. faecium,as these two species account for the overwhelming majority of human enterococcal infections (Table 1). Introduction Intrinsic Resistance Enterococci are Gram-positive, facultative anaerobic organisms characterized by their ability to grow at 6.5% NaCl concentra- β-lactams and cephalosporins. Growth of most bacteria depends tions and at high pH and to hydrolyze bile-esculin and L- upon enzymatic linkage of pentapeptide precursor molecules into pyrrolidonyl-B-naphthylamide (PYR). Formerly considered mem- a peptidoglycan cell wall. The enzymes responsible for these cross- bers of Lancefield group D streptococcus, DNA homology studies linking reactions are referred to as penicillin binding proteins suggested that they are a distinct genus. Enterococci were (PBPs) because β-lactams (structural analogs of pentapeptide previously considered commensal organisms of little clinical precursors) bind covalently and disrupt normal cell wall growth. importance, but have emerged as serious nosocomial pathogens Attachment of β-lactam agents to PBPs results in impaired cell responsible for endocarditis and infections of the urinary tract, wall synthesis and, in most cases, programmed cell death via bloodstream, meninges, wounds and the biliary tract, among creation of reactive oxygen species. Enterococci express low- others. Recent surveillance data indicate that the enterococcus is affinity PBPs (PBP5 in E. faecium, PBP4 in E. faecalis) that bind the third most commonly isolated nosocomial pathogen (12% of weakly to β-lactam antibiotics. As a result, minimum inhibitory all hospital infections), behind only coagulase-negative staphylo- concentrations (MICs) for penicillins are typically 2–8 mg/ml for 2 7 coccus and Staphylococcus aureus. The rise in prevalence of E. faecalis and 8–16 mg/ml for E. faecium, much higher than enterococcal infections in humans is influenced to some degree by MICs for streptococci and related Gram-positive organisms that the ability of enterococci to escape the action of our most do not contain chromosomally-encoded low-affinity PBP genes. commonly used antibiotics. The influence of antibiotics is most At the population level, enterococcal MICs have increased over 9,10 11 directly seen on the extent to which enterococci colonize the time. Galloway-Pena et al. demonstrated two distinct clades gastrointestinal tract. Animal data have clearly shown the of E. faecium. These clades have PBP5 enzymes that vary in relationship between exposure to parenteral antibiotics, especially affinity, a result of differences in amino acid sequence and extended-spectrum cephalosporins and agents with potent activity transcriptional regulation. Overproduction of non-mutated low- against anaerobic bacteria, and high level gastrointestinal affinity PBPs represents a relatively rare mechanism by which 3 7,12 colonization by ampicillin-resistant Enterococcus faecium. The enterococci express low-level resistance to penicillins. relationship between colonization and subsequent infection is also Early studies by Jawetz et al. indicated that enterococci were not killed by penicillin when exposed to drug concentrations in the range of the MIC (a phenomenon known as tolerance). *Correspondence to: Louis B. Rice; Email: lrice@lifespan.org Tolerance in E. faecalis has been attributed to removal of reactive Submitted: 04/16/12; Revised: 06/25/12; Accepted: 06/26/12 http://dx.doi.org/10.4161/viru.21282 oxygen species by the enzyme superoxide dismutase. In other www.landesbioscience.com Virulence 421 Table 1. Mechanisms of resistance to E. faecium and E. faecalis Antibiotic Mechanism Associated Phenotype Intrinsic, Host range References resistance of resistance enzyme sporadic or associated MGE Aminoglycosides Low cell wall - Low-level aminoglycoside resistance, Intrinsic E. faecalis 8–10 permeability synergy preserved Ribosome mutation - High-level aminoglycoside resistance Sporadic E. faecalis 42 with MIC . 128,000 mg/ml E. faecium Aminoglycoside- Aac(6’)-Ii Low-level tobramycin and kanamycin Intrinsic E. faecium 11 modifying enzyme resistance (AME) AME Aph(3’)-IIIa Low-level kanamycin resistance pJH1 E. faecium 43 AME Ant(4’’)-Ia Low-level resistance to kanamycin, plP810 E. faecium 44 tobramycin, amikacin and neomycin AME Aph(2’’)-Ia-Aac(6’)Ie High-level gentamicin resistance Tn5281 E. faecalis 34 E. faecium AME Aph(2’’)-Ib High-level gentamicin resistance Unknown E. faecium 136 AME Aph(2’’)-Ic High-level gentamicin resistance pYN134 E. faecalis 38 E. faecium AME Aph(2’’)-Id High-level gentamicin resistance Unknown E. faecium 40 AME Ant(6’)-Ia High-level streptomycin resistance Tn1546, Inc.18, E. faecalis 37, 137, 138 Tn5382 E. faecium AME Ant(3’’)-Ia High-level streptomycin resistance pR538–1 E. faecium 37, 41 Ribosome-modifying EfmM Tobramycin and kanamycin resistance Intrinsic E. faecium 12 methyltransferase b-lactams and cephalosporins PBP4/5 production - Low-level penicillin resistance; moderate Intrinsic E. faecalis 3 to high-level cephalosporin resistance E. faecium PBP4/5 point mutation - High-level ampicillin and imipenem Sporadic E. faecalis 25–27 resistance E. faecium Altered cell wall L,D-transpeptidase b-lactam resistance Intrinsic E .faecium 139, 140 Destruction of b-lactamase b-lactam resistance Tn552 and others E. faecalis 4 b-lactam ring on bla genes E. faecium Glycopeptides Synthesis of VanA, VanH, VanY, Resistance to vancomycin +/2 Tn1546, Inc.18 E. faecalis 47 alternative cell wall VanX, VanR, VanS teicoplanin depending on the E. faecium phenotype Lincosamides ABC-efflux pump Lsa Resistance to clindamycin, Intrinsic E. faecalis 14 streptogrammin A and B ABC-efflux pump MsrC Low-level resistance to streptogramin B Intrinsic E. faecium 16 compounds ABC-efflux pump VgaD Streptogramin A resistance Putative E. faecium 83 transposon Acetyltransferase VatD (SatA) Streptogramin A resistance Putative E. faecium 77 transposon Acetyltransferase VatH Streptogramin A resistance Putative E. faecium 83 transposon Acetyltransferase VgbA Streptogramin B resistance Unknown E. faecium 79 Acetyltransferase VatE (SatG) Streptogramin A resistance Unknown E. faecium 78, 141 Altered ribosome ErmA MLS phenotype Tn554 E. faecalis 142 E. faecium Altered ribosome ErmB MLS phenotype Tn917,Tn1545 E. faecalis 16, 20 E. faecium 422 Virulence Volume 3 Issue 5 Table 1. Mechanisms of resistance to E. faecium and E. faecalis (continued) Antibiotic Mechanism Associated Phenotype Intrinsic, Host range References resistance of resistance enzyme sporadic or associated MGE Linezolid rRNA point G2576T, G2505A, Linezolid resistance Sporadic E. faecalis 89–91 mutations L4(F101L) E. faecium Methylated rRNA Cfr Linezolid, lincosamides, pEF-01 E. faecalis 94 streptogramin A resistance E. faecium Daptomycin Altered membrane- Cardiolipin Contributes to Daptomycin resistance Sporadic E. faecalis 104, 105 bound protein sythetase through an unknown mechanism E. faecium Altered membrane- GdpD Daptomycin resistance, effect is Sporadic E. faecalis 105 bound protein amplified in combination liaF mutation E. faecium Altered membrane- LiaF Daptomycin resistance when combined Sporadic E. faecalis 105 bound protein with gdpD mutation E. faecium Gram-positive species, downregulation or absence of a two- activity conferred by expression of the lsa gene. lsa is related component signal transduction VncR/S autolytic system also structurally to ATP-binding cassette (ABC)-efflux pumps, suggest- 15 24 contributes to penicillin tolerance, but this mechanism has not ing drug efflux as a possible mechanism, and was found in 180/ been demonstrated in enterococcus. Tolerance may be induced 180 strains of E. faecalis and 0/189 other enterococcus species, when penicillin is administered by pulsed-dosing. As such, suggesting the gene is intrinsic to E. faecalis. In general, for clinical penicillin-naive enterococcal strains may appear susceptible in resistance to quinupristin-dalfopristin to occur, the bacteria must be 16,17 vitro but develop tolerance after exposure to the drug. resistant to both streptogramin A and streptogramin B. E. faecium Aminoglycosides. Both E. faecium and E. faecalis are harbors a different putative ABC-efflux pump encoded by the intrinsically resistant to clinically achievable concentrations of intrinsic msrC gene. This gene, a close relative of msrA and msrB aminoglycosides. In E. faecalis, MICs vary for the aminoglyco- in staphylococci, confers low-level resistance (MIC 1–2 mg/ml) to sides, with the greatest degree of resistance seen to streptomycin streptogramin B compounds, explaining the elevated quinupristin- (MIC up to 500 mg/ml). Intrinsic resistance in E. faecalis is dalfopristin MICs seen when E. faecium acquires a separate attributed to an inability of the aminoglycoside to enter the cell determinant that confers streptogramin A resistance alone. (where they act by inhibiting ribosomal protein synthesis), as Trimethoprim-sulfamethoxazole. Most bacteria lack the ability demonstrated in experiments by Moellering and colleagues in the to absorb folate from the environment and as such require de 18,19 early 1970s. When enterococci were exposed to radiolabeled novo folate synthesis in order to produce nucleic acids. The aminoglycoside with or without penicillin, higher intracellular antibiotic combination trimethoprim-sulfamethoxazole inhibits aminoglycoside concentrations were achieved in the presence of two sequential steps in the tetrahydrofolate synthesis pathway, the cell wall synthesis inhibitor. The combination of cell wall thereby inhibiting folate synthesis and synergistically killing a active agents and aminoglycosides also resulted in bactericidal broad spectrum of bacterial species. Enterococci are unusual in activity (bactericidal synergism). These studies provide physiologic that they can absorb folic acid from the environment, bypassing context to the long-standing observations of improved clinical the effects of trimethoprim-sulfamethoxazole. Therefore, in vitro outcomes with aminoglycoside-penicillin combination therapy. testing of enterococcal susceptibility to trimethoprim-sulfa- Some enterococci also express chromosomally-encoded methoxazole in a media devoid of folate will yield a susceptible enzymes that increase the MIC of aminoglycosides and prevent result. Despite this apparent in vitro susceptibility, trimetho- synergism. Ubiquitous among E. faecium, the aminoglycoside 6' prim-sulfamethoxazole is ineffective in treating serious entero- 28,29 acetyltransferase [AAC(6')-Ii] confers resistance to tobramycin coccus infections. with MICs as high as 1000 mg/ml and to kanamycin. Additionally, an efmM-encoded m C methyltransferase in Acquired Resistance E. faecium confers low-level resistance to dibekacin, tobramycin and kanamycin. EfmM methylates the 16S rRNA resulting in a Acquired resistance in enterococci (that which is not intrinsic to sterically-hindered ribosome target site. the species) can occur through sporadic mutations or through Intrinsic enzyme-mediated high-level resistance to neither acquisition of foreign genetic material. Horizontal gene exchange gentamicin nor streptomycin has been described in enterococci. among enterococci occurs through the transfer of pheromone- As such, these drugs retain synergistic activity in enterococci and sensitive or broad host range plasmids, or through the movement have consequently emerged as the drugs of choice to achieve of transposons. With few exceptions, multiple plasmids and synergism in severe infections caused by either E. faecium or transposons can be identified in clinical strains. These elements E. faecalis. may interact with each other and with the bacterial chromosome Lincosamides and streptogramins. E. faecalis are intrinsically to form composite mobile elements. For recent reviews of the resistant to clindamycin (a lincosamide), quinupristin (streptogra- plasmids and transposons in enterococci, refer to Palmer and min B class) and dalfopristin (streptogramin A class) through Hagstead, respectively. www.landesbioscience.com Virulence 423 Pheromone-responsive plasmids are found predominantly in an MIC of 32 mg/ml). Ceftobiprole shows good in vitro activity 41,42 E. faecalis. Chromosomally encoded lipoprotein fragments against E. faecalis with no reports of resistance to date, but is (“pheromones”) released by recipient cells are sensed by nearby ineffective against penicillin-resistant clinical strains of E. 43,44 donor cells and stimulate production of aggregation substance faecium. (Asa1, PrgB and others), encoded by the plasmid. Aggregation Aminoglycosides. While intrinsic mechanisms result in low- substance interacts with enterococcal binding substance (EBS) on level aminoglycoside resistance, acquisition of mobile genetic the surface of the recipient cell and stimulates recipient-donor elements typically underlies high-level aminoglycoside resistance contact that promotes conjugation. These plasmids transmit in both E. faecium and E. faecalis. Ensuing MICs range from genetic information in a highly efficient manner between 2,000 mg/ml to as high as 128,000 mg/ml. Among the genes that E. faecalis strains (10 /donor cell during 4 h of mating), but encode high-level resistance, the most concerning are those that are largely restricted to this species. pRUM plasmids in E. faecium result in gentamicin and streptomycin resistance because these are similar to pheromone-responsive plasmids in E. faecalis in that antibiotics are used for synergistic therapy of serious enterococcal they transfer at a high frequency but exhibit a narrow host range. infections. In contrast, broad host range plasmids are capable of High-level gentamicin resistance most frequently occurs through transferring genetic information to other gram-positive and even acquisition of a bifunctional gene encoding APH(2'')-Ia-AAC(6')- 30 27 45 gram-negative species, but at a lower frequency (10 /donor cell Ie. These enzymes inactivate gentamicin (and structurally related during 4 h of mating) than pheromone-responsive plasmids. aminoglycosides) by phosphorylation at the 2'hydroxy position of Transfer of these plasmids requires close contact between cells. gentamicin and simultaneous acetylation of the 6'hydroxy position 46,47 Inc.18-type plasmids are well-known broad host range plasmids of the other aminoglycosides. The modified antibiotic is no that have been implicated in the transfer of vancomycin resistance longer capable of binding to its target on the 30S ribosomal subunit determinants to S. aureus in recent years. and thereby loses antibacterial activity. Strains that contain aph(2'')- Three types of transposons are responsible for most gene Ia-aac(6')-Ie are clinically resistant to all aminoglycosides except for mobility in enterococci, Tn3 family transposons, composite streptomycin. The aph(2'')-Ia-aac(6')-Ie gene is most commonly transposons, and conjugative transposons. The prototypical Tn3 flanked by IS256 in a composite transposon designated Tn4001 in family transposons are Tn917 [conferring macrolide, lincosamide S. aureus and Tn5281 in E. faecalis. and streptogramin resistance (MLS )] and Tn1546 (conferring Several other genes have been identified that confer gentamicin B B 49–51 glycopeptide resistance), whereas the prototypical conjugative resistance, including aph(2'')-Ic, aph(2'')-Id and aph(2'')-Ib. In transposon is Tn916, which confers resistance to minocycline and comparison with aph(2'')-Ia-aac(6')-1e, these genes are minor tetracycline. Composite transposons can readily be formed by contributors to gentamicin resistance in enterococci. Their the interaction of related IS elements that are liberally sprinkled prevalence varies by geographical region. Importantly, MICs for throughout the genome of most clinical enterococcal strains. The enterococci harboring aph(2'')-Ic may be as low as 256 mg/ml, an movement of these IS elements not only confers mobility to MIC which would be interpreted as gentamicin-susceptible by resistance genes, but it promotes cointegration of plasmids with labs that use an MIC of 500 mg/ml as a cut-off to determine high- other plasmids and with the bacterial chromosome. level gentamicin resistance. Despite the lower MIC, bacteria β-lactams. Enterococci may develop increased resistance to expressing these enzymes are resistant to the synergistic activity of penicillins through acquisition of β-lactamases or PBP4/5 cell wall active agents and gentamicin. Thus, in geographical mutations. Plasmid-mediated bla genes (encoding β-lactamases) area where aph(2'')-Ic is present, laboratories should be alerted to were first described in E. faecalis in 1983. Since that time, lower the threshold MIC for gentamicin to enhance detection of enterococcal β-lactamase production has been rare and described enterococci that would be resistant to synergy. predominantly in E. faecalis. The bla genes in enterococcus are High-level resistance to streptomycin occurs most commonly identical to those in S. aureus and are often encoded by remnants through enzymatic modification of the antibiotic or by single of staphylococcal β-lactamase transposon Tn552. point mutations to the ribosome. Two well-described adenylyl- High-level penicillin resistance in E. faecium is most commonly transferases, Ant(6')-Ia and Ant(3'')-Ia, are capable of inactivating 48,52 associated with accumulation of point mutations in the penicillin streptomycin (and structurally related aminoglycosides). binding region of PBP5. A variety of point mutations have been Enterococci can also develop ribosomal mutations that result in 36,37 38 described in both E. faecium and E. faecalis. Although these streptomycin resistance. Whereas resistance caused by aminogly- point mutations likely originated de novo in individual bacteria coside-modifying enzymes (AME) will typically have MICs in the under selective pressure from antibiotics, chromosome-to-chro- 4,000 to 16,000 mg/ml range, ribosomal mutations result in mosome transfer of low affinity pbp5 genes has been documented MICs of 128,000 mg/ml. in vitro and likely contributes to the dissemination of high-level Other acquired AMEs have been identified in enterococci, penicillin resistance in E. faecium. including Aph(3')-IIIa, an aminoglycoside phosphotransferase Ceftaroline and ceftobiprole, fifth generation cephalosporins, that confers resistance to kanamycin and Ant(4'')-Ia, a have activity against enterococcus, but may be prone to emergence nucleotidyltransferase that confers resistance to tobramycin, 40 55 of resistance with increased clinical use. Clark et al. subjected amikacin, neomycin and kanamycin. As these enzymes do not E. faecalis to serial passages of ceftaroline and identified two confer gentamicin or streptomycin resistance, they are of less resistant isolates (one with an MIC of 8 mg/ml and the other with clinical significance. 424 Virulence Volume 3 Issue 5 Glycopeptides. The acquisition of glycopeptide resistance by to D-lac. Host enzymes ligate D-ala-D-lac to the tripeptide enterococci has been an epidemiological and antimicrobial precursor, yielding the low affinity pentapeptide precursor. Full dilemma for the past 25 years. First described in 1988, resistance to glycopeptides, however, requires not only construc- glycopeptide-resistant enterococci (GRE) have since emerged as tion of the altered precursor, but also elimination of normal 33,57,58 a major cause of nosocomial infections. The majority of GRE precursors. VanX hydrolyzes D-ala-D-ala to its constituent infections are attributed to E. faecium, although glycopeptide amino acids, which allows D-ala-D-lac to be the sole substrate for resistance occurs in E. faecalis and other enterococcus species as cell wall synthesis. VanY hydrolyzes the terminal D-ala from any well. Currently in the United States, an estimated 30% of clinical normal pentapeptide precursor, rendering it useless for normal cell 56 60 enterococcus isolates are resistant to glycopeptides. wall construction. The mechanism by which VanZ augments Vancomycin acts by binding to the D-ala-D-ala terminus of the resistance is unknown, but when present it confers decreased pentapeptide precursor, thereby inhibiting cell wall synthesis. susceptibility to teicoplanin. Additional open reading frames Glycopeptide-resistant organisms modify these pentapeptide VanW and VanV have been described on the VanB operon; their precursors, replacing the terminal D-ala with D-lac or D-ser. functions also are not yet known. These modified cell wall precursors bind glycopeptides with Expression of the genes for VanA, H, X, Y and Z are all 1,000-fold lower affinity than do normal precursors. To create the regulated by VanR and VanS, a two-component sensor-transducer modified precursors at least seven enzymes are required. Using the system that is part of the VanA operon within Tn1546. While the VanA cassette as a model, these enzymes are VanA, H, X, Y, Z, R specific regulatory factors are not known, the presence of and S (Fig. 1). Initially, cellular pyruvate is converted to d-lactate glycopeptides in the environment results in activation of VanS by the VanH dehydrogenase. The VanA ligase then ligates D-ala through autophosphorylation. Activated VanS then phosphorylates Figure 1. An illustration of the VanA resistance mechanism as it relates to normal cell wall synthesis. The top pathway denotes normal cell wall synthesis, and the mechanisms by which VanX and VanY disrupt this pathway. The shaded pathway denotes construction of a modified cell wall that is resistant to vancomycin. Adapted from Gold et al. www.landesbioscience.com Virulence 425 VanR. Phosphorylated VanR increases VanH, A, X, Y and Z The complex enzymatic pathways that confer glycopeptide transcription through interaction with specific promoter regions. resistance predate the emergence of GRE in the late 1980s. VanR also interacts with its own promoter region, augmenting E. gallinarum and E. casseliflavus exhibit innate low-level resistance 63 75 VanR and VanS transcription. Clinical strains that harbor the through a chromosomally-encoded VanC operon and have been VanA operon but contain deletions in VanR and VanS genes have implicated as a source of the genes seen in other Van 76,77 been isolated and are susceptible to both vancomycin and phenotypes. Additionally, a number of soil and bowel teicoplanin. This suggests that VanR activity is required for the organisms have been identified as harboring VanB genes and 64,65 full expression of the VanA operon. may have played a role in the transfer of glycopeptide-resistance 78-82 VanA and VanB operons are by far the most prevalent in genes to E. faecium. Enterococci are increasingly recognized as human GRE infections. In the VanA phenotype, the enterococcus belonging to two distinct clades, one that predominates in the is resistant to both vancomycin and teicoplanin. In the VanB hospital environment and another within the community. These phenotype, vancomycin but not teicoplanin induces resistance clades differ genetically, and may have diverged between 300,000 resulting in a vancomycin resistant, teicoplanin-susceptible to a million years ago. The nosocomial clade has acquired phenotype; however, constitutive expression (which may be virulence and resistance determinants that confer a selective selected by teicoplanin exposure) results in resistance to both advantage in this setting. Acquisition of the VanA cassette in the compounds. VanC resistance is intrinsic to E. gallinarum and late 1980s likely conferred further advantage that contributed to E. casseliflavus. A total of nine resistance operons have been the observed increase in prevalence of infections due to E. faecium. described. They may be grouped by their ligase activity. Operons Streptogramins. The streptogramin B/A combination quinu- that encode D-lac ligases result in high-level resistance with MICs pristin-dalfopristin is one of two antibiotics approved by the FDA . 256 mg/ml (VanA, VanB, VanD and VanM) while operons for treatment of infections caused by vancomycin-resistant that encode D-ser ligases result in low-level resistance with MICs E. faecium. Because E. faecalis are intrinsically resistance to 31,66–69 8–16 mg/ml (VanC, VanE, VanG, VanL and VanN). Of streptogramins, the majority of genes that confer horizontally- the low-level resistance phenotypes, only VanN has been shown transferable resistance have been isolated from E. faecium. to be transferable. Between 1 to 12% of E. faecium isolates are resistant to 84,85 Horizontal transfer of the Van genes occurs through a variety of streptogramins. There are three mechanisms by which mechanisms. VanA is mobilized on Tn3-family transposon acquired genetic elements cause streptogramin resistance: acetyla- Tn1546.Tn1546 is found on both non-conjugative and tion of the antibiotic, efflux of the antibiotic, and dimethylation conjugative plasmids. Inc.18 plasmids are broad host range of the 23S rRNA target site. To date, 12 genes that cause plasmids that have been implicated in the transfer of the VanA streptogramin resistance have been described in enterococci, operon to methicillin-resistant S. aureus. Vancomycin-resistant although additional genes have been described in staphylococci S. aureus (VRSA) has been found in clinical settings in a handful and streptococci. of cases. Werner et al. demonstrated in vitro that interspecies The widespread use of virginamycin, a veterinary streptogramin transfer of Tn1546 is relatively uncommon compared with A compound, was associated with extensive resistance among intraspecies transfer. It appears that while broad host-range enterococci isolated from farm animals and agricultural sewage. plasmids can transfer between species, their stability within Consequently, quinupristin-dalfopristin resistance is most com- different species varies. As such, broad host range plasmids mon in environmental samples, although the prevalence in containing an intact copy of Tn1546 may transfer resistance to nosocomial infections with resistance is increasing. Enzymatic staphylococci more stably, since the transposon can transfer to acetylation of streptogramin A compounds was the first resistance replicons within the staphylococcal strain that are stable. mechanism described in the class. Virginamycin acetyltransferase Staphylococcal variants that have acquired broad host range genes vatD, vatE and vatH are among the streptogramin resistance plasmids with Tn1546 variants that have lost their ability to genes with probable veterinary origins. vatD and vatE (formerly transfer through deletion of or insertion into the transposition called satG) have been isolated from plasmids alongside erm and genes will exhibit an unstable phenotype due to the instability of vgbA genes (described below) that reduce susceptibility to the plasmid in the staphylococcal milieu. Additionally, in vitro streptogramin B—thus providing full resistance to quinupristin- 86–89 studies demonstrating transfer of Tn1546 from enterococcus to dalfopristin. One plasmid has been identified with both vatD 72,73 90 S. aureus have occurred in E. faecalis. Sequence homology has and the VanA operon, resulting in resistance to both been observed between plasmids found in VRSA isolates and vancomycin and quinupristin (but not dalfopristin) when GRE isolates taken from VRSA infected patients, with the most expressed in recipient cells in vitro. VatH may be seen in overlap occurring with E. faecalis isolates. Compared with conjunction with another streptogramin acetyltransferase, VgbA, E. faecium, VanA-containing E. faecalis are relatively uncommon the only known acetyltransferase with activity against strepto- in the clinical setting. If E. faecalis is a more effective (but less gramin B in enterococci. All of the above acetyltransferase genes common) donor than E. faecium, then this may help to explain have been isolated exclusively from E. faecium, with the exception why VanA in staphylococci is rare. VanB is most often carried on of vatE which has been isolated from E. faecium and from a carried on Tn5382/1549 or related conjugative transposons. E. faecalis in a veterinary setting. VanB carrying transposons have been identified in pheromone- The ABC-efflux channel VgaD also plays a role in acquired 30,31 sensitive and conjugative plasmids. streptogramin resistance, independent of the intrinsic ABC-efflux 426 Virulence Volume 3 Issue 5 channels encoded by lsa genes in E. faecalis and msrC gene in was the first enterococcus harboring cfr to be reported in the E. faecium (described above). VgaD has been described only in literature, although human isolates of E. faecalis and E. faecium E. faecium. vgaD was found on a plasmid with vatH, both of with cfr were reported in a 2010 abstract. Overall, linezolid which confer only streptogramin A resistance. To date, no other resistance remains rare in enterococci. acquired streptogramin efflux pumps have been described. Daptomycin. Daptomycin is a lipoprotein with bactericidal Perhaps the best understood mechanism of streptogramin activity against enterococci. While not FDA approved for resistance is dimethylation of the 23S rRNA. This resistance treatment of GRE, it is often used by clinicians for this 104-106 mechanism, which confers the MLS or MLS phenotype occurs purpose. The epidemiology of daptomycin resistance in A B through acquisition of either the ermA or ermB genes on broad enterococcus (defined as MIC . 4 mg/ml) was recently reviewed host range plasmids such as pAMβ1. If these plasmids also contain by Kelesidis et al. Rates of daptomycin resistance in this study vatE or vatD genes, then they confer resistance to quinupristin- were approximately 0.6% (111 daptomycin resistant isolates/ dalfopristin when acquired by a recipient cell. 17,084 enterococcus isolates total). In general, E. faecium is more Linezolid. Prior to FDA approval in 2000, reports of linezolid likely than E. faecalis to express daptomycin resistance, although resistance in enterococci existed but were rare. The emergence of resistance has been reported in both species. The increased linezolid resistance occurred slowly and only in sporadic cases prevalence of daptomyicin resistance in E. faecium may reflect associated with prolonged exposure. The industry-sponsored increased use of daptomycin with this species compared with LEADER trial has monitored linezolid efficacy from 2004 to E. faecalis, which is usually susceptible to penicillins. Daptomycin 2009 and has found yearly resistance rates between 0.49 and resistance appears to be less common in North America than in 56 94 107 1.83%. In contrast, Pogue et al. found linezolid resistance in Asia or Europe. 20% of GRE samples from the University of Pittsburgh Medical Daptomycin incorporates itself into the cell membrane of Center. Only 25% of isolates in their study were associated with Gram-positive organisms in the presence of physiologic calcium prior linezolid exposure, suggesting clonal spread. concentrations and promotes leakage of intracellular potassium Linezolid is a first-in-class oxazolidinone, an entirely synthetic into the extracellular space, resulting in cell death by destruction 108-110 class of antibiotics that binds to the initiation complex and of the transcellular potassium gradient. Normal cell inhibits protein synthesis. Most bacteria, including the enter- membrane polarity is required for daptomycin intercalation. In ococci, have multiple copies of the genes encoding 23S rRNA. staphylococci, alteration of the cell membrane charge by virtue of E. faecalis have four copies of the gene and E. faecium six modification of cell membrane lipoproteins has been associated 96 111 copies. with reduced daptomycin susceptibility. In theory, the presence of multiple gene copies makes A number of genes resistance from sporadic mutations less likely because the have been described in staphylococci that contribute to unaffected gene copies would mask the effect of the mutated daptomycin resistance, none of which have been identified in gene. However, recombination between susceptible and resistant enterococcus to date. While the mechanism of daptomycin copies (referred to as “gene conversion”) will yield strains with resistance in enterococcus remains unresolved, several reports have multiple mutated copies under persistent linezolid selective elucidated gene mutations associated with enterococcus dapto- 113,114 pressure. In clinical isolates, a mutation in one E. faecium mycin resistance. rRNA gene conferred an MIC of 8–16 mg/ml. The same mutation Palmer et al. created three daptomycin-resistant strains by in . 3 rRNA genes conferred an MIC between 64–128 mg/ml. exposing E. faecalis to increasing daptomycin concentrations until A variety of point mutations that confer linezolid resistance have stable resistance was identified. They then performed complete been identified, the most common of which is G2576T. In the genome sequencing of the strains before and after emergence of most recent LEADER study results (2009), the G2576T daptomycin resistance and identified seven gene mutations. Of mutation was identified in all eight of the linezolid-resistant the seven mutations observed in this study, only EF1797 and enterococci strains isolated in the United States. Four of the eight EF0631 gene mutations were identified in all three resistant strains found in this study were isolated in Louisville, KY and strains. EF1797 encodes a putative membrane protein that may 56,97 appeared clonally related. Other sporadic point mutations be involved in phosphatidylserine and sphingolipid synthesis, but have been associated with linezolid resistance, including G2505A its function has yet to be determined. EF0631 encodes a putative 98-100 and L4 (F101L). cardiolipin sythetase (cls), a transphosphatidylase involved in the In 2006, the transferable cfr gene was identified in S. aureus as synthesis of the cell membrane protein cardiolipin. One specific the source of resistance to linezolid, lincosamides and strepto- mutation in this gene, R218Q, was found in two of the resistant gramin A compounds, among others. Cfr encodes an rRNA strains and occurs in the presumed active domain of the EF0631 methyltransferase that modifies an adenosine in the linezolid- enzyme. Through comparison with a DNA sequence database, binding region on the 23S rRNA, preventing antibiotic binding. the authors identified one other E. faecalis strain with an EF0631 It is hypothesized that the cfr gene emerged from animal strains of frameshift mutation, but this isolate had a daptomycin-susceptible bacteria that were exposed to natural compounds with an rRNA phenotype. 101,102 114 binding site similar to linezolid. In 2011, cfr was identified In a similar study, Arias et al. compared the nucleotide in an E. faecalis strain (designated EF-01) from a cattle farm in sequence and cell membrane proteins of E. faecalis isolates before China. In this strain, the gene was located on a plasmid and after the development of daptomycin resistance in a patient (pEF-01) and flanked by IS1216, suggesting transposability. This with enterococcus bacteremia. Genome sequencing of the www.landesbioscience.com Virulence 427 resistant strain revealed three mutated genes: cls, gdpD and liaF.A In uncomplicated, fully susceptible E. faecalis and E. faecium cardiolipin synthetase mutation was identified but when the infections, ampicillin remains the preferred therapy. In the mutant gene was placed in daptomycin-sensitive enterococcus uncommon presence of β-lactamase, combination with a strain the MIC did not change. The same cls mutation was β-lactamase inhibitor such as sulbactam may improve outcomes. observed in other E. faecalis and E. faecium strains resistant to When complicated infections such as endocarditis occur in daptomycin. The other two gene mutations, gdpD (glyceropho- susceptible enterococcal infections, an aminoglycoside should be sphoryl diester phosphodiesterase) and liaF (lipid II cycle- added to a cell wall active agent for synergistic killing, as has been interfering antibiotic protein), did have an impact on MICs the standard for almost 60 years. Among aminoglycosides, only when reconstituted in the daptomycin-susceptible strain. The liaF gentamicin and streptomycin should be considered for synergistic mutation increased the MIC from 1 to 4 mg/ml. The gdpD therapy. Historically, twice-daily or three times daily aminoglyco- mutation did not increase the MIC, but the combination of both side dosing regimens have been used. In streptococcus infections, proteins increased the MIC to 12 mg/ml. Mutations in both gdpD once-daily aminoglycoside dosing was shown to be effective in and liaF were also identified in other resistant strains of E. faecalis humans. For enterococcal endocarditis, though, once-daily and E. faecium, but were not demonstrated in the Palmer study. aminoglycoside dosing has only been studied in animal models 122–124 125,126 Thus, cardiolipin synthetase, GdpD and LiaF are cell membrane with evidence for and against its use. Differences proteins associated with daptomycin resistance. Given that a between these studies likely reflect the pharmacodynamic and number of different membrane-associated proteins have been pharmacokinetic differences between the animal models. In linked to reduced daptomycin susceptibility in staphylococci, it humans, the efficacy of once-daily aminoglycoside dosing has seems likely that more genes conferring enterococcal resistance to not been established for enterococcus infections. As such, daptomycin will be identified in the future. guidelines continue to recommend three times daily dosing for Tigecycline. Tigecycline, a novel glycylcycline antibiotic, gained gentamicin and twice-daily dosing for streptomycin. In the FDA approval in 2005 for complicated intra-abdominal infections, presence of high-level penicillin resistance, synergy has been skin and soft tissue infections, and community-acquired pneu- observed in animal models with the combination of aminoglyco- monia. It has been used off-label to successfully treat MRSA and sides and other cell wall active antibiotics including vancomycin 115 128 GRE infections. Typical tigecycline MICs for enterococcus range or daptomycin. from 0.125 mg/ml to 0.25 mg/ml, while MICs . 0.5 mg/ml are In the instance of complicated enterococcal infections resistant considered resistant. Early surveillance studies of tigecycline showed to high-levels of gentamicin and streptomycin, an alternative no cases of resistant enterococcus, agent must be used for synergistic activity. Despite relative although two case reports of E. faecalis strains with MICs of 2 mg/ml and 6 mg/ml, respectively, resistance to both agents, the combination of ceftriaxone and 117,118 129 have been described. A more recent study from Taiwan ampicillin has been shown to be efficacious in animals. In case reviewed antimicrobial resistance among 219 VRE isolates and reports and prospective case-series, 56 patients have been treated 130-132 found two isolates with a tigecycline MIC of 0.5, and one isolate with this combination with success rate of 71.4% (40/56); with an MIC of 1, with a trend toward increasing tigecycline MIC although these numbers may reflect publication bias. The over time. The mechanism of tigecycline resistance in presumed benefit of ceftriaxone-ampicillin combination therapy enterococcus is unknown. In staphylococcus, tigecycline resistance is attributed to full saturation of PBPs 2–4, which cannot be is mediated by a novel family of efflux pumps, but these genes achieved with either agent alone. By inhibiting all PBPs, the have not been demonstrated in enterococcus. bacteria have no alternative enzyme with which to build a cell Other antibiotics. Resistance occurs to other antibiotics wall. In in vitro and animal model studies, similar synergistic including macrolides, tetracyclines, chloramphenicol, fosfomycin, bactericidal activity has been shown with other cell wall active rifampin and quinolones. These resistance mechanisms will not be combination therapies, including ceftriaxone-fosfomycin and 134 135 described in this review, as resistance to these antimicrobial agents ampicillin-imipenem, but not with ampicillin-ertapenem. is so common that they are seldom involved in treatment of Treatment of glycopeptide-resistant enterococcus. Vancomycin- enterococcus infections. resistant enterococci pose particular problems for treatment because the strains which harbor VanA and VanB resistance are also typically Management resistant to other classes of antibiotics. While only linezolid and quinupristin-dalfopristin have FDA approval for treatment of GRE Because of the differences in resistance patterns between infections, other antimicrobial agents including daptomycin, E. faecium and E. faecalis, it is imperative to differentiate the tigecycline, fosfomycin, quinolones, tetracyclines and new fifth pathogen to the species level and perform susceptibility testing on generation cephalosporins exhibit in vitro activity and have been strains isolated from patients with clinical infections. Treatment of used with success in individual cases. In uncomplicated cases, enterococcal infections depends upon (1) the species, (2) the monotherapy based upon the antibiotic susceptibility profile is resistance patterns present in the clinical isolate and (3) the appropriate. In complicated cases such as endocarditis, the ideal location and severity of the infection. Uncomplicated enterococcal therapy for GRE has not been determined. infections may be adequately treated with monotherapy, whereas Both linezolid and quinupristin-dalfopristin have been shown severe infections such as endocarditis benefit from a synergistic to be efficacious in treatment of complicated GRE infections and 56,136 regimen. are FDA approved for this indication. Linezolid has been 428 Virulence Volume 3 Issue 5 used for GRE endocarditis in both E. faecalis and E. faecium, both other empirical regimens, there were significantly more adverse with and without additional agents. To date, it has not been events and a non-significant trend toward higher mortality. As shown that combination therapy is more efficacious than such, tigecycline monotherapy should not be considered as first monotherapy in this setting. Because linezolid is not bactericidal, line for treatment of GRE infections. Tigecycline demonstrates in treatment of GRE endocarditis with linezolid remains controver- vitro synergism with a number of other agents, including rifampin sial. Quinupristin-dalfopristin can be efficacious against and daptomycin, although these combinations have not been E. faecium, but should not be used to treat E. faecalis due to evaluated beyond small case series in humans. the intrinsic presence of lsa-mediated resistance (described above). When using quinupristin-dalfopristin for treatment of severe or Future Directions complicated GRE infections, combination therapy may be necessary although the optimal choice and dose of adjunct Over the years enterococci have demonstrated the potential to antibiotic has yet to be determined. Several studies have compared harbor and transfer resistance genes and as such have become an linezolid to quinupristin-dalfopristin. In a small, single-center important clinical pathogen. A better understanding of resistance study, Chong et al. found increased resistance and increased mechanisms to daptomycin and tigecycline is needed and will aid number of days of bacteremia in patients treated with in the prediction and prevention of epidemiologic spread. Several quinupristin-dalfopristin. Several other studies also reported more new drugs are emerging as potential options for GRE treatment. 56,138 resistance to quinupristin-dalfopristin than linezolid, suggest- Ceftaroline has been shown to be more efficacious than linezolid ing that of the two linezolid may be superior for GRE treatment. in animals and may play a larger role in the future. Use of daptomycin for GRE infections, particularly endocard- Additionally, arbekacin, which is not currently available in the itis, is appealing because of its bactericidal activity against United States, has demonstrated synergistic killing in combina- enterococci. While monotherapy may be adequate in many tion with penicillins even in the presence of high-level gentamicin 106,139 146 GRE infections, daptomycin failure has been reported. Arias and streptomycin resistance. A number of antibiotic combina- et al. reported subsequent response to the combination of tions, including those mentioned in the management section, daptomycin/gentamicin/ampicillin after failing daptomycin have shown in vitro synergistic activity and are promising as monotherapy, which may be explained by a synergistic effect of potential treatment modalities for complicated GRE infections, the triple therapy. Daptomycin synergy has been described in but must first be evaluated more rigorously in humans. The novel vitro with ampicillin, cephalosporins, imipenem, rifampin and glycopeptide oritavancin is currently under investigation and 140-143 gentamicin. shows promise in treating GRE infections. In addition, non- As with quinupristin-dalfopristin, there may be a role for adjunct antibiotics to achieve a synergistic effect, antimicrobial pharmacotherapy targeted at specific virulence although appropriate agents and dosing regimens have not been factors (such as anti-adhesions) may play a preventative or adequately evaluated in humans. therapeutic role in the management of enterococcal infections. Tigecycline has also been used off-label for treatment of GRE. Future directions of research must focus on development of new Cai et al. performed a meta-analysis of randomized trials to antimicrobial agents. Finally, efforts must continue to prevent evaluate the use of tigecycline for GRE infections. 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The efficacy and safety of quinupristin/ gentamicin or beta-lactam antibiotics against faecalis native-valve endocarditis and in vitro data on dalfopristin for the treatment of infections caused by Staphylococcus aureus and Enterococci by FIC index double beta-lactam activity. Scand J Infect Dis 2008; vancomycin-resistant Enterococcus faecium. J and timed-kill curves. J Chemother 2005; 17:614-21; 40:968-72; PMID:18767002; http://dx.doi.org/10. Antimicrob Chemother 1999; 44:251-61; PMID: PMID:16433191 1080/00365540802398945 10473233; http://dx.doi.org/10.1093/jac/44.2.251 143. Pankey G, Ashcraft D, Patel N. In vitro synergy of 131. Euba G, Lora-Tamayo J, Murillo O, Pedrero S, Cabo 137. Chong YP, Lee SO, Song EH, Lee EJ, Jang EY, Kim SH, daptomycin plus rifampin against Enterococcus fae- J, Verdaguer R, et al. Pilot study of ampicillin- et al. 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Journal

VirulenceTaylor & Francis

Published: Aug 15, 2012

Keywords: enterococcus; antibiotic resistance; review; treatment

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