VanR. Phosphorylated VanR increases VanH, A, X, Y and Z transcription through interaction with specific promoter regions. VanR also interacts with its own promoter region, augmenting VanR and VanS transcription.63 Clinical strains that harbor the VanA operon but contain deletions in VanR and VanS genes have been isolated and are susceptible to both vancomycin and teicoplanin. This suggests that VanR activity is required for the full expression of the VanA operon.64,65 VanA and VanB operons are by far the most prevalent in human GRE infections. In the VanA phenotype, the enterococcus is resistant to both vancomycin and teicoplanin. In the VanB phenotype, vancomycin but not teicoplanin induces resistance resulting in a vancomycin resistant, teicoplanin-susceptible phenotype; however, constitutive expression (which may be selected by teicoplanin exposure) results in resistance to both compounds. VanC resistance is intrinsic to E. gallinarum and E. casseliflavus. A total of nine resistance operons have been described. They may be grouped by their ligase activity. Operons that encode D-lac ligases result in high-level resistance with MICs . 256 mg/ml (VanA, VanB, VanD and VanM) while operons that encode D-ser ligases result in low-level resistance with MICs 8–16 mg/ml (VanC, VanE, VanG, VanL and VanN).31,66–69 Of the low-level resistance phenotypes, only VanN has been shown to be transferable. Horizontal transfer of the Van genes occurs through a variety of mechanisms. VanA is mobilized on Tn3-family transposon Tn1546. Tn1546 is found on both non-conjugative and conjugative plasmids. Inc.18 plasmids are broad host range plasmids that have been implicated in the transfer of the VanA operon to methicillin-resistant S. aureus.33 Vancomycin-resistant S. aureus (VRSA) has been found in clinical settings in a handful of cases. Werner et al.70 demonstrated in vitro that interspecies transfer of Tn1546 is relatively uncommon compared with intraspecies transfer. It appears that while broad host-range plasmids can transfer between species, their stability within different species varies. As such, broad host range plasmids containing an intact copy of Tn1546 may transfer resistance to staphylococci more stably, since the transposon can transfer to replicons within the staphylococcal strain that are stable. Staphylococcal variants that have acquired broad host range plasmids with Tn1546 variants that have lost their ability to transfer through deletion of or insertion into the transposition genes will exhibit an unstable phenotype due to the instability of the plasmid in the staphylococcal milieu.71 Additionally, in vitro studies demonstrating transfer of Tn1546 from enterococcus to S. aureus have occurred in E. faecalis.72,73 Sequence homology has been observed between plasmids found in VRSA isolates and GRE isolates taken from VRSA infected patients, with the most overlap occurring with E. faecalis isolates.74 Compared with E. faecium, VanA-containing E. faecalis are relatively uncommon in the clinical setting. If E. faecalis is a more effective (but less common) donor than E. faecium, then this may help to explain why VanA in staphylococci is rare. VanB is most often carried on a carried on Tn5382/1549 or related conjugative transposons. VanB carrying transposons have been identified in pheromone- sensitive and conjugative plasmids.30,31 The complex enzymatic pathways that confer glycopeptide resistance predate the emergence of GRE in the late 1980s. E. gallinarum and E. casseliflavus exhibit innate low-level resistance through a chromosomally-encoded VanC operon75 and have been implicated as a source of the genes seen in other Van phenotypes.76,77 Additionally, a number of soil and bowel organisms have been identified as harboring VanB genes and may have played a role in the transfer of glycopeptide-resistance genes to E. faecium.78-82 Enterococci are increasingly recognized as belonging to two distinct clades, one that predominates in the hospital environment and another within the community. These clades differ genetically, and may have diverged between 300,000 to a million years ago.83 The nosocomial clade has acquired virulence and resistance determinants that confer a selective advantage in this setting. Acquisition of the VanA cassette in the late 1980s likely conferred further advantage that contributed to the observed increase in prevalence of infections due to E. faecium. Streptogramins. The streptogramin B/A combination quinu- pristin-dalfopristin is one of two antibiotics approved by the FDA for treatment of infections caused by vancomycin-resistant E. faecium. Because E. faecalis are intrinsically resistance to streptogramins, the majority of genes that confer horizontally- transferable resistance have been isolated from E. faecium. Between 1 to 12% of E. faecium isolates are resistant to streptogramins.84,85 There are three mechanisms by which acquired genetic elements cause streptogramin resistance: acetyla- tion of the antibiotic, efflux of the antibiotic, and dimethylation of the 23S rRNA target site. To date, 12 genes that cause streptogramin resistance have been described in enterococci, although additional genes have been described in staphylococci and streptococci. The widespread use of virginamycin, a veterinary streptogramin A compound, was associated with extensive resistance among enterococci isolated from farm animals and agricultural sewage. Consequently, quinupristin-dalfopristin resistance is most com- mon in environmental samples, although the prevalence in nosocomial infections with resistance is increasing.84 Enzymatic acetylation of streptogramin A compounds was the first resistance mechanism described in the class. Virginamycin acetyltransferase genes vatD, vatE and vatH are among the streptogramin resistance genes with probable veterinary origins. vatD and vatE (formerly called satG) have been isolated from plasmids alongside erm and vgbA genes (described below) that reduce susceptibility to streptogramin B—thus providing full resistance to quinupristin- dalfopristin.86–89 One plasmid has been identified with both vatD and the VanA operon,90 resulting in resistance to both vancomycin and quinupristin (but not dalfopristin) when expressed in recipient cells in vitro. VatH may be seen in conjunction with another streptogramin acetyltransferase, VgbA, the only known acetyltransferase with activity against strepto- gramin B in enterococci.88 All of the above acetyltransferase genes have been isolated exclusively from E. faecium, with the exception of vatE which has been isolated from E. faecium and from E. faecalis in a veterinary setting.91 The ABC-efflux channel VgaD also plays a role in acquired streptogramin resistance, independent of the intrinsic ABC-efflux 426 Virulence Volume 3 Issue 5