Enterococcus species

MICROBIOLOGY

Enterococcus species are gram-positive, facultative anaerobic cocci that are morphologically similar to streptococci on Gram stain (181). The normal habitat of these microorganisms is the gastrointestinal tract of human and other mammals, although they can be isolated from the oropharynx, female genital tract, and skin. Most recently, 36 species of enterococci have been described, however 26 have been associated with human infection (65, 87, 225). Enterococcus faecalis is the most common human pathogen, but Enterococcus faecium has become increasingly prevalent in hospital-acquired infections. All the other enterococcal species together constitute less than 5% of enterococcal infections (87,225). These other species associated with human infections include Enterococcus gallinarum, Enterococcus casseliflavus, Enterococcus avium, Enterococcus cecorum, Enterococcus durans, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium and Enterococcus raffinosus (49, 65, 87, 95,110,163, 203, 208,270).

EPIDEMIOLOGY

Enterococci are not as virulent as other gram-positive cocci and often occur as a component of a polymicrobial infection in debilitated hosts. Their increasing resistance to antimicrobial agents has led to their emergence as superinfecting nosocomial pathogens in patients receiving broad spectrum antibiotic therapy (79, 272, 286).

Vancomycin resistant enterococci (VRE) occur in both acute and long term care settings. When first introduced into a facility, an outbreak of VRE infection may occur. In acute outbreaks, the VRE isolates typically represent a single clone, or a limited number of clones, as identified by pulsed-field gel electrophoretic analysis of bacterial DNA (27, 66). After endemicity has become established, multiple clones of VRE are usually present (173, 176). A meta-analysis has reported that vancomycin resistance is an independent risk factor for mortality in patients with enterococcal bacteremia (51).

Patients with asymptomatic colonization of the gastrointestinal tract by VRE exceed those with clinically recognized infection by a ratio of 10:1 or greater (27). Thus, there is a potentially large reservoir of patients harboring VRE who may be the source of transmission to other patients. Unless these colonized patients are identified by appropriate surveillance procedures, they can continue to serve as reservoirs of VRE.

Risk factors for acquisition of or infection with VRE include admission to a critical care unit, severity of illness, exposure to other patients with VRE, duration of hospitalization, and exposure to antimicrobials (35, 58, 101,176, 263,272, 283). Antimicrobials exposures epidemiologically linked to VRE acquisition include vancomycin, cephalosporins, quinolones and agents with anti-anaerobic activity (29, 58, 76, 79,100,101,148,173, 201, 248). Receipt of the latter group of agents leads to a marked increase in stool density of VRE as well (53, 57,249). It should be noted that a meta-analysis concluded that many prior studies finding an association between receipt of vancomycin and VRE suffered from a number of flaws including selection of an inappropriate control group and failure to control for duration of hospitalization (30, 100). When these factors were taken into account, the association between VRE acquisition and antecedent vancomycin exposure was not statistically significant in this study.

Evidence is clear that with the consumption of antimicrobial agents that lack activity in vitro to enterococci administered to humans and food animals there is an association with an increase in antimicrobial resistance to that agent. Evidence suggests a relationship between streptogramin, aminoglycoside and glycopeptide resistance genes between humans and animals (56, 104, 105, 112). The degree of risk to humans related to the administration to animals of antimicrobial agents remains very controversial (112).

CLINICAL MANIFESTATION

Urinary tract infections and bacteremia are among the most common manifestations of enterococcal infection. Endocarditis is the most serious infection caused by enterococci, although it consists of only about 3% of enterococcal bacteremias (273). Enterococci are also commonly found in intraabdominal, pelvic, wound, and soft tissue infections, but in these cases they are often part of a mixed infection due to aerobic and anaerobic bacteria. Much less common are enterococcal meningitis, osteomyelitis, and septic arthritis.

LABORATORY DIAGNOSIS

Enterococci are readily and quickly identified in the clinical microbiology laboratory. On gram stainthey appear as gram-positive cocci in pairs and short chains. On blood agar plates they appear as grey colonies and are usually alpha-hemolytic. A rapid biochemical test can rapidly identify colonies of enterococci within minutes based on the ability of almost all enterococcal species to hydrolyze pyrrolidonyl-beta-naphthylamide (PYR). As all enterococci produce leucine aminopeptidase, this test is used on some rapid streptococcal identification panels. Other older tests that are used less frequently include the bile-esculin test, growth on broth containing 6.5% NaCl and ability to grow at both 10oC and 45oC. For identification of newer species of enterococci, a combination of conventional biochemical tests, and evaluation of DNA content is needed.

PATHOGENESIS

Enterococci are less virulent than many other bacteria that cause infections in humans. Some E. faecalis factors such as cytolysin (“hemolysin”), aggregation substance, gelatinase, serine protease, enterococcal surface protein, Ace protein, and enterococcal polysaccharide antigen, which have been associated with virulence in vitro and in animal models (85, 273). Some of these traits may play a pathogenic role in certain human infections, but this has not yet been proven conclusively.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Enterococci are relatively resistant to many antibiotics that are active against gram positive cocci including cephalosporins, macrolides, and clindamycin. Antibiotics with varying degrees of in vitro activity against enterococci include the penicillins (especially penicillin, ampicillin, and piperacillin), glycopeptides (vancomycin and teicoplanin), carbapenems (imipenem and meropenem), aminoglycosides, tetracyclines (tetracycline and doxycycline), quinolones (including ciprofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin), chloramphenicol, rifampin, the streptogramin combination quinupristin/dalfopristin and the oxazolidinone linezolid. The penicillins and the glycopeptides have the best activity, and ampicillin typically has greater in vitro killing ability than vancomycin (37). Enterococci have intrinsic low-level resistance to the aminoglycosides due to the decreased ability of these agents to penetrate the cell wall, but this can be overcome by the addition of cell wall-active agents (such as the penicillins and glycopeptides) that result in synergistic killing of the organisms (171). Antimicrobial agents undergoing development such as the oritavancin and dalbavancin, both of which are new glycopeptides, the lipoglycopeptide telavancin, iclaprim, which is a diaminopyrimidine, the glycylcycline tigecycline, also exhibit in vitro activity against enterococci (7, 11, 76, 82, 114, 116, 138, 180, 200, 213, 230, 234, 236).

In Vitro and In Vivo (Animal Data) Activity for Aminoglycoside-Resistant Enterococci

High-level gentamicin resistance (MICs > 500 - 2,000 mg/ml) in enterococci is usually due to the presence of the “bifunctional” aminoglycoside-modifying enzyme encoded by the aac(6’)-Ie-aph(2”)-Ia gene (9, 69). This enzyme modifies the aminoglycoside and eliminates synergism between a cell wall-active agent (such as ampicillin or vancomycin) and gentamicin, plus essentially all clinically available aminoglycosides except streptomycin. High-level streptomycin resistance can be caused by the streptomycin-modifying enzymes ANT(6’)-Ia or ANT(3”)-Ia or by a change in the ribosome binding site, and also eliminates synergism with the cell wall-active agents (43a, 62, 128, 199). Nosocomial isolates that possess genes for high-level resistance to both gentamicin and streptomycin are not uncommon (45, 87, 276).

In an in vitro study, both vancomycin and teicoplanin were bacteriostatic and not bactericidal against E. faecalis with high-level gentamicin resistance, and antagonism was often seen when either agent was combined with ciprofloxacin (266). In the same study, ampicillin alone was bactericidal against 8 of 13 E. faecalis, and ampicillin plus ciprofloxacin was bactericidal against all 13 E. faecalis strains (266). In a rabbit endocarditis model with a beta-lactamase-producing, high-level gentamicin resistant E. faecalis strain, ampicillin/sulbactam reduced bacterial titers in vegetations more effectively than vancomycin after 7 days, although neither regimen could sterilize the heart valve (134).

The combination of amoxicillin plus cefotaxime can exhibit an in vitro bacteriostatic synergistic effect against amoxicillin-susceptible E. faecalis isolates. This could be explained by the partial saturation of penicillin-binding proteins 2 and 3 by cefotaxime combined with the total saturation of penicillin-binding proteins 4 and 5 by amoxicillin (152). The combination of ampicillin plus ceftriaxone in time-kill studies produced synergistic killing against 10 of 10 ampicillin-susceptible E. faecalis isolates. Furthermore, ampicillin plus ceftriaxone in experimental E. faecalis rabbit endocarditis significantly lowered bacterial titers in aortic valve vegetations compared to ampicillin alone (83). However, no clinical data are available to confirm the superiority of this combination over ampicillin alone for infections caused by ampicillin-susceptible E. faecalis.

Although high-level aminoglycoside resistance is synonymous with resistance to synergism, there are rare enterococci with gentamicin MICs < 500 µg/ml that are also resistant to the synergistic effect of a cell wall-active agent plus gentamicin. Moellering and colleagues have detected several E. faecalis with gentamicin MICs of only 8 µg/ml that are resistant to ampicillin-gentamicin synergism but susceptible to ampicillin-tobramycin synergism (170). Hayden and colleagues have reported five E. faecium with gentamicin MICs between 4 and 32 µg/ml that are resistant to ampicillin-gentamicin synergism (103). The mechanisms of these resistance phenotypes have not yet been determined. A new gentamicin resistance gene, aph(2”)-Ic, has been found in E. faecalis, E. faecium, and E. gallinarum isolates (40). This gene compromises ampicillin-gentamicin synergism but confers a gentamicin MIC of typically only 256 µg/ml. If these three enterococcal phenotypes become more prevalent, synergy testing of a cell wall-active agent combined with gentamicin may be indicated in selected clinical situations, such as enterococcal endocarditis or meningitis, to confirm the efficacy of the antimicrobial combination utilized for therapy (43).

Heretofore, only gentamicin and streptomycin have been used for high-level aminoglycoside testing in enterococci, since the aac(6’)-Ie-aph(2”)-Ia gene confers high-level resistance to essentially all the clinically available aminoglycosides (including gentamicin, amikacin, tobramycin, netilmicin, and kanamycin) except for streptomycin. A second gene, aph(2”)-Id, that confers high-level gentamicin resistance has been detected (267). This gene also confers resistance to tobramycin, netilmicin, and kanamycin, but not to amikacin. Studies performed on the E. casseliflavus from which the gene was isolated showed synergistic killing with the combination of ampicillin and amikacin (267). However, ampicillin plus amikacin did not achieve as much killing against several E. faecium isolates that possess the aph(2”)-Id gene (267). Therefore, only a small percentage of enterococcal isolates with high-level gentamicin resistance might be susceptible to the combination of a cell wall-active agent plus amikacin.

The new aminoglycoside arbekacin is modified to a lesser degree than gentamicin is by the bifunctional AAC(6’)-Ie-APH(2”)-Ia enzyme (111). Ampicillin plus arbekacin produced in vitro synergistic killing against 40% of enterococci that possess the aac(6’)-Ie-aph(2”)-Ia gene (123). Compared to ampicillin alone, ampicillin plus arbekacin was significantly more effective in reducing bacteria in vegetations in a rabbit infective endocarditis model caused by an E. faecalis isolate that contained aac(6’)-Ie-aph(2”)-Ia (120). Ampicillin plus arbekacin has also produced in vitro synergistic killing against 8 of 13 vancomycin-, ampicillin-, and gentamicin-resistant E. faecium that possess the aph(2”)-Id gene (121).

In Vitro and In Vivo (Animal Data) for Enterococci Resistant to Penicillins and Glycopeptides, But Susceptible to Aminoglycosides

High-level penicillin resistance in enterococci is due predominantly to over-expression of penicillin-binding protein 5 (PBP 5), which has low affinity for the penicillins, but is able to substitute for the functions of the susceptible penicillin-binding proteins when they are inhibited by the beta-lactam agents (2, 71, 91, 141,142, 241). For an E. faecium strain resistant to penicillin (MIC = 200 µg/ml) but susceptible to gentamicin, no in vitro synergistic bactericidal activity was observed when penicillin was combined with gentamicin, and the combination did not significantly lower bacterial counts in vegetations in a rat endocarditis model when compared with no therapy (26). However, Torres and colleagues have found in vitro synergism when high levels of penicillin are combined with gentamicin against some E. faecium isolates with high-level penicillin resistance (MIC > 128 µg/ml), but low-level gentamicin resistance. Synergism was exhibited in nine of twelve strains (penicillin MIC = 200 µg/ml) when penicillin at 100 µg/ml was combined with gentamicin (5 µg/ml) (264). In addition, synergism was seen in all three strains for which the penicillin MIC was 400 µg/ml when penicillin at 200 µg/ml was combined with gentamicin at 5 µg/ml (264).

Glycopeptide resistance in enterococci is due the synthesis of modified peptidoglycan precursors that have decreased affinity for vancomycin and teicoplanin (10,136). Most glycopeptide-resistant clinical isolates are of the VanA or VanB phenotype, although VanA to VanG phenotypes have been described. Strains with the VanA phenotype have high-level resistance to both vancomycin (MICs = 64 - >1024 µg/ml) and teicoplanin (MICs = 16 - 512 µg/ml), while strains with the VanB phenotype have varying levels of resistance to vancomycin (MICs = 4 - 1024 µg/ml), but are susceptible to teicoplanin (10, 136). Heteroresistance to vancomycin has also been identified (3). E. gallinarum, E. casseliflavus, and E. flavescens strains are intrinsically resistant to vancomycin (MICs = 4 - 32 µg/ml), but remain susceptible to teicoplanin, and are of the VanC phenotype (136, 188, 223). Teicoplanin appears to be effective therapy against enterococcal strains lacking glycopeptide resistance determinants. In a rat endocarditis model, teicoplanin was actually more efficacious than vancomycin against a beta-lactamase-producing strain with high-level gentamicin resistance (281).

Teicoplanin’s efficacy for the treatment of VanB-type VRE is not as promising. Teicoplanin plus gentamicin produced in vitro bactericidal synergism against an E. faecalis resistant to vancomycin but susceptible to teicoplanin and gentamicin (12). However, teicoplanin resistance can be selected for in vitro with both E. faecalis and E. faecium strains (102), and teicoplanin-resistant E. faecalis mutants have arisen during teicoplanin therapy in a rabbit endocarditis model (12). The in vivo emergence of resistance to teicoplanin during vancomycin therapy for E. faecium (VanB phenotype) bacteremia has also been observed (102).

For strains truly resistant to ampicillin, vancomycin, and teicoplanin but still susceptible to aminoglycosides, several options have been suggested. The combination of ciprofloxacin plus rifampin plus gentamicin substantially reduced bacterial counts in vegetations in a rat endocarditis model (277). This triple antimicrobial combination has been used with success in two cases of enterococcal bacteremia (147). Ciprofloxacin plus gentamicin, ciprofloxacin plus rifampin, and ciprofloxacin plus rifampin plus gentamicin all showed bactericidal activity in time-kill studies (147). The activity of these combinations is related to the intrinsic activity of the fluoroquinolone. The newer quinolones with greater potency in vitro than ciprofloxacin against enterococci, such as moxifloxacin and gatifloxacin, may prove in the future to be better therapeutic choices than ciprofloxacin. Unfortunately, fluoroquinolone resistance in clinical enterococcal isolates is not uncommon (107, 117, 118, 156, 244).

Penicillin plus vancomycin plus gentamicin has produced in vitro synergistic killing against clinical enterococcal isolates resistant to vancomycin (240). In an E. faecium strain where a synergistic bacteriostatic effect between penicillin and vancomycin was demonstrated in vitro, the triple combination of high-dose penicillin plus vancomycin plus gentamicin proved effective in a rabbit endocarditis model. However, a bacterial subpopulation resistant to penicillin/vancomycin synergism was frequently isolated from vegetations at the end of therapy (31). In a subsequent study using the same model, the triple combination of ceftriaxone plus vancomycin plus gentamicin was even more effective in reducing bacterial counts than the combination of either penicillin plus vancomycin plus gentamicin or penicillin plus teicoplanin plus gentamicin. Still, a subpopulation resistant to ceftriaxone/vancomycin synergism emerged in 10% to 20% of the animals (32). Other investigators have not found the triple combination of ampicillin plus vancomycin plus gentamicin to be reliably bactericidal in vitro against highly ampicillin-resistant, vancomycin-resistant, gentamicin-susceptible E. faecium strains (77).

In Vitro and In Vivo (Animal Data) Activity for Enterococci Resistant to Penicillins, Glycopeptides, and Aminoglycosides

The combinations of ampicillin (or penicillin) plus vancomycin, imipenem plus vancomycin, and ceftriaxone plus vancomycin (or teicoplanin) have shown bacteriostatic synergism in vitro against some enterococci resistant to penicillin, glycopeptides, and aminoglycosides (96,135). However, bacteriostatic synergism may be limited to specific strains (92, 99, 103), and bactericidal synergism has not been shown with these combinations (36, 99,103, 131,135). The triple combination of ampicillin (MIC = 16 µg/ml) plus imipenem (MIC = 32 µg/ml) plus vancomycin (MIC = 512 µg/ml) exhibited bactericidal synergistic activity in vitro against an E. faecium isolate (22). Ampicillin plus imipenem was highly active against the same E. faecium isolate in a rabbit endocarditis model, but efficacy was not increased by the addition of vancomycin to the regimen (22). In the same model, imipenem plus vancomycin was significantly more effective than ampicillin alone or ampicillin plus vancomycin. The authors suggested that ampicillin plus imipenem synergism may be due to the saturation of different penicillin-binding proteins by the two agents (22, 72, 84).

Ampicillin plus ciprofloxacin has been demonstrated to produce in vitro synergistic killing against some of these multiresistant strains that were still susceptible to ciprofloxacin, but in a rabbit endocarditis model this combination did not produce a significant reduction of bacteria in vegetations (131, 132). Ciprofloxacin plus novobiocin was bactericidal in a time-kill study, and produced a significant decrease in bacterial counts in vegetations in a rabbit endocarditis model (131, 217). Linezolid was more active than vancomycin in decreasing vegetation size caused by vancomycin-resistant E. faecium in a rat endocarditis model (205). The combination of quinupristin-dalfopristin with doxycycline resulted in less resistance to either agent when administered in combination than with either agent alone, in an in vitro endocarditis model (1).

ANTIMICROBIAL THERAPY

Since the human reservoir is the gastrointestinal tract, polymicrobial infections involving the gastrointestinal tract, urinary tract, and female genital tract are the primary infections. Infections of the urinary tract, soft tissue, and intraabdominal infections, and perhaps some cases of septic arthritis, can be treated with a single antimicrobial agent, especially in patients with normal host defenses (167, 181, 222). For bacteremia (without endocarditis), combination antibiotic therapy is often used but studies are not definitive. Some studies suggest that enterococcal bacteremia without endocarditis can be treated with a single agent (88, 95, 153), although the sources of bacteremia were not considered, which may be an important factor in determining outcome (106). Other studies suggest that combination therapy may be more effective than monotherapy therapy for serious infections such as bacteremia (167, 181, 191). In one prospective, observational study of 110 serious enterococcal infections, 71% of patients who received appropriate combination therapy (cell wall-active agent + aminoglycoside) achieved clinical cure compared to 53% of patients who received an active single agent only (p = 0.08) (207). 

For monotherapy in patients without penicillin allergy, the drug of choice is ampicillin (MIC usually two to four-fold lower than penicillin). Beta-lactamase-producing enterococci had been a concern, since they are resistant to ampicillin but are not detected by routine ampicillin susceptibility testing (182, 184). However, it appears now that they are rare, and many hospitals that have screened for beta-lactamase production in enterococci for several years have not found any (87). If isolated, they can be treated with ampicillin/sulbactam. If the organism is resistant to ampicillin, a glycopeptide such as vancomycin may be used for monotherapy. Imipenem offers no advantage over ampicillin against (beta-lactamase negative) enterococci in vitro nor in animal endocarditis models (13, 61, 232). We have seen a few E. faecalis isolates that are susceptible to ampicillin (MIC = 0.5 -1.0 µg/ml) but relatively resistant to imipenem (MIC > 8.0 µg/ml). However, in situations such as empiric therapy for complex intraabdominal infections, where coverage that includes enterococci may be prudent, imipenem (or piperacillin/tazobactam or ampicillin/sulbactam) might be substituted for regimens that contain ampicillin. A summary of treatment recommendations for enterococcal infection due to strains susceptible in vitro to glycopeptides is shown in Table 1.

Urinary Tract Infections

Urinary tract infections are the most common infection caused by enterococci and are often associated with urinary catheters. Enterococcal urinary tract infections not accompanied by bacteremia generally require only single drug therapy. If the organism is susceptible, ampicillin is the drug of choice. Vancomycin can be used if the organism is ampicillin-resistant. Linezolid or quinupristin/dalfopristin are reasonable alternatives if the enterococcus is resistant to both ampicillin and vancomycin.

For simple urinary tract infections, a quinolones with a low MIC for a particular isolate might be considered as an alternative, but caution must be exerted since enterococcal superinfections have occurred in patients treated with ciprofloxacin for infections caused by other bacteria (67, 285).

Complicated urinary tract infections as prostatitis and pyelonephritis are less common. They can be treated with the same agents used for simple urinary tract infections, but the duration of therapy would be longer. A seriously ill patient with pyelonephritis or perinephric abscess may benefit from combination therapy with a beta-lactam agent plus an aminoglycoside. Nitrofurantoin and fosfomycin exhibit excellent activity in vitro versus urinary enterococcal isolates including VRE strains (209, 256). Oral rifampin plus nitrofurantoin has cured a case of chronic prostatitis due to vancomycin-resistant E. faecium (256).

Intraabdominal Infections

The therapeutic recommendations outlined in this chapter are based on studies of predominantly E. faecium and E. faecalis. Optimal antimicrobial therapy for E. gallinarum, E. casseliflavus, E. avium, E. cecorum, E. durans, E. hirae, E. malodoratus, E. mundtii, E. pseudoavium and E. raffinosus is not known. However, based on in vitro data and anecdotal reports, it would seem reasonable to suggest that therapy for these enterococcal species is the same as that for E. faecium and E. faecalis.

Intraabdominal infections are polymicrobial in origin in which coverage for enteric bacteria (E. coli, Klebsiella pneumonia, etc.), and anaerobes (Bacteroides fragilis), must be covered including Enterococcus species. Broad spectrum therapy for the gastrointestinal flora mentioned above include ampicillin/sulbactam, piperacillin/tazobactam, and imipenem.

A case control study has suggested that empiric therapy for enterococci be especially considered for hepatobiliary or pancreatic infection, where both the prevalence of enterococci and the rate of enterococcal bacteremia are high (44).

Endocarditis

The necessity for combination antibiotic therapy is well established for enterococcal endocarditis. Improved outcome has been demonstrated in patients who received a synergistic combination of a cell wall-active agent plus an aminoglycoside, compared to patients who received monotherapy (59, 78, 125, 157, 161, 167, 181, 278). Cell wall-active antimicrobial agents such as the penicillins and glycopeptides, when combined with aminoglycosides, produce a synergistic bactericidal effect against susceptible strains of enterococci due to the enhanced intracellular penetration and the use of the aminoglycoside in the presence of the cell wall-active agent (172).

Penicillin (or ampicillin) plus gentamicin is the most commonly used combination for enterococcal endocarditis, although penicillin plus streptomycin has been the most studied combination regimen for enterococcal endocarditis. No direct comparative studies of efficacy between penicillin (or ampicillin) plus streptomycin versus penicillin plus gentamicin have been done, although streptomycin may be more effective than gentamicin in treatment of enterococcal endocarditis (279). In a study of streptomycin-resistant enterococcal endocarditis, 16 of 20 (80%) patients treated with penicillin plus gentamicin were cured, compared with a cure in 33 of 36 (92%) patients treated with penicillin plus streptomycin for streptomycin-susceptible enterococci in the same study (279). This higher relapse rate in patients treated with penicillin plus gentamicin was also higher than the relapse rate among patients treated with penicillin plus streptomycin in previous studies (125, 157, 161). Streptomycin has traditionally been given intramuscularly, which involves greater pain for the patient, although intravenous streptomycin has been given to a few patients and seemed to be well-tolerated (175). Streptomycin is predominantly ototoxic, and gentamicin is primarily nephrotoxic; while nephrotoxicity is often reversible, ototoxicity is often not (278). Moreover, gentamicin serum levels are more readily available to aid in monitoring for potential toxicity, and gentamicin is less expensive than streptomycin. A sufficient number of patients have been treated successfully with penicillin (or ampicillin) plus gentamicin that this is a well-accepted regimen (161, 167, 224, 278). For these reasons, gentamicin has replaced streptomycin as the more commonly used aminoglycoside in combination regimens for enterococcal endocarditis.

The recommended streptomycin dosing in enterococcal endocarditis is 7.5 mg/kg IM every 12 hours, with target peak serum levels of 15-30 µg/ml (161, 278). Gentamicin is usually given at 1 mg/kg IV every eight hours with target peak serum levels of > 3 µg/ml (161, 278). Treatment should continue for at least 4 weeks. Patients with symptoms greater than 3 months duration before initiation of appropriate therapy and patients with prosthetic valve endocarditis should receive antimicrobial therapy for at least 6 weeks (224, 279). Animal data do not support the use of once-daily dosing of aminoglycosides in enterococcal endocarditis (68, 158). However, one patient with E. faecalis pulmonic and tricuspid endocarditis was treated successfully with ampicillin and once-daily gentamicin (253). The combination of vancomycin plus an aminoglycoside has not been as extensively studied, so vancomycin should be used only when the patient has a significant history of allergy to the penicillins (278). The addition of ciprofloxacin to a regimen of ampicillin plus gentamicin was associated with cure in a case of relapsing E. faecalis endocarditis (137, 227). In selected patients, a shortened course of aminoglycosides may be considered. A 5-year nationwide prospective study in Sweden during 1995-1999 identified 881 definite episodes of infective endocarditis (195). Definite enterococcal endocarditis was diagnosed in 93 episodes (11%), the largest series of enterococcal endocarditis so far presented. Mortality during treatment was 16%, the relapse rate was 3%, and clinical cure was achieved in the remaining 81% of the episodes. Clinical cure was achieved with a median duration of cell wall-active antimicrobial therapy of 42 days combined with an aminoglycoside (median treatment time, 15 days). International guidelines generally recommend a 4-6-week combined synergistic treatment course with a cell wall-active antibiotic and an aminoglycoside. Treatment regimens in Sweden often include a shortened aminoglycoside treatment course in order to minimize adverse effects in older patients. In this study, fatal outcome seemed not to be due to the shortened aminoglycoside therapy course. In some enterococcal endocarditis episodes, shortening the duration of aminoglycoside therapy to 2-3 weeks requires further study.

Endocarditis due to vancomycin resistant Enterococcus is rare. The literature consists of single case reports, with most patients having serious underlying disease including transplantation, dialysis and health care associated infection (4, 8, 14, 18,19,24, 28, 39, 81, 122, 126, 159, 206, 260, 262, 265, 271,274,275, 278, 282). Most patients survived despite the lack of bactericidal therapy and valve replacement. The optimal therapy for this infection remains undefined, as comparative data are not available, patients were treated with various and multiple agents in combination and sequentially over varying periods of time.

Meningitis

Most experts would concur that treatment of enterococcal meningitis requires combination therapy so that maximal bactericidal activity may be achieved (15, 167, 181). However, in contrast to endocarditis, there are scant clinical data available to state unequivocally that combination therapy is superior to monotherapy in meningitis. In a review of enterococcal meningitis, thirty of thirty-two cases had data on antibiotic therapy (247). The majority of patients (20 of 30) received penicillin or ampicillin plus an aminoglycoside (three patients also received intrathecal gentamicin); there was only one death in this group, compared with one death in the group of four patients who received penicillin or ampicillin alone. One patient failed his initial regimen of ampicillin plus chloramphenicol, but recovered when the chloramphenicol was replaced by gentamicin. One severely ill patient received chloramphenicol plus gentamicin, and subsequently died (247). Ciprofloxacin has been reported to cure one case of E. faecalis meningitis in an infant (127). The combination of quinupristin/dalfopristin plus chloramphenicol cured a case of neonatal E. faecium meningitis that had failed therapy with teicoplanin plus chloramphenicol (89). A child with E. faecium meningitis was treated successfully with chloramphenicol (208). Intrathecal teicoplanin has been used successfully to treat a case of E. faecium meningitis (149). Intraventricular plus intravenous quinupristin/dalfopristin plus intravenous chloramphenicol sterilized the CSF of a patient with vancomycin-resistant E. faecium shunt infection who had failed therapy with chloramphenicol alone (268). Linezolid used alone for 28 days cured a patient with vancomycin-resistant E. faecium meningitis who had failed therapy with chloramphenicol (284). Linezolid used for 3 weeks plus gentamicin for 5 days sterilized the CSF of a second patient with vancomycin-resistant enterococcal meningitis (97).

Therapy for Strains Resistant to Aminoglycosides

Treatment of patients with endocarditis caused by enterococci with high-level resistance to aminoglycosides is associated with a high incidence of failure or relapse (166). Therapy for strains resistant to all aminoglycosides is usually limited to the use of ampicillin alone. Vancomycin alone is potentially less efficacious. Optimal duration of therapy with ampicillin alone is not known, but the observation that valve cultures at surgery are positive after as much as one month of ampicillin therapy suggests that longer courses than the traditional 4 to 6 weeks, such as 8 to 12 weeks should be ly considered (59, 124, 278). Continuous, rather than intermittent, infusion of ampicillin may prove beneficial since there are data showing its greater efficacy in sterilizing cardiac vegetations and improving survival in a rat endocarditis model (259). Cardiac valve replacement may well be required for a cure in many of these patients (59, 166, 224, 278).

A patient with ampicillin- and vancomycin-susceptible but gentamicin- and streptomycin-resistant E. faecalis endocarditis was initially treated with ampicillin (4g IV q6h) plus vancomycin. Both peak and trough serum bactericidal titers were 1:2. After imipenem was added (500 mg IV q6h), the peak and trough serum bactericidal titers increased to 1:128 and 1:64, respectively. A total of 6 weeks of antibiotics was given and the patient was cured (6). The authors suggested that the increased serum bactericidal activity seen after the addition of imipenem may be due to the saturation of different penicillin-binding proteins (6). The same regimen of ampicillin plus vancomycin plus imipenem was used successfully in treating a case of gentamicin-resistant enterococcal bacteremia without endocarditis (5). Tripodi and colleagues reported microbiological and clinical cure of ampicillin-susceptible but gentamicin-resistant E. durans endocarditis with the combination of ampicillin (MIC = 0.5 µg/ml) plus ciprofloxacin (MIC = 8 µg/ml) after failure with ampicillin plus gentamicin (265). The efficacy of the treatment was predicted in vitro by time-kill studies.

Therapy for Strains Resistant to Penicillins and Glycopeptides But Susceptible to Aminoglycosides

If the cell wall-active agents (penicillins and glycopeptides) are inactive against some enterococci, the antibiotic combinations of cell wall-active agents plus aminoglycosides will no longer be synergistic. Given the in vitro resistance, for certain enterococcal strains discussed previously, synergism may be limited chiefly by the achievable penicillin serum concentration. Since 5 million units of penicillin G infused intravenously can achieve a peak serum concentration of 135 µg/ml (134), the authors conclude that some gentamicin-susceptible E. faecium strains with penicillin MICs between 50 and 200 µg/ml may be treated with high-dose penicillin plus gentamicin (264).

These findings for penicillin have been assumed to be true for ampicillin, also, because the two agents’ mechanism of action is the same. Since peak ampicillin serum levels of 109 to 150 µg/ml can be attained after a 2-gram intravenous dose (75, 214), some enterococci with an ampicillin MIC up to 64 or even 128 µg/ml may prove to be susceptible to ampicillin-gentamicin synergism if high-dose ampicillin is used. A hemodialysis patient with ampicillin-resistant (MIC = 32 µg/ml) and gentamicin-resistant (MIC = 1,000 µg/ml) E. faecium bacteremia was treated successfully with ampicillin 2 grams IV q6h and streptomycin (MIC = 32 µg/ml) 500 mg twice weekly after failing therapy with doxycycline + chloramphenicol (54). A patient with vancomycin-resistant E. faecium endocarditis had persistent bacteremia during therapy with 12 g of ampicillin (MIC = 64 µg/ml) per day plus gentamicin and subsequently with quinupristin/dalfopristin. Blood cultures finally became sterile when therapy was changed to ampicillin 20 g per day plus gentamicin (183).

A patient with ampicillin-resistant (MIC = 64 µg/ml) E. faecium bacteremia failed therapy with continuous infusion ampicillin (20 g/day) plus gentamicin (MIC < 500 µg/ml) q12h, but was cured with continuous infusion ampicillin/sulbactam (20 g ampicillin/10 g sulbactam) plus gentamicin q12h (162). No bactericidal effect was seen when the patient was on ampicillin plus gentamicin (serum ampicillin concentration of 103 mg/ml), but a serum bactericidal titer of 1:2 was detected when the patient was on ampicillin/sulbactam plus gentamicin (serum ampicillin concentration of 130 mg/ml). It is possible that, via unknown mechanism, sulbactam may slightly enhance the activity of ampicillin against certain strains of enterococci (162).

In an open trial of teicoplanin therapy for enterococcal endocarditis, 5 of 7 patients treated with teicoplanin alone and 6 of 7 patients treated with teicoplanin plus an aminoglycoside were cured (233). In a study of teicoplanin therapy for endocarditis caused by Gram-positive bacteria, five patients with E. faecalis endocarditis were treated with teicoplanin alone, and all five were cured (216).

Therapy for Strains Resistant to Penicillins, Glycopeptides, and Aminoglycosides

The terms “VRE” and “VREF” are used commonly to describe these multiply resistant strains, which to date have been predominantly E. faecium. Antibiotic selection is most problematic for these strains (Table 2). At the current time, linezolid is approved for the treatment of VRE and is the drug of choice. Based on in vitro susceptibility results and anecdotal reports, daptomycin and quinupristin-dalfopristin also warrant consideration.

Various other bacteriostatic antimicrobials with less in vitroactivity than the penicillins, glycopeptides, and aminoglycosides have been tried either alone or in combination against multiresistant enterococci. Oral rifampin plus nitrofurantoin has cured a case of chronic prostatitis due to vancomycin-resistant E. faecium (256). Chloramphenicol therapy for multiresistant enterococci in 16 severely ill patients in one study showed somewhat encouraging results (189). Eight of 14 patients in whom a clinical response could be determined showed improvement. Four patients were treated with rifampin in addition to chloramphenicol; most patients received other antibiotics that alone do not have activity against enterococci. Eleven of the 16 patients had a drainage procedure or debridement performed. In a study of E. faecium infections in liver transplant recipients, chloramphenicol was used as monotherapy in 16 cases, and 6 patients died (202). Single cases of successful therapy using chloramphenicol alone or in combination with vancomycin or rifampin have also been reported,(130,207, 208). In another study of vancomycin-resistant Enterococcus bacteremia treated with chloramphenicol, 22 of 36 patients demonstrated a clinical response, and 34 of 43 patients showed a microbiological response (133). However, no significant effect on mortality by chloramphenicol usage could be demonstrated (133). Lynch and colleagues studied 4 strains of E. faecalis and 1 strain of E. faecium and demonstrated efflux of chloramphenicol in all the strains (150). Their results suggest that many wild-type strains of E. faecalis, and presumably also of E. faecium, possess endogenous efflux pumps that excrete chloramphenicol (150). Therefore, chloramphenicol use probably should be limited to those cases where no other agents would likely be effective.

Intravenous doxycycline used alone for two weeks in a patient with catheter-related sepsis and probable endocarditis resulted in clearing of the bacteremia, but the patient subsequently died of congestive heart failure (130). Oral doxycycline for two weeks, plus removal of the Hickman catheter presumed to be the source of the bacteremia, was successful in treating a case of E. faecium bacteremia (174). An immunocompromised patient with vancomycin- and ampicillin-resistant E. faecium bacteremia who appeared to fail therapy with quinupristin/dalfopristin plus gentamicin was cured with five days of intravenous tetracycline followed by two months of oral doxycycline (with occasional periods of intravenous tetracycline when he could not tolerate oral therapy) (108).

The streptogramin combination quinupristin/dalfopristin has been used for treatment of E. faecium, but not E. faecalis, which are intrinsically resistant to the combination. Among 15 cases of multiresistant E. faecium infection treated with quinupristin/dalfopristin, three patients were cured of their infection, 5 had recurrence of the infection, and in 7 cases, the outcome was indeterminate (50). Blood cultures became negative for enterococcus during treatment in all patients with bacteremia. However, catheters were removed in the patients with catheter-related bacteremia prior to therapy, so it is not known whether removal of catheters alone would have been curative (50). Vancomycin-resistant E. faecium-associated mortality was significantly lower in a group of 20 patients with vancomycin-resistant E. faecium bacteremia treated with quinupristin/dalfopristin compared with an historical cohort of 42 patients with vancomycin-resistant E. faecium bacteremia treated with other agents (146). In another study, bacteriologic eradication occurred in 17 of 23 evaluable patients with serious E. faecium infections treated with quinupristin/dalfopristin (280). In a multicenter study of quinupristin/dalfopristin for vancomycin-resistant E. faecium infections, clinical success was achieved in 73.6% (142 of 193) of evaluable patients, and the bacteriological success rate was 70.5% (110 of 156), resulting in an overall success rate of 65.4% (102 of 156) (169). Successful treatment with quinupristin/dalfopristin for E. faecium vertebral osteomyelitis, peritonitis, ventriculitis, aortic graft infection, and endocarditis has also been reported (60, 81, 129, 150, 186, 229, 247, 254, 274). Quinupristin/dalfopristin has also been used successfully in treating pediatric patients (50). Since quinupristin/dalfopristin is not bactericidal against E. faecium, combining other agents with quinupristin/dalfopristin may be a reasonable approach in selected cases. A case of vancomycin-resistant E. faecium endocarditis with persistently positive blood cultures after two weeks of therapy with quinupristin/dalfopristin was cured after intravenous doxycycline and oral rifampin were added to the quinupristin/dalfopristin and therapy continued for 8 more weeks (159). Since E. faecium strains resistant to quinupristin/dalfopristin can be selected in vitro without difficulty (164), it is not surprising that emergence of increased resistance to quinupristin/dalfopristin has appeared during therapy for E. faecium infections (42, 145, 169, 280). Also, superinfection with E. faecalis has occurred during quinupristin/dalfopristin therapy for E. faecium infections (41, 169, 280). The agent is only available by intravenous infusion. Myalgias in 6.6% or patients, arthralgias in 9.1% and reports of antimicrobial resistance have been limiting features (60, 104).  

The oxazolidinones are a new class of antimicrobials that inhibit bacterial protein synthesis (143, 239, 252). Linezolid is a semisynthetic oxazolidinone agent that exhibits bacteriostatic in vitro and in vivo activity against enterococci (21, 63, 73, 192, 204, 226, 235). Although linezolid has in vitro activity against vancomycin-resistant E. faecalis, it has only received approval for vancomycin-resistant E. faecium infections because of the lack of patients with E. faecalis isolates in the phase III trials. In one case report, a neutropenic patient with ampicillin- and vancomycin-resistant E. faecium bacteremia was treated successfully with 14 days of linezolid (600 mg IV q12h) plus gentamicin. Time-kill studies with linezolid plus gentamicin did not show in vitro synergism (193). In another case report, a patient with acute myelogenous leukemia developed vancomycin-resistant E. faecium bacteremia after bone marrow transplantation. Blood cultures were persistently positive during 10 weeks of therapy with quinupristin/dalfopristin, and despite the addition of chloramphenicol and doxycycline at various times (160). The source of the E. faecium bacteremia was deemed to be an extensive central venous thrombus. The E. faecium remained susceptible in vitro to quinupristin/dalfopristin during therapy. Antimicrobial therapy was changed to intravenous linezolid alone and blood cultures became negative 8 days later, and all subsequent blood cultures were negative. The patient received 6 weeks of intravenous linezolid followed by 6 weeks of oral linezolid, and had no further complications (160). In an open-label, non-comparative, non-randomized compassionate-use program for linezolid, in which 66% of 826 treatment courses were prescribed for the treatment of VRE, the clinical and microbiological cure rates were 81% and 86% respectively (17). Sites of infection included bloodstream, intra-abdominal, complicated skin and soft tissue, urinary tract and bone.

In the largest case series published to date, 15 patients infected with vancomycin-resistant E. faecium were treated with linezolid after all other available therapeutic options were tried (39). The median duration of therapy was 20.5 (+ 3.5) days. Microbiologic cure was achieved in all 10 patients who survived and completed therapy, including a patient with infective endocarditis, who was treated for 42 days. All 7 patients alive at long-term follow-up were free of infection. No deaths were attributable to the index infection (39). Linezolid use has been reported in immunosuppressed patients. In a prospective, randomized study comparing quinupristin-dalfopristin with linezolid in forty cancer patients infected with VREF, comparable clinical efficacy was seen. Clinical response was seen in 58% of patients treated with linezolid vs. 43% treated with quinupristin-dalfopristin. (219). Five of six liver recipients with sepsis secondary to intra-abdominal VRE infection were cured at end of treatment, although a sixth patient relapsed with a linezolid-resistant E. faecium strain (144).

Although no comparative trials of linezolid have been done in patients with endocarditis, osteomyelitis, or meningitis, multiple case reports have been described. Oral linezolid was successful in treating a case of vancomycin-resistant E. faecium endocarditis that failed sequential monotherapy with chloramphenicol and quinupristin/dalfopristin (14). Oral linezolid was successful in treating a case of vancomycin–resistant E. faecium endocarditis in a renal transplant recipient with HIV infection. (8). Linezolid was also reported to be successful in treating cases of E. faecalis prosthetic valve endocarditis with (220) and without (275) high-level gentamicin-resistance. Failure of therapy for endocarditis with linezolid was noted in another report (287). Intravenous linezolid was successful in treating a patient with MRSA and VRE bacteremias secondary to vertebral osteomyelitis who failed therapy with intravenous vancomycin and oral amoxicillin and fusidic acid (165). Oral linezolid was reported to be successful in treating a case of E. faecalis (221) and E. faecium osteomyelitis (261) Although only bacteriostatic, there have been several case reports of successful treatment with linezolid of patients with VREF meningitis, including patients in the postoperative period, persons with infections associated with a device, and patients with infections in the setting of hyperinfection with yloides stercoralis (97, 246, 284).

The emergence of linezolid resistance during therapy is uncommon (288). Resistant mutants can be generated at a low frequency having mutations involving the domain V peptidyltransferase center of 23S rRNA, which is the same mutation in as in linezolid-resistant MRSA. How stable the resistance is in these isolates is uncertain. Other centers have isolated increased numbers of linezolid-resistant VRE and have noted a higher incidence of linezolid resistance emerging during therapy (1 of 45) (86). However, prior use with linezolid is not necessary before the development of resistance (185). A case of linezolid-resistant E. faecalis was isolated in a cord blood stem cell recipient following treatment with linezolid for VRE bacteremia (52). Three cases of linezolid resistant E. faecalis were reported after prolonged treatment with linezolid for VRE. One of these patients had been diagnosed with VRE aortic and mitral valve endocarditis that was sensitive to ampicillin. The patient was treated for six weeks with linezolid. Two weeks following treatment, the patient was readmitted with third-degree heart block and VRE bacteremia. The patient was desensitized to penicillin and treated successfully with ampicillin (25). Given the complexity in determining optimal antimicrobial therapy for multiply resistant enterococci (“VRE/VREF”), consultation with an infectious diseases specialist may be prudent in these cases.

Daptomycin is a novel cyclic lipopeptide that is a fermentation product of Streptomyces roseosporus with a unique mechanism of action. It acts specifically at bacterial cytoplasmic membrane wit multiple effects on cellular function including inhibition of lipoteichoic acid synthesis, disruption of membrane potential and inhibition of peptidoglycan synthesis. It displays rapid concentration-dependent killing and is bactericidal even in the stationary phase of growth. The agent is currently FDA approved in the United States for management of complicated skin and soft tissue infection. Current recommended dosage is 4 mg/kg once daily, however in clinical trials of serious staphylococcal and enterococcal infection, doses of 6 mg/kg/24 hours were used. In vitro studies of 289 isolates of E. faecalis demonstrated MICs < = 2 µg/ml in all isolates to daptomycin (109). A large multicenter European study with in vitro studies of 40 isolates of vancomycin-resistant E. faecalis and 114 isolates of vancomycin-resistant E. faecium demonstrated MICs<2 µg/ml in all isolates (47). In vitro activity of daptomycin against enterococci from the nosocomial and community environments in Portugal were studied. 1151 isolates were obtained, all of which demonstrated MICs <= 4 µg/ml (194). Similarly, 89 strains of VRE were tested in vitro. Daptomycin MICs were <=2 and <=4 µg/ml for E. faecalis and E. faecium, respectively (113).  In vitro studies have demonstrated additive or indifferent interactions with other antibiotics. Antagonism, as determined by kill curve studies, has not been observed. Daptomycin has been reported to show synergism in vitro with aminoglycosides, rifampin and beta lactams against some VRE (38, 243). In an in vitro study using 20 isolates of vancomycin-susceptible E. faecalis, daptomycin showed synergistic activity with ceftriaxone, cefepime and imipenem against 65%, 35% and 35% of the isolates, respectively (243). Unfortunately, very limited clinical data exists. A phase III trial comparing linezolid to daptomycin for the treatment of VRE was terminated early due to difficulty enrolling patients (33). Daptomycin-resistant strains are very difficult to generate in vitro (38, 238, 242). Resistance to daptomycin on therapy with the agent is rare, having been reported in 3 patients with enterococcal infection. The emergence of resistance to daptomycin occurred in 2 of more than 1000 (<0.2%) infected subjects across the entire set of Phase 2 and 3 clinical trials (one S. aureus and one E. faecalis). A case was reported where there was emergence of daptomycin resistance (MICs >32 µg/ml) in E. faecium during daptomycin therapy (140). Furthermore, a case of daptomycin resistance that developed during daptomycin therapy for E. faecalis has also been reported (178). At this time, no mechanism of resistance to daptomycin has been identified, there are no known transferable elements and cross-resistance has not been observed with any other class of antibiotic. Daptomycin appears to be a promising drug with good in vitro bactericidal activity against enterococci regardless of vancomycin susceptibility; however, data regarding clinical outcomes is lacking.

Tigecycline is a semisynthetic glycylcycline antimicrobial agent that is similar in structure to minocycline, but with excellent in vitro activity versus gram-positive bacteria including VRE. It is a bacteriostatic agent in vitro versus enterococci. The agent has been recently approved in the United States for therapy of complicated skin soft tissue and intraabdominal infection. It has linear pharmacokinetics, has a Cmax of 0.87 µg/ml a Cmin of 0.13 µg/ml, and AUC0-24hrs of 4.7 µg/h/ml, a t ½ of 42 hrs and significant tissue uptake (179). The drug is administered by intravenous infusion only, and in initial clinical trials had nausea that was more common than comparators (190, 245).

Antimicrobial agents undergoing development include dalbavancin and oritavancin which are both new glycopeptides, the lipoglycopeptide telavancin, and iclaprim, which is a diaminopyrimidine inhibitor of microbial dihydrofolate reductase. Dalbavancin is an investigational semisynthetic, glycopeptide antibiotic with excellent in vitro activity against gram-positive bacteria. It is active in vitro against vancomycin susceptible enterococci, and vancomycin resistant enterococci containing the VanB phenotype (250). It is structurally related to teicoplanin, and thereby will likely be of limited utility for therapy of vancomycin-resistant enterococci (154). Dalbavancin has a long half life 9-12 d; a single infusion of 1000mg results in mean plasma concentrations of >35mg/L for a 7 day period (94). It is being studied in skin soft tissue and catheter bloodstream infection with preliminary results showing clinical and bacteriologic success rates similar to comparators (94, 218) The oligosaccharide, evernimicin, and fluoroquinolone clinafloxacin exhibit good in vitro enterococcal activity, but did not complete clinical trials. (46, 80, 115, 119, 139, 187, 234, 237, 269). The new aminoglycoside arbekacin shows preliminary promise in treating some high-level gentamicin-resistant enterococci. Arbekacin is currently available only in Japan, where it is used to treat gentamicin- and methicillin-resistant Staphylococcus aureus infections (197).

ADJUNCTIVE THERAPY

Although infections by VRE and VREF appear to be increasing, such organisms are not necessarily highly virulent. There may be clinical settings where the patient will recover even when no appropriate antimicrobial therapy is available. For example, catheter-related bacteremias might sometimes be treatable with catheter removal alone (88, 129). Surgical site infections, skin and soft tissue infections, and intraabdominal abscesses may be manageable by surgical debridement and drainage and treated with antibiotics active against other gastrointestinal flora (44, 88, 129).

ENDPOINTS FOR MONITORING THERAPY

Duration of antimicrobial therapy for enterococcal infections depends predominantly on the site of infection and the patient’s clinical response to therapy. Treatment for simple urinary tract infections may require only a few days of oral or intravenous antibiotics. Bacteremia without endocarditis may require 10 to 14 days of antibiotics and typically depends on how quickly the patient responds to therapy. If the source of infection cannot be removed, such as central venous catheters that must remain or abscesses that cannot be drained, the duration of antimicrobial therapy might naturally be longer. As mentioned previously, endocarditis in certain clinical situations can require a minimum of 6 weeks of antibiotics.

VACCINES

There are no vaccines for this bacterium.

INFECTION CONTROL

Colonized patients are the primary reservoir of VRE. Patient to patient transmission occurs primarily via indirect transmission by health-care workers (34). Medical devices, such as electronic rectal thermometers, have also been implicated (147). VRE are relatively hardy and can persist for prolonged periods in the environment, and the immediate surroundings of a colonized patient may be heavily contaminated (20). The role of environmental contamination in transmission remains to be precisely defined. The epidemiology of vancomycin resistant E. faecalis is similar to that of vancomycin resistant E. faecium (196).

The Hospital Infection Control Practices Advisory Committee (HICPAC) has published “Recommendations for Preventing the Spread of Vancomycin Resistance” (92). They are summarized in Tables 3 and 4.

Key principals underlying an effective control strategy include:

1. The hospital laboratory must be able to accurately identify VRE. Automated microtitre systems may be unreliable.

2. The number of asymptomatically colonized patients exceeds the number of clinically infected patients by many fold. The former group of patients are a reservoir for spread of VRE; surveillance via stool or rectal swab cultures of patients at risk are needed to detect VRE carriage.

3. VRE infected or colonized patients must be identified and placed into appropriate isolation as rapidly as possible.

4. Since most transmission occurs via health care workers, hospital staff must be familiar with, and must follow, isolation and control procedures (Table 4).

5. Contamination of the environment and of medical equipment may play a role in transmission; effective disinfection procedures are necessary.

6. VRE carriers who are re-admitted or transferred to other facilities must be quickly identified and placed into isolation.

7. Antibiotic usage should be controlled. Although current CDC recommendations stress control of vancomycin usage, the strength of the association between VRE and vancomycin is controversial (see Section II-C). Reduction in the use of cephalosporins and agents with potent anaerobic activity may be beneficial.

Implementation of a multi-faceted control strategy such as that outlined in the HICPAC recommendations has reportedly led to a reduction in the rate of VRE transmission in several acute care facilities. In the setting of an acute outbreak in a facility or unit in which VRE was previously present at low levels, vigorous implementation of such a strategy may lead to the elimination of VRE (66) or return to baseline levels (27). Even after establishment of endemic VRE in a facility, transmission can be significantly reduced by a sustained and vigorous intervention that addresses key control issues (173). A coordinated, multi institutional control strategy has resulted in a sustained reduction in the prevalence of VRE among hospitals and long-term care facilities in a large geographic region (198).

The majority of patients colonized with VRE in long-term care facilities appear to have acquired the organism during an acute care hospitalization (184). Patient to patient transmission appears to occur at a much lower rate than in acute care facilities. This may be due to the lower level of medical care and infrequency of invasive procedures in long-term care. Thus, there is little justification for denying a patient colonized with VRE to a long-term care facility. Administration of antibiotics prolongs the duration of VRE carriage in long-term care patients; thus antibiotics should be administered only when clearly indicated. Recommendations for control of VRE in the long term care facility have been published (Table 5).

Testing of the molecular relatedness of isolates is a well established method for investigation of epidemics of hospital acquired infection. Pulse field gel electrophoresis is the method of choice for delineation of the relatedness of strains, however for evaluation of the possibility of gene dissemination, PCR methods are needed (55, 70). The use of the tests for endemic infection control requires further investigation. In one Chicago hospital system (210, 211) ,data on nosocomial infection was collected during a 24 month period before and 60 month after implementing a new program that included routine molecular testing of VRE, drug resistant gram-negative bacteria and methicillin-resistant Staphylococcus aureus. During the intervention period, infections per 1,000 patient days fell 13 percent, and the percentage of hospitalized patients with nosocomial infections decreased 23 percent. The rate of infection fell to 43 percent below the U.S. rate. Approximately 50 deaths were avoided in a 5 year period. The typing laboratory costs for the program were $ 400,000 per year, with a savings of $5.00 for each dollar spent in relation to nosocomial infection reduction. In this study, cost savings by use of the molecular tests for endemic nosocomial infection were accomplished by a combination of establishment of clonality of isolates so that early intervention could be accomplished and by determination of the unrelatedness of isolates, thereby avoiding unneeded and costly epidemic investigation. Cost reduction was also accomplished by earlier recognition of person to person spread of isolates as compared to traditional surveillance, and molecular testing was used to establish the presence of pseudoepidemics also avoiding further epidemic investigation.

SUMMARY AND CONCLUSION

Although part of the normal intestinal flora and once felt to be innocuous endogenous pathogens, enterococci have proven to have much more complex interactions with the human host, having emerged in recent years as important nosocomial pathogens. Strains with resistance to multiple antimicrobials are on the rise, posing significant therapeutic and epidemiological challenges. In order to achieve the goal of minimizing the impact of resistance, a more comprehensive, multidisciplinary effort is needed, including a better understanding of the epidemiology and pathogenicity of these micro-organisms, judicious use of antimicrobials, effective infection control measures in hospitals, and reduction of resistance in reservoirs including the environment and animal husbandry.

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Table 1. Antimicrobial Therapy for Enterococcus faecalis Susceptible to Glycopeptides [Download PDF]

Infection	Antibiotic(s) primary: alternative	Comments
Urinary tract infection  Intraadominal infection	Ampicillin: Vancomycin, Nitrofurantoin Fosfomycin Ampicillin: Beta lactamase inhibitors, Vancomycin	Nitrofurantoin only for (cystitis) with isolates susceptible, not in sepsis or renal failure, usual duration 7-10d Not essential to treat for Enterococcus in all intraabdominal infection, unless organisms cultured, patient severely ill, duration 10-14d
Endocarditis	Ampicillin or Penicillin plus Gentamicin: Streptomycin, vancomycin (Penicillin allergy)	To be used in combination  for the treatment of enterococcal endocarditis caused by organisms susceptible in vitro to either agent; streptomycin is used when gentamicin cannot be used because of high level resistance. Ampicillin plus gentamicin for 4-6 weeks is treatment of choice for endocarditis
Intravenous Catheter Bacteremia	Ampicillin: Vancomycin	Duration 10-14d, some patients (single positive blood culture will respond to removal of the line alone

 See table 2 for drug dosages

Table 2. Antimicrobial Therapy for Vancomycin Resistant Enterococci (VRE)[Download PDF]

Antibiotic(s) primary	Dose, Duration	Comments
Ampicillin	12g/d IV	For rare ampicillin-susceptible isolates of Enterococcus faecium;vancomycin resistant E. faecalis are usually susceptible
Gentamicin or streptomycin	1 mg/kg q 8 hrs to achieve serum peaks of 3-4 mg/ml and trough <1 mg/ml for endocarditis, treat for at least 4-6 weeks	To be used in combination with ampicillin for the treatment of enterococcal endocarditis caused by organisms susceptible in vitro to either agent; streptomycin is used when gentamicin cannot be used because of resistance
Linezolid	600 mg PO or IV q 12 hr	For linezolid-susceptible isolates of E faecium and E faecalis.  An agent of choice for serious enterococcal VREF infections
Daptomycin	Use dose of 6 mg/kg/24 hrs for serious enterococcal infection; 6-8 weeks for endocarditis.	Not approved for treatment of VRE infection. Not approved for treatment of endocarditis. Limited clinical information for VREF, but bactericidal activity makes therapy with this is agent a consideration for serious infections
Antibiotic(s) alternative	Dose, Duration	Comments
Doxycycline	100 mg PO or IV q 12 hr	Not a first line therapy. For susceptible isolates, not bacteremia or endocarditis
Nitrofurantoin	100 mg PO Q 6 hr	For urinary tract infections (cystitis) with isolates susceptible to nitrofurantoin, not indicated in renal failure
Fosfomycin	3 g X1	For urinary tract infections (cystitis) with isolates susceptible to fosfomycin
Chloramphenicol	50 mg/kg/d IV (in q 6hr divided doses)	For chloramphenicol-susceptible isolates of E faecium and E. faecalis. Not a first-line therapy
Tigecycline	100 mg IV then 50 mg IV q 12 hrs	Not indicated for VRE, approved in US for skin soft tissue infection, excellent in-vitro activity vs VRE
Quinupristin/dalfopristin	7.5 mg/kg Q8hr IV	For-susceptible isolates of E faecium only

Table 3. Summary of Recommendations for Preventing the Spread of Vancomycin Resistance (adapted from CDC-HICPAC). [Download PDF]

1. Appropriate use of vancomycin
	a. Treatment of infection due to B-lactam resistant gram-positive organisms.  b. Treatment of infection due to gram-positive organisms in patients with serious beta-lactam allergy. c. Treatment of antibiotic associated colitis in cases of metronidazole failure or potentially life threatening illness.  d. Endocarditis prophylaxis, as recommended by the American Heart Association (Dajani).  e. Prophylaxis for surgical procedures involving implantation of a prosthesis in institutions with a high rate of infection due to MRSA or methicillin-resistant S. epidermidis.
2. Education Program
	a. Include physicians, nurses, pharmacy and laboratory personnel, students, and all other direct patient care providers.  b. Program should include information on epidemiology of VRE and impact of VRE on cost and outcome of patient care.
3. Role of the Microbiology Laboratory
	a. Laboratory should be able to identify and speciate enterococci. b. Fully automated methods of testing enterococci for susceptibility testing are unreliable; disk diffusion, gradient disk diffusion, agar dilation, or manual broth dilution are acceptable.  c. Vancomycin resistance should be confirmed by repeating one of the above tests, or by streaking onto brain heart infusion containing 6 ug/ml of vancomycin. Preliminary and confirmatory identification of VRE should be immediately reported to patient care personnel and infection control.  d. Screening for VRE should be conducted periodically in hospitals where VRE has not been previously detected.
4. Prevention and control of nosocomial transmission of VRE
	a. For all hospitals, including those with no or infrequent isolation of VRE:
		1. Notify appropriate staff immediately when VRE are detected.  2. Educate clinical staff about hospital policies regarding VRE colonized or infected patients so that appropriate procedures can be implemented immediately.  3. Establish systems for monitoring process and outcome measures.  4. Isolation precautions to prevent patient to patient transmission of VRE: REFER TO TABLE 2.
	b. In Hospitals with endemic VRE of continued VRE transmission despite implementation of above measures:
		a. Focus initial control efforts on critical care units and other areas where VRE transmission rates are highest.  b. Where feasible cohort staff caring for VRE-positive and VRE-negative patients.  c. Carriage of enterococci by hospital staff are rarely implicated in transmission. Investigation and culturing of hospital staff should be at the direction of infection control staff.  d. Verify that environmental disinfection procedures are adequate, and that procedures are correctly performed.  e. Consider sending representative VRE isolates to reference laboratories for strain typing as an aid in identifying reservoirs and patterns of transmission.

Table 4.  Isolation precautions to prevent patient to patient transmission of VRE (Adapted from CDC-HICPAC) [Download PDF]

1. Place VRE colonized or infected patients in single rooms, or cohort with other patients with VRE.
2. Wear gloves when entering the room of a VRE-infected or colonized patient.
3. Wear a gown when entering the room of a VRE-infected or colonized patient if:
	a. Substantial contact with the patient or environmental surfaces in the room is anticipate.  b. The patient is incontinent  c. The patient has an ileostomy, colostomy or wound drainage not contained by dressing.
4. Remove gloves and gown before leaving the patient’s room and wash hands immediately with an antiseptic soap or waterless antiseptic agent.
5. Dedicate the use of non-critical items, such as stethoscope, sphygmomanometer or rectal thermometer to a single patient or cohort of isolated patients. Devices must be disinfected before used on other patients.
6. Obtain stool or rectal swab cultures of roommates of patients newly found to be infected of colonized with VRE. Perform additional patient screening at the discretion of the infection control staff.
7. Adopt a policy for determining when patients infected or colonized with VRE can be removed from isolation precautions. As VRE colonization may be prolonged, negative cultures from multiple sites on 3 separate occasions at least one week apart is recommended.
8. The hospital should adopt a system by which infected and colonized patients can be recognized and placed into isolation promptly on transfer or re-admission.
9. Develop a plan, in consultation with public health authorities, for discharge or transfer of colonized or infection patients to other health facilities, including nursing homes and home health care.

Table 5. Recommendations for control of VRE in long-term care facilities (adapted from Brennen et al.) [Download PDF]

1. Patients colonized with VRE should not be denied admission to long-term care.

2. Patients colonized with VRE should be placed in private rooms or cohorting them with other colonized patients.

3. Staff should wear gowns and gloves during patient activities likely to result in VRE transmission. This includes dressing changes, bathing, changing bed linens, toileting, and care of indwelling catheters.

4. Hands must be washed after patient contact.

5. Patients who are colonized with VRE who are continent of stool and who do not have wounds that cannot be contained by dressings may attend activities such as physical therapy and recreation.

6. Antibiotic therapy should be given only when clearly indicated.

7. If a patient colonized with VRE is transferred to another health care facility, the receiving institution should be notified of the patient’s status.

What's New

Heintz BH, et al. Vancomycin-resistant enterococcal urinary tract infections. Pharmacotherapy 2010;30(11):1136-49.

Ergaz Z, et al. Elimination of Vancomycin-Resistant Enterococci from a Neonatal Intensive Care Unit Following an Outbreak. J Hosp Infect. 2010 Apr;74:370-6.

Kosowska-Shick K, Clark C, et al. Activity of Telavancin Against Staphylococci and Enterococci Determined by MIC and Resistance Selection Studies. Antimicrob Agents Chemother. 2009 Oct; 53:4217-24.

Theilacker C, Jonas D, et al. Outcomes of Invasive Infection due to Vancomycin-Resistant Enterococcus faecium during a Recent Outbreak. Infection. 2009 Aug 7. [Epub ahead of print]

Climo MW et al. The Effect of Daily Bathing with Chlorhexidine on the Acquisition of Methicillin-Resistant Staphylococcus aureus, Vancomycin-resistant Enterococci, and Healthcare-associated Bloodstream Infections: Results of a Quasi-experimental Multicenter Trial. Crit Care Med. 2009 Apr 20. [Epub ahead of print]

Hall RG 2nd, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med. 2008 Jun; 121(6):515-8.

Arias CA, et al.  Failure of daptomycin monotherapy for endocarditis caused by an Enterococcus faecium strain with vancomycin-resistant and vancomycin-susceptible subpopulations and evidence of in vivo loss of the vanA gene cluster. Clin Infect Dis 2007; 45:1343-1346.

Cunha BA, et al.  E. faecalis vancomycin-sensitive enterococcal bacteremia unresponsive to a vancomycin tolerant strain successfully treated with high-dose daptomycin.  Heart Lung 2007;36(6):456-61.

Gavalda J, et al.  Brief Communication: Treatment of Enterococcus faecalis Endocarditis with Ampicillin plus Ceftriaxone.  Ann Intern Med 2007;146:574-579.

Milstone AM, et al.  Cerebrospinal Fluid Penetration and Bacteriostatic Activity of Linezolid against Enterococcus faecalis in a Child with a Ventriculoperitoneal Shunt Infection.  Pediatr Neurosurg 2007;43:406-409.

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