Enterococci Infections in Transplant Recipients

Authors: Katherine Reyes, M.D., Marcus Zervos, M.D.

Enterococci are gram-positive, facultative anaerobic cocci that are morphologically similar to streptococci on gram strain (63). 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. There have been 23 enterococcal species identified (50). 60% of isolates from monitored infections are Enterococcus faecalis and 20% are Enterococcus faecium. The others are E. casseliflavus, E. gallinarum, E. avium, E. raffinosus, E. hirae, E. cecorum, E. durans, and E. mundtii (86).

Enterococci are the second leading cause of nosocomial infection, the second most common pathogen for nosocomial bacteremia, and the most common cause of hospital acquired urinary tract infection (37). It ranks second as a cause of catheter-associated blood stream infection in general medical patients (52). Attributable mortality when isolated from the blood is up to 36% (11). The emergence of resistant strains, especially of vancomycin-resistant enterococci (VRE), has led to their emergence as super-infecting nosocomial pathogens in immune compromised patients in the hospital setting. Patients with VRE when compared with matched controls have a longer hospital length of stay, 15.1 vs. 8.5 days, higher costs, $52,449 vs. 31,915, greater chance of admission to the intensive care unit 25 vs. 14%, and transfer to extended care facility, 51 vs. 35% (11). Recent data showed a significant increase in the isolation of glycopeptide-resistant enterococci from patients hospitalized in the transplant surgery ward. In this study there was an increase from 1.3% of 160 enterococcal strains isolated in 2004 to 18% of enterococci resistant to vancomycin in 2005 (57).

Vancomycin resistant enterococci colonize then infect the ill, immunosuppressed patients. The gastrointestinal tract is the most important reservoir. Enteric VRE colonization usually precedes infection. Skin colonization is frequent via the patients’ feces. VRE also contaminate the patients’ environment, and have been isolated from health care workers’ hands/gloves (78). The most important control measures include control of antimicrobial agents and measure to interrupt indirect contact transmission.


Enterococci are less virulent than many other bacteria that cause infections in humans. E. faecalis factors include cytolysin (“hemolysin”), aggregation substance, gelatinase, serine protease, enterococcal surface protein, Ace protein, and enterococcal polysaccharide antigen. These virulence factors have been associated with adverse effect and mortality in vitro and in animal models (29, 87). The pathogenic role of these factors in human infections has not been established. Enterococci are also capable of producing biofilms (59), and thereby are associated with chronic infections. According to the National Institutes of Health, biofilms contribute to over 80% of microbial infections (47). Bacteria in biofilms colonize catheters, artificial cardiac pacemakers, prosthetic heart valves and orthopedic devices and in association with antimicrobial resistance results in difficulty to manage these infections.

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Colonization of the intestinal tract is a key factor in the development of infection. Overall prevalence rate of fecal VRE colonization was 13.6% (24). Multivariate models have shown the presence of an invasive device and the duration of any antimicrobial treatment predicted colonization. The crude mortality rate for patients with VRE colonization was 24.5% but VRE colonization was not an independent predictor of mortality (75). Once colonized, persistence and level of colonization will be affected by use of antimicrobial agents (18). Whether vancomycin resistant enterococcal colonization leads to infection depends on the health status of the patient. Whereas immunocompetent patients colonized with VRE are at low risk for infection, compromised hosts such as transplant recipients have an increased likelihood of developing infection following colonization. Patients colonized with VRE either before or after transplant tend to have longer stays in the hospital, with mortality at 90 days significantly greater among those who acquired VRE after transplant (53). Stem cell transplant patients colonized with VRE were twice as likely to die by day 100 post transplant compared to non-colonized patients (98), while among liver transplant candidates and recipients those with VRE colonization had an increased risk of both VRE infection and of death compared with non-colonized patients (73). There is no significant difference in the prevalence or incidence of new colonization between non-transplant patients and prior or current transplant recipients, although overall prevalence at admission is usually higher in the prior transplant group (10). Genotypic analysis of VRE isolates from transplant patients showed that a proportion of cases of newly detected VRE carriage may represent prior colonization not detected at admission (10).

Risk factors for acquisition of or infection with vancomycin-resistant enterococci include admission to a critical care unit, severity of illness, temporal and geographic exposure to other patients with VRE, duration of hospitalization, and exposure to antimicrobials. Antimicrobial activity against anaerobes appears to be the most important factor for promoting persistent high-density VRE stool colonization in the mouse model (16). Antimicrobial agents with minimal enterococcal activity (e.g., ticarcillin, vancomycin, ceftriaxone) promote establishment of VRE colonization while those with more potent activity inhibit colonization in the mouse model (17). Factors associated with VRE bacteremia are hematologic malignancy, solid-organ transplant, liver cirrhosis, kidney disease with or without dialysis, pressure ulcer, invasive devices, and immunosuppressive therapy (89).

Among liver transplant patients, enterococcus is the most commonly isolated from bile samples in the early period after transplantation (41), and the second cause of gram positive blood stream infection (8). VRE infection is associated with prior antibiotic use, multiple abdominal surgeries, biliary complications. Significant risk factors for enterococcal bacteremia after liver transplant are Roux-en-Y choledochojejunostomy, a cytomegalovirus-seropositive donor, prolonged transplantation time, and biliary structuring. VRE infected patients also utilized more hospital resources (26), and resulted to a decreased survival compared to non-VRE control patients (8). In renal transplant patients enterococcus is the second most common organism causing urinary tract infections (3), and the fourth leading cause of antimicrobial-resistant bacterial infections (48). Among heart transplant recipients, it is the second cause of ventricular assist devices infection used as a bridge to cardiac transplantation. Patients with infected ventricular assist devices wait longer for transplantation while those who develop enterococcus ventricular assist devices endocarditis have a shorter survival (61). In stem cell transplant recipients, vancomycin-resistant enterococcal bloodstream infection has been shown to develop in 34.2% of colonized patients by day 35, compared to 1.8% without colonization (92). VRE bacteremia was associated with a significant decrement in survival and frequent microbiologic failure, despite therapy (92).

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Clinical Manifestations

Since the human reservoir is the gastrointestinal tract, polymicrobial infections involving the gastrointestinal tract, urinary tract, and female genital tract are the primary infections caused by enterococci. Urinary tract infections and bacteremia are among the most common infections encountered. Endocarditis is the most serious infection caused by enterococci, majority of VRE endocarditis are due to E. faecium and are hospital-acquired, with the common underlying diseases being dialysis and transplantation (80). It ranks high as a common cause of surgical site infections in liver and kidney transplant patients (6, 71), often as part of mixed infection. Enterococcal meningitis is rare but has an overall mortality of 21% (68). Most infections are caused E. faecalis. The presence of severe underlying disease is the most important prognostic factor associated with mortality with odds ratio of 6.8 (68). Enterococcal meningitis may be categorized as postoperative or spontaneous, with spontaneous infections having a higher frequency of bacteremia. Much less common enterococcal infections are osteomyelitis, septic arthritis. Enterococcal-associated lower respiratory tract infections have been reported (33), however are very rare, and sputum cultures when positive for enterococcus can usually be disregarded.

Laboratory Diagnosis

Enterococci are 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 (31). 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. For in vitro susceptibility testing, the VITEK2 version 4.01 software is reliable for the identification and detection of glycopeptide-resistant enterococci.  This was compared to the reference broth microdilution method and showed overall essential agreements for antimicrobial susceptibility testing with results of 94.2% for vancomycin, 95.9% for teicoplanin, 100% for quinupristin-dalfopristin and 97.5% for linezolid (1).

Molecular techniques such as polymerase chain reaction along with standard culture studies are being used to detect VRE colonization, infection, and outbreaks (98). Newer techniques are available for more rapid identification of strain. Polymerase chain reaction has been used to detect the presence certain resistance genes in VRE (72). The more rapid tests allow for quicker identification of patients with VRE which is of use for treatment and control purposes.

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Enterococci are intrinsically resistant in vitro to many antimicrobial agents that are active against gram positive cocci including cephalosporins, macrolides, and clindamycin. Agents 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, and gatifloxacin), chloramphenicol and rifampin. The streptogramin combination quinupristin/dalfopristin, glycolipopeptides (daptomycin), glycylcycline tigecycline and oxazolidinone (linezolid) are active in vitro versus most strains. The penicillins and the glycopeptides have the best activity, and ampicillin typically has greater in vitro killing ability than vancomycin (13).

Glycopeptide and beta-lactam resistance is now a common feature of the majority of the E. faecium hospital isolates. Resistance to aminoglycosides, quinupristin-dalfopristin, linezolid (39) and daptomycin (40) has likewise emerged.


High-level gentamicin resistance (minimum inhibitory concentrations of 500 - 2,000 mg/ml) in enterococci is usually due to the presence of the “bifunctional” aminoglycoside-modifying enzyme (66). High-level streptomycin resistance can be caused by a gene that encodes the streptomycin-modifying enzyme or by a change in the ribosome binding site, and also eliminates synergism with the cell wall-active agents (21). High-level penicillin resistance is due predominantly to modification of penicillin-binding proteins which result to low affinity for the penicillins (4). Glycopeptide resistance in turn is due the synthesis of modified peptidoglycan precursors that have decreased affinity for vancomycin and teicoplanin (2, 45). Most glycopeptide-resistant clinical isolates are of the VanA or VanB phenotype, although VanA to VanG phenotypes have been described. Emerging linezolid resistance has been reported which has included small clusters of infection and may be related to prolonged linezolid use (90). 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 (28). Resistance to daptomycin of both E. faecalis and E. faecium could develop during daptomycin therapy (46, 62). 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. Quinupristin-dalfopristin resistance is considered to be linked to agricultural use of streptogramin (36, 90).

Currently, multi-drug resistant enterococci occurs in both acute and long term care settings. In a study of gram positive bacterial strains collected during 2007 to 2008 among hospitals located in the United States, vancomycin resistance rate among E. faecalis and E. faecium were 5.4% and 75.4%, respectively (74). In the same study none of the E. faecalis, and 0.5% of E. faecium were resistant to daptomycin, with very similar minimum inhibitory concentrations distributions to daptomycin when compared from strains of 2002 to 2003. E. faecalis that are vancomycin resistant containing an INC18 plasmid in patients co-colonized with MRSA have been linked to development of vancomycin resistant Staphylococcus aureus (72).

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Ampicillin is the treatment of choice for susceptible strains of enterococci. Strains that produce beta-lactamase are resistant to ampicillin, although when initially identified were a concern, these strains have now disappeared (30). For beta-lactamase-producing enterococci, ampicillin/sulbactam may be used. If the organism is resistant to ampicillin, or a patient is intolerant of penicillin, a glycopeptide such as vancomycin may be used for monotherapy. Combination therapy with the addition of gentamicin is used for enterococcal endocarditis. Streptomycin can be used if gentamicin resistant, streptomycin susceptible. Individual isolates maybe susceptible to nitrofurantoin and tetracycline but are poor agents for treatment with resistance generally emerging quickly.

New antimicrobial agents, such as tigecycline, lipoglycopeptides (dalbavancin, oritavancin, and telavancin) and cephalosporins with activity against E. faecalis, may have potential activity against certain resistant enterococcal strains in specific clinical settings, as may some older antibiotics, such as ampicillin, chloramphenical, doxycycline, minocycline and nitrofurantoin (5). Telavancin at clinically attainable concentrations is shown to be active against bacteria embedded in biofilm and inhibited biofilm formation at concentrations below the MIC (44). This agent should be only considered for patients with vancomycin susceptible enterococci.

The newer Food and Drug Administration approved drug for specific enterococcal infections are as follows, urinary tract infection: linezolid; bacteremia: linezolid and quinipristin-dalfopristin; complicated intraabdominal infection: tigecycline (vancomycin susceptible enterococci); complicated skin and skin structure infection: linezolid, daptomycin (vancomycin susceptible enterococci), tigecycline (vancomycin susceptible enterococci), quinipristin-dalfopristin, telavancin (vancomycin susceptible enterococci).

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. A summary of treatment recommendations for enterococcal infection due to strains susceptible in vitro to glycopeptides is shown in  Table 1.

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Urinary tract infections are the most common clinical infection caused by enterococci. It is also the most predominant infectious complication after renal transplantation, and as a result symptomatic urinary tract infections among these patients warrant pathogen-specific therapy guided by culture and susceptibility data (3). Therapy of asymptomatic bacteriuria is generally not needed (3). Enterococcal urinary tract infections not accompanied by bacteremia generally require only single drug therapy. If the organism is susceptible, and the patient is not allergic to therapy, 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.

Complicated urinary tract infections such 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 (67, 84). Oral rifampin plus nitrofurantoin was shown effective for chronic prostatitis due to vancomycin-resistant E. faecium for susceptible isolates (84).


Intraabdominal infections are polymicrobial in origin in which coverage for enteric bacteria (Escherichia coli, Klebsiella pneumonia, etc.), and anaerobes (Bacteroides fragilis), must be covered including Enterococcus species. Broad spectrum therapy for the gastrointestinal flora include ampicillin/sulbactam, piperacillin/tazobactam, tigecycline and imipenem. Linezolid showed a trend toward improved survival in liver transplant patients (26).

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Bacteremia in the absence of endocarditis without an identifiable focus is generally related to an indwelling venous catheter when it occurs in the hospital setting (77). For catheter-related blood stream infection due to enterococcus, current guidelines recommend removal of short term central venous catheters with directed antimicrobial therapy for 7 to 14days, while salvage of long term catheters may be considered with antimicrobial therapy for 7 to 14 days with the condition that if the patient deteriorates or has persistent bacteremia such catheters need to be removed (55). Vancomycin resistance and the emergence of linezolid resistance among enterococci strains causing bacteremia necessitate alternative therapies. Daptomycin is a useful agent (25, 60). In a retrospective study involving thirty patients, the median duration of therapy on daptomycin was 13 days (range 1-42 days), median dose administered was 6 mg/kg (range 3.7-8 mg/kg), microbiologic cure was achieved in 80% of the patients, and clinical success occurred in 59% (25). The addition of gentamicin does not alter the pharmacokinetic profile or enhance the bactericidal activity of daptomycin against enterococcal isolates (15).


The necessity for combination antibiotic therapy is well established for enterococcal endocarditis. Penicillin (or ampicillin) plus gentamicin is the most commonly used combination regimen for enterococcal endocarditis, although penicillin plus streptomycin has been the most studied combination. 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 (93). Penicillin (or ampicillin) plus gentamicin is the well-accepted regimen given the tolerability and toxicities of both aminoglycosides, and given the sufficient number of patients who have been treated successfully (94). Gentamicin is usually given at doses 1 ug/kg intravenously every eight hours with target peak serum levels of  > 3 ug/ml (94), and serum trough levels of 1 to 2. The recommended streptomycin dosing in enterococcal endocarditis is 7.5 mg intramuscularly every 12 hours, with target peak serum levels of 15-30 ug/ml (94). Treatment should continue for at least 6 weeks (93). Animal data do not support the use of once-daily dosing of aminoglycosides in enterococcal endocarditis (51). 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 (94).

Endocarditis due to vancomycin resistant enterococcus is rare, with most patients having serious underlying disease including transplantation, dialysis and health care associated infections. Although there are some case reports of linezolid efficacy for VRE infective endocarditis, even in a transplant recipient (7), current overall data remains limited and conflicting. Further studies are needed to elucidate the role of linezolid, or combination therapies in the treatment of infective endocarditis due to VR E. faecalis.

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Most experts would concur that treatment of enterococcal meningitis requires combination therapy so that maximal bactericidal activity may be achieved. However, in contrast to endocarditis, there are scant clinical data available to state unequivocally that combination therapy is superior to monotherapy in meningitis. Base of review of literature, the following have been used to treat enterococcal meningitis, penicillin or ampicillin plus an aminoglycoside, including intrathecal gentamicin (81), ciprofloxacin (42), combination of quinupristin/dalfopristin plus chloramphenicol (32), intrathecal teicoplanin (49), intraventricular plus intravenous quinipristin/dalfopristin plus intravenous chloramphenicol (87), linezolid alone (56, 97), linezolid plus gentamicin (34), and intrathecal streptomycin (88). In a clinical study of 39 cases treated with ampicillin, penicillin or vancomycin, with or without aminoglycosides, the median duration of therapy was 18 days (range 1-85 days), mortality was similar in patients treated with beta-lactams (18%), glycopeptides (14%) or other antibiotics (25%), as well in patients treated with monotherapy (16%) or combination therapy (22%) (68).


The treatment of multidrug-resistant enterococcal infections is a challenge.  Table 2 shows the antimicrobial therapy options. Therapy of strains resistant to aminoglycosides, quinupristin-dalfopristin, linezolid or daptomycin is unsettled.

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 in endocarditis, 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 6 weeks, such as 8 to 12 weeks should be strongly considered (20). 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 (85).

If the strain is resistant to the cell wall-active agents (penicillins and glycopeptides), the antibiotic combinations of cell wall-active agents plus aminoglycosides will no longer be synergistic. There are reports of cure with continuous infusion ampicillin/sulbactam plus gentamicin given every 12 hours (54), suggesting that sulbactam may slightly enhance the activity of ampicillin against certain strains of enterococci. New antimicrobial agents such as tigecycline, lipoglycopeptides (dalbavancin, oritavancin and telavancin) and cephalosporins with activity against E. faecalis (ceftobiprole and ceftaroline) will likely be of limited use, because of concurrent resistance to these agents. Other bacteriostatic antimicrobials with less in vitro activity than the penicillins, glycopeptides, and aminoglycosides have been tried either alone or in combination against multiresistant enterococci such as oral rifampin plus nitrofurantoin (84), chloramphenicol, doxycycline, minocycline and nitrofurantoin for selected infections (5).

The oxazolidinones are a new class of antimicrobials that inhibit bacterial protein synthesis. Linezolid is a semisynthetic oxazolidinone agent that exhibits bacteriostatic in vitro and in vivo activity against enterococci (9).  Time-kill studies with linezolid plus gentamicin did not show in vitro synergism (64). Linezolid use has been reported in immunosuppressed patients. When compared with quinupristin-dalfopristin in a prospective, randomized study linezolid showed comparable efficacy for multiresistant enterococci (70). Although no comparative trials of linezolid have been done in patients with endocarditis, osteomyelitis, or meningitis, multiple case reports have been described.

Daptomycin is a novel cyclic lipopeptide which displays rapid concentration-dependent killing and is bactericidal even in the stationary phase of growth. In vitro studies have demonstrated additive or indifferent interactions with other antibiotics. Daptomycin has been shown to have synergy with rifampicin for certain isolates of vancomycin-resistant enterococci, and in vivo daptomycin with rifampicin was noted to have increased efficacy and reduced the incidence of rifampicin resistance (79). Resistance to daptomycin on therapy with the agent is rare but have been reported. Ampicillin may enhance the activity of daptomycin in VRE infective endocarditis (76).

Tigecycline is a semisynthetic glycylcycline antimicrobial agent that is bacteriostatic agent in vitro versus enterococci. Tigecycline and linezolid inhibit both E. faecalis and E. faecium at low concentrations; daptomycin is somewhat more potent against the latte (22). Tigecycline is administered by intravenous infusion only.

The streptogramin combination quinupristin/dalfopristin has been used successfully for treatment of E. faecium vertebral osteomyelitis, peritonitis, ventriculitis, aortic graft infection, and endocarditis (32, 83, 95, 96). Quinupristin/dalfopristin however is limited by its lack of activity against vancomycin-resistant E. faecalis.

The investigational agents dalbavancin and telavancin are more potent than vancomycin against vancomycin-susceptible organisms. Dalbavancin inhibits vanB type VRE at low concentrations, but is not active against vanA type VRE. Telavancin is less active against VRE than against vancomycin-susceptible enterococci, but minimum inhibitory concentrations are lower than those of vancomycin against VRE (22).

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Although infections by multiresistant enterococci appear to be increasing, such organisms are not necessarily highly virulent. Surgical site infections, skin and soft tissue infections, and intraabdominal abscesses may be manageable by surgical debridement and drainage, accompanied by antibiotics active against other gastrointestinal flora (43). Removal of central venous catheters are recommended for catheter-related blood stream infections. Cardiac valve replacement maybe necessary for enterococcal endocarditis caused by multiresistant strains (58).


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. Endocarditis generally requires a minimum of 6 weeks of antibiotics.


There are no vaccines for this bacterium.


Transmission of enterococcus can occur through direct contact with colonized or infected patients (19), or via contaminated patient care equipments or environmental surfaces. Contamination of hands, gloves and gowns of health care workers during routine care have been documented (35, 78). In a study to characterize infection control experience in cooperative care center for transplant patients over a 6.5 year period, the most common healthcare-associated infection was intravascular catheter-related bloodstream infection (65). There was no evidence of environmental contamination with vancomycin resistant enterococci, but acquisition was documented (65). Surface contamination with VRE has been shown to be secondary to failure to clean rather than to a faulty cleaning procedure or product (38). Increasing the volume of disinfectant applied to environmental surfaces, providing education for Environmental Services staff, and instituting feedback with black-light marker improved cleaning and reduced the frequence of VRE contamination (29). Daily chlorhexidine bathing among intensive care unit patients may reduce the acquisition of VRE by 50%, with significant reductions in bacteremia (14). Control measures to reduce the incidence of vancomycin resistant enterococci colonization and infection have included education of health care personnel with implementation of hand-washing practices and compliance, targeted surveillance cultures, isolation, pre-emptive isolation of high-risk patients, and restriction of antibiotic use (82).

Several studies have reported controlling VRE infection by means of active detection by surveillance culture and use of isolation for all colonized patients in healthcare settings where the pathogens are epidemic or endemic, in academic and nonacademic hospitals, and in acute care, intensive care, and long-term care settings (23). Active surveillance has likewise been shown to reduced the incidence of VRE bacteremia (69). However the Association for Professionals in Infection Control and Epidemiology, Inc and Society for Healthcare Epidemiology of America do not support legislation to mandate use of active surveillance cultures to screen for VRE (91).

The Hospital Infection Control Practices Advisory Committee has published “Recommendations for Preventing the Spread of Vancomycin Resistance” (12). 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 is 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. Reduction in the use of cephalosporins and agents with potent anaerobic activity may be beneficial.

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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.


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Table 1. Antimicrobial Therapy for Enterococcus Susceptible to Glycopeptides  

Infection Antibiotic(s) primary:alternative Comments
Urinary tract infection






Intraabdominal infection



Nitrofurantoin Fosfomycin



Ampicillin: Beta lactamase inhibitors, Vancomycin
Nitrofurantoin is only for cystitis with isolates susceptible, not for use in sepsis or if with 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 Emphasis on removal of the line

 See table 2 for drug dosages

Table 2. Antimicrobial Therapy for Vancomycin Resistant Enterococci (VRE)

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 ug/ml and trough <1 ug/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 VRE infections.
Daptomycin 6 mg/kg/24 hrs.

6-8 weeks for endocarditis.

Not approved for treatment of VRE infection. Limited clinical information, but bactericidal activity makes therapy with this is agent a consideration for serious infections.
Antibiotic(s) alternative


Dose, Duration


100 mg PO or IV q 12 hr


Not a first line therapy. For susceptible isolates, not for bacteremia or endocarditis
Nitrofurantoin 100 mg PO Q 6 hr For cystitis with isolates susceptible to nitrofurantoin; not to be used if there is renal failure
Fosfomycin 3 g X 1 dose For 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 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).

1.      Appropriate use of vancomycin
  1. Treatment of infection due to B-lactam resistant gram-positive organisms 
  2. Treatment of infection due to gram-positive organisms in patients with serious beta-lactam allergy 
  3. Treatment of antibiotic associated colitis in cases of metronidazole failure or potentially life threatening illness. 
  4. Endocarditis prophylaxis, as recommended by the American Heart Association (Dajani). 
  5. 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
  1. Include physicians, nurses, pharmacy and laboratory personnel, students, and all other direct patient care providers. 
  2. 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
  1. Laboratory should be able to identify and speciate enterococci 
  2. Fully automated methods of testing enterococci for susceptibility testing are unreliable; disk diffusion, gradient disk diffusion, agar dilation, or manual broth dilution are acceptable. 
  3. 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. 
  4. 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
  1. 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
  2. In Hospitals with endemic VRE of continued VRE transmission despite implementation of above measures: 
    1. Focus initial control efforts on critical care units and other areas where VRE transmission rates are highest. 
    2. Where feasible cohort staff caring for VRE-positive and VRE-negative patients. 
    3. 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. 
    4. Verify that environmental disinfection procedures are adequate, and that procedures are correctly performed. 
    5. 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 reference cdc)

  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 anticipated. 

    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.

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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]

Cunha BA, et al.  E. faecalis vancomycin-sensitive enterococcal bacteremia unresponsive to a vancomycin tolerant strain successfully treated with high-dose daptomycin.  Heart Lung 200736(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.

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.

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Clinical Manifestations

Laboratory Diagnosis