Enterococci Infections in Transplant Recipients

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

Monograph
Tables
What's New
Reviews
History

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.

Pathogenesis

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.

Epidemiology

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).

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.

SUSCEPTIBILITY

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.

RESISTANCE MECHANISMS

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).

THERAPY

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.

URINARY TRACT INFECTION

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

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).

BACTEREMIA

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).

ENDOCARDITIS

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.

MENINGITIS

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).

THERAPY FOR MULTIRESISTANT ENTEROCOCCI

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).

ADJUNCTIVE THERAPY

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).

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

PROPHYLAXIS

There are no vaccines for this bacterium.

INFECTION CONTROL MEASURES

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.

SUMMARY AND CONCLUSIONS

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.

REFERENCES

1. Abele-Horn M, Hommers L, Trabold R, Frosch M. Validation of VITEK 2 version 4.01 software for detection, identification, and classification of glycopeptides-resistant enterococci. J Clin Microbiol 2006;44:71-6. [PubMed]

2. Alam MR, Donabedian S, Brown W, Gordon J, Chow JW, Zervos MJ, Hershberger E. Heteroresistance to vancomycin in Enterococcus faecium. J Clin Microbiol 2001;39:3379-81. [PubMed]

3. Alangaden G. Urinary Tract Infections in Renal Transplant Recipients. Curr Infect Dis Rep 2007;9:475-9. [PubMed]

4. Al-Obeid S, Gutmann L, Williamson R. Modification of Penicillin-binding proteins of Penicillin-resistant Mutants of Different Species of Enterococci. J Antimicrob Chemother 1990;26:613-8. [PubMed]

5. Arias CA, Murray BE. Emergence and Management of Drug-resistant Enterococcal Infections. Expert Rev Anti Infect Ther 2008;6:637-55. [PubMed]

6. Asensio A, Ramos A, Cuervas-Mons V, Cordero E, Sanchez-Turrion V, Blanes M, Cervera C, Gavalda J, Aguado JM, Torre-Cisneros J. Red de Estudio de la Infeccion en el Trasplante-Grupo de Estudio de la Infeccion en el Trasplante. Effect of Antibiotic Prophylaxis on the Risk of Surgical Site Infection in Orthotopic Liver Transplant. Liver Transpl 2008;14:799-805. [PubMed]

7. Babcock HM, Ritchie DJ, Christiansen E, Starlin R, Little R, Stanley S. Successful Treatment of Vancomycin-resistant Enterococcus Endocarditis with Oral Linezolid. Clin Infect Dis 2001;32:1373-5. [PubMed]

8. Bedini A, Codeluppi M, Cocchi S, Guaraldi G, Di Benedetti F, Venturelli C, Masetti M, Prati F, Mussini C, Borghi V, Girardis M, Gerunda GE, Rumpianesi F, Esposito R. Gram-positive Bloodstream Infections in Liver Transplant Recipients: Incidence, Risk Factors, and Impact on Survival. Transplant Proc 2007;39:1947-9. [PubMed]

9. Bostic GD, Perri MB, Thal LA, Zervos MJ. Comparative In Vitro and Bactericidal Activity of Oxazolidinone Antibiotics Against Multidrug-resistant Enterococci. Diagn Microbiol Infect Dis 1996;173:909-13. [PubMed]

10. Calderwood MS, Mauer A, Tolentino J, Flores E, van Besien K, Pursell K, Weber SG. Epidemiology of vancomycin-resistant enterococci among patients on an adult stem cell transplant unit: observations from an active surveillance program. Infect Control Hosp Epidemiol 2008;29:1019-25. [PubMed]

11. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and Economic Outcomes of Vancomycin-resistant Enterococci. Arch Int Med 2002;162:2223-8. [PubMed]

12. Centers for Disease Control and Prevention. Recommendations for Preventing the Spread of Vancomycin Resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 1995;44(RR-12):1-13. [PubMed]

13. Cercenado E, Eliopoulos GM, Wennersten CB, Moellering RC Jr. Influence of High-level Gentamicin Resistance and Beta-hemolysis on Susceptibility of Enterococci to the Bactericidal Activities of Ampicillin and Vancomycin. Antimicrob Agents Chemother 1992;36:2526-8. [PubMed]

14. Climo MW, Sepkowitz KA, Zuccotti G, Fraser VJ, Warren DK, Perl TM, Speck K, Jernigan JA, Robles JR, Wong ES. The Effect of Daily Bathing with Chlorhexidine on the Acquisition of Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant Enterococcus, and Healthcare-associated Bloodstream Infections: Results of a Quasi-Experimental Multicenter Trial. Crit Care Med 2009;37:2097-8. [PubMed]

15. DeRyke CA, Sutherland C, Zhang B, Nicolau DP, Kuti JL. Serum Bactericidal Activities of High-dose Daptomycin With and Without Coadministration of Gentamicin Against isolates of Staphylococcus aureus and Enterococcus species. Antimicrob Agents Chemother 2006;50:3529-34. [PubMed]

16. Donskey CJ, Hanrahan JA, Hutton RA, Rice LB. Effect of Parenteral Antibiotic Administration on Persistence of Vancomycin-resistant Enterococcus faecium in the Mouse Gastrointestinal Tract. J Infect Dis 1999;180:384-390. [PubMed]

17. Donskey CJ, Hanrahan JA, Hutton RA, Rice LB. Effect of Parenteral Antibiotic Administration on the Establishment of Colonization with Vancomycin-Resistant Enterococcus faecium in the Mouse Gastrointestinal Tract. J Infect Dis 2000;181:1830-1833. [PubMed]

18. Donskey CJ, Chowdhry TK, Hecker MT, Hoyen CK, Hanrahan JA, Hujer AM, Hutton-Thomas RA, Whalen CC, Bonomo RA, Rice LB. Effect of Antibiotic Therapy on the Density of Vancomycin-resistant Enterococci in the Stool of Colonized Patients. N Engl J Med 2000;343:1925-32. [PubMed]

19. Duckro AN, Blom DW, Lyle EA, Weinstein RA, Hayden MK. Transfer of Vancomycin-resistant Enterococci via Health Care Worker Hands. Arch Intern Med 2005;14;165:302-7. [PubMed]

20. Eliopoulos GM. Aminoglycoside Resistant Enterococcal Endocarditis. Infect Dis Clinics N Am 1993;7:117-33. [PubMed]

21. Eliopoulos GM, Farber BF, Murray BE, Wennersten C, Moellering RC Jr. Ribosomal Resistance of Clinical Enterococcal Isolates to Streptomycin. Antimicrob Agents Chemother 1984;25:398-9. [PubMed]

22. Eliopoulos GM. Microbiology of Drugs for Treating Multiply Drug-resistant Gram-positive Bacteria. J Infect 2009;59 Suppl 1:S17-24. [PubMed]

23. Farr BM. What To Think If the Results of the National Institutes of Health Randomized Trial of Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococcus Control Measures Are Negative (and Other Advice to Young Epidemiologists): A Review and an Au Revoir. Infect Control Hosp Epidemiol 2006 Oct;27(10):1096-106. [PubMed]

24. Freitas MC, Pacheco-Silva A, Barbosa D, Silbert S, Sader H, Sesso R, Camargo LF. Prevalence of vancomycin-resistant Enterococcus fecal colonization among kidney transplant patients. BMC Infect Dis 2006 Aug 22;6:133. [PubMed]

25. Gallagher JC, Perez ME, Marino EA, LoCastro LG, Abrardo LA, MacDougall C. Daptomycin therapy for vancomycin-resistant enterococcal bacteremia: a retrospective case series of 30 patients. Pharmacotherapy 2009;29:792-9 [PubMed]

26. Gearhart M, Martin J, Rudich S, Thomas M, Wetzel D, Solomkin J, Hanaway MJ, Aranda-Michel J, Weber F, Trumball L, Bass M, Zavala E, Steve Woodle E, Buell JF. Consequences of vancomycin-resistant Enterococcus in liver transplant recipients: a matched control study. Clin Transplant 2005;19:711-6. [PubMed]

27. Gilmore MS, Coburn PS, Nallapareddy SR, Murray BE. Enterococcal virulence. In: Gilmore MS, ed. The Enterococci. Pathogenesis, Molecular Biology, and Antibiotic Resistance. Washington, DC: ASM Press, 2002:301-354. [PubMed]

28. Gonzales RD, Schreckenberger PC, Graham MB, Kelkar S, DenBesten K, Quinn JP. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001;357:1179. [PubMed]

29. Goodman ER, Platt R, Bass R, Onderdonk AB, Yokoe DS, Juang SS. Impact of an Environmental Cleaning Intervention on the Presence of Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci on Surfaces in Intensive Care Unit Rooms. Infect Control Hosp Epidemiol 2008;29:593-9. [PubMed]

30. Gordon S, Swenson JM, Hill BC, et al. Antimicrobial Susceptibility Patterns of Common and Unusual Species of Enterococci Causing Infections in the United States. J Clin Microbiol 1992;30:2373-8. [PubMed]

31. Gordon DB, DeGirolami PC, Golivar S, Karafotias G, Eichelberger K. A comparison of the identification of group A streptococci and enterococci by two rapid pyrrolidonylaminopeptidase methods. Am. J. Clin. Pathol 1988;89:210–12. [PubMed]

32. Gransden WR, King A, Marossy D, Rosenthal E. Quinupristin/dalfopristin in neonatal Enterococcus faecium meningitis. Arch Dis Child Fetal Neonatal Ed 1998;78:F235-6. [PubMed]

33. Grupper M, Kravisov A, Potasman I. Enterococcal-associated Lower Respiratory Tract Infections: A Case Report and Literature Review. Infection 2009;37(1):60-4. [PubMed]

34. Hachem R, Afif C, Gokasian, Raad I. Successful Treatment of Vancomycin-Resistant Enterococcus Meningitis with Linezolid. Eur J Clin Microbiol Infect Dis 2001;20:432-434. [PubMed]

35. Hayden MK, Blom DW, Lyle EA, Moore CG, Weinstein RA. Risk of Hand or Glove Contamination After Contact With Patients Colonized With Vancomycin-Resistant Enterococcus or the Colonized Patients' EnvironmentInfect Control Hosp Epidemiol 2008;29:149-54. [PubMed]

36. Hershberger E, Donabedian S, Konstantinou K, Zervos MJ. Quinupristin-Dalfopristin Resistance in Gram-Positive Bacteria: Mechanism of Resistance and Epidemiology. Clin Infect Dis 2004;1;38 (1);92-8. [PubMed]

37. Hidron HI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, Fridkin SK. for the National Healthcare Safety Network Team and Participating National Healthcare Safety Network Facilities Antimicrobial-Resistant Pathogens Associated With Healthcare-Associated Infections: Annual Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect Control and Hosp Epidemiol 2008;29:996-1011 [PubMed]

38. Hota B, Blom DW, Lyle EA, Weinstein RA, Hayden MK. Interventional evaluation of environmental contamination by vancomycin-resistant enterococci: failure of personnel, product, or procedure? J Hosp Infect 2009;71(2):123-31. [PubMed]

39. Jenkins I. Linezolid- and vancomycin-resistant Enterococcus faecium Endocarditis: Successful Treatment with Tigecycline and Daptomycin. J Hosp Med 2007;2(5):343-4. [PubMed]

40. Kanafani ZA, Federspiel JJ, Fowler VG Jr. Infective Endocarditis Caused by Daptomycin-resistant Enterococcus faecalis: a Case Report. Scand J Infect Dis 2007;39(1):75-7. [PubMed]

41. Kawecki D, Chmura A, Pacholczyk M, Lagiewska B, Adadynski L, Wasiak D, Malkowski P, Sawicka-Grzelak A, Rokosz A, Szymanowska A, Swoboda-Kopec E, Wroblewska M, Rowinski W, Durlik M, Paczek L, Luczak M. Bacteria isolated from bile samples of liver recipients in the early period after transplantation: epidemiology and susceptibility of the bacterial strains. Transplant Proc 2007;39(9):2807-11. [PubMed]

42. Krcméry V Jr, Filka J, Uher J, et al. Ciprofloxacin in Treatment of Nosocomial Meningitis in Neonates and in Infants: Report of 12 Cases and Review. Diagn Microb Infect Dis 1999;35:75-80. [PubMed]

43. Lai KK. Treatment of vancomycin-resistant Enterococcus faecium infections. Arch Intern Med 1996;156:2579-84.[PubMed]

44. LaPlante KL, Mermel LA. In Vitro Activities of Telavancin and Vancomycin Against Biofilm-produciing Staphylococcus aureus, S. epidermidis, and Enterococcus faecalis Strains. Antimicrob Agents Chemother 2009;53(7):3166-9. [PubMed]

45. Leclercq R, Courvalin P. Resistance to Glycopeptides in Enterococci. Clin Infect Dis 1997;24:545-56. [PubMed]

46. Lewis JS 2nd, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 2005;49(4):1664-5. [PubMed]

47. Lewis K. Riddle of biofilm resistance. Antimicrob Agents Chemother 2001;45:999–1007. [PubMed]

48. Linares L, Cervera C, Cofan F, Ricart MJ, Esforzado N, Torregrosa V, Oppenheimer F, Campistol JM, Marco F, Moreno A. Epidemiology and Outcomes of Multiple Antibiotic–Resistant Bacterial Infection in Renal Transplantation Transplant Proc 2007;39(7):2222-4. [PubMed]

49. Losonsky GA, Wolf A, Schwalbe RS, Nataro J, Gibson CB, Lewis EW. Successful treatment of meningitis due to multiple resistant Enterococcus faecium with a combination of intrathecal teicoplanin and intravenous antimicrobial agents. Clin Infect Dis 1994;19:163-5. [PubMed]

50. Low DE, Keller N, Barth A, Jones RN. Clinical Prevalence, Antimicrobial Susceptibility, and Geographic Resistance Patterns of Enterococci: Results from the SENTRY Antimicrobial Surveillance Program, 1997–1999. Clin Infect Dis 2001;32(suppl 2):S133-S145. [PubMed]

51. Marangos MN, Nicolau DP, Quintiliani R, Nightingale CH. Influence of gentamicin dosing interval on the efficacy of penicillin-containing regimens in experimental Enterococcus faecalis endocarditis. J Antimicrob Chemother 1997;39:519-22. [PubMed]

52. Marschall J, Leone C, Jones M, Nihill D, Fraser VJ, Warren DK. Catheter-Associated Bloodstream Infections in General Medical Patients Outside the Intensive Care Unit: A Surveillance Study. Infect Control Hosp Epidemiol 2007;28(8):905-9. [PubMed]

53. McNeil SA, Malani PN, Chenoweth CE, Fontana RJ, Magee JC, Punch JD, Mackin ML, Kauffman CA. Vancomycin-Resistant Enterococcal Colonization and Infection in Liver Transplant Candidates and Recipients: A Prospective Surveillance Study. Clin Infect Dis 2006;15;42(2):195-203. [PubMed]

54. Mekonen ET, Noskin GA, Hacek DM, Peterson LR. Successful treatment of persistent bacteremia due to vancomycin-resistant, ampicillin-resistant Enterococcus faecium. Microb Drug Resist 1995;1:249-53. [PubMed]

55. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP, Raad II, Rijnders BJA, Sherertz RJ, Warren DK. Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009;1;49(1):1-45. [PubMed]

56. Mizell KN, Carter JE. Vancomycin-resistant Enterococcus faecium Meningitis Successfully Treated with Linezolid. South Med J 2008;101(5):569-70. [PubMed]

57. Mlynarczyk G, Grzybowska W, MlynarczykA, Tyski S, Kawecki D, Luczak M, Chmura A, Rowinski W. Significant Increase in the Isolation of Glycopeptides-resistant Enterococci from Patients Hospitalized in the Transplant Surgery Ward in 2004-2005. Transplant Proc 2007;39(9):2883-5. [PubMed]

58. Moellering RC Jr. The Garrod Lecture. The Enterococcus: A Classic Example of the Impact of Antimicrobial Resistance on Therapeutic Options. J Antimicrob Chemother 1991;28:1-12. [PubMed]

59. Mohamed JA, Huang DB. Biofilm formation by enterococci. J Med Microbiol 2007;56(Pt 12):1581-8. [PubMed]

60. Mohr JF, Friedrich LV, Yankelev S, Lamp KC. Daptomycin for the Treatment of Enterococcal Bacteraemia: Results from the Cubicin Outcomes Registry and Experience (CORE). Int J Antimicrob Agents 2009;33(6):543-87. [PubMed]

61. Monkowski DH, Axelrod P, Fekete T, Hollander T, Furukawa S, Samuel R. Infections associated with ventricular assist devices: epidemiology and effect on prognosis after transplantation. Transpl Infect Dis 2007;9(2):114-20. [PubMed]

62. Munoz-Price LS, Lolans K, Quinn JP. Emergence of resistance to daptomycin during treatment of vancomycin-resistant Enterococcus faecalis infection. Clin Infect Dis 2005;41(4):565-6. [PubMed]

63. Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990;3:46-65. [PubMed]

64. Noskin GA, Siddiqui F, Stosor V, Kruzynski J, Peterson LR. Successful treatment of persistent vancomycin-resistant Enterococcus faecium bacteremia with linezolid and gentamicin. Clin Infect Dis 1999;28:689-90. [PubMed]

65. Nusair A, Jourdan D, Medcalf S, Marion N, Iwen PC, Fey PD, Reed E, Langnas A, Rupp ME. Infection Control Experience in a Cooperative Care Center for Transplant Patients. Infect Control Hosp Epidemiol 2008;29(5):424-9.[PubMed]

66. Patterson JE, Zervos MJ. High-level Gentamicin resistance in Enterococci: Epidemiology, Microbiology and Genetic Basis. Rev Infect Dis 1990;12:644-652. [PubMed]

67. Perri MB, Hershberger E, Ionescu M, Lauter C, Zervos MJ. In vitro Susceptibility of Vancomycin-resistant Enterococci (VRE) to Fosfomycin. Diagn Microbiol Infect Dis 2002;42(4):269-71. [PubMed]

68. Pintado V, Cabellos C, Moreno S, Meseguer MA, Ayats J, Viladrich PF. Enterococcal Meningitis: A Clinical Study of 39 Cases and Review of the Literature. Medicine (Baltimore) 2003;82(5):346-64. [PubMed]

69. Price CS, Paule S, Noskin GA, Peterson LR. Active Surveillance Reduces the Incidence of Vancomycin-Resistant Enterococcal Bacteremia. Clin Infect Dis 2003;1;37(7):921-8. [PubMed]

70. Raad I, Hachem R, Hanna H, Afif C, Escalante C, Kantarjian H, Rolston K. Prospective, randomized study comparing quinupristin–dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections. J Antimicrob Chemother 2004;53(4):646-9. [PubMed]

71. Ramos A, AsensioA, Munez E, Torre-Cisneros J, Montejo M, Aguado JM, Cofan F, Carratala J, Len O, Cisneros JM. Incisional Surgical Site Infection in Kidney Transplantation. Urology 2008;72(1):119-23. [PubMed]

72. Reyes K, Malik R, Moore C, Donabedian S, Perri M, Johnson L, Zervos M. Evaluation of Risk Factors for Co-Infection or Co-Colonization with Vancomycin-Resistant Enterococcus and Methicillin-Resistant Staphylococcus aureus. Accepted for publication, J Clin Microbiol 2009. [PubMed]

73. Russell DL, Flood A, Zaroda TE, Acosta C, Riley MM, Busuttil RW, Pegues DA. Outcomes of Colonization with MRSA and VRE Among Liver Transplant Candidates and Recipients. Am J Transplant 2008;8(8):1737-43. [PubMed]

74. Sader HS, Jones RN. Antimicrobial Susceptibility of Gram-positive Bacteria Isolated from US Medical Centers: results of the Daptomycin Surveillance Program (2007-2008). Diagn Microbiol Infect Dis 2009;65(2):158-62. [PubMed]

75. Sakka V, Tsiodras S, Galani L, Antoniadou A, Souli M, Galani I, Pantelaki M, Siafakas N, Zerva L, Giamarellou H. Risk factors and predictors of mortality in patients colonized with vancomycin-resistant enterococci. Clin Microbiol Infect 2008;14(1):14-21. [PubMed]

76. Sakoulas G, Moise PA, Nizet V. Ampicillin Enhances the Activity of Daptomycin by Alteration of Surface Charge in Vancomycin-resistant Enterococcus faecium. Poster presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy 2009, San Francisco, CA, September 12-15, 2009. Abstract E-806. [PubMed]

77. Sandoe JA, Witherden IR, Au-Yeung HK, Kite P, Kerr KG, Wilcox MH. Enterococcal intravascular catheter-related bloodstream infection: management and outcome of 61 consecutive cases. J Antimicrob Chemother 2002;50(4):577-82. [PubMed]

78. Snyder DM, Thom KA, Furuno JP, Perencevich EN, Roghmann MC, Strauss SM, Netzer G, Harris AD. Detection of Methicillin-resistant Staphylococcus aureus and Vancomycin-resistant Enterococci by Healthcare Workers on Infection Control Gown and Gloves. Infect Control Hosp Epidemiol 2008;29(7):583-9. [PubMed]

79. Steenbergen JN, Mohr JF, Thorne GM. Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies. J Antimicrob Chemother 2009;64(6):1130-8. [PubMed]

80. Stevens MP, Edmond MB. Endocarditis Due to VancomycinResistant Enterococci: Case Report and Review of the Literature. Clin Infect Dis 2005;15;41(8):1134-42. [PubMed]

81. Stevenson KB, Murray EW, Sarubbi FA. Enterococcal meningitis: report of four cases and review. Clin Infect Dis 1994;18:233-9. [PubMed]

82. Tacconelli E, Cataldo MA. Vancomycin-resistant enterococci (VRE): transmission and control. Int J Antimicrob Agents 2008;31(2):99-106. [PubMed]

83. Tan TY, Pitman I, Penrose-Stevens A, Simpson BA, Flanagan PG. Treatment of a vancomycin-resistant Enterococcus faecium ventricular drain infection with quinupristin/dalfopristin and review of the literature. J Infect 2000;41:85-97. [PubMed]

84. Taylor SE, Paterson DL, Yu VL. Treatment options for chronic prostatitis due to vancomycin-resistant Enterococcus faecium. Eur J clin Microbiol Infect Dis 1998;17:798-800. [PubMed]

85. Thauvin C, Eliopoulos GM, Willey S, Wennersten C, Moellering RC Jr. Continuous-infusion Ampicillin Therapy of Enterococcal Endocarditis in Rats. Antimicrob Agents Chemother 1989;31:139-43. [PubMed]

86. Tsai JC, Hsueh PR, Lin HM, Chang HJ, Ho SW, Teng LJ. Identification of Clinically Relevant Enterococcus Species by Direct Sequencing of groES and Spacer Region . J Clin Microbiol 2005;43(1):235-41. [PubMed]

87. Tush GM, Huneycutt S, Phillips A, Ward JD. Intraventricular quinupristin/dalfopristin for the treatment of vancomycin-resistant Enterococcus faecium shunt infection. Clin Infect Dis 1998;26:1460-1. [PubMed]

88. Varelas PN, Rehman M, Pierce W, Wellwood J, Chua T, Revankar S. Vancomycin-resistant enterococcal meningitis treated with intrathecal streptomycin. Clin Neurol Neurosurg 2008;110(4):376-80. [PubMed]

89. Vergis EN, Shankar N, Chow JW, Hayden MK, Snydman DR, Zervos MJ, Linden PK, Wagener MM, Muder RR. Association between the Presence of Enterococcal Virulence Factors Gelatinase, Hemolysin, and Enterococcal Surface Protein and Mortality among Patients with Bacteremia Due to Enterococcus faecalis. Clin Infect Dis 2002;35:570-5. [PubMed]

90. Wang JL, Hsueh PR. Therapeutic Options for Infections due to Vancomycin-resistant Enterococci. Expert Opin Pharmacother 2009;10(5):785-96. [PubMed]

91. Weber SG, Huang SS, Oriola S, Huskins WC, Noskin GA, Harriman K, Olmsted RN, Bonten M, Lundstrom T, Climo MW, Roghmann MC, Murphy CL, Karchmer TB. Legislative mandates for use of active surveillance cultures to screen for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: Position statement from the Joint SHEA and APIC Task Force. Am J Infect Control 2007;35(2):73-85. [PubMed]

92. Weinstock DM, Conlon M, Iovino C, Aubrey T, Gudiol C, Riedel E, Young JW, Kiehn TE, Zucotti G. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant 2007;13(5):615-21. [PubMed]

93. Wilson WR, Wilkowske CJ, Wright AJ, Sande MA, Geraci JE. Treatment of streptomycin-susceptible and streptomycin-resistant enterococcal endocarditis. Ann Intern Med 1984;100:816-23. [PubMed]

94. Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D, Bisno AL, Ferrieri P, Shulman ST, Durack DT. Antibiotic Treatment of Adults With Infective Endocarditis Due to Streptococci, Enterococci, Staphylococci, and HACEK Microorganisms. JAMA 1995;274:1706-13. [PubMed]

95. Winston DJ, Emmanouilides C, Kroeber A, Hindler J, Bruckner DA, Territo MC, Busuttil RW. Quinupristin/dalfopristin Therapy for Infections Due to Vancomycin-Resistant Enterococcus faecium. Clin Infect Dis 2000;30:790-7. [PubMed]

96. Yelamanchili S, Cunliffe NA, Miles RS. Prosthetic valve endocarditis caused by a vancomycin-resistant Enterococcus faecalis. J Infect Dis 1998;36:348-9. [PubMed]

97. Zeana C, Kubin CJ, Della-Latta P, Hammer SM. Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis 2001;33:477-82. [PubMed]

98. Zirakzadeh A, Patel R. Vancomycin-Resistant Enterococci: Colonization, Infection, Detection, and Treatment. Mayo Clin Proc 2006;81(4):529-36. [PubMed]

Table 1. Antimicrobial Therapy for Enterococcus Susceptible to Glycopeptides

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

Infection

Antibiotic(s) primary:alternative

Comments

Urinary tract infection

Intraabdominal infection

Ampicillin

Vancomycin

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 Doxycycline	Dose, Duration 100 mg PO or IV q 12 hr	Comments 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
Treatment of infection due to B-lactam resistant gram-positive organisms Treatment of infection due to gram-positive organisms in patients with serious beta-lactam allergy Treatment of antibiotic associated colitis in cases of metronidazole failure or potentially life threatening illness. Endocarditis prophylaxis, as recommended by the American Heart Association (Dajani). 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
Include physicians, nurses, pharmacy and laboratory personnel, students, and all other direct patient care providers. 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
Laboratory should be able to identify and speciate enterococci Fully automated methods of testing enterococci for susceptibility testing are unreliable; disk diffusion, gradient disk diffusion, agar dilation, or manual broth dilution are acceptable. 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. 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
For all hospitals, including those with no or infrequent isolation of VRE: Notify appropriate staff immediately when VRE are detected. Educate clinical staff about hospital policies regarding VRE colonized or infected patients so that appropriate procedures can be implemented immediately. Establish systems for monitoring process and outcome measures. Isolation precautions to prevent patient to patient transmission of VRE In Hospitals with endemic VRE of continued VRE transmission despite implementation of above measures: Focus initial control efforts on critical care units and other areas where VRE transmission rates are highest. Where feasible cohort staff caring for VRE-positive and VRE-negative patients. 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. Verify that environmental disinfection procedures are adequate, and that procedures are correctly performed. 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)

Place VRE colonized or infected patients in single rooms, or cohort with other patients with VRE.
Wear gloves when entering the room of a VRE-infected or colonized patient.
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.
Remove gloves and gown before leaving the patient’s room and wash hands immediately with an antiseptic soap or waterless antiseptic agent.
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.
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.
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.
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.
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.