AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Enterococci are part of the normal intestinal flora of humans and animals but are also important pathogens responsible for serious infections. The genus Enterococcus includes more than 17 species, but only a few cause clinical infections in humans. With increasing antibiotic resistance, enterococci are recognized as feared nosocomial pathogens that can be challenging to treat.

Enterococcus species are hardy, facultative anaerobic organisms that can survive and grow in many environments. In the laboratory, enterococci are distinguished by their morphologic appearance on Gram stain and culture (gram-positive cocci that grow in chains) and their ability to (1) hydrolyze esculin in the presence of bile, (2) grow in 6.5% sodium chloride, (3) demonstrate pyrrolidonyl arylamidase and leucine aminopeptidase, and (4) react with group D antiserum. Before they were assigned their own genus, they were known as group D streptococci.

Enterococcus faecalis and Enterococcus faecium are the most prevalent species cultured from humans, accounting for more than 90% of clinical isolates. Other enterococcal species known to cause human infection include Enterococcus avium, Enterococcus gallinarum, Enterococcus casseliflavus, Enterococcus durans, Enterococcus raffinosus and Enterococcus mundtii.¹ E faecium represents most vancomycin-resistant enterococci (VRE).

Isolation of enterococci resistant to multiple antibiotics has become increasingly common in the hospital setting.² According to National Nosocomial Infections Surveillance (NNIS) data from January 2003 through December 2003, more than 28% of enterococcal isolates in ICUs of the more than 300 participating hospitals were vancomycin-resistant. Clonal spread is the dominant factor in the dissemination of multidrug-resistant enterococci in North America and Europe.³ Virulence and pathogenicity factors have been described using molecular techniques. Several genes isolated from resistant enterococci (agg, gelE, ace, cylLLS, esp, cpd, fsrB) encode virulence factors such as the production of gelatinase and hemolysin, adherence to caco-2 and hep-2 cells, and capacity for biofilm formation.^{4, 3}

Enterococci have both an intrinsic and acquired resistance to antibiotics, making them important nosocomial pathogens. Intrinsically, enterococci tolerate or resist beta-lactam antibiotics because they contain penicillin-binding proteins (PBPs); therefore, they are still able to synthesize some cell-wall components. They are intrinsically resistant to penicillinase-susceptible penicillin (low level), penicillinase-resistant penicillins, cephalosporins, nalidixic acid, aztreonam, macrolides, and low levels of clindamycin and aminoglycosides. They use already-formed folic acid, which allows them to bypass the inhibition of folate synthesis, resulting in resistance to trimethoprim-sulfamethoxazole.

Enterococci also have acquired resistance, which includes resistance to penicillin by beta-lactamases, chloramphenicol, tetracyclines, rifampin, fluoroquinolones, aminoglycosides (high levels), and vancomycin. The genes that encode intrinsic or acquired vancomycin resistance result in a peptide to which vancomycin cannot bind; therefore, cell-wall synthesis is still possible.

Unlike streptococcal species, enterococci are relatively resistant to penicillin, with minimum inhibitory concentrations (MICs) that generally range from 1-8 mcg/mL for E faecalis and 16-64 mcg/mL for E faecium. Therefore, exposure to these antibiotic agents inhibits but does not kill these species. Combining a cell wall–active agent such as ampicillin or vancomycin with an aminoglycoside may result in synergistic bactericidal activity against enterococci.

The acquisition of vancomycin resistance by enterococci has seriously affected the treatment and infection control of these organisms. VRE, particularly E faecium strains, are frequently resistant to all antibiotics that are effective treatment for vancomycin-susceptible enterococci, which leaves clinicians treating VRE infections with limited therapeutic options.

Newer antibiotics (eg, quinupristin-dalfopristin, linezolid, daptomycin, tigecycline) with activity against many VRE strains have improved this situation, but resistance to these agents has already been described. A mutation (G2576U) in the domain V of the 23S rRNA is responsible for linezolid resistance,³ whereas resistance to quinupristin-dalfopristin may be the result of several mechanisms: modification of enzymes, active efflux, and target modification. Resistance of E faecalis and E faecium to daptomycin, a newer cyclic lipopeptide antibiotic that acts on the bacterial cell membrane, has also been reported.⁵

Six phenotypes of vancomycin resistance, termed VanA, VanB, VanC, VanD, VanE, and VanG, have been described. The VanA and VanB phenotypes are clinically significant and mediated by 1-2 acquired transferable operons that consist of 7 genes in 2 clusters termed VANA and VANB operons. In 1988, these gene clusters first were reported in enterococcal strains. VanA is carried on a transposon Tn1546 that is almost always plasmid-mediated.

In the United States and Europe, the 3 major phenotypes include VanA, VanB, and VanD. VanA is the most common, and enterococcal isolates exhibit high-level resistance to both vancomycin and teicoplanin, while VanB isolates have variable resistance to vancomycin and remain susceptible to teicoplanin. The VanC phenotype is mediated by the chromosomal VANC1 and VANC2 genes, which are constitutively present in E gallinarum (VANC1) and E casseliflavus (VANC2). These genes confer relatively low resistance levels to vancomycin and are not transferable. To date, the VanD, VanE, and VanG phenotypes have been described in only a few strains of enterococci.

Three patients infected with vancomycin-resistant Staphylococcus aureus (VRSA) have been reported in the United States.^{6, 7} The in vivo conjugative transfer potential of the vanA resistance gene from vancomycin-resistant E faecalis to methicillin-resistant S aureus (MRSA) was confirmed in the first of these cases. This poses an emerging threat to patient safety. E faecium isolates with a complex-17 lineage have also emerged in hospital and community settings in 5 continents over just the past 2 decades. This continued global spread of resistant organisms and the creation of new, highly virulent pathogens from transfer of resistance genes underscore the importance of infection control and prevention, active surveillance, and use of appropriate antibiotics.

Pathophysiology

Infections commonly caused by enterococci include urinary tract infections, endocarditis, bacteremia, catheter-related infections, wound infections, and intra-abdominal and pelvic infections. Many infecting strains originate from the patient's intestinal flora. From here, they can spread and cause urinary tract infection, intra-abdominal infection, and surgical wound infection. Bacteremia may result with subsequent seeding of more distant sites. For example, genitourinary tract infection or instrumentation often precedes the onset of enterococcal endocarditis. Meningitis, pleural space infections, and skin and soft-tissue infections have also been reported.

Intestinal colonization with resistant enterococcal strains is more common than clinical infection; for example, in Cleveland, VRE stool isolates outnumber clinical isolates by a factor of 10 in hospitals in which active VRE surveillance is performed. If infection occurs, it usually develops in those who are previously colonized. Colonized patients are a potential source for the spread of organisms to the hands of health care workers, the environment, and other patients. Antibiotic-selective pressure facilitates the spread of resistant enterococcal strains by promoting overgrowth of these strains in the intestinal tract. Enterococci can survive for long periods on environmental surfaces, contributing to their transmission. VRE have been isolated from all objects and sites in health care facilities.

For colonization development and infection with VRE, antimicrobial and nonantimicrobial risk factors have been identified. Vancomycin use is associated with VRE colonization and infection, but prior exposure is not required for colonization. Third-generation cephalosporins, aminoglycosides, aztreonam, ciprofloxacin, imipenem, clindamycin, and metronidazole have been associated with VRE colonization. Nonantimicrobial risk factors (eg, increased duration of exposure to individuals colonized with VRE and close proximity to other colonized patients) increase the likelihood of VRE exposure.

Individuals at risk for colonization include critically ill patients who have received lengthy courses of antibiotics (particularly those in long-term care facilities), solid-organ transplant recipients and patients with hematologic malignancies, and health care workers. Unfortunately, spontaneous decolonization is uncommon, and antimicrobials are unlikely to eradicate VRE colonization. Identified risk factors for VRE bacteremia include prior intestinal colonization, prior long-term antibiotic use, increased severity of illness, hematologic malignancy, bone marrow transplant, mucositis, neutropenia, indwelling urinary catheters, corticosteroid treatment, chemotherapy, and parenteral nutrition.

Frequency

United States

According to recent NNIS surveys, enterococci remain in the top 3 most common pathogens that cause nosocomial infections. Enterococci frequently cause urinary tract infections, bloodstream infections, and wound infections in hospitalized patients. Nosocomial enterococcal infections typically occur in very ill debilitated patients who have been exposed to broad-spectrum antibiotics. They are the fourth most common cause of nosocomial bloodstream infections in the United States.

In 1989, VRE was first reported in New York City; subsequently, VRE has spread rapidly throughout the United States. From 1989-1993, the NNIS surveys reported that the percentage of enterococcal isolates exhibiting vancomycin resistance increased from 0.3% to 7.9%, with a 34-fold rise seen in ICUs. In 2003, the percentage of nosocomial enterococcal isolates exhibiting vancomycin resistance in ICU patients increased to more than 28%—an increase of 12% compared with 1998-2002.

NNIS data reveal the pooled mean for vancomycin-resistant Enterococcus species from all ICUs, non-ICU inpatient areas, and outpatient areas were 13.9%, 12%, and 4.6%, respectively, from 1998 through June 2004. VRE was initially isolated mainly in large university hospitals, but subsequent reports demonstrate the presence of significant VRE epidemics in community hospitals and chronic care facilities, whereby a single clone can easily spread. VRE is isolated almost exclusively from hospitalized (or recently hospitalized) individuals.

International

In contrast, Europe appears to have a large community reservoir of VRE without as rapid an increase in incidence of hospital-associated infections seen in the United States. In European countries, VanA-type VRE has been isolated from various farm animals, chicken carcasses, other meat products, and wastewater samples from sewage treatment plants. In 1994, a German community screened 100 healthy people for VRE, and 12% were found to be carriers.

In Europe, the use of avoparcin, a glycopeptide antibiotic, as a growth promoter for farm animals has been proposed to explain the epidemiology of VRE. Until banned by the European Union in 1997, avoparcin had been used in several European countries and provided a selective pressure for the emergence and spread of vancomycin-resistant genes. This hypothesis is supported by a Danish study that found VanA-type VRE in chicken stool samples from farms using avoparcin but not in samples from farms not using avoparcin. Among the Saxony-Anhalt region in Germany, the prevalence of VRE fecal colonization in healthy individuals after discontinuing avoparcin use in animal husbandry decreased from 12% to 3%, concurrent with a similar decrease in the prevalence of VRE in German poultry products.

Several outbreaks of VRE colonization⁸ and infection have been reported by hospitals in Europe³ and have been associated with increased mortality rates.⁹ A Korean study documented unexpectedly high levels of resistance in VRE isolates to daptomycin, linezolid, and tigecycline despite the rare use of these antibiotics in Korean hospitals.¹⁰

Mortality/Morbidity

• In general, the virulence of enterococci is lower than that of organisms such as S aureus. However, enterococcal infections often occur in debilitated patients and as part of polymicrobial infections. These factors limit the ability of investigators to determine the independent contribution of enterococcal infections to mortality and morbidity.
• Vancomycin-resistant bacteremia increases the length of hospital stay by an average of 2 weeks, and studies calculate an attributable mortality rate of up to 37% from these infections. Mortality rates associated with enterococcal infections may exceed 50% in critically ill patients, those with solid tumors, and some transplant patients. Bacteremia caused by VRE strains carries higher mortality rates than does bacteremia due to vancomycin-susceptible strains.¹¹ Despite the availability of antimicrobial agents with greater potency against VRE, one study of 113 patients with VRE bacteremia reported that such agents did not significantly change clinical outcomes.¹²

Sex

• In general, enterococcal infections are distributed equally between the sexes.
• Although urinary tract infections are more common in healthy women than in healthy men, enterococci are an uncommon cause of uncomplicated cystitis in this setting.
• In published series of enterococcal endocarditis, men often outnumber women.

Age

• Enterococcal infections are more common in elderly patients because of various associated factors that are more common in these patients. For example, urinary tract catheterization and instrumentation are more common in elderly populations. Abdominal surgery for diverticulitis or biliary tract disease is also performed more commonly in elderly persons. In a recent series, most cases of enterococcal endocarditis occurred in elderly individuals.
• In neonates, enterococci occasionally cause bacteremia and meningitis. Outbreaks of enterococcal infections, including VRE infections, have been reported in neonatal ICUs, pediatric ICUs, and hematology/oncology units, but, overall, VRE infections are less common in pediatric patients than in adults.¹³

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Urinary tract infections
• • The most common type of infection caused by enterococci is usually nosocomial (associated with urinary tract catheterization or instrumentation).
  • Cystitis and pyelonephritis are common infections.
  • Occasionally, prostatitis and perinephric abscesses may develop.
  • Occasional infections may occur in young healthy women (<5%).
• Bacteremia
• • Sources of enterococcal bacteremia include the urinary tract, intra-abdominal foci, wounds, and intravascular catheters, especially catheters in femoral locations.
  • Community-acquired enterococcal bacteremia is more commonly associated with endocarditis (up to 36% of cases) than nosocomial bacteremia (0.8%).
  • Nosocomial enterococcal bacteremias may arise from various sources. Polymicrobial bacteremias including enterococci and other bowel flora should increase the index of suspicion for an intra-abdominal source. Other sources may include surgical sites and burn wounds infections.
  • Blood cultures that grow enterococci may be positive because of contamination of the skin with these organisms. A blood culture positive for Enterococcus species in the absence of evidence of ongoing infection should raise this possibility.
• Endocarditis
• • Enterococci cause 5-15% of all endocarditis cases.
  • Enterococcal endocarditis usually occurs in older patients, particularly men.
  • The presentation of enterococcal endocarditis is typically subacute and infrequently associated with peripheral stigmata of endocarditis. Enterococcal endocarditis of native valves carries a relatively low short-term mortality rate.
  • Most cases of enterococcal endocarditis are left-sided. In two recent series of endocarditis caused by vancomycin-resistant enterococci (VRE), the aortic valve was involved more often than the mitral valve.^{14, 15}
  • E faecalis causes most cases of endocarditis. Vancomycin-resistant E faecium is more likely to cause endocarditis than other VRE species, especially cases acquired nosocomially.
  • Risk factors for enterococcal endocarditis may include urinary tract infection or instrumentation.
• Intra-abdominal and pelvic infections
• • Such infections include biliary tract infection, intra-abdominal abscess, spontaneous bacterial peritonitis, endometritis, and salpingitis.
  • Enterococci are usually part of mixed aerobic and anaerobic flora.
  • Antimicrobial regimens with minimal in vitro antienterococcal activity are often effective in treating mixed infections; therefore, the pathogenicity of enterococci in this setting is questionable.
  • Antienterococcal bactericidal activity is recommended when blood culture results are positive for enterococci.
  • In more seriously ill patients, enterococcal infections have been associated with higher risk of treatment failure and mortality. Consider administering antibiotics with antienterococcal activity to immunocompromised patients at high risk for bacteremia, patients with peritonitis and valvular heart disease, patients with severe sepsis of abdominal origin who have recently received broad-spectrum antibiotics, and patients with persistent intra-abdominal fluid collections without clinical improvement.¹⁶
• Other infections
• • Enterococcal wound infections often manifest as part of a mixed infection.
  • Enterococcal meningitis is uncommon and is usually associated with neurosurgical procedures or anatomic defects, accounting for only 0.3-6% of cases.
  • Neonatal sepsis may occur.
  • Respiratory tract infections can develop. However, isolation of enterococci from respiratory secretions usually represents colonization rather than infection.
  • Other uncommon infections caused by enterococci include osteomyelitis and septic joint infections.

Physical

Physical examination findings in patients with enterococcal infections vary widely and depend on the associated infectious syndrome; therefore, direct the examination according to the patient's symptoms and laboratory findings.

• Evaluate the patient for suprapubic or flank tenderness if laboratory findings are consistent with enterococcal urinary tract infection.
• If the patient has enterococcal bacteremia, carefully evaluate the patient for signs consistent with endocarditis, which include the following:
• • Fever
  • Peripheral stigmata (Janeway lesions, Osler nodes, Roth spots, petechiae or splinter hemorrhages)
  • New heart murmur (usually a regurgitant murmur)
  • Splenomegaly
• Examine the abdomen carefully for signs of organ tenderness, for peritoneal signs of peritonitis, and for ascites.
• Examine prosthetic devices and the local skin (eg, orthopedic, cardiac, catheter insertion sites) for signs of infection, including erythema, swelling, tenderness, and/or warmth.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The appropriate laboratory studies depend on the potential clinical syndrome present. Ideally, before administering empirical antibiotic therapy, obtain cultures from sites suspected to be infected, including blood, urine, peritoneal fluid, joint fluid, CSF, and/or pyogenic fluid collections in soft tissue.
• Blood cultures are usually indicated in patients with possible infection who also require hospitalization. If endocarditis is suspected, obtain 3 sets of blood cultures over 1 hour or longer.
• • A blood culture positive for Enterococcus species in a patient with a polymicrobial infection from an intra-abdominal source indicates the need for antimicrobial therapy, including activity against enterococci.
  • A blood culture positive for Enterococcus species (especially if multiple cultures are positive) also warrants an evaluation for endocarditis if clinical features suggest this diagnosis. Echocardiography should be performed to help evaluate for cardiac vegetations.
• Susceptibility testing is essential for all enterococcal isolates that require antimicrobial therapy.
• Stool specimens, perirectal cultures that grow resistant Enterococcus, or both are the criterion standard for evaluating vancomycin-resistant enterococci (VRE) colonization.

Imaging Studies

• Echocardiography
• • Echocardiography should be performed when enterococcal endocarditis is suggested.
  • Transthoracic echocardiography is often performed as an initial screening test; if endocarditis is strongly suggested and the transthoracic echocardiography findings are negative, transesophageal echocardiography should be performed.
• Abdominal CT scanning
• • A CT scan of the abdomen is indicated if symptoms or signs indicate a renal or gastrointestinal source of infection or if no clear focus of infection is evident elsewhere.
  • In elderly and/or immunocompromised patients, an intra-abdominal source of infection may manifest as minimal localizing signs or symptoms.
  • The scan may be ordered to include images of the pelvis in patients with suspected sigmoid or rectal disease, pelvic inflammatory disease (PID), or prostatic infection.
• Ultrasonography: Ultrasonography of the kidneys, liver, and/or pelvis may be useful in determining whether an abscess is present and may be performed before CT scan or as an adjunct to CT scanning in selected cases.

Other Tests

• Susceptibility testing
• • Blood isolates of enterococci should be tested for susceptibility. Routine testing should include penicillin or ampicillin, vancomycin, and high-level aminoglycosides. The Clinical and Laboratory Standards Institute (CLSI), formerly the National Committee for Laboratory Standards (NCCLS), recommends screening enterococci for high-level resistance to both gentamicin and streptomycin.
  • Urine isolates should be tested for susceptibility to ampicillin and nitrofurantoin.
  • For VRE isolates associated with infection, susceptibility testing should include a formal MIC determination for ampicillin and an assessment of beta-lactamase production in selected isolates. In addition, susceptibility testing should be requested for linezolid and may be considered for daptomycin, tigecycline, and quinupristin-dalfopristin, although not all of these antibiotics are FDA-approved for VRE infections. CLSI interpretive criteria are not available for non–FDA-approved indications or for certain organisms, so results must be interpreted using expert microbiological and clinical infectious-disease advice.

Procedures

Surgical incision and drainage of skin or soft-tissue abscesses or radiology-guided aspiration of abscess material may be required in certain enterococcal infections. In many cases, removal of prosthetic devices, such as vascular catheters, shunts, and prosthetic cardiac valves or orthopedic devices, is necessary to facilitate cure of the infection. Some vascular catheters may be exchanged over a wire and antibiotic lock therapy can be attempted, but the device should be permanently removed if failure occurs.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Antimicrobial therapy
• • Prior to treatment of enterococcal infections, all suspected intravenous lines, intra-arterial catheters, and urinary catheters should be removed, if possible, and abscesses drained. Infections that do not require bactericidal therapy are usually treated with a single antibiotic directed toward enterococci; these infections include urinary tract infections, most intra-abdominal infections, and uncomplicated wound infections. Some studies find that monotherapy is adequate treatment in many patients with enterococcal bacteremia without evidence of endocarditis. In clinical practice, combination therapy with a cell wall–active agent and a synergistic aminoglycoside should be considered for treating serious enterococcal infections in critically ill patients and in those with evidence of sepsis, as well as in patients with endocarditis, meningitis, osteomyelitis, or joint infections.
  • Ampicillin is the drug of choice for monotherapy of susceptible E faecalis infection. For most isolates, the MIC of ampicillin is 2- to 4-fold lower than that of penicillin. For rare strains that are resistant to ampicillin because of beta-lactamase production, ampicillin plus sulbactam may be used. Vancomycin should be used in patients with a penicillin allergy or infections with strains that have high-level penicillin resistance due to altered PBPs. Nitrofurantoin is effective in the treatment of enterococcal urinary tract infections, including many caused by vancomycin-resistant enterococci (VRE) strains. As more experience is gained with the use of linezolid, daptomycin, and tigecycline, these drugs may be used more commonly to treat VRE infections.
  • Combination therapy with a cell wall–active agent (eg, ampicillin, vancomycin) and an aminoglycoside (eg, gentamicin, streptomycin) is necessary to adequately treat enterococcal endocarditis. This combination results in synergistic bactericidal activity against susceptible enterococcal strains. At least 4 weeks of combination therapy is recommended for the treatment of enterococcal endocarditis. Six weeks of combination therapy is recommended in patients with symptoms that persisted for more than 3 months before starting therapy, in patients who relapsed after shorter courses of therapy, and in patients with prosthetic valves.
  • If vancomycin is used in the course of treatment for endocarditis, a 6-week rather than 4-week course of therapy is recommended. Combination therapy is also recommended to treat enterococcal meningitis, usually for at least 2-3 weeks. Intravenous linezolid or intravenous plus intraventricular quinupristin-dalfopristin have also been used to successfully treat meningitis.
  • The emergence of enterococcal strains with multidrug-resistant determinants has significantly complicated the management of enterococcal infections. Vancomycin should be used to treat infections with strains that exhibit high-level resistance to ampicillin. Test strains with high-level gentamicin resistance for high-level streptomycin resistance. For gentamicin-resistant strains, the only alternative is streptomycin, as tobramycin and amikacin are not active. Treatment options are limited for endocarditis caused by strains that exhibit high-level resistance to all aminoglycosides. For E faecalis infection, prolonged therapy with high doses of ampicillin plus imipenem-cilastatin or ampicillin plus ceftriaxone may be considered.¹⁷ For E faecium infection, either linezolid or daptomycin may be effective, and quinupristin-dalfopristin or tigecycline could be considered. Surgical approaches may be necessary (see Surgical Care).
  • For VRE infections, base the treatment on infection severity and in vitro susceptibility of the strain to other antibiotics. Uncomplicated urinary tract infections have been treated successfully with nitrofurantoin. Isolates that remain relatively susceptible to penicillin or ampicillin (MICs of 0.5-2 mcg/mL) may be treated with high doses of these agents. Doxycycline, chloramphenicol, and rifampin in various combinations have been used to treat VRE infections, but the newer antibiotic choices are also now available.^{18, 19}
  • The streptogramin combination antibiotic quinupristin-dalfopristin targets the bacterial 50S ribosome and inhibits protein synthesis. It is available intravenously for the treatment of E faecium infections but is not effective against E faecalis strains.
  • Linezolid, an oxazolidinone antibiotic, is available orally and intravenously and is used to treat infections caused by E faecium and E faecalis strains, including VRE. Linezolid may be particularly useful in patients who require oral or outpatient therapy (when intravenous therapy is undesirable), who are intolerant to glycopeptides, or who have impaired renal function.²⁰ Linezolid has been FDA-approved for use in infants and children.²¹ Unfortunately, linezolid-resistant VRE isolates have already been reported.^{22, 23}
  • Daptomycin, a lipopeptide antibiotic that works by altering the bacterial membrane function, is indicated for the treatment of vancomycin-susceptible E faecalis–complicated skin infections. It became available in 2003, and, although it has in vitro activity against all strains of enterococci, the data regarding its use in E faecium and VRE infections are still somewhat limited, although encouraging.²⁴ Daptomycin may be the only drug with bactericidal activity against enterococci when used as sole antibiotic therapy.¹⁹ However, resistance in a VRE isolate has been reported.⁵ It may provide optimal activity in serious enterococcal infections when dosed at 6 mg/kg daily.²⁵
  • Tigecycline, a glycylcycline antibiotic released in 2005, can be used to treat gram-positive, gram-negative, and anaerobic bacterial infections. It can be used to treat vancomycin-sensitive E faecalis infections, and, although it has in vitro activity against E faecium and VRE (including E casseliflavus and E gallinarum), as with daptomycin, clinical data are limited.
  • Teicoplanin is a glycopeptide that is used outside of the United States. It has demonstrated in vitro activity against E gallinarum and E casseliflavus, but not against the most common VanA, type VREF.
  • Dalbavancin is a new antibiotic that is structurally related to vancomycin and teicoplanin; however, it is not yet FDA-approved. It will be marketed especially for MRSA infections but also has activity against non-VRE enterococci. It has a very long half-life, so weekly administration is possible.
  • Oritavancin is a new parenteral semisynthetic glycopeptide that is active against all gram-positive pathogens, including VRE. Its advantages include once-daily dosing, good penetration into macrophages, in vitro activity against bacteria embedded in biofilms, and low adverse drug reaction potential.²⁶ A new drug application was filed with the FDA in February 2008.

Surgical Care

• Surgery may be indicated for the treatment of some enterococcal infections.
• • In patients with enterococcal endocarditis, valve-replacement surgery may be indicated for management of refractory congestive heart failure, failure of medical therapy to clear bacteremia, valve ring abscess, or development of septic emboli after initiation of therapy.
  • For enterococcal intra-abdominal infections, surgery may be indicated for cholecystitis or intra-abdominal abscess, among other conditions.
  • For enterococcal catheter-associated infections, removal of the line may be indicated.

Consultations

• Consultation with an infectious diseases specialist should be considered for all patients with serious infections caused by Enterococcus species, particularly when multiresistant strains are isolated.
• Consult with hospital infection control policy experts when treating patients with colonization or infection with VRE.

Diet

In patients who are persistently colonized with VRE, attempts are occasionally made to eradicate the bacteria. Enteral antibiotics such as bacitracin rarely achieve long-term success. In a small recent study, probiotic therapy (Lactobacillus rhamnosus GG in yogurt) was used to successfully clear VRE colonization and infection in renal patients.²⁷

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications.

Drug Category: Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients with enterococcal endocarditis or other serious enterococcal infections may receive prolonged outpatient antibiotic therapy.
• • These patients should receive regular follow-up care to assess complications from the infection or their medical therapy.
  • Routine weekly follow-up care should include a CBC count and serum creatinine evaluation. The erythrocyte sedimentation rate and/or C-reactive protein level are monitored by some clinicians. The normalization or stabilization of these parameters may be used to help determine the total duration of antibiotic therapy.
  • The need for monitoring vancomycin peak and trough levels has been questioned in recent years; however, if patients are to receive prolonged courses of vancomycin, routinely check at least one trough level. In patients with enterococcal endocarditis, especially when caused by drug-resistant organisms, peaks of 30-45 mcg/mL and trough levels of 10-15 mcg/mL are recommended.
• The antibiotics used to treat enterococcal infections may be associated with various adverse effects that require monitoring.
• • Aminoglycosides may cause renal insufficiency due to acute tubular necrosis or hearing loss due to ototoxicity.
  • Ampicillin may cause thrombocytopenia or renal insufficiency due to interstitial nephritis.
  • Vancomycin therapy is occasionally associated with neutropenia.
• Linezolid can cause myelosuppression in patients receiving therapy for more than 2 weeks and therefore need at least weekly CBC counts while on therapy.
• Daptomycin can cause significant myopathy and should be discontinued in patients with signs and symptoms of myopathy along with an increase in creatine kinase of greater than 5 times the upper limits of normal or in asymptomatic patients with an increase of greater than 10 times the upper limits of normal.

Transfer

• When possible, patients with enterococcal endocarditis should be treated initially in or near a facility with personnel capable of performing open heart surgery.
• Serious enterococcal infections such as endocarditis, meningitis, osteomyelitis, and prosthetic joint infections should be managed in conjunction with an infectious diseases specialist.

Deterrence/Prevention

• To prevent endocarditis, antibiotics are prescribed to some at-risk cardiac patients prior to dental or invasive oral procedures. Enterococci are a rare cause of endocarditis following genitourinary tract or gastrointestinal tract procedures. Recently published guidelines advise that the administration of antibiotics solely to prevent endocarditis is not recommended in patients who undergo a genitourinary or gastrointestinal tract procedure.²⁸
• In addition to medical and surgical treatment, the management of enterococcal colonization and infection also includes measures to limit the spread of vancomycin-resistant enterococci (VRE). In 2006, the Healthcare Infection Control Practices Advisory Committee published guidelines on the management of multidrug-resistant organisms, including VRE, in healthcare settings. This resource can be found at the Centers for Disease Control and Prevention Web site.
• In 1994, the US Centers for Disease Control Hospital Infection Control Practices Advisory Committee published recommendations for preventing and controlling the spread of vancomycin resistance. Specific recommendations were made for surveillance measures to identify patients colonized or infected with VRE, for isolation measures to prevent person-to-person transmission of VRE, and for the prudent use of vancomycin.
• Surveillance measures to identify patients colonized or infected with VRE include the following:
• • At hospitals where VRE has not been detected previously, clinical enterococcal isolates should be periodically screened for vancomycin resistance.
  • Once VRE is identified in a medical facility, all clinical enterococcal isolates should be tested for vancomycin resistance. Some form of surveillance for intestinal colonization is recommended because most patients harboring VRE are not identified when only clinical samples are screened.
• Isolation measures to prevent person-to-person transmission include the following (also see the CDC’s Guideline for Isolation Precautions:²⁹
• • Hand washing with antimicrobial soaps and hand rubs with alcohol-based solutions is critical to prevent spread of organisms.
  • Place patients with VRE infections in private rooms or in rooms with other infected patients.
  • Wear gloves when entering a VRE-colonized or VRE-infected room, and wear a gown if substantial contact with patients or their environment is anticipated.
  • Remove gloves and gown before leaving the room, and wash with antiseptic soap or with alcohol-based gel if the gloves are not visibly soiled.
  • Dedicate the use of items such as stethoscopes, blood pressure cuffs, and thermometers to a single patient (or group of patients) colonized or infected with VRE. In addition, all room surfaces should be disinfected on a regular schedule.
• The above isolation measures, in combination with surveillance cultures, have been effective in eliminating small VRE outbreaks caused by dissemination of single strains of VRE. These measures may not be as effective in the setting of large polyclonal VRE outbreaks. In a study from an ICU of a hospital experiencing a large polyclonal outbreak, the use of gloves and gowns was not more effective than the use of gloves alone in preventing rectal VRE colonization. In a neonatal ICU, however, control of transmission of multiclonal VRE strains was achieved through a multifaceted approach that included active surveillance cultures of all neonates, DNA fingerprinting of all isolates, contact isolation, staff education, use of waterless hand antiseptics, and removal of electrical thermometers.³⁰
• Vancomycin restriction guidelines include the following:
• • Limit use to situations in which vancomycin is clearly indicated.
  • Treat proven or possible serious infection due to susceptible pathogens in patients with serious beta-lactam allergies.
  • Treat proven or possible serious infections caused by beta-lactam–resistant, gram-positive organisms (eg, oxacillin-resistant S aureus [ORSA or MRSA] or methicillin-resistant coagulase-negative staphylococci).
  • Treat Clostridium difficile colitis that is severe or unresponsive to metronidazole therapy.
  • Use for single-dose surgical prophylaxis in patients at high risk for MRSA or methicillin-resistant S epidermidis and occasionally for endocarditis prophylaxis, as recommended by the American Heart Association.
  • Vancomycin-prescribing interventions do not always reduce VRE colonization and infection.³¹ Studies have shown that other infection-control measures in addition to vancomycin-prescribing restrictions are more likely to control VRE colonization and infection.³²
• Restriction of other antibiotics include the following:
• • In a prospective study of VRE-colonized patients, the authors have demonstrated that antianaerobic antibiotics promote persistent high-density stool colonization. Limiting the use of these agents in colonized patients may also help to limit the spread of VRE.
  • In a prospective cohort study, an enhanced infection-control strategy, including a program for reducing total antimicrobial use, resulted in reduced VRE transmission in an oncology unit compared with standard VRE infection-control practices.
  • Compared with the standard infection-control period, the use of vancomycin, imipenem-cilastatin, ceftazidime, ciprofloxacin, aztreonam, and gentamicin during the enhanced infection control period was significantly reduced.
  • The incidence of both VRE bloodstream infections and rectal colonization decreased significantly during the enhanced infection-control period.
• The risk of VRE acquisition in hospitalized patients is increased when environmental culture results are positive and/or when a room has been occupied by a patient with VRE colonization or infection.³³ Adequate environmental cleaning should be a priority. Simple educational interventions directed at the housekeeping staff can improve decontamination of environmental surfaces.³⁴
• Bathing of hospitalized patients should reduce the bacterial burden, including drug-resistant bacteria such as VRE. Daily bathing with chlorhexidine-impregnated bathing cloths was shown to reduce colonization of patients' skin, health care workers' hands, and environmental surfaces, as well as the incidence of VRE acquisition by other patients in one intensive care unit.³⁵
• In conclusion, active surveillance cultures for VRE, use of isolation for colonized and infected patients, appropriate antibiotic use, adequate patient care, and environmental cleaning are important interventions that should be implemented in order to control the transmission of VRE.³⁶

Complications

Endocarditis may occur as a complication of enterococcal infection at a remote site if bacteremia occurs. For example, some cases of endocarditis are preceded by intravascular catheter infections or urinary tract infection or instrumentation.

Prognosis

Enterococcal bacteremia tends to occur in very debilitated patients, making the exact contribution of the bacteremia to mortality difficult to determine. Nevertheless, studies have estimated the attributable mortality rate of enterococcal bacteremia to be 31-37%. Even with current therapeutic regimens, the mortality rate of enterococcal endocarditis remains approximately 20%.

Patient Education

Direct patients to the CDC Web site for answers to some frequently asked questions about VRE.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Vancomycin-resistant enterococci (VRE) infections: Consultation with an infectious diseases specialist is recommended for all serious infections due to VRE strains. Because of coexisting resistance to multiple antibiotics, few effective therapeutic regimens may be available. Linezolid, daptomycin, tigecycline, and quinupristin-dalfopristin are effective against many VRE strains, but resistance may develop during therapy with these agents, particularly if undrained foci of infection remain. These regimens should not be administered in clinical situations without expert guidance. Special laboratory testing may be required if such antibiotics or combinations are used.
• Enterococcal endocarditis: Consultation with an infectious diseases specialist is suggested for most patients with enterococcal endocarditis. These infections require prolonged courses of therapy with potentially toxic antimicrobial regimens. Infectious disease physicians are experienced in monitoring the course of treatment and in making appropriate therapeutic adjustments.
• Legislation aimed at controlling antimicrobial-resistant pathogens, including VRE, has been introduced in at least 2 US states. The Society for Healthcare Epidemiology of America (SHEA) and the Association for Professionals in Infection Control and Epidemiology (APIC) have developed a joint position statement in response to the proposed legislative actions. The authors do not support state legislation mandating use of active surveillance cultures to screen for VRE, but do support collaboration between state and local public health authorities and institutional infection prevention and control experts.³⁷

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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