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

The French word enterocque first was used in 1899 by Thiercelin to describe gram-positive cocci of enteric origin that formed pairs and short chains. Enterococcus species, Streptococcus bovis, and Streptococcus equines originally were grouped together as group D streptococci (Lancefield classification). However, DNA hybridization studies showed that enterococci are biologically, serologically, and genetically different from streptococci, and enterococci now are placed in a separate genus. Enterococcus currently is recognized as one of the most common causes of nosocomial infections and is becoming increasingly resistant to numerous antibiotics, including vancomycin.

Pathophysiology

Enterococci are gram-positive, catalase-negative, facultative anaerobes that grow as diplococci in short chains. They can be differentiated from other catalase-negative gram-positive cocci by their ability to hydrolyze esculin in the presence of 40% bile salts, grow in 6.5% sodium chloride at 45°C, and produce pyrrolidonylarylamidase (ie, PYR reaction).

The genus Enterococcus includes 17 species. Most human clinical isolates are due to either E faecalis (74-90%) or E faecium (5-16%). Occasionally, human infections can be due to Enterococcus raffinosus, Enterococcus casseliflavus, Enterococcus durans, or Enterococcus avium. Enterococci are normal flora of the gastrointestinal tract of humans and animals. They also may be found in oral secretions, the upper respiratory tract, skin, and the vagina.

Enterococci normally inhabit the bowel, so determining whether the microbe is a true pathogen or just happens to be associated with an illness is difficult. Enterococcus frequently is isolated from polymicrobial wounds and intra-abdominal and pelvic infections, but whether enterococci contribute to the pathogenesis of these infections is often uncertain. Clinical trials have demonstrated that patients with such infections recover without any specific anti-enterococcal therapy. In animal models, injection of enterococci rarely causes peritonitis or subcutaneous infection, but synergy may exist between enterococci and other organisms (especially anaerobes).

The pathogenesis of enterococcal infections is poorly understood, but several possible virulence factors exist. Hemolysin/bacteriocin is a plasmid-encoded protein that generally is accepted as a virulence factor. Hemolysin causes lysis of human erythrocytes, functions as a bacteriocin, and is active against other gram-positive cocci. This protein has been demonstrated to increase virulence in several animal models.

Aggregation substance is a plasmid-encoded surface protein that causes clumping or aggregation of enterococci. This substance may mediate adherence to urinary tract epithelial cells, resulting in urinary tract infection (UTI), and may promote adherence to endocardial tissue, resulting in endocarditis.

Gelatinase is an extracellular zinc endopeptidase similar to the elastase produced by Pseudomonas aeruginosa and has been found to be produced by a large percentage of Enterococcus faecalis isolates from hospitalized patients and patients with endocarditis. Enterococcus faecium may have a carbohydrate moiety that makes it resistant to phagocytosis. Enterococcus also contains lipoteichoic acid, which may cause an exaggerated host inflammatory response.

Frequency

United States

Enterococcal infection is the second most common cause of hospital-acquired infection in the United States. Studies have demonstrated an increased incidence of enterococcal bacteremia in the general pediatric population, from 7 cases of bacteremia per 1000 in 1986 to 48 per l000 in 1991. Between 1989 and 1993, the percentage of infections caused by vancomycin-resistant Enterococcus (VRE) in the United States has increased 20-fold, from 0.3-7.9%.

International

VRE and VRE infection increasingly have become a worldwide public health threat since first recognized in the mid 1980s.

Mortality/Morbidity

Neonatal infections are associated with a 6% mortality rate in early-onset septicemia, which rises to 15% in late-onset infections associated with necrotizing enterocolitis. In general, enterococcal sepsis is implicated in 7-50% of fatal cases.

Race

No racial predilection exists.

Sex

No predilection is reported for either sex, although enterococcal endocarditis is more common in adult men.

Age

Adults are infected more commonly than children (excepting the neonatal period). Most of the literature regarding invasive enterococcal infections in children focuses on the neonatal period and indicates that approximately 50% of newborn infants are colonized with E faecalis by age 1 week. Older children who develop bacteremia have underlying risk factors.

CLINICAL

Section 3 of 10  

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

History

• Historical risk factors for acquisition of VRE and enterococcal infections include history of the following:
• • Prolonged hospitalization
  • Long stay in ICU
  • Surgical reexploration following liver transplantation
  • Prior use of antibiotics, mainly vancomycin and cephalosporins
  • Immunocompromised state
  • Breakdown of normal physical barriers (eg, gastrointestinal tract, skin, urinary tract)
  • Neurosurgical procedures and use of neurosurgical devices
• Recent surveillance by perirectal culture for vancomycin resistant enterococci (VRE) and nasal culture for methicillin-resistant Staphylococcus aureus (MRSA) conducted between 2002 and 2003 revealed a co-colonization rate of 2.7% in 65 of 2,440 patients in an ICU. Significant risk factors included older age, male sex, hospitalization in an ICU, and antibiotic use during previous hospitalization within a year.
• The SENTRY Antimicrobial Surveillance Program, performed between 1997-2002 to assess blood stream infections (BSI) in the United States, Europe, and Latin America, documented that the incidence of oxacillin-resistant S aureus (39.1%) and vancomycin-resistant enterococci (17.7%) were highest in the United States.
• In a review of 451 patients on chronic dialysis, 60 (13%)were found to be colonized with VRE associated with increased mortality of 50%, compared with 10% in noncolonized patients. This also imposes challenges upon infection control measures and medical care for these patients.

Physical

• Urinary tract infections: VRE is an infrequent cause of UTI in healthy children. When an enterococcal UTI occurs in children, it usually is acquired nosocomially. Risk factors for UTIs caused by enterococci include the following:
• • Indwelling urinary catheters
  • Instrumentation of the urinary tract
  • Structural abnormalities of the urinary tract: In a retrospective review of 257 episodes of UTI over 5 years, Enterococcus faecalis was identified in 5.1% (13), and 9 of these patients had significant underlying anatomic abnormality.
  • Bacteremia: This may be polymicrobial, probably reflecting the severity of the underlying disease. In adults, the genitourinary tract is the most common entry site for enterococcal bacteremia, but it is implicated much less frequently in the etiology of enterococcal bacteremia in children. However, in a study by Christie and colleagues, urosepsis was the etiology of 12% of episodes of nosocomial enterococcal bacteremia in hospitalized children.
  • BSI: BSI due to VRE is an independent predictor of mortality, and duration of hospital stay is prolonged in BSI secondary to VRE, compared with vancomycin-susceptible enterococci (VSE) (4.5 d vs <1 d). In a study of more than 2000 hematology-oncology (including transplant) patients, rectal colonization of VRE was close to 5%, of which E faecium constituted 84%. Among these patients with VRE, 29% eventually developed bacteremia. A negative predictive value as high as 99.9% for the risk of bacteremia was documented in this study.
• Endocarditis: In contrast to adults, in whom enterococci cause up to 15% of cases of endocarditis, these organisms rarely infect the heart valves of children.
• Intra-abdominal infections: Enterococcus often is isolated from polymicrobial abdominal or pelvic abscesses. In a 1993 study by Bonadio, 5 cases of enterococcal bacteremia occurred in previously healthy infants with gastroenteritis, 6 cases were associated with bowel obstruction, and 1 case was associated with appendicitis without perforation.
• Meningitis: Although Enterococcus rarely causes meningitis in otherwise healthy children and adults, it is known to cause meningitis and ventriculitis in children with ventriculoperitoneal (VP) shunts.
• Neonatal infections: Enterococci account for as many as 10% of cases of neonatal bacteremia and septicemia. Incidence of neonatal enterococcal septicemia increased from 0.12 per 1000 live births in 1982 to 0.8 per 1000 live births in 1986. Enterococcus may cause early-onset (within 7 d of birth) or late-onset (>7 d) neonatal sepsis. Early-onset sepsis caused by enterococci is milder than that caused by group B streptococcal sepsis. Most cases of enterococcal bacteremia in neonates are nosocomial. Central venous catheters, necrotizing enterocolitis, and intra-abdominal surgery are risk factors. Enterococcus may cause focal skin and soft tissue infections, meningitis, and conjunctivitis in the neonate. Most neonatal infections are caused by E faecalis.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Enterococcal infections usually are acquired nosocomially. Differential diagnoses include any nosocomial infection (eg, meningitis/ventriculitis, intra-abdominal or pelvic abscess, skin/soft tissue infection) caused by other microorganisms.

WORKUP

Section 5 of 10  

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

Lab Studies

• Diagnosis
• • Enterococcal infections are diagnosed once the organism has been isolated from a blood culture or other normally sterile site. Isolation from a stool culture is not evidence of invasive infection. The significance of isolating Enterococcus from polymicrobial intra-abdominal, wound, and pelvic infections has yet to be determined. Test all isolated organisms for resistance to beta-lactam antibiotics, aminoglycosides, and glycopeptides. Multiple antibiotic-resistant isolates also may need to be tested for resistance to fluoroquinolones, quinupristin/dalfopristin, doxycycline, and chloramphenicol.
  • Test ampicillin resistance by determining the minimal inhibitory concentration (MIC) and detecting beta-lactamase production. Although isolates with an MIC of greater than 16 mcg/mL are considered resistant, high doses of ampicillin (up to 20 g/d in adults) may be effective for MICs up to 64 mcg/mL. Enterococcus with gentamicin MICs of greater than 500 mcg/mL and streptomycin MICs of greater than 1000-2000 mcg/mL (depending on method used) are considered highly resistant and nonsynergistic for use of the aminoglycoside as part of combination therapy. Vancomycin MICs are difficult to determine, but agar dilution screening using brain-heart infusion agar supplemented with 16 mcg/mL vancomycin is reliable, as is the standard broth microdilution method.
• Antimicrobial resistance and susceptibility
• • Enterococcus demonstrates 2 types of resistance.
    • Intrinsic resistance (low-level resistance) is chromosomally mediated and nontransferable.
    • Acquired resistance (high-level resistance) is mediated by plasmids and transposons and can be transferred from one bacterium to another.
  • Beta-lactam resistance is due to production of low-affinity penicillin-binding proteins. Enterococci are inherently resistant to cephalosporins, clindamycin, and semisynthetic penicillins, such as nafcillin, oxacillin, and methicillin. All enterococci have intrinsic low-level resistance to aminoglycosides.
  • Vancomycin-resistant enterococci: Three major phenotypes of vancomycin resistance have been described in enterococci.
    • Van A is characterized by high-level resistance to vancomycin (MIC >64 mcg/mL) and teicoplanins (MIC >32 mcg/mL). This phenotype is mediated by a transposon (Tn 1546) that carries 7 genes, and it usually is seen in E faecium.
    • Van B phenotype has variable levels of resistance to vancomycin (MIC 4-1000 mcg/mL) but not teicoplanin. It is mediated by transposons (Tn 1547). This phenotype usually is seen in E faecium, but it also is seen in E faecalis.
    • Van C phenotype is limited to certain species of enterococci. This phenotype demonstrates low-level vancomycin resistance (MIC 8-32 mcg/mL) and is susceptible to teicoplanin.

Imaging Studies

• According to the site and type of infection, the following imaging studies may be considered:
• • Brain computed tomography (CT) scan
  • Abdominal CT scan
  • Renal ultrasonography
  • Heart echocardiography
  • Plain film radiographs (eg, chest radiography)

Procedures

• Lumbar puncture or shunt aspiration is recommended to evaluate for meningitis or VP shunt infection.

TREATMENT

Section 6 of 10  

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

Medical Care

The following are guidelines for antimicrobial therapy. Adjust based on antibiotic susceptibility.

• Ampicillin/penicillins are the drugs of choice if the Enterococcus is susceptible.
• Ampicillin alone can be used to treat minor localized infections in an otherwise healthy host.
• Antibiotics containing beta-lactamase inhibitors (eg, clavulanate, sulbactam) can be used if resistance is due to production of beta-lactamase.
• Single drug therapy is effective treatment for UTI and enterococcal bacteremia without endocarditis. Nitrofurantoin is an alternative to penicillins for uncomplicated UTIs.
• • Penicillin or ampicillin plus aminoglycoside (for synergism to produce bactericidal activity) are to be used in the following:
  • • Neonatal septicemia
    • Endocarditis
    • Meningitis
• Guidelines from the Infectious Diseases Society of America (IDSA) on intra-abdominal infections do not recommend empiric enterococcal coverage for community-acquired infections. However, for hospital-acquired abdominal infections, if enterococci are isolated, antibiotic coverage is recommended.
• • For strains with high-level resistance to beta-lactams, aminoglycosides, and glycopeptides, quinupristin/dalfopristin (Synercid) or linezolid (Zyvox) may be used.
  • A 7-month-old formerly premature infant with ventriculitis secondary to E faecium who was successfully treated with a 3-week course of linezolid at a dose of 10 mg/kg/dose 3 times a day has been reported. Therapy was well tolerated. Resistance to linezolid can develop after prolonged antibiotic therapy (>21 days).
  • • Quinupristin/dalfopristin inhibits bacterial protein synthesis and is approved for patients older than 16 years for serious or life-threatening infections associated with vancomycin-resistant E faecium bacteremia.
    • Synercid is not effective against E faecalis.
  • Endocarditis is treated as follows:
  • • Treatment of endocarditis due to susceptible strains of enterococci consists of combination therapy with parenteral ampicillin (or penicillin G) plus parenteral gentamicin (or streptomycin) for a minimum of 4-6 weeks (4 wk if symptoms are present <3 mo vs 6 wk if symptoms are present >3 mo).
    • Patients with severe penicillin allergy should be treated with vancomycin plus gentamicin or streptomycin.
    • Endocarditis due to enterococci highly resistant to beta-lactams (usually E faecium) may be treated with vancomycin plus an aminoglycoside.
    • Endocarditis caused by beta-lactamase–producing strains of E faecalis can be treated with ampicillin-sulbactam plus an aminoglycoside.
    • Endocarditis caused by Van B strains of enterococci can be treated with high-dose ampicillin plus an aminoglycoside if resistance to these agents is not present; otherwise, teicoplanin (investigational drug in the United States) plus an aminoglycoside should be used.
    • For endocarditis of native or prosthetic valve due to multiple drug–resistant vancomycin-resistant E faecium, 8 weeks of linezolid is recommended. For endocarditis of native or prosthetic valve due to vancomycin-resistant E faecalis, a combination of imipenem and ampicillin or cephalosporin and ampicillin for 8 weeks is recommended.
    • High-dose continuous infusion ampicillin (200-300 mg/kg/d) may be an option to dosing every 4-6 hours in the treatment of nonsynergistic enterococcal endocarditis.
    • Doses of gentamicin for treatment of enterococcal endocarditis are aimed to reach a serum concentration peak of only 3-5 mcg/mL. The dose is 3 mg/kg/d instead of the usual 6-7.5 mg/kg/d.
    • Streptomycin usually is not given unless gentamicin resistance and synergism for streptomycin are present.
  • Meningitis and septicemia should be treated with bactericidal regimens. With meningitis, the duration of therapy is usually 2-3 weeks. If there is an underlying predisposing cutaneous defect, such as congenital cutis aplasia, 3-4 weeks of therapy may be required.

Surgical Care

• Catheter-associated sepsis: Remove catheter promptly.
• Infected VP shunt: An infected VP shunt should be removed promptly and an external ventricular drain placed (ventriculostomy).
• Endocarditis due to aminoglycoside-nonsynergistic strains: Valve replacement may be necessary.

Consultations

Treat patients with enterococcal infections in consultation with an infectious disease consultant.

MEDICATION

Section 7 of 10  

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

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

FOLLOW-UP

Section 8 of 10  

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

Deterrence/Prevention

• A unified effort by all physicians is necessary to slow increasing morbidity and mortality rates associated with VRE. The Hospital Infection Control Advisory Committee has published the following policies to limit the spread of VRE:
• • Routine screening for vancomycin resistance among clinical isolates
  • Contact isolation of colonized or infected persons (ie, gown, gloves, hand washing)
  • Restriction of instruments used in patient care to an infected or colonized patient's room only (including electronic thermometers with probe sheaths)
  • Thorough decontamination of environmental surfaces
  • Vancomycin not recommended for routine surgical prophylaxis, primary treatment of antibiotic-associated colitis, prophylaxis of low birth weight infants, and dialysis prophylaxis
  • Active surveillance for VRE in ICU
• An epidemiologic surveillance study performed in a large neonatal intensive care unit (NICU) over 3 years has shown that combining routine contact precautions, active screening cultures, and rep-PCR aids in the detection and reduction of the clonal spread of VRE. An electronic thermometer was identified as a source in one of the clonal outbreaks. This is also supported by applying a mathematical model using simulators, which suggests that VRE colonization in a 10-bed ICU can be reduced by more than 60% by isolating patients upon admission until the surveillance cultures obtained at admission are negative for VRE.
• Standard and contact precautions are indicated in children with VRE infection or colonization. These precautions should continue until the patient is no longer receiving antibiotics and culture results from multiple body sites and indwelling urinary catheter or colostomy sites, if present, are negative on at least 3 separate occasions (>1 wk apart).
• Refer to Endocarditis, Bacterial for further details and recommendations issued by the American Heart Association (AHA) for prevention of bacterial endocarditis.
• Oral bacitracin had been shown to eradicate enterococci from stool better than vancomycin. However, recurrences have been noted after about 1-3 weeks after completion of treatment.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Do not consider vancomycin as an alternative to ampicillin-susceptible enterococci.
• Remove catheters and devices promptly when they are associated with enterococcal infection.
• The combinations of ampicillin plus aminoglycosides or vancomycin (if Enterococcus is resistant to ampicillin) plus aminoglycosides are recommended to treat neonatal sepsis, meningitis, and endocarditis.

REFERENCES

Section 10 of 10

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

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Article Last Updated: Jul 26, 2006