Pediatric Enterococcal Infection

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 is currently recognized as one of the most common causes of nosocomial infections and is becoming increasingly resistant to numerous antibiotics, including vancomycin. See the image below.

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; thus, determining whether the microbe is a true pathogen or just happens to be associated with an illness is difficult. Enterococcus is frequently isolated from polymicrobial wounds and intra-abdominal and pelvic infections; however, 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 antienterococcal therapy. In animal models, injection of enterococci rarely causes peritonitis or subcutaneous infection, but synergy may be observed between enterococci and other organisms (especially anaerobes).

Bacteremia is speculated to occur as a result of translocation or organisms from the gastrointestinal tract and is more commonly seen following removal of large sections of the bowel and with gastrointestinal pathology.

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.

During chemotherapy, an imbalance was noted between colonization of anaerobic and aerobic bacteria in the gut. In pediatric patients with acute myeloid leukemia, chemotherapy is associated with a 10,000-fold reduction in fecal anaerobes and 100-fold increase in enterococci.[1]

United States data

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. A 12% increase in vancomycin-resistant Enterococcus (VRE) hospital-acquired infections in the ICU was reported in 2004, with a rate of about 28%.[2]

International data

VRE and VRE infection have increasingly become a worldwide public health threat since the condition was first recognized in the mid-1980s. Among 210 bile samples obtained from 2001-2004 from 79 adult liver transplant recipients within 30 days of transplantation, approximately 75% yielded bacterial strains, of which 36% showed enterococci.[3] Among this same cohort, gram-positive organisms constituted about 78% of surgical site infections, and aminoglycoside-resistant enterococci was reported in 24%.

Race-, sex-, and age-related demographics

No racial predilection is noted.

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

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.

Morbidity/mortality

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.

See the list below:

• Historical risk factors for acquisition of vancomycin-resistant Enterococcus (VRE) and enterococcal infections include history of the following[4] :

  • 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, GI tract, skin, urinary tract)

  • Neurosurgical procedures and use of neurosurgical devices

• Recent surveillance by perirectal culture for 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 (BSIs) in the United States, Europe, and Latin America, documented that the incidence of oxacillin-resistant S aureus (39.1%) and VRE (17.7%) were highest in the United States.[5]

• 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.[6] This also poses challenges to infection control measures and medical care for these patients.

• In a 2-year study of 1330 ICU admissions, 638 patients were at risk for acquisition; any VRE-colonized room occupants within the previous 2 weeks and a positive room culture result were independent risk factors for the acquisition of VRE.[7] This reinforces the necessity of thoroughly cleaning rooms prior to admitting new patients.

• Papadimitriou-Olivgeris conducted a prospective study to determine the prevalence of and risk factors for VRE colonization in 497 patients admitted to the intensive care unit (ICU) during a 24-month period.[8] Risk factors for VRE carriage upon admission to the ICU included the following: duration of previous hospitalization; glycopeptide administration; chronic heart failure; malignancy; insulin-dependent diabetes mellitus; and previous enterococcal infection (VRE and/or VSE). Risk factors for VRE colonization during ICU stay included the following: quinolone administration; chronic obstructive pulmonary disease; chronic renal failure; and number of VRE-positive patients in nearby beds. Risk factors for enterococcal infection during stays in the ICU included administration of third- or fourth-generation cephalosporins; use of cortisone before ICU admission; and VRE colonization. Enteral nutrition was found to be a protective factor.[8]

See the list below:

• Urinary tract infections: VRE is an infrequent cause of urinary tract infection (UTI) in healthy children. When an enterococcal UTI occurs in children, it is usually 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, E faecalis was identified in 5.1% (13); 9 of these patients had significant underlying anatomic abnormality.[9, 10]

  • 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 is implicated much less frequently in the etiology of enterococcal bacteremia in children. However, in a study by Christie et al, urosepsis was the etiology of 12% of episodes of nosocomial enterococcal bacteremia in hospitalized children.[11]

  • 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%.[12] 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 as many as 15% of cases of endocarditis, these organisms rarely infect the heart valves of children.

• Intra-abdominal infections: Enterococcus is often 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.[13]

• 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.[14] Most neonatal infections are caused by E faecalis.

A study by Lubell et al that compared Gram-negative and enterococcal UITs reported that ≥ grade 3 vesicoureteral reflux and hydronephrosis were associated with enterococcal UTI and that urinalysis was more sensitive for the Gram-negative UTI group than the enterococcal UTI group.[15]

See Pathophysiology.

See the list below:

• 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 and studies have not supported the need for empiric enterococcal antimicrobial coverage for these organisms in managing bowel perforations. 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 (≤ 20 g/d in adults) may be effective for MICs as much as 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 is usually 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 is also 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.

See the list below:

• According to the site and type of infection, the following imaging studies may be considered:

  • Brain CT scanning

  • Abdominal CT scanning

  • Renal ultrasonography

  • Heart echocardiography

  • Plain film radiography (eg, chest radiography)

See the list below:

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

The following are guidelines for antimicrobial therapy in patients with enterococcal infections. 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 urinary tract infection (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.[16] 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 native valve 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 is not usually 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 an underlying predisposing cutaneous defect is present, such as congenital cutis aplasia, 3-4 weeks of therapy may be required.

  • In a study of 98 adult patients with VRE bacteremia, 30 were treated with daptomycin, and 68 were treated with linezolid.[17] Daptomycin was noted to be as effective as linezolid. No elevation of creatine kinase levels or rhabdomyolysis was noted.

  • A study by Santos et al that characterized 132 enterococcal clinical isolates obtained from cancer patients between 2013 and 2014 found that the predominant species was E. faecalis (108 isolates) and that even though 44.7% of the isolates were multidrug-resistant, all isolates were susceptible to fosfomycin, linezolid and glycopeptides.[18]

See the list below:

• Catheter-associated sepsis: Remove promptly catheter.

• Infected ventriculoperitoneal (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.

See the list below:

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

Class Summary

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

Ampicillin (Omnipen, Polycillin, Principen)

Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria.

Gentamicin (Garamycin)

Inhibits protein synthesis by irreversibly binding to bacterial 30S and 50S ribosomes.

Vancomycin (Vancocin)

Inhibits cell wall synthesis by binding to carboxyl units on peptide subunits containing free D -alanyl-D-alanine. Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in treatment of septicemia and skin structure infections.

Linezolid (Zyvox)

Inhibits formation of initiation complex in protein synthesis by preventing formation of tRNA-mRNA-70S and 30s subunit ternary complex. Binds to the 23S ribosomal RNA of the 50S subunit to prevent complex formation.

Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of VRE.

Quinupristin and dalfopristin (Synercid)

First of a class of antimicrobial agents known as streptogramins. Works by irreversibly binding to 50S and 70S ribosomes, which results in inhibition of protein synthesis. Used to treat serious or life-threatening bacteremia associated with vancomycin-resistant E faecium.

Penicillin G (Pfizerpen)

Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Nitrofurantoin (Macrobid, Furadantin, Macrodantin)

Nitrofurantoin is an alternative to penicillins for uncomplicated UTIs. Synthetic nitrofuran that interferes with bacterial carbohydrate metabolism by inhibiting acetylcoenzyme A. Bacteriostatic at low concentrations (5-10 mcg/mL) and bactericidal at higher concentrations.

Dalbavancin (Dalvance)

Dalbavancin is a lipoglycopeptide antibiotic that prevents cross-linking by interfering with cell wall synthesis. It is indicated for acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive bacteria in pediatric patients from birth. It is effective against ABSSSI caused by Enterococcus faecalis (vancomycin-susceptible isolates). 

See the list below:

• A unified effort by all physicians is necessary to slow increasing morbidity and mortality rates associated with vancomycin-resistant Enterococcus (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 ICU (NICU) over 3 years has shown that combining routine contact precautions, active screening cultures, and rep-polymerase chain reaction (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.

• In a large study of 5939 ICU patients, oropharyngeal or digestive decontamination resulted in a reduction in mortality of 3% at 4 weeks of hospitalization compared with standard care.[19]