1342  Part XVII  ◆  Infectious Diseases

Chapter 186 
Enterococcus
David B. Haslam

Enterococcus, long recognized as a pathogen in select populations, has

become a common and particularly troublesome cause of hospital-
acquired infection over the past 2 decades. Enterococci were formerly
classified with Streptococcus bovis and Streptococcus equinus as Lance-
field group D streptococci but are now placed in a separate genus and
are notorious for their frequent resistance to antibiotics.

ETIOLOGY
Enterococci are Gram-positive, catalase-negative facultative anaerobes
that grow in pairs or short chains. Most are nonhemolytic (also called
γ-hemolytic) on sheep blood agar, although some isolates have α- or
β-hemolytic activity. Enterococci are distinguished from most Lance-
field groupable streptococci by their ability to grow in bile and hydro-
lyze esculin. Enterococci are able to grow in 6.5% NaCl and hydrolyze
L-pyrrolidonyl-β-naphthylamide, features used by clinical laboratories
to distinguish enterococci from group D streptococcus. Identification
at the species level is enabled by differing patterns of carbohydrate
fermentation.

EPIDEMIOLOGY
Enterococci are normal inhabitants of the gastrointestinal tract of
humans, and organisms throughout the animal kingdom, suggesting

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 Chapter 186  ◆  Enterococcus  1343

they are highly evolved to occupy this niche. Oral secretions and dental
plaque, the upper respiratory tract, skin, and vagina may also be colo- Table 186-1 Intrinsic Resistance Mechanisms Among
nized by Enterococcus. Enterococcus faecalis is the predominant organ- Enterococci
ism, with colonization commonly occurring in the 1st wk of life. By ANTIMICROBIAL MECHANISM
the time of adulthood, E. faecalis colonization is nearly ubiquitous.
Enterococcus faecium colonization is less consistent, although approxi- Ampicillin, penicillin Altered binding protein
mately 25% of adults harbor this organism. Disruption of the normal Aminoglycoside (low level) Decreased permeability, altered
intestinal microbiota by antibiotic exposure or hematopoietic stem cell ribosomal binding
transplantation markedly enriches for fecal enterococcal abundance
Clindamycin Altered ribosomal binding
and dramatically increases the risk of subsequent bloodstream
infection. Erythromycin Altered ribosomal binding
E. faecalis accounts for approximately 80% of enterococcal infec- Tetracyclines Efflux pump
tions, with almost all of the remaining infections caused by E. faecium.
Only rarely are other species, such as Enterococcus gallinarum and Trimethoprim-sulfamethoxazole Utilize exogenous folate
Enterococcus casseliflavus, associated with invasive infection, but these
organisms are notable for their intrinsic low-level vancomycin resis-
tance. Whole-genome sequencing suggests that the patient’s indige-
nous flora is the source of enterococcal infection in most cases. Table 186-2 Acquired Resistance Mechanisms Among
However, direct spread from person to person or from contaminated Enterococci
medical devices may occur, particularly within newborn nurseries and
intensive care units where nosocomial spread has resulted in hospital ANTIMICROBIAL MECHANISM
outbreaks. Ampicillin, penicillin (high level) Mutation of PBP5

PATHOGENESIS Aminoglycoside (high level) Enzyme modification

Enterococci are not aggressively invasive organisms, usually causing
disease only in children with damaged mucosal surfaces or impaired
immune response. Their dramatic emergence as a cause of nosocomial
infection is predominantly a result of their resistance to antibiotics
commonly used in the hospital setting. Hospital-associated entero-
cocci generally lack CRISPR (clustered regularly interspaced short
palindromic repeats) elements. Their diverse antimicrobial resistance
repertoire is likely related to deficient CRISPR-mediated defense
against phage-mediated horizontal gene transfer. Secreted and cell-
surface molecules are implicated in pathogenesis. Adhesion-promoting
factors such as the surface protein Eps likely account for the propensity
of these organisms to cause endocarditis and urinary tract infections
(UTIs). The ability to form biofilms likely facilitates the colonization
of urinary and vascular catheters. Other proposed virulence factors
include cytolysin, aggregation substance, gelatinase, and extracellular
superoxide.
Antimicrobial Resistance
Enterococci are highly resistant to cephalosporins and semisynthetic
penicillins such as nafcillin, oxacillin, and methicillin. They are mod-
erately resistant to extended-spectrum penicillins such as ticarcillin
and carbenicillin. Ampicillin, imipenem, and penicillin are the most
active β-lactams against these organisms. Some strains of E. faecalis
and E. faecium demonstrate decreased resistance to β-lactam antibiot-
ics due to mutations in penicillin binding protein 5. In addition, occa-
sional strains of E. faecalis produce a plasmid-encoded β-lactamase
similar to that found in Staphylococcus. These isolates are completely
resistant to penicillins, necessitating the combination of a penicillin
plus a β-lactamase inhibitor or the use of imipenem or vancomycin.
Any active drug may be insufficient if used alone for serious infections
wherein high bactericidal activity is desired (Tables 186-1 and
186-2).
All enterococci have intrinsic low-level resistance to aminoglyco-
sides because these antibiotics are poorly transported across the
Enterococcus cell wall. Concomitant use of a cell wall active agent, such
as a β-lactam or glycopeptide antibiotic, improves the permeability of
the cell wall for the aminoglycosides, resulting in synergistic killing.
However, some isolates demonstrate high-level resistance, defined as
mean inhibitory concentration (MIC) >2,000 µg/mL a result of modi-
fication or inactivation of aminoglycoside agents. Strains demonstrat-
ing high-level resistance, and even some moderately resistant isolates,
are not affected synergistically by aminoglycosides and cell wall–active
antibiotics.
Resistance to almost all other antibiotic classes, including tetracy-
clines, macrolides, and chloramphenicol, has been described among
Quinolones DNA gyrase mutation
Chloramphenicol Efflux pump
Glycopeptide Altered cell wall binding
Quinupristin/dalfopristin Ribosomal modification, efflux
pump
Linezolid Point mutation
Daptomycin Unknown
the enterococci, necessitating individual susceptibility testing for these
antibiotics when their use is considered. Despite apparent susceptibil-
ity in vitro, trimethoprim-sulfamethoxazole has poor activity in vivo
and should not be used as the primary agent against Enterococcus
infections.
Vancomycin has traditionally been effective against Enterococcus
isolates, but resistance to vancomycin, defined as MIC >32 µg/mL, and
other glycopeptides, including teicoplanin, is increasingly common.
The emergence of vancomycin-resistant Enterococcus (VRE) has
become a major challenge in the care of hospitalized patients. In par-
ticular, mortality in patients with VRE bloodstream infections is con-
siderable, and treatment is complicated by frequent resistance of VRE
to most other antibiotic classes. Both high- and moderate-level resis-
tance are described in E. faecalis and E. faecium. High-level resistance
(MIC ≥64 µg/mL) can be transferred by way of conjugation and
usually results from plasmid-mediated transfer of the vanA gene.
High-level resistance is most common among E. faecium, but is
increasingly seen among E. faecalis isolates. Moderate-level resistance
(MIC 8-256 µg/mL) results from a chromosomal homolog of vanA,
known as vanB. Isolates that harbor the vanB gene are only moderately
resistant to vancomycin and initially demonstrate susceptibility to tei-
coplanin, although resistance can emerge during therapy. Resistance to
newer agents, including linezolid and daptomycin, is rare thus far.
Linezolid resistance is a result of mutations in the 26S ribosomal
subunit, whereas daptomycin resistance is associated with mutations
in genes required for membrane synthesis and repair.
CLINICAL MANIFESTATIONS
Enterococcus infections traditionally occurred predominantly in
newborn infants; infection in older children is increasingly common.
Most Enterococcus infections occur in patients with breakdown of
normal physical barriers such as the gastrointestinal tract, skin, or
urinary tract. Other risk factors for Enterococcus infection include

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1344  Part XVII  ◆  Infectious Diseases
prolonged hospitalization, indwelling vascular catheters, prior use of
antibiotics, and compromised immunity.
Neonatal Infections
Enterococcus accounts for up to 15% of all neonatal bacteremia and
septicemia. Like group B streptococcus infections, Enterococcus infec-
tions are seen in 2 distinct settings in neonatal patients. Early-onset
infection (<7 days of age) may mimic early-onset group B streptococ-
cus septicemia, but tends to be milder. Early-onset Enterococcus sepsis
most often occurs in full-term infants who are otherwise healthy. Late-
onset infection (≥7 days of age) is associated with risk factors such as
extreme prematurity, presence of an intravascular catheter, or necrotiz-
ing enterocolitis, or it follows an intraabdominal surgical procedure.
Symptoms in late-onset disease are more severe than those in early-
onset disease and include apnea, bradycardia, and deteriorating respi-
ratory function. Focal infections such as scalp abscess and catheter
infection are commonly associated. Mortality rates range from 6% in
early-onset septicemia to 15% in late-onset infections associated with
necrotizing enterocolitis.
Enterococci are an occasional cause of meningitis. In neonates in
particular, meningitis usually occurs as a complication of septicemia.
Alternatively, the organism may gain access to the central nervous
system by way of contiguous spread, such as through a neural tube
defect or in association with an intraventricular shunt. Enterococcus
meningitis can be associated with minimal abnormality of cerebrospi-
nal fluid.
Infections in Older Children
Enterococcus rarely causes UTIs in healthy children but accounts for
approximately 15% of cases of nosocomially acquired UTIs in both
children and adults. Presence of an indwelling urinary catheter is the
major risk factor for nosocomial UTIs. Enterococcus is frequently iso-
lated in intraabdominal infections following intestinal perforation or
surgery. The significance of enterococci in polymicrobial infections has
been questioned, although reported mortality rates are higher when
intraabdominal infections include enterococci. Enterococcus is increas-
ingly common as a cause of nosocomial bacteremia; these organisms
accounted for approximately 10% of nosocomial bloodstream infection
in children, ranking second only to coagulase-negative staphylococci.
Predisposing factors for enterococcal bacteremia and endocarditis
include an indwelling central venous catheter, gastrointestinal surgery,
immunodeficiency, and cardiovascular abnormalities. Risk factors for
vancomycin-resistant enterococcal bacteremia include prolonged
mechanical ventilation, immunosuppression, and recent vancomycin
exposure.
TREATMENT
Treatment of invasive Enterococcus infections must recognize that
these organisms are resistant to antimicrobial agents frequently used
as empirical therapy. In particular, cephalosporins should not be relied
upon in situations where Enterococcus is known or suspected to be
involved. In general, in the immunocompetent host, minor localized
infections caused by susceptible Enterococcus can be treated with ampi-
cillin alone. Antibiotics containing β-lactamase inhibitors (clavulanate
or sulbactam) provide advantage only for the few organisms whose
resistance is owing to production of β-lactamase. In uncomplicated
UTIs, nitrofurantoin is efficacious when the organism is known to be
sensitive to this antibiotic.
Invasive infections, such as sepsis, meningitis, and endocarditis, are
usually treated with a combination of penicillin or ampicillin and an
aminoglycoside when the isolate is susceptible. Vancomycin can be
substituted for the penicillins in allergic patients, but should be used
with an aminoglycoside, because vancomycin alone is not bactericidal.
Endocarditis from strains possessing high-level aminoglycoside resis-
tance may relapse even after prolonged therapy. High-dose or continu-
ous infusion penicillin has been proposed for treatment of these
infections in adults, yet ultimately valve replacement may be necessary.
In patients with catheter-associated enterococcal bacteremia, the
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catheter should be removed promptly in most cases, although salvage
of infected lines has occurred with the combined use of ampicillin or
vancomycin with an aminoglycoside.
Treatment of Vancomycin-Resistant
Enterococci
The treatment of serious infections caused by multiresistant,
vancomycin-resistant strains is particularly challenging. Linezolid, an
oxazolidinone antibiotic that inhibits protein synthesis, is bacterio-
static against most E. faecium and E. faecalis, including vancomycin-
resistant isolates. Response rates are generally over 90%, including
cases of bacteremia and sepsis, and this antibiotic has become the
preferred agent in treatment of VRE infections in many institutions.
Anecdotal reports reveal the success of linezolid in treating meningitis
caused by vancomycin-resistant enterococci. Unfortunately, as seen
with other antibiotics, linezolid resistance is documented and nosoco-
mial spread of these organisms can occur. Linezolid frequently causes
reversible bone marrow suppression after prolonged use and is associ-
ated with rare occurrences of lactic acidosis and irreversible peripheral
neuropathy. Serotonin syndrome may be seen in patients taking con-
comitant selective serotonin uptake inhibitor antidepressants. Oxa-
zolidinones in development include tedizolid, which has better in vitro
activity against enterococci and appears to have favorable pharmaco-
kinetic and toxicity profiles when compared to linezolid.
Quinupristin/dalfopristin is a combined streptogramin antibiotic
that inhibits bacterial protein synthesis at 2 different stages. It has
activity against most E. faecium strains, including those with high-level
vancomycin resistance. Approximately 90% of E. faecium strains are
susceptible to quinupristin/dalfopristin in vitro. Notably, it is inactive
against E. faecalis and therefore should not be used as the sole agent
against Gram-positive organisms until culture results exclude the pres-
ence of E. faecalis. Studies in children suggest that this antibiotic is
effective and generally well tolerated, though episodes of arthralgia and
myalgia during therapy are reported. Emergence of resistance to
quinupristin/dalfopristin is rare but has been demonstrated.
Newer antibiotics with reliable activity against VRE include dapto-
mycin and tigecycline. Daptomycin is a cyclic lipopeptide that is
rapidly bactericidal against a broad range of Gram-positive organisms.
The antibiotic inserts into the bacterial cell wall, causing membrane
depolarization and cell death. It has been approved for the treatment
of adults with serious skin and soft tissue infections, right-sided endo-
carditis, and bacteremia due to susceptible organisms. Most strains of
VRE (both E. faecium and E. faecalis) are susceptible to daptomycin in
vitro, and its efficacy in adult patients with VRE appears to be similar
to that of linezolid. Experience with daptomycin in children is limited,
particularly in the setting of Enterococcus infections. However, based
on the experience with adult patients, daptomycin may be an alterna-
tive to linezolid when resistance or side-effects limit utility of that
antibiotic. Daptomycin dosages may need to be higher in children
when compared to adults because of more rapid renal clearance. The
antibiotic has unreliable activity in the lung and therefore should not
be used as a sole agent to treat pneumonia. Resistance of both Staphy-
lococcus aureus and Enterococcus to daptomycin has rarely been
described, sometimes arising during therapy. Ceftaroline, a fifth-
generation cephalosporin with activity against methicillin-resistant S.
aureus, has activity against many E. faecalis strains and may be highly
synergistic with daptomycin against daptomycin-nonsusceptible
strains.
Tigecycline is the first clinically available glycylcycline antibiotic, an
expended-spectrum derivative of the tetracycline family. The agent
inhibits protein synthesis by binding to the 30S ribosome and is bac-
teriostatic against susceptible organisms. Tigecycline has broad activity
against Gram-positive, Gram-negative, and anaerobic organisms,
including methicillin-resistant S. aureus and VRE, and is approved for
the treatment of adults with skin and soft-tissue infections and intraab-
dominal infections caused by susceptible organisms. Its efficacy in VRE
infections has not yet been demonstrated in clinical trials and there is
little published experience with the use of tigecycline in children thus
far. Like other tetracycline antibiotics, tigecycline use may cause dis-
coloration of the teeth, and its use in children younger than 8 yr of age
should generally be avoided. Gastrointestinal side effects are common
and may be intolerable.

Prevention
Strategies for preventing enterococcal infections include timely
removal of urinary and intravenous catheters and debridement of
necrotic tissue. Infection control strategies, including surveillance cul-
tures, patient and staff cohorting, and strict gown and glove isolation
are effective at decreasing colonization rates with vancomycin-resistant
enterococci. Unfortunately, these organisms may persist on inanimate
objects such as stethoscopes, complicating efforts to limit their noso-
comial spread. In order to prevent the emergence and spread of van-
comycin resistant organisms, the Centers for Disease Control and
Prevention has developed a series of guidelines for prudent vancomy-
cin use. Antibiotics with broad activity against anaerobic organisms are
also thought to contribute to colonization with VRE, suggesting that
prudent use of such antibiotics may also help limit spread of VRE.
Decolonization strategies have been attempted but are generally inef-
fective in eradicating skin or gastrointestinal carriage of VRE. In par-
ticular, antimicrobial therapy is not indicated for this purpose. The role
of probiotic agents in eliminating VRE colonization is currently
unclear, but may be a useful adjunct to prudent antimicrobial usage
and other infection control interventions in limiting nosocomial
spread of VRE.

Bibliography is available at Expert Consult.

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 Chapter 186  ◆  Enterococcus  1345.e1

Bibliography Practices Advisory Committee (HICPAC), Infect Control Hosp Epidemiol

Arias CA, Murray BE: The rise of the Enterococcus: beyond vancomycin
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