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Historically classified as group D streptococci, enterococci
are now classified as a separate genus with at least 35 different
species.
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Only two species, Enterococcus faecalis and Enterococcus
faecium, account for all but a rare case of human disease. E
faecalis is responsible for about 80% to 90% of
human cases, but several studies show a rising proportion of cases
due to E faecium. Enterococci are facultatively
anaerobic oxidase- and catalase-positive gram-positive cocci that
normally inhabit the bowel Approximately half of newborn infants
have acquired colonization with enterococci by 1 week of age. These
very hardy organisms grow at temperatures of 10°C to 60°C (50°F–140˚F)
and remain viable for weeks on environmental surfaces such as bed rails,
sinks, faucets, and doorknobs. Human-to-human spread is common in
hospital settings.
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Enterococci are generally not highly invasive pathogens and are
typically classified as opportunists. They lack not only the major
exotoxins and endotoxins associated with virulent streptococci and
staphylococci, but also the enzymes that enable rapid tissue spread. Infections
are most often associated with prolonged hospitalization particularly
in intensive care or hematology/oncology units; use of broad-spectrum
antibiotics; indwelling lines; immunocompromised state; or loss
of integrity of the gastrointestinal tract, urinary tract, or skin.1
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Clinical Manifestations
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The three most common types of infection associated with enterococci
are urinary tract infection (UTI), polymicrobial abdominal infections,
and bacteremia or sepsis. Although infrequent, cases of focal organ
infection, such as endocarditis, meningitis, and wound infections,
may be severe. UTI caused by enterococci almost never occurs in
otherwise healthy children. They are most often associated with indwelling
urinary catheters and account for approximately 15% of
nosocomial UTIs in children. Anatomic urinary tract anomalies, particularly
vesicoureteral reflux, are more common in community-acquired enterococcal UTIs
than those associated with gram-negative Enterobacteriaceae.2
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Enterococci may be involved in intra-abdominal polymicrobial
infections following intestinal perforation such as ruptured appendix
or necrotizing enterocolitis. Although there has been controversy regarding
the pathogenic role of enterococci in such infections, most authorities
recommend adding an antibiotic to cover for enterococci in such
infections.3 Enterococcal bacteremia or sepsis
in children may not be identified with a specific focus, but common
risk factors are use of broad-spectrum antibiotics or intravascular catheters
in association with underlying conditions such as surgery, immunosuppression, transplants,
or major organ dysfunction.4 Bacteremia without
a focal infection may result in a self-limited illness or a severe
and life-threatening illness, particularly in newborns or children
with underlying disease. Bacteremia is often polymicrobial with
other enteric microorganisms. Mortality occurs in up to 25% of
cases, but is hard to separate from the underlying health problems.
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In newborns, infection may present as early onset sepsis in the
first several days of life, similar to early onset group B streptococcal sepsis.
However, most neonatal enterococcal infections are nosocomial and
occur after the second week of life, typically in the setting of bacteremia
attributable to line infection or necrotizing enterocolitis.5,6 The
most common presenting signs are apnea, bradycardia, respiratory
dysfunction, fever or hypothermia, and abdominal distention.
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Enterococci are easily isolated on standard bacterial culture
plates or broth media. They are distinguished from nonenterococcal,
catalase-negative, gram-positive cocci by the PYR reaction (hydrolysis
of L-pyrrolidinyl-β-naphthylamide), the ability
to hydrolyze esculin in the presence of 41% bile salts,
and growth in 6.5% NaCl at 10°C to 45°C.
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The most important aspect of treating enterococcal infections
is determination of antibiotic susceptibility.7 Enterococci
have an intrinsic resistance to cephalosporins, monobactams, antistaphylococcal
penicillins, clindamycin, and aminoglycosides. For penicillin-susceptible
strains, ampicillin is considered more active than penicillin. Generally, E
faecium are more resistant to beta-lactam antibiotics than strains
of E faecalis. Although low-grade beta-lactam resistance
is mediated by beta-lactamase production, most beta-lactam resistance
is high grade and mediated by altered penicillin-binding protein.
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Aminoglycoside resistance, due to decreased drug uptake, is either
low- or high-grade (minimal inhibitory concentration >2000 mcg/ml). In
beta-lactam–susceptible enterococci, the combination of
ampicillin or penicillin and an aminoglycoside improves aminoglycoside
uptake and results in synergistic activity. However, synergy is
not possible with high-grade resistant enterococci.
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Resistance to the glycopeptide antibiotics, vancomycin and teicoplanin,
is mediated by the production of novel peptidoglycan, with decreased
affinity for glycopeptides. This alters the ability of vancomycin
and teicoplanin to inhibit cell wall formation. Resistance is transferred
by gene clusters Van A, B, C, D, F, and G, carried in transposon
1546. Although the gene clusters vary in the degree of resistance
to vancomycin or teicoplanin, for practical clinical purposes they
are grouped as vancomycin-resistant enterococci (VRE).8-10
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Most enterococci are susceptible to linezolid, the first of a
new class of synthetic antibiotics called oxazolidinones. However,
there are now reports in the United States and Europe of linezolid-resistant
enterococci.11
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Ampicillin alone is the antibiotic of choice for UTIs with susceptible
enterococci (about 98% of E faecalis and
15% of E faecium). Serious infections
such as meningitis, sepsis, and endocarditis must be treated with the
addition of an aminoglycoside to achieve synergistic, bactericidal
activity.1 Unfortunately, high-level aminoglycoside
resistance, which precludes synergistic activity, is increasing
among enterococci. For ampicillin-resistant enterococci, vancomycin
is the antibiotic of choice. However, vancomycin-resistant strains
of enterococci are increasing at an alarming rate. The National Nosocomial
Surveillance Network Database—USA reported a vancomycin
resistance rate of 28.5% among enterococci causing hospital-associated
infections in intensive care units in 2004. This was a 12% increase
from 1991.12 Several hospital outbreaks of VRE
have been reported in children.8 Antibiotic selection
for treatment of VRE must depend on laboratory susceptibility profiles
because many strains are multiple-drug resistant. Some E
faecalis VRE retain ampicillin susceptibility, whereas
most E faecium VRE do not.1
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If linezolid resistance is confirmed in a VRE E faecium strain,
it is most likely to remain susceptible to quinupristin-dalfopristin,
a combined streptogramin antibiotic (safety and efficacy has not
been established in children younger than 16 years). Unfortunately,
quinupristin-dalfopristin is not active against E faecalis.
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Prevention of further spread of VRE will depend on appropriate
control measures such as active surveillance for VRE in intensive care
settings, contact isolation to minimize person-to-person transmission,
and restriction of the use of vancomycin and other broad-spectrum
antibiotics.13,14