3

Treatment of enterococcal infections

TopicGraphics (4)
Outline
 SUMMARY AND RECOMMENDATIONS
 INTRODUCTION
 CLINICAL APPROACH
o Approach to susceptible strains
o Approach to resistant strains
 High-level penicillin resistance
 High-level aminoglycoside resistance
 Vancomycin resistance
o Approach to specific infections
 Urinary tract infection
 Bacteremia
 Endocarditis
 Meningitis
 ANTIBIOTIC AGENTS
o Parenteral agents with VRE activity
 Linezolid
 Daptomycin
 Clinical use
 Susceptibility breakpoints
 Oritavancin
 New-generation tetracycline derivatives
 Quinupristin-dalfopristin
 Teicoplanin
 Telavancin
o Combination therapy
o Alternative agents
 INFORMATION FOR PATIENTS
 SUMMARY AND RECOMMENDATIONS
 REFERENCES
GRAPHICS view all
 Tables
o Rx susceptible enterococcal bacteremia
o Rx resistant enterococcal bacteremia
o Rx enterococcal cystitis
o Rx enterococcal meningitis
RELATED TOPICS
 Acute complicated urinary tract infection (including pyelonephritis) in adults and adolescents
 Antimicrobial therapy of left-sided native valve endocarditis
 Antimicrobial therapy of prosthetic valve endocarditis
 Infections of cerebrospinal fluid shunts
 Intravascular non-hemodialysis catheter-related infection: Treatment
 Mechanisms of antibiotic resistance in enterococci
 Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue
infections
 Microbiology of enterococci
 Patient education: Vancomycin-resistant enterococci (The Basics)
 Serotonin syndrome (serotonin toxicity)
 Vancomycin-resistant enterococci: Epidemiology, prevention, and control
AUTHORS:
Barbara E Murray, MD
 4

William R Miller, MD
SECTION EDITOR:
Daniel J Sexton, MD
DEPUTY EDITOR:
Milana Bogorodskaya, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2024.
This topic last updated: Aug 25, 2022.

INTRODUCTION Enterococcal species can cause a variety of infections,

including urinary tract infections, bacteremia, endocarditis, and meningitis.
The antimicrobial agents available for treatment of enterococcal infection are
reviewed here, followed by treatment approaches for clinical syndromes
caused by enterococci. Other issues related to enterococci are discussed in
detail separately. (See "Mechanisms of antibiotic resistance in
enterococci" and "Vancomycin-resistant enterococci: Epidemiology,
prevention, and control" and "Microbiology of enterococci".)
Infections due to Enterococcus faecalis tend to be more virulent than
infections due to Enterococcus faecium. In addition, bacteremia due to E.
faecalis is more likely to be associated with endocarditis than bacteremia due
to E. faecium. Clinical isolates of E. faecalis tend to be considerably more
susceptible to beta-lactam agents than clinical isolates of E. faecium, with
isolates of E. faecalis testing susceptible to ampicillin, whereas most E.
faecium isolates are resistant to ampicillin (minimum inhibitory concentration
≥16 mcg/mL). Another susceptibility trait that helps distinguish these two
species is that isolates of E. faecalis are resistant to quinupristin-
dalfopristin while E. faecium isolates are usually susceptible to quinupristin-
dalfopristin.
CLINICAL APPROACH
Approach to susceptible strains — Enterococci are less susceptible to
penicillin and ampicillin compared with most streptococci; even when these
cell wall–active agents inhibit enterococci, they often do not kill
them; vancomycin is even less bactericidal. E. faecium clinical isolates are
more resistant to penicillin than E. faecalis (minimum inhibitory concentration
for 90 percent of strains [MIC90] >16 mcg/mL versus 2 to 4 mcg/mL,
respectively); MICs of ampicillin are usually one dilution lower than those of
penicillin. Piperacillin activity is similar to that of penicillin,
and imipenem generally is active against penicillin-susceptible E. faecalis. Cell
wall-active agents with less or no clinically relevant activity against
enterococci include nafcillin, oxacillin, ticarcillin, ertapenem, most
cephalosporins, and aztreonam.
Enterococci are also relatively impermeable to aminoglycosides, and the
serum concentrations of aminoglycosides required for bactericidal activity are
 5

much higher than can be achieved safely in humans. However, the

simultaneous use of a cell wall-active agent raises the permeability of the cell
so that an intracellular bactericidal aminoglycoside concentration can be
achieved [1]. Bactericidal antimicrobial activity is warranted in clinical
circumstances of life-threatening infection. (See 'Approach to specific
infections' below.)
Enterococcal isolates are usually tested for susceptibility to ampicillin,
penicillin, and vancomycin. The presence of beta-lactamase (identical to one
found in Staphylococcus aureus) is very rare; it confers resistance to penicillin
and ampicillin when large numbers of organisms are present (such as in the
setting of a valvular vegetation), even though the organism may test
susceptible using standard laboratory inocula. Thus, to rule out this
possibility in patients with life-threatening enterococcal infection (such as
meningitis or endocarditis), some experts recommend that the isolate be
screened for beta-lactamase production with nitrocefin, a chromogenic
cephalosporin, even if ampicillin susceptible. There are also rare reports of
more highly penicillin- and/or imipenem-resistant isolates of E. faecalis with
retained ampicillin susceptibility (MIC ≤8 mcg/mL) albeit with higher-than-
usual MICs [2,3]; this has been associated with specific amino acid changes in
the low-affinity penicillin-binding protein (PBP4) of E. faecalis and mutations in
the promoter for the gene [4]. If using a beta-lactam antibiotic other than
ampicillin (ie, penicillin or piperacillin) in treating severe enterococcal
infections, we suggest verification of isolate susceptibility to penicillin by the
clinical microbiology lab.
Traditionally, the standard of care for severe enterococcal infection (such as
endocarditis) has been penicillin or ampicillin combined with an
aminoglycoside to generate synergistic bactericidal activity. A newer regimen,
the combination of ampicillin and ceftriaxone, has yielded clinical cure rates
equivalent to that of ampicillin plus gentamicin for E. faecalis endocarditis
regardless of whether the isolates expressed high-level aminoglycoside
resistance [5]. In general, we favor the combination of ampicillin and
ceftriaxone as it avoids the toxicity of aminoglycosides [1].
For circumstances in which penicillin or ampicillin plus an aminoglycoside is
used to generate bactericidal activity, the isolate should be tested for high-
level resistance to gentamicin and streptomycin. If the organism is reported
as susceptible to high levels of an aminoglycoside ("SYN-S" indicates
"susceptible to synergism"), then it may be assumed that synergism will be
achieved when that aminoglycoside is combined with ampicillin; an
aminoglycoside should never be used alone for treatment of enterococcal
infection. Strains that are resistant to high levels of gentamicin are resistant
to synergism with tobramycin, netilmicin, and amikacin (in addition to
 6

gentamicin), but some of these strains lack high-level resistance to

streptomycin and thus will still demonstrate synergism with that agent [6,7].
(See 'Approach to specific infections' below.)
Even for strains lacking high-level resistance to gentamicin, tobramycin, and,
particularly, amikacin should be avoided. All E. faecium are resistant to
synergism with tobramycin due to a species-specific aminoglycoside acetyl
transferase, and the majority of E. faecium and E. faecalis fail to show
synergism with amikacin.
Ampicillin or penicillin are the preferred cell wall-active agents to use with an
aminoglycoside; vancomycin should be substituted only in the setting of high-
level beta-lactam resistance or hypersensitivity with an inability to desensitize
[8]. Combinations of ampicillin or penicillin
with gentamicin or streptomycin are preferable to vancomycin-
aminoglycoside combinations since the latter pose a greater risk of
nephrotoxicity. Gentamicin is more convenient since determination of serum
gentamicin concentrations is more readily available than serum streptomycin
levels. As mentioned above, amikacin and tobramycin are generally avoided,
and laboratories do not test these aminoglycosides.

Regimens for treatment of bacteremia due to susceptible enterococci in adults

Table 1
Antibiotic regimens and doses for treatment of bacteremia due to susceptible
strains are outlined in the table (table 1).

Monotherapy regimens for treatment of bacteremia due to resistant enterococci in

adults*
Table 2
Approach to resistant strains — The major categories of resistant
enterococci include those with high-level penicillin and ampicillin resistance,
those with high-level aminoglycoside resistance, and those
with vancomycin resistance (table 2) [9].
High-level penicillin resistance — Penicillin/ampicillin resistance is usually
due to alterations in PBP-5, a low-affinity PBP of E. faecium. In addition,
penicillin/ampicillin resistance (MIC ≥16 mcg/mL) generally indicates that the
strain is E. faecium.
In the setting of infection due to such organisms when bactericidal therapy is
needed (eg, endocarditis), vancomycin (or teicoplanin, where available),
or daptomycin (8 to 10 mg/kg intravenously [IV] daily) could be used with an
aminoglycoside. In the presence of high-level aminoglycoside resistance or
concern for nephrotoxicity, high-dose daptomycin (10 to 12 mg/kg IV daily)
may be used; daptomycin may also demonstrate synergism with or
 7

enhancement by other agents such as ampicillin. If resistance is due to beta-

lactamase production, ampicillin-sulbactam may be used as the cell wall
agent. Success with high-dose ampicillin and high-dose ampicillin-sulbactam
(in conjunction with aminoglycosides) has been described in case reports (for
strains resistant to ampicillin that did not produce beta-lactamase) [10,11].
Regimens and doses for treatment of bacteremia due to enterococci with
high-level penicillin resistance are outlined in the table (table 2).
High-level aminoglycoside resistance — When using an aminoglycoside to
achieve synergistic, bactericidal therapy (eg, in the setting of endocarditis),
testing of enterococci should include high-level aminoglycoside-resistance
testing for both gentamicin and streptomycin, since one agent may have
activity even when the other does not. Aminoglycoside monotherapy should
never be used, and a cell wall-active agent should only be combined with an
aminoglycoside to which the organism is found to be "synergism
susceptible." Aminoglycosides reported as "SYN-R" (for "resistant to
synergism") or as MIC ≥500 mcg/mL of gentamicin or ≥2000 mcg/mL of
streptomycin should not be used; other aminoglycosides should generally be
avoided.
Combination beta-lactam therapy is an option for treatment of infective
endocarditis (IE) due to E. faecalis with or without high-level aminoglycoside
resistance. Benefit from double beta-lactam combinations may be due to
saturation of different penicillin-binding protein targets. The combination
of ampicillin with ceftriaxone demonstrated efficacy in experimental
endocarditis due to E. faecalis strains that were highly resistant to
aminoglycosides and in treatment of E. faecalis endocarditis in humans.
[5,12,13].
Regimens and doses for treatment of endocarditis and other infections due
to enterococci with high-level aminoglycosides resistance are discussed in
detail separately [5]. (See "Antimicrobial therapy of left-sided native valve
endocarditis", section on 'Resistance to penicillin, aminoglycosides, and
vancomycin'.)
Vancomycin resistance — The optimal approach for treatment of
enterococcal infection due to vancomycin-resistant E. faecium is uncertain.
One agent, linezolid, is US Food and Drug Administration (FDA) approved for
treatment of infections caused by vancomycin-resistant enterococci (VRE;
prior FDA approval of quinupristin-dalfopristin has been removed). The utility
of this agent for treatment of endocarditis is uncertain, although there are
anecdotal cases suggesting some utility. The resistance profile of VRE isolates
should be evaluated carefully in conjunction with infectious diseases
expertise when selecting appropriate therapy for such organisms. The
 8

approach to treatment of such isolates should be assessed in each individual

case. (See 'Approach to specific infections' below.)
Vancomycin-resistant E. faecium isolates often have concurrent high-level
resistance to beta-lactams and aminoglycosides. In contrast, vancomycin-
resistant E. faecalis are usually susceptible to penicillin and ampicillin, as are E.
gallinarum and E. casseliflavus (which are intrinsically vancomycin resistant).
The newer agents, linezolid, daptomycin, and tigecycline, have activity against
both vancomycin-resistant E. faecalis and E. faecium, whereas quinupristin-
dalfopristin has activity against E. faecium but not E. faecalis.
Regimens for treatment of bacteremia due to VRE are outlined in the table
(table 2).
Approach to specific infections — Important infections due to enterococci
include urinary tract and wound infections, bacteremia, endocarditis, and
meningitis. Urinary tract infections (UTIs) generally do not require bactericidal
therapy, and urinary catheter-associated bacteriuria often resolves with
removal of the catheter. When therapy for enterococcal urinary tract isolates
is indicated, monotherapy is sufficient. In the setting of invasive infections
such as endocarditis, meningitis, and bacteremia (in the setting of
valvulopathy and/or critical illness), bactericidal activity is warranted
(although linezolid has been successful in vancomycin-resistant E.
faecium meningitis). In such cases, synergistic activity of penicillin
or ampicillin in combination with gentamicin (or streptomycin), or ampicillin
plus ceftriaxone (or cefotaxime), is generally required (E. faecalis). Testing for
high-level resistance to gentamicin and streptomycin should be performed
when combination therapy with an aminoglycoside is considered.
(See 'Approach to susceptible strains' above.)
In general, determining the clinical significance of an enterococcus recovered
from a patient should be tailored to individual patient circumstances, since
isolation of an enterococcus does not necessarily require targeted therapy.
Enterococci can also be colonizers (such as in respiratory specimens or
urinary catheters) or part of a mixed infection (such as in polymicrobial
cultures in the setting of intra-abdominal surgery or traumatic wounds) for
which therapy is being administered for more virulent organisms. E.
faecalis infections tend to be more virulent than E. faecium and therefore
should command greater attention when the clinical significance of culture
data is in question.

It should be noted that, even when an acute infection due to VRE has
resolved, in many cases, fecal colonization may persist for prolonged periods
of time.
 9

Urinary tract infection — The urinary tract is the most common site from
which enterococci are recovered; this may result from urinary colonization,
simple cystitis, complicated UTI including pyelonephritis, perinephric abscess,
or prostatitis [14]. Most enterococcal UTIs are nosocomial and/or associated
with obstruction, urinary catheterization, or instrumentation [15-17]. In one
study of uncomplicated cystitis in premenopausal women, growth of
enterococci from a midstream urine culture was not predictive of bladder
bacteriuria as assessed by a contemporaneously collected catheter urine
sample [18]. Thus, recovering enterococci from the urine of otherwise healthy
young females reporting symptoms of cystitis may not necessitate treatment
of this organism, especially if another uropathogen is present. Bacteremia in
the setting of enterococcal UTI is relatively uncommon [19].
Management should include removal of urinary catheters if possible; this
intervention alone has been observed to resolve enterococcal urinary
catheter-associated infections/colonization in some cases [20]. If susceptibility
is documented, the best options for oral therapy of enterococcal lower UTIs
are amoxicillin, nitrofurantoin, or fosfomycin; dosing is outlined in the table
(table 3) [21]. Nitrofurantoin achieves excellent therapeutic levels in the urine
but is not adequate for treatment of pyelonephritis or enterococcal infection
at other sites. Fosfomycin has FDA approval for treatment of uncomplicated
UTIs caused by E. faecalis (as well as Escherichia coli), although many E.
faecium strains are also susceptible to fosfomycin [22,23]. IV ampicillin may
also be considered (see below).
Alternative oral agents include linezolid or a fluoroquinolone, although data
on their efficacy for the treatment of enterococcal UTIs are limited; the latter
should not be used as monotherapy in the setting of bacteremia since
achievable serum levels of fluoroquinolones are frequently close to the
minimum inhibitory concentrations [24-32].
For patients with complicated UTI and for patients unable to tolerate oral
therapy, the majority of strains are E. faecalis and ampicillin is the drug of
choice. Aminopenicillins generally achieve high urinary concentrations with
oral or IV administration [33]; an IV dose of 1 gram every 6 hours is
reasonable for uncomplicated UTIs. Higher doses may be needed if there is
evidence of pyelonephritis or concurrent bacteremia. Vancomycin is an
appropriate alternative if the organism is susceptible.
For patients with lower urinary tract disease initially treated with a parenteral
regimen with clinical improvement and whose isolate demonstrates beta-
lactam susceptibility, completion of therapy with oral amoxicillin may be
sufficient. (See "Acute complicated urinary tract infection (including
pyelonephritis) in adults and adolescents", section on 'Directed antimicrobial
therapy'.)
 10

For UTIs due to ampicillin- and vancomycin-resistant E.

faecium strains, ampicillin may still be effective even for strains of E.
faecium with ampicillin MIC >64 mcg/mL, since ampicillin is concentrated in
the urine. In two small retrospective studies, cure rates for treatment of UTI
due to ampicillin-resistant VRE with aminopenicillins (oral amoxicillin or IV
ampicillin) and non-beta-lactams were similar (84 versus 88 percent,
respectively) [34,35]. Linezolid (excreted approximately 30 percent unchanged
in the urine) or daptomycin are other considerations. For UTI caused by
vancomycin-resistant E. faecalis, ampicillin should suffice
since vancomycin and ampicillin resistance have not been reported together
in the same E. faecalis isolate.

There are no specific clinical data on the duration of therapy for enterococcal
UTIs. For uncomplicated cystitis, we suggest 5 days of therapy. A longer
duration of 7 to 10 days may be warranted for complicated infections,
depending on patient circumstances and clinical response.

Bacteremia — Portals of entry for enterococcal bacteremia include the

gastrointestinal tract, the urinary tract, intravascular catheters, and wounds
(such as ulcers or burns) [14,36-40].

We believe that antimicrobial therapy for enterococcal bacteremia is

generally warranted in the setting of two or more positive blood cultures, a
single positive blood culture accompanied by signs of sepsis, or a single
positive blood culture together with a positive enterococcal culture from
another usually sterile site.

Many experts favor deferring antimicrobial therapy for enterococcal

bacteremia in the setting of an immunocompetent patient with a single
positive blood culture in the absence of clinical evidence for sepsis or in
patients who have a polymicrobial infection and are improving on
appropriate therapy for a more virulent organism [41,42]. For circumstances
in which an intravascular catheter is the likely source of the bacteremia,
catheter removal alone may be sufficient to cure the infection. However, if
febrile, most patients should be empirically started on antibiotics after
detection of enterococci and after additional cultures are obtained, while
awaiting sensitivity results; such therapy can generally be discontinued after
five to seven days if symptoms have resolved, repeat cultures drawn at 24
hours are negative, and no valvular abnormality is found.
Most cases of enterococcal bacteremia due to species other than E.
faecalis are not associated with endocarditis [15,36,38,43-46]. The relative risk
of endocarditis in patients with E. faecalis bacteremia is higher but still
relatively low, unless the bacteremia is prolonged, of community onset, has
 11

an unclear source, or when a prosthetic valve is present. Septic shock in the

setting of enterococcal bacteremia is uncommon and should raise suspicion
for a polymicrobial infection with accompanying gram-negative bacilli.
(See "Intravascular non-hemodialysis catheter-related infection: Treatment".)
A bedside clinical score may be a useful tool for prediction of endocarditis
and need for echocardiogram in some patients with enterococcal
bacteremia. The DENOVA score uses six criteria with each counting for one
point: duration of symptoms ≥7 days; evidence of embolization; number of
positive blood cultures (two or more); unknown origin of bacteremia; prior
heart valve disease; auscultation of a heart murmur. A cutoff score <3 points
suggested a very low risk for enterococcal IE, with a sensitivity and specificity of
100 percent and 85 percent, respectively [47].
In the absence of suspected endocarditis or critical illness, enterococcal
bacteremia may be treated with monotherapy (table 1 and table 2) [39,41,48].
●Treatment of bacteremia due to susceptible enterococci consists
of ampicillin; vancomycin (or teicoplanin, where available) may be
administered in the setting of beta-lactam resistance or allergy.
●For bacteremia due to ampicillin-resistant, vancomycin-susceptible E.
faecium, reasonable therapeutic choices include vancomycin (or
teicoplanin where available) or daptomycin (8 to 10 mg/kg/day); high-
dose ampicillin may be used if the ampicillin MIC is ≤32 mcg/mL.
(See 'Daptomycin' below.)
●For bacteremia due to ampicillin- and vancomycin-resistant E.
faecium, daptomycin (8 to 10 mg/kg/day) or linezolid (administered
orally or IV) are reasonable therapeutic choices; high-
dose ampicillin may be used if the ampicillin MIC is ≤32 mcg/mL [49]. We
prefer daptomycin if a parenteral agent is needed; linezolid is a useful
drug if a patient may be treated with oral therapy.
(See 'Daptomycin' below.)

When therapy is deemed warranted, optimal duration of antimicrobial

therapy for treatment of enterococcal bacteremia is uncertain. For
uncomplicated infection, five to seven days of therapy is likely adequate if
repeated blood cultures drawn at 24 hours are negative.

In the setting of suspected endocarditis or critical illness, combination

therapy should be given (table 1). For E. faecalis, we favor the regimen
of ampicillin plus ceftriaxone since it avoids the toxicity of aminoglycosides;
use of a cell wall-active agent in combination with a synergistically active
aminoglycoside is also acceptable, with penicillin or ampicillin preferred
over vancomycin [50].For ampicillin-susceptible E. faecium, there is little
information because such infections are rare; the combination of a cell wall-
 12

active agent plus an aminoglycoside (if no high-level resistance) may be

preferred, since one in vitro study found that the combination of ampicillin
plus ceftriaxone was not reliably active for all isolates, despite low ampicillin
MICs [51]; on the other hand, demonstration of in vitro synergism can be
concentration dependent. We feel that ampicillin plus ceftriaxone would still
be a consideration if there is high-level resistance to all aminoglycosides, if
there is high risk of aminoglycoside nephrotoxicity or if toxicity appears
during aminoglycoside therapy. Data on combination regimens for treatment
of enterococcal endocarditis are outlined in detail separately.
(See "Antimicrobial therapy of left-sided native valve endocarditis", section on
'Enterococci'.).
The optimal approach for treatment of nonendocarditis infections caused by
resistant enterococci is uncertain. Linezolid is the only drug approved by the
FDA for treatment of bacteremia due to VRE, although it is a bacteriostatic
agent and was approved in an era when relatively few treatment options
were available. Daptomycin, a bactericidal agent, is FDA approved
for vancomycin susceptible E. faecalis in skin and skin structure infections;
there were insufficient vancomycin-resistant strains or E. faecium for FDA
approval for these organisms. It has become an important agent for
treatment of severe VRE infection based on its in vitro profile, despite
absence of randomized clinical trials [52]. Some meta-analyses suggested a
survival benefit of linezolid over daptomycin [53-55] but are limited by
methodologic shortcomings of the underlying literature. Conversely, a
retrospective cohort study including 644 patients noted treatment with
linezolid was associated with significantly higher treatment failure and
greater 30-day all-cause mortality compared with daptomycin [56]. Further
study is needed.
In the setting of a prosthetic valve and sustained high-grade bacteremia, the
duration should reflect presumed endocarditis/intravascular infection (even
in the absence of echocardiographic evidence for vegetation); the approach is
outlined separately. (See "Antimicrobial therapy of prosthetic valve
endocarditis".)
Endocarditis — The approach to selection of antimicrobial therapy for
treatment of enterococcal endocarditis is discussed in detail separately.
(See "Antimicrobial therapy of left-sided native valve
endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".)
Patients with enterococcal endocarditis and unclear source of infection
appear to warrant colonoscopy [57,58]. This was suggested in a retrospective
study including 142 patients with IE due to E. faecalis who underwent
colonoscopy; the overall rate of colorectal disease was 70.4 percent, and the
prevalence of advanced adenomas and colorectal carcinoma was 14.8 percent
 13

[58]. Since most patients with enterococcal endocarditis are also in an age
group that should be considered for colonoscopy, this seems a reasonable
approach.
Meningitis — Enterococci rarely cause meningitis in normal adults [59]. Most
cases of enterococcal meningitis occur in patients with head trauma,
neurosurgery, intraventricular or intrathecal catheters, or anatomic defects of
the central nervous system (CNS) [60,61]. Rarely, enterococcal meningitis can
be a complication of high-grade bacteremia in patients with enterococcal
endocarditis or immunodeficiency such as acquired immunodeficiency
syndrome (AIDS) or hematologic malignancy [59,60]. Enterococcal meningitis
is also seen in the setting of neonatal sepsis and has also been described in
association with Strongyloides hyperinfection [62,63].
The optimal approach for treatment of enterococcal meningitis is not certain.
Combination therapy is warranted; options for treatment of meningitis are
outlined in the table (table 4) [59,60,64]. For infection due to E. faecalis, we
favor treatment with ampicillin, ceftriaxone, and gentamicin (assuming high-
level resistance to gentamicin is not present), despite the lack of clinical
studies supporting this regimen. We favor once-daily aminoglycoside, for the
theoretical possibility that higher peaks would favor greater cerebrospinal
fluid penetration. For patients failing to respond to systemic antibiotics,
addition of intraventricular antibiotics (vancomycin or daptomycin +/-
gentamicin) may be reasonable. Daptomycin has poor CNS penetration; if
used for treatment of CNS infection, daptomycin should be administered
intraventricularly as well as IV [65]. (See "Infections of cerebrospinal fluid
shunts".)
Treatment of enterococcal meningitis caused by E. faecium strains resistant to
penicillin, aminoglycosides, and vancomycin is a difficult challenge; we favor
IV linezolid. If there is a lack of response, we favor daptomycin (IV and
intraventricular). Quinupristin-dalfopristin (IV plus intraventricular) is an
alternative choice although experience with intraventricular administration is
limited [65-78]. Rifampin (if susceptible) may be a useful adjunctive agent, as
might intraventricular gentamicin added to intraventricular daptomycin [79-
81]. Chloramphenicol should not be used for treatment of enterococcal
meningitis. Tigecycline has been used in case reports with either
intraventricular daptomycin or intraventricular tigecycline [82].
The precise duration of therapy for enterococcal meningitis is uncertain. In
concurrence with the Infectious Diseases Society of America clinical practice
guidelines for health care associated ventriculitis and meningitis, we suggest
treatment for at least 10 days [83]. If multiple cultures are positive, it is
reasonable to extend treatment for 10 to 14 days after the last positive
culture.
 14

ANTIBIOTIC AGENTS
Parenteral agents with VRE activity
Linezolid — Linezolid is a bacteriostatic, synthetic oxazolidinone antibiotic
that is US Food and Drug Administration (FDA) approved for use in
vancomycin-resistant enterococci (VRE) infections. It binds to the
peptidyltransferase center of the 50S ribosome, preventing peptide bond
formation and thus the addition of new amino acids [84]. Resistance can
emerge from mutations or by acquisition from other organisms; a mobile
gene, cfr, encoding a methyltransferase that modifies 23S ribosomal
ribonucleic acid (rRNA), which confers resistance to linezolid as well
as clindamycin, chloramphenicol, pleuromutilins, and streptogramin A, has
been found in staphylococci [85,86] and more recently in enterococci [87].
Other plasmid-borne resistant determinants, such as optrA and poxtA, encode
ribosomal protection factors that leads to increased minimum inhibitory
concentrations (MICs) for oxazolidinones (linezolid and tedizolid) and
chloramphenicol [88,89].
Linezolid may be given orally (the preferred route when feasible) or
parenterally. It has high bioavailability after oral administration, and it
achieves therapeutic levels in most tissues.
Early data on linezolid were obtained in the setting of compassionate use
programs. One report describing its compassionate use in nearly 500 patients
with a variety of VRE infections (46 percent bacteremia, 10 percent
endocarditis, 31 percent catheter infection) reported a cure in 81 percent of
cases [90]. Another report describing its compassionate use in 85 solid organ
transplant recipients with VRE infection (43 with bacteremia) demonstrated
resolution of infection in 63 percent of cases [91]. However, linezolid failure
and resistance have also been reported [92,93].
Safety concerns limit the use of linezolid, particularly in the setting of
prolonged use. Adverse effects include thrombocytopenia, anemia, lactic
acidosis, peripheral neuropathy, and ocular toxicity. When administered with
serotonergic agents (particularly selective serotonin reuptake inhibitors),
linezolid can induce serotonin syndrome due to its inhibition of monoamine
oxidase [94,95]. (See "Serotonin syndrome (serotonin toxicity)".)
Thrombocytopenia associated with linezolid use appears to occur more
frequently in the setting of end-stage kidney disease and typically resolves
after discontinuation of the drug [96]. Neuropathy (peripheral and, less
commonly, optic) as well as lactic acidosis are uncommon but important side
effects of linezolid. Peripheral neuropathy can be severe and may not resolve
after drug discontinuation [97-99].
 15

Appropriate linezolid dosing is 600 mg every 12 hours orally or intravenously

(IV). Blood counts and serum chemistries should be monitored at least weekly
during linezolid therapy.
Daptomycin
Clinical use — Daptomycin is a bactericidal cyclic lipopeptide antibiotic that
causes depolarization of the bacterial cell membrane [100]. It was approved
by the FDA for treatment of skin and skin structure infections, including those
caused by vancomycin-susceptible E. faecalis. Daptomycin is likely efficacious
for treatment of skin and skin structure infections due to vancomycin-
resistant E. faecalis or E. faecium, although the number of isolates in the study
was insufficient to support FDA approval. For some strains, including ones
with decreased daptomycin susceptibility, daptomycin is potentiated by the
addition of ampicillin and/or ceftaroline, even in the setting of resistance to
these agents [101,102], and several anecdotal cases have reported using
ampicillin plus daptomycin for E. faecalis endocarditis [103]. Potentiation still
occurs with strains that became nonsusceptible strains via the liaFSR pathway
but not when the organism used the yyc pathway to become nonsusceptible
[104,105].
Some favor the use of daptomycin for treatment of E. faecium infections that
are resistant in vitro to ampicillin and vancomycin, particularly bloodstream
infections, even though daptomycin has not been approved by the FDA for E.
faecium [106-108]. The daptomycin MICs for E. faecium are higher than those
for E. faecalis, which in turn are higher than those for staphylococci. Data
suggest that many enterococcal strains with a daptomycin MIC of 3 to 4
mcg/mL already have mutations that can eliminate the bactericidal activity of
the antibiotic, yet were previously reported as susceptible [109-112].
(See 'Susceptibility breakpoints' below.)
The addition of ampicillin or ceftaroline (even in the setting of resistance to
these agents) may enhance binding of daptomycin and increase its activity, as
mentioned above [101,102,104,105]; some favor use of these combinations
for severe infection including VRE endocarditis [113].
FDA approved daptomycin dosing for complicated skin and skin structure
infections is 4 mg/kg IV once daily. Minimum dosing for bloodstream
infections is 6 mg/kg IV once daily (the approved dose for staphylococcal
bacteremia).
In the setting of enterococcal bloodstream infections, and particularly
endocarditis, we favor higher daptomycin doses of 8 to 12 mg/kg/day. This is
supported by both clinical and pharmacodynamic data [49,114-117]. In a
study of 114 patients treated with daptomycin monotherapy, a free drug area
under the concentration-time curve to MIC ratio (fAUC/MIC) threshold of
>27.43 was predictive of patient survival. Using a Monte Carlo simulation, the
 16

authors calculated only a 1.5 to 5.5 percent probability of achieving this target
using a 6 mg/kg/day dose of daptomycin for isolates with an MIC of 4
mcg/mL [114]. A second study of 240 patients that examined the probability
of achieving therapeutic levels of daptomycin based on pharmacokinetic
modeling found a 100 percent probability of threshold attainment at a 10
mg/kg/day dose for isolates with MICs of 2 mcg/mL or less, and 95.2 percent
probability at 12 mg/kg/day for isolates with an MIC of 4 mcg/mL [115]. A
retrospective study of more than 900 patients with VRE bacteremia in the
Veterans Affairs hospital system found that high-dose daptomycin regimens
(≥10 mg/kg/day) were associated with reduced 30-day mortality (risk ratio
0.83, 95% CI 0.74-0.94) compared with standard-dose (6 mg/kg/day) and
medium-dose (8 mg/kg/day) regimens, respectively [49]. Both medium- and
high-dose regimens were also associated with improved rates of
microbiologic clearance compared with standard dosing. A study of 112
patients from Taiwan reported similar results; higher dose regimens (≥9
mg/kg/day) associated with lower mortality (20 percent) compared with
medium (7 to 9 mg/kg/day) and standard (<7 mg/kg/day) doses (33 and 50
percent, respectively) [116]. Among the small number of patients treated with
higher dose therapy, treatment appeared to be safe and no dose dependent
association between daptomycin and creatine kinase elevation was seen.
Clinical data supporting combination therapy are less robust. An analysis
of daptomycin combination therapy regimens (mostly with beta-lactams)
found that combination therapy increased survival at a lower fAUC/MIC
threshold than daptomycin monotherapy (fAUC/MIC ratio >12.3 for
combination versus >27.4 for monotherapy) [115]. In a small observational
cohort study of 114 patients with VRE bacteremia treated with daptomycin (n
= 27; 23.7 percent) or daptomycin plus a beta-lactam (n = 87; 76.3 percent), no
significant differences in mortality between the two groups were seen at the
end of therapy [118]. A subgroup analysis comparing patients treated with
high-dose daptomycin (≥9 mg/kg/day) plus a beta-lactam with patients
receiving daptomycin monotherapy or low-dose daptomycin plus a beta-
lactam demonstrated increased survival in the high-dose combination group;
however, the observational nature of the study and small number of patients
warrant further study. For vancomycin-resistant E. faecium bacteremia with
daptomycin MICs in the 3 to 4 mcg/mL range, we favor combination therapy
with high-dose daptomycin plus ampicillin and suggest management in
consultation with an infectious diseases specialist.
Patients receiving daptomycin should be evaluated regularly for clinical
evidence of myopathy [119]. Serial measurements of serum creatine kinase
should be obtained at least weekly (more often in the setting of renal
insufficiency); the drug should be discontinued in patients with symptomatic
 17

myopathy and creatine phosphokinase (CPK) ≥5 times the upper limit of

normal (ULN) or in asymptomatic patients with CPK ≥10 times ULN.
Susceptibility breakpoints — The original Clinical and Laboratory Standards
Institute (CLSI) daptomycin breakpoints for enterococci considered strains
with a daptomycin MIC of ≤4 mg/L as susceptible. In 2019,
the Enterococcus spp CLSI breakpoints were revised [120]. For E. faecium, CLSI
lists no S category; an MIC of ≤4 mcg/mL is considered susceptible dose
dependent based on a dose of 8 to 12 mg/kg/day, and an MIC of ≥8 mcg/mL
is considered resistant. For other Enterococcus spp, an MIC of ≤2 mcg/mL is
considered susceptible, an MIC of 4 mcg/mL is considered intermediate, and
an MIC of ≥8 mcg/mL is considered resistant, based on a dose of 6
mg/kg/day. In August 2020, the FDA also revised their breakpoints to match
the CLSI breakpoints for vancomycin-susceptible E. faecalis; however, these
breakpoints are only for the FDA-approved indication of complicated skin and
soft tissue infections at a dose of 4 mg/kg/day. The FDA has not recognized
any breakpoints for E. faecium because of a paucity of data on E.
faecium strains and dosing regimens.
The CLSI recommends only the broth dilution method with Mueller-Hinton
broth adjusted to a final calcium ion concentration of 50 mg/L. However, data
suggest that MIC determination for daptomycin by both broth microdilution
and Etest is unreliable and with poor interlaboratory reproducibility [121].
Due to the apparent inaccuracy of the tests, clinical judgment should be
exercised when treating "daptomycin-susceptible" VRE bacteremia and other
deep-seated infections with this antibiotic. (See "Mechanisms of antibiotic
resistance in enterococci".)
Oritavancin — Oritavancin is a semisynthetic glycopeptide that inhibits cell
wall synthesis and has in vitro bactericidal activity against staphylococci and
enterococci, including vancomycin-resistant strains [122-124]; its activity
appears to be increased against some VRE by an aminoglycoside (if no high-
level aminoglycoside resistance is present). There are no trial data to support
its use for VRE, although there have been anecdotal reports of its use [125].
Oritavancin was approved in 2014 for treatment of acute bacterial skin and
skin structure infections due to susceptible organisms, including E.
faecalis [126]. The drug has a half-life of 100 hours, allowing for single-dose
therapy for skin and skin structure infections.
Data on oritavancin are discussed further separately. (See "Methicillin-
resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft
tissue infections", section on 'Dalbavancin, oritavancin, and telavancin'.)
New-generation tetracycline derivatives — Tigecycline, eravacycline,
and omadacycline are new-generation tetracycline antibiotics with in vitro
bacteriostatic activity against many gram-positive pathogens (including
 18

methicillin-resistant S. aureus [MRSA], VRE, and penicillin-

resistant Streptococcus pneumoniae), some gram-negative bacteria (important
exceptions include Pseudomonas, Proteus, Providencia,
and Morganella species), anaerobes, and atypical species.
Tigecycline does not have FDA approval for treatment of VRE, although it has
been approved for treatment of complicated skin and skin structure
infections and intra-abdominal infections, including infections in which
vancomycin-susceptible E. faecalis were recovered. Many VRE isolates are
susceptible to tigecycline, based on in vitro and animal model data, and MICs
of tigecycline are usually lower for E. faecium than for E. faecalis or
staphylococci [127-129].
Given concerns regarding achieving adequate tigecycline serum drug
concentrations, caution should be used with tigecycline for the treatment of
patients with bacteremia [130]. Approved tigecycline dosing is 100 mg IV
once, followed by 50 mg IV every 12 hours [131,132]. Major adverse effects
include nausea and vomiting. There are reports of higher doses of tigecycline
being used for other organisms to improve levels and with prolonged
infusion using drug diluted in higher volumes to reduce nausea [133].
Tigecycline is difficult to use for outpatient therapy because of the instability
of IV preparations.
Tigecycline may be useful for patients with VRE infection who are intolerant of
other agents or when VRE are present along with other pathogens that are
susceptible to tigecycline. In addition, tigecycline may also be useful when the
biliary system is the source of bacteremia since the drug is eliminated via the
hepatobiliary tree. Tigecycline may also be useful in the setting of renal
insufficiency. Anecdotal reports have used tigecycline with daptomycin for
VRE infections, including endocarditis and meningitis [78,134,135]. In 2010,
the FDA issued a boxed warning of increased all-cause mortality in patients
receiving tigecycline compared with that of other drugs used to treat a variety
of serious infections.
Omadacycline is a new oral tetracycline approved for skin and soft tissue
infections (including E. faecalis) and for community-acquired pneumonia. It is
available as an oral as well as IV formulation and has in vitro activity against E.
faecium that is equal to or slightly less than tigecycline [136,137]. The FDA lists
omadacycline MIC breakpoints for E. faecalis only for acute bacterial skin
infections, with isolates ≤0.25 mcg/mL considered sensitive, 0.5 mcg/mL
intermediate, and ≥1 mcg/mL as resistant. While it might be considered for
off-label use as a potential option for VRE infections that are deemed suitable
for oral therapy, the only in vivo data indicating efficacy for enterococci was
an experimental peritonitis model [138]. Omadacycline is only approximately
 19

30 percent excreted in the urine and this class in general has not performed
well in urinary tract infections [139].
Eravacycline is approved for complicated intra-abdominal infections (cIAI) due
to susceptible organisms including E. faecalis and E. faecium and is available
as an IV formulation. In two randomized controlled trials comparing
eravacycline with ertapenem and meropenem, respectively, in treatment of
cIAI, similar clinical cure rates were seen in the microbiologic intention to
treat population for both E. faecalis (83.3 versus 87 percent) and E.
faecium (84.4 versus 90.6 percent) [140,141].
Quinupristin-dalfopristin — Quinupristin-dalfopristin is a mixture of
streptogramin antibiotics with in vitro activity against VRE; a previous FDA
approval for the treatment of vancomycin-resistant E. faecium infections [142]
was subsequently withdrawn. It has poor activity against E. faecalis due to a
species-specific adenosine triphosphate (ATP)-binding protein [143,144].
Central venous access requirements and adverse effects limit the use of
quinupristin-dalfopristin; these include metabolic interactions, severe
myalgias, arthralgias, nausea, and hyperbilirubinemia. (See "Mechanisms of
antibiotic resistance in enterococci".)
In a study of 396 patients with VRE infections treated with quinupristin-
dalfopristin (including bacteremia, intra-abdominal infections, urinary tract
infections, and skin infections), the overall efficacy of quinupristin-dalfopristin
(both clinical and bacteriologic success) was 66 percent [145]. Clinical
response to quinupristin-dalfopristin is comparable with that
of linezolid [146].
Teicoplanin — Teicoplanin is a glycopeptide that is not available in the United
States [147]. It has in vitro activity against E. gallinarum and E.
casseliflavus (VanC VRE) as well as most VanB-type VRE, although it is rarely
active against VanA-type VRE. Some VanB VRE mutant strains are
constitutively resistant to teicoplanin and have emerged after drug exposure
in vitro and in vivo [148,149]. (See "Mechanisms of antibiotic resistance in
enterococci", section on 'Vancomycin resistance'.)
In countries where it is available, teicoplanin may be used for treatment of
infections due to susceptible enterococci. For patients with normal renal
function, it should be administered with loading doses of 6 mg/kg (12 mg/kg
for serious infections) every 12 hours for three doses (up to five doses for
serious infections) followed by 6 mg/kg (12 mg/kg for serious infections)
every 24 hours. The addition of an aminoglycoside
(gentamicin or streptomycin, in the absence of high-level resistance to one of
these drugs) should be considered to reduce the emergence of VanB mutants
resistant to teicoplanin.
 20

Telavancin — Telavancin is a lipoglycopeptide approved for complicated skin

and skin structure infections caused by susceptible gram-positive bacteria,
including S. aureus and vancomycin-susceptible E. faecalis. There are no
clinical data regarding use of telavancin for other enterococcal infections, but
it is about fourfold more potent than vancomycin against enterococci (eg, the
MIC for 90 percent of strains [MIC90] is 0.12 mcg/mL), with little to no increase
in MICs against VanB strains; for VanA strains, the MIC90 has been reported as
4 to 16 mcg/mL in various studies (versus >256 mcg/mL for vancomycin) [150-
152].
Combination therapy — Data on additional therapeutic combinations for
treatment of infections due to VRE are limited. Options, depending on
susceptibility, include:
●Daptomycin with gentamicin (or streptomycin)
and/or ampicillin or ceftaroline [87,101,102,153]
●Daptomycin plus tigecycline [78,134,135]
●Daptomycin, gentamicin, and rifampin [154]
●Ampicillin plus quinupristin-dalfopristin [155,156]
●Quinupristin-dalfopristin with doxycycline and rifampin [157]
●Quinupristin-dalfopristin plus minocycline [158]
●Ampicillin plus a fluoroquinolone (ciprofloxacin or ofloxacin) [159]
Alternative agents — Fluoroquinolones may be useful for treatment of
enterococcal urinary tract infections in some circumstances. There are several
case reports of success with moxifloxacin (usually with amoxicillin given
before or after) for enterococcal prostatitis caused by susceptible organisms
[160,161]. We would also consider using moxifloxacin plus amoxicillin for
enterococcal prostatitis; this combination was one of the step-down regimens
for enterococcal endocarditis in the Partial Oral versus Intravenous Antibiotic
Treatment of Endocarditis (POET) study. Combination therapy of a
fluoroquinolone plus amoxicillin offers a theoretical advantage of decreasing
the emergence of fluoroquinolone resistance. Whether concentrations of
amoxicillin in the prostate are sufficient to achieve this effect is not
known. Tetracycline and chloramphenicol may demonstrate in vitro activity
against some strains of enterococci, but they are only bacteriostatic against
these organisms [162,163]. Clinical success and failure with chloramphenicol
has been described, but the toxicity of this agent limits its usefulness [164-
166]. (See 'Urinary tract infection' above.)
Most enterococci in the United States are resistant to erythromycin and other
macrolides. In addition, although some enterococcal isolates demonstrate in
vitro susceptibility to trimethoprim-sulfamethoxazole (TMP-SMX), testing is
not recommended because, in vivo, enterococci can use exogenous folic
acid and bypass the block in folate synthesis induced by TMP-SMX [14] and
 21

there is a lack of data on clinical efficacy. Therefore, TMP-SMX should not be

used for treatment of enterococcal infections, even if in vitro susceptibility
testing suggests sensitivity [167-169].
INFORMATION FOR PATIENTS UpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

●Basicstopic (see "Patient education: Vancomycin-resistant enterococci

(The Basics)")
SUMMARY AND RECOMMENDATIONS
●Approach to susceptible strains − Enterococci are relatively resistant
to the killing effects of cell wall-active agents (penicillin, ampicillin,
and vancomycin) and are impermeable to aminoglycosides. Antibiotic
regimens and doses for susceptible strains are outlined in the table
(table 1). (See 'Approach to susceptible strains' above.)
●Approach to resistant strains − The major categories of resistant
enterococci include those with high-level penicillin
and ampicillin resistance and those with vancomycin resistance.
Antibiotic regimens and doses for resistant strains are outlined in the
tables (table 2). (See 'Approach to resistant strains' above.)
●Approach to specific infections
•Urinary tract infection − Options for oral treatment of enterococcal
urinary tract infections (UTIs) are outlined in the table (table 3). For
patients with lower UTI caused by susceptible strains, we suggest
treatment with amoxicillin, fosfomycin, or nitrofurantoin (Grade 2B).
For patients Enterococcus faecalis with complicated UTI and for
patients unable to tolerate oral therapy, we suggest
parenteral ampicillin (Grade 2B). (See 'Urinary tract infection' above.)
•Bacteremia
 22

-We recommend antimicrobial therapy for treatment of two or

more positive blood cultures, a single positive blood culture
accompanied by signs of sepsis, or a single positive blood culture
together with a positive enterococcal culture from another
usually sterile site (Grade 1B). Options for monotherapy and
combination therapy are outlined in the tables (table 2). For
uncomplicated infection, five to seven days of therapy is likely
adequate. (See 'Bacteremia' above.)
-For treatment of enterococcal bacteremia with suspected
endocarditis or critical illness, we recommend combination
antimicrobial therapy over monotherapy (Grade 1B). Of the
combination antimicrobial regimens, we
suggest ampicillin plus ceftriaxone for E. faecalis since it avoids
the toxicity of aminoglycosides (Grade 2B); use of a cell wall-
active agent in combination with a synergistically active
aminoglycoside is also acceptable. (See 'Bacteremia' above.)
•Endocarditis − The treatment of enterococcal endocarditis is
discussed in detail separately. (See "Antimicrobial therapy of left-
sided native valve endocarditis" and "Antimicrobial therapy of
prosthetic valve endocarditis".)
•Meningitis − For treatment of enterococcal meningitis, we
recommend combination antimicrobial therapy over monotherapy
(Grade 1C). Of the combination antimicrobial regimens, we
suggest ampicillin, ceftriaxone, and gentamicin (table 4) (Grade 2C).
(See 'Meningitis' above.)
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