1199CHAPTER 149 Enterococcal Infections

independent of the patient’s clinical status, VRE infection increases the

risk of death over that among individuals infected with a glycopeptidesusceptible enterococcal strain.

The epidemiology of enterococcal disease and the emergence of

VRE have followed slightly different trends in other parts of the world

than in the United States. In Europe, the emergence of VRE in the

mid-1980s was seen primarily in isolates recovered from animals and

healthy humans rather than from hospitalized patients. The presence

of VRE was associated with the use of the glycopeptide avoparcin as

a growth promoter in animal feeds; this association prompted the

European Union to ban the use of this compound in animal husbandry

in 1996. However, after an initial decrease in the isolation of VRE from

animals and humans, the prevalence of hospital-associated VRE infections has slowly increased in certain European countries, with important regional differences. For example, rates of vancomycin resistance

among E. faecium clinical isolates in Europe are highest in Greece,

Ireland, Romania, Hungary, Slovakia, and Poland (25–35%), whereas

rates in the Scandinavian countries and the Netherlands are <5%.

These regional differences have been attributed in part to the implementation of aggressive “search-and-destroy” infection-control policies in countries such as the Netherlands; these policies have kept the

frequency of nosocomial methicillin-resistant Staphylococcus aureus

(MRSA) and VRE very low. Despite regional differences, Europe has

seen a general trend of increasing rates of VRE over the past decade,

though these rates continue to be much lower than in the United States.

The reasons are not totally understood, although it has been postulated

that this difference is related to the higher levels of human antibiotic

use in the United States. Recent data have also shown increasing rates

of enterococcal resistance to vancomycin in Latin American countries,

with 34% of clinical E. faecium isolates found to be resistant in a multicenter study including hospitals from Colombia, Venezuela, Ecuador,

and Peru. In Asia, rates of vancomycin resistance among enterococci

appear to be similar to those in U.S. hospitals.

The ability to sequence bacterial genomes has increased our

understanding of bacterial diversity, evolution, pathogenesis, and

mechanisms of antibiotic resistance. The genome sequences of

>8000 enterococcal strains are currently available, and some have been

entirely closed and annotated. This has allowed researchers to trace the

evolutionary trajectory of enterococci from their origin to the emergence of hospital-adapted clones. Sequence analysis suggests the genus

appeared ~400 million years ago with the advent of terrestrial animals.

Several key features aided in this transition, including the ability to

recombine large portions of chromosomal DNA from the core genome

and a malleable accessory genome consisting of plasmids, phages, and

mobile genetic elements. This genomic plasticity contributes to the

rising rates of antibiotic resistance seen within the genus and, in particular, in E. faecium.

A large proportion of the genomes available for analysis belong to

E. faecium, due to its importance as a nosocomial pathogen and the

epidemiologic surveillance projects to track the spread of vancomycinresistant strains. The population can be divided into two large groups,

or clades, of organisms: a hospital-associated clade A and a communityassociated clade B. The hospital-associated clade appears to be evolving

rapidly, and genomic comparisons suggest that this lineage emerged

75–80 years ago—a time point that coincides with the introduction of

antimicrobial drugs—and evolved, perhaps continuously, from animal

strains, not from human commensal isolates. Strains belonging to clade

A are more frequently identified as isolates causing invasive disease and

are more likely to carry drug resistance determinants, whereas clade B

isolates largely retain a susceptible phenotype.

One reason for the propensity of clade A strains to acquire resistance

determinants is that they more frequently lack a functional CRISPRcas system (short for clustered regularly interspaced short palindromic

repeats). These systems serve as a primitive “immune system” and

provide a genome defense for bacteria to protect them from foreign

DNA, such as phages, but they also serve to reduce the frequency

of acquisition of resistance genes borne on mobile genetic elements.

Another reason for their survival in the hospital environment is that

clade A isolates tend to possess alleles of penicillin-binding protein

5 (PBP5) associated with high-level β-lactam resistance in E. faecium

and may express higher levels of this enzyme than commensal strains.

A notable feature of the distribution of strains in clade A in some

studies is that they share a relatively recent common ancestor with E.

faecium of livestock origin. Use of antibiotics in animal husbandry as

both therapeutics and growth promoters has been linked to resistance

in several important contexts, including glycopeptides as mentioned

above. This suggests continued surveillance, and an expanding understanding of the population structure of enterococci may help identify

potential reservoirs of resistance and inform policy to limit their

spread.

■ CLINICAL SYNDROMES

Urinary Tract Infection and Prostatitis Enterococci are wellknown causes of nosocomial UTI—the most common infection caused

by these organisms (Chap. 135). Enterococcal UTIs are usually associated with indwelling catheterization, instrumentation, or anatomic

abnormalities of the genitourinary tract, and it is often challenging to

differentiate between true infection and colonization (particularly in

patients with chronic indwelling catheters). Their role as pathogens

in otherwise healthy premenopausal woman with acute cystitis is less

clear, with data from one study suggesting that enterococci recovered

from mid-stream urine cultures were not predictive of bacteriuria

in a subsequent catheterized specimen. The presence of leukocytes

in the urine in conjunction with systemic manifestations (e.g., fever)

or local signs and symptoms of infection with no other explanation

and a positive urine culture (≥105

 CFU/mL) suggests the diagnosis.

Moreover, enterococcal UTIs often occur in critically or chronically

ill patients whose comorbidities may obscure the diagnosis. In many

cases, removal of the indwelling catheter may suffice to eradicate the

organism without specific antimicrobial therapy. In rare circumstances,

UTIs caused by enterococci may run a complicated course, with the

development of pyelonephritis and perinephric abscesses that may

be a portal of entry for bloodstream infections (see below). Enterococci are also known causes of chronic prostatitis, particularly in men

whose urinary tract has been manipulated surgically or endoscopically.

These infections can be difficult to treat since the agents most potent

against enterococci (i.e., aminopenicillins and glycopeptides) penetrate

prostatic tissue poorly. Chronic prostatic infection can be a source of

recurrent enterococcal bacteremia.

Bacteremia and Endocarditis Bacteremia without endocarditis

is another frequently encountered presentation of enterococcal disease. Intravascular catheters and other devices are commonly associated with these bacteremic episodes (Chap. 142). Other well-known

sources of enterococcal bacteremia include the gastrointestinal and

hepatobiliary tracts; pelvic and intraabdominal foci; and, less frequently, wound infections, UTIs, and bone infections. In the United

States, enterococci are ranked second (after staphylococci) as etiologic

agents of central line–associated bacteremia. Patients with enterococcal

bacteremia usually have comorbidities and have been in the hospital

for prolonged periods; they commonly have received several courses

of antibiotics. Several studies indicate that the isolation of E. faecium

from the blood may lead to worse outcomes and higher mortality

rates than when other enterococcal species are isolated; this finding

may be related to the higher prevalence of vancomycin and ampicillin

resistance in E. faecium than in other enterococcal species, with the

consequent reduction of therapeutic options. In some cases (usually

when the gastrointestinal tract is the source), enterococcal bacteremia

may be polymicrobial, with gram-negative organisms isolated at the

same time. In addition, several cases have been documented in which

enterococcal bacteremia was associated with Strongyloides stercoralis

hyperinfection syndrome in immunocompromised patients.

Enterococci are important causes of community- and health care–

associated endocarditis, ranking second after staphylococci in the

latter infections. The presumed initial source of bacteremia leading

to endocarditis is the gastrointestinal or genitourinary tract—e.g., in

patients who have malignant and inflammatory conditions of the gut

or have undergone procedures in which these tracts are manipulated.

1200 PART 5 Infectious Diseases

The affected patients tend to be male and elderly and to have other

debilitating diseases and heart conditions. Both prosthetic and native

valves can be involved; mitral and aortic valves are affected most often.

Community-associated endocarditis (usually caused by E. faecalis) also

occurs in patients with no apparent risk factors or cardiac abnormalities. Endocarditis in women of childbearing age was well described in

the past. The typical presentation of enterococcal endocarditis is a subacute course of fever, weight loss, malaise, and cardiac murmur; typical

stigmata of endocarditis (e.g., petechiae, Osler’s nodes, Roth’s spots) are

found in only a minority of patients. Atypical manifestations include

arthralgias and manifestations of metastatic disease (splenic abscesses,

hiccups, pain in the left flank, pleural effusion, and spondylodiscitis).

Embolic complications are variable and can affect the brain. Heart failure is a common complication of enterococcal endocarditis, and valve

replacement may be critical in curing this infection, particularly when

multidrug-resistant organisms or major complications are involved.

Several clinical scoring systems (designated NOVA and DENOVA)

have been proposed to help differentiate enterococcal bacteremia from

true endocarditis. The duration of therapy is usually 4–6 weeks, with

more prolonged courses suggested for multidrug-resistant isolates in

the absence of valvular replacement.

Meningitis Enterococcal meningitis is an uncommon disease

(accounting for only ~4% of meningitis cases) that is usually associated with neurosurgical interventions and conditions such as shunts,

central nervous system (CNS) trauma, and cerebrospinal fluid (CSF)

leakage. In some instances—usually in patients with a debilitating

condition, such as cardiovascular or congenital heart disease, chronic

renal failure, malignancy, receipt of immunosuppressive therapy, or

HIV/AIDS—presumed hematogenous seeding of the meninges is seen

in infections such as endocarditis or bacteremia. Fever and changes in

mental status are common, whereas overt meningeal signs are less so.

CSF findings are consistent with bacterial infection—i.e., pleocytosis,

with a predominance of polymorphonuclear leukocytes (average,

~500/μL), an elevated serum protein level (usually >100 mg/dL), and a

decreased glucose concentration (average, 28 mg/dL). Gram’s staining

yields a positive result in about half of cases, with a high rate of organism recovery from CSF cultures; the most common species isolated are

E. faecalis and E. faecium. Complications include hydrocephalus, brain

abscesses, and stroke. As mentioned before for bacteremia, an association with Strongyloides hyperinfection has also been documented.

Intraabdominal, Pelvic, and Soft Tissue Infections As mentioned earlier, enterococci are part of the commensal microbiota of

the gastrointestinal tract and can produce spontaneous peritonitis in

cirrhotic individuals and in patients undergoing chronic ambulatory

peritoneal dialysis (Chap. 132). These organisms are commonly found

(usually along with other bacteria, including enteric gram-negative

species and anaerobes) in clinical samples from intraabdominal and

pelvic collections. The presence of enterococci in intraabdominal

infections is sometimes considered to be of little clinical relevance.

Several studies have shown that the role of enterococci in intraabdominal infections originating in the community and involving previously

healthy patients is minor since surgery and broad-spectrum antimicrobial drugs that do not target enterococci are often sufficient to treat

these infections successfully. In the past few decades, however, these

organisms have become prominent as a cause of intraabdominal infections in hospitalized patients because of the emergence and spread of

vancomycin resistance among enterococci and the increase in rates of

nosocomial infections due to multidrug-resistant E. faecium isolates.

In fact, several studies have now documented treatment failures due to

enterococci, with consequently increased rates of postoperative complications and death among patients with intraabdominal infections.

Thus, anti-enterococcal therapy is recommended for nosocomial peritonitis in immunocompromised and severely ill patients who have had

a prolonged hospital stay, have undergone multiple procedures, have

persistent abdominal sepsis and collections, or have risk factors for the

development of endocarditis (e.g., prosthetic or damaged heart valves).

Conversely, specific treatment for enterococci in the first episode of

intraabdominal infection originating in the community and affecting

previously healthy patients with no important cardiac risk factors for

endocarditis does not appear to be beneficial.

Enterococci are commonly isolated from soft tissue infections (Chap.

129), particularly those involving surgical wounds (Chap. 142). In fact,

these organisms rank third as agents of nosocomial surgical-site infections, with E. faecalis the most frequently isolated species. The clinical

relevance of enterococci in some of these infections—as in intraabdominal infections—is a matter of debate; differentiating between

colonization and true infection is sometimes challenging, although in

some cases, enterococci have been recovered from lung, liver, and skin

abscesses. Diabetic foot and decubitus ulcers are often colonized with

enterococci and may be the portal of entry for bone infections.

Other Infections Enterococci are well-known causes of neonatal

infections, including sepsis (mostly late-onset), bacteremia, meningitis,

pneumonia, and UTI. Outbreaks of enterococcal sepsis in neonatal

units have been well documented. Risk factors for enterococcal disease in newborns include prematurity, low birth weight, indwelling

devices, and abdominal surgery. Enterococci have also been described

as etiologic agents of bone and joint infections, including vertebral

osteomyelitis, usually in patients with underlying conditions such as

diabetes or endocarditis. Similarly, enterococci have been isolated

from bone infections in patients who have undergone arthroplasty

or reconstruction of fractures with the placement of hardware. Since

enterococci can produce a biofilm that is likely to alter the efficacy of

anti-enterococcal agents, treatment of infections that involve foreign

material is challenging, and removal of the hardware may be necessary

to eradicate the infection. Rare cases of enterococcal pneumonia, lung

abscess, and spontaneous empyema have been described.

TREATMENT

Enterococcal Infections

GENERAL PRINCIPLES

Enterococci are intrinsically resistant and/or tolerant to several

antimicrobial agents. (Tolerance is defined as lack of killing by drug

concentrations 32 times higher than the minimal inhibitory concentration [MIC].) Monotherapy for endocarditis with a β-lactam

antibiotic (to which many enterococci are tolerant) has produced

disappointing results, with high relapse rates after the end of

therapy. However, the addition of an aminoglycoside to a cell wall–

active agent (a β-lactam or a glycopeptide) increases cure rates and

eradicates the organisms; moreover, this combination is synergistic

and bactericidal in vitro. Therefore, for many decades, combination

therapy with a cell wall–active agent and an aminoglycoside was

the standard of care for endovascular infections caused by enterococci. This synergistic effect can be explained, at least in part, by

the increased penetration of the aminoglycoside into the bacterial

cell, presumably as a result of cell-wall alterations produced by

the β-lactam (or glycopeptide). Nonetheless, attaining synergistic bactericidal activity in the treatment of severe enterococcal

infections—particularly those caused by E. faecium—has become

increasingly difficult because of the development of resistance to

virtually all antibiotics available for this purpose.

The treatment of E. faecalis differs substantially from that of E.

faecium (Tables 149-1 and 149-2), mainly because of differences in

resistance profiles (see below). For example, resistance to ampicillin and vancomycin is rare in E. faecalis, whereas these antibiotics

are only infrequently useful against current isolates of E. faecium.

Moreover, as a consequence of the challenges and therapeutic limitations posed by the emergence of drug resistance in enterococci,

valve replacement may need to be considered in the treatment of

endocarditis caused by multidrug-resistant enterococci. Less severe

infections are often related to indwelling intravascular catheters;

removal of the catheter increases the likelihood of enterococcal

eradication by a subsequent short course of appropriate antimicrobial therapy.

1201CHAPTER 149 Enterococcal Infections

TABLE 149-1 Suggested Regimens for the Management of Infections

Caused by Enterococcus faecalis

CLINICAL SYNDROME SUGGESTED THERAPEUTIC OPTIONSa

Endovascular infections

(including endocarditis)

• Ampicillinb

 (12 g/d IV in divided doses q4h) plus

ceftriaxone (2 g IV q12h)

• Ampicillinb

 (12 g/d IV in divided doses q4h or by

continuous infusion) or penicillin (18–30 mU/d IV

in divided doses q4h or by continuous infusion)

plus an aminoglycosidec

• Vancomycind

 (15 mg/kg IV per dose) plus an

aminoglycosidec

• High-dose daptomycine

 ± another active agentf

• Ampicillinb

 plus imipenem

Nonendovascular

bacteremiag

• Ampicillin (12 g/d IV in divided doses q4h) or

penicillin (18 mU/d IV in divided doses q4h) ± an

aminoglycosidec

 or ceftriaxone

• Vancomycind

 (15 mg/kg IV per dose)

• High-dose daptomycine

 ± another active agentf

• Linezolid (600 mg IV/PO q12h)

Meningitis • Ampicillin (20–24 g/d IV in divided doses q4h)

or penicillin (24 mU/d IV in divided doses q4h)

plus an aminoglycosidec,h and consider adding

ceftriaxone (2 g IV q12h)

• Vancomycin (500–750 mg IV q6h)d plus an

aminoglycosidec

 or rifampin

• Linezolid

• High-dose daptomycine

 (plus intrathecal

daptomycin) ± another active agentf

Urinary tract infections

(uncomplicated)

• Fosfomycin (3 g PO, one dose)i

• Ampicillin (500 mg IV or PO q6h)

• Nitrofurantoin (100 mg PO q6h)

a

Authors’ preferences are underlined for each category; many of the regimens

are off-label. b

In rare cases, β-lactamase-producing isolates may be present.

Because these isolates are not detected by conventional determination of the

minimal inhibitory concentration, additional tests (e.g., the nitrocefin disk) are

recommended for isolates from endocarditis. The use of ampicillin/sulbactam

(12–24 g/d) is suggested in these cases. c

Only if the organism does not exhibit highlevel resistance (HLR) to aminoglycosides. This test is performed by the clinical

microbiology laboratory only for gentamicin or streptomycin (growth of enterococci

on agar containing gentamicin [500 μg/mL] or streptomycin [2000 μg/mL]). If HLR is

documented, the aminoglycoside will not act synergistically with the other agent in

the combination. However, HLR to one of these aminoglycosides does not indicate

resistance to the other agent (as reported individually). HLR to gentamicin implies

lack of synergism with tobramycin and with amikacin. Gentamicin (1–1.5 mg/kg

IV q8h) and streptomycin (15 mg/kg per day IV/IM in two divided doses) are the

only two recommended aminoglycosides. d

Vancomycin is recommended only as

an alternative to β-lactam agents in cases of allergy or toxicity plus the inability

to desensitize. Specific pharmacologic targets for trough concentrations have

not been clinically evaluated in enterococcal bacteremia; trough concentrations

of 15–20 mg/L have been associated with increased rates of nephrotoxicity.

Cerebrospinal fluid (CSF) concentrations in meningitis should be determined.

Vancomycin-resistant strains of E. faecalis have been reported. e

Consider doses

of 10–12 mg/kg once daily if used in combination and 10–12 mg/kg per day if used

alone. Monitoring of creatine phosphokinase levels is recommended throughout

therapy because of possible rhabdomyolysis. f

Potentially active agents may include

an aminoglycoside (if HLR is not detected), ampicillin, ceftaroline, tigecycline, or a

fluoroquinolone (which, if the isolate is susceptible, may be favored in meningitis).

The presence of mutations in liaFSR seems to increase susceptibility to ampicillin

and ceftaroline, and combinations of daptomycin with these compounds are

bactericidal in vitro against such strains. g

In selected cases of catheter-associated

bacteremia, removal of the catheter and a short course of therapy (~5–7 days)

may be sufficient. A single positive blood culture that is likely to be associated

with a catheter in a patient who is otherwise doing well may not require therapy

after removal of the catheter. Patients at high risk for endovascular infections

or with severe disease may benefit from synergistic combination therapy. h

The

addition of intrathecal or intraventricular therapy with gentamicin (2–10 mg/d) if the

organism does not exhibit HLR or with vancomycin (10–20 mg/d) when the isolate

is susceptible has been suggested by some authorities. The addition of systemic

rifampin (a good CSF-penetrating agent) may be considered. The combination of

ampicillin and ceftriaxone may have clinical benefit (by analogy with endocarditis),

but no cases treated with this combination have been reported; the authors would

use this combination. i

Approved by the U.S. Food and Drug Administration only

for uncomplicated urinary tract infections caused by vancomycin-susceptible E.

faecalis.

TABLE 149-2 Suggested Regimens for the Management of Infections

Caused by Vancomycin- and Ampicillin-Resistant Enterococcus faecium

CLINICAL SYNDROME SUGGESTED THERAPEUTIC OPTIONSa

Endovascular infections

(including endocarditis)

• High-dose daptomycinb

 plus another agentc

 ± an

aminoglycosided

• Linezolid (600 mg IV q12h)

• High-dose ampicillin (if MIC is ≤64 μg/mL) ± an

aminoglycosided

• Ampicillin plus imipenem (if the ampicillin MIC

is ≤32 μg/mL)

• Q/De

 (22.5 mg/kg per day in divided doses q8h) ±

another active agentf

Nonendovascular

bacteremiag

• High-dose daptomycinb

 ± another agentc

 ± an

aminoglycosided

• Linezolid (600 mg IV q12h)

• Q/D (22.5 mg/kg per day in divided doses q8h) ±

another active agentf

Meningitis • Linezolid (600 mg IV q12h) ± another CSFpenetrating active agenth

• High-dose daptomycinb

 (plus intraventricular

daptomycin) ± another CSF-penetrating active

agenth,i

• Q/D (22.5 mg/kg per day in divided doses q8h

plus intraventricular Q/D)j

 ± another active

agenth

Urinary tract infections • Fosfomycin (3 g PO, one dose)k

• Nitrofurantoin (100 mg PO q6h)

• Ampicillin or amoxicillin (2 g IV/PO q4–6h)l

a

Authors’ preferences are underlined for each category; many of these regimens

are off-label. b

Daptomycin at doses of 10–12 mg/kg once daily is suggested

(off-label). Close monitoring of creatine phosphokinase levels is recommended

throughout therapy because of possible rhabdomyolysis. c

Potentially active agents

may include ampicillin or ceftaroline (even if the infecting strain is resistant in vitro)

or tigecycline. In vitro synergism of daptomycin with ampicillin or ceftaroline has

been observed against some isolates that subsequently become nonsusceptible

to daptomycin during therapy. The synergism of daptomycin and β-lactams is

associated with mutations in liaFSR. Consider combination therapy if the minimal

inhibitory concentration (MIC) of daptomycin is ≥3 μg/mL. d

Only if the organism

does not exhibit high-level resistance to aminoglycosides (see Table 149-1, footnote

c). e

Quinupristin/dalfopristin (Q/D) lost U.S. Food and Drug Administration (FDA)

approval for infections due to vancomycin-resistant Enterococcus. f

Agents that

may be useful in combination with Q/D (if the isolate is susceptible to each agent)

include doxycycline with rifampin (one reported case) or fluoroquinolones (one

reported case). g

In selected cases of catheter-associated bacteremia, removal of

the catheter and a short course of therapy (~5–7 days) may be sufficient. A single

positive blood culture that is likely to be associated with a catheter in a patient

who is otherwise doing well may not require therapy after removal of the catheter.

h

Fluoroquinolones (e.g., moxifloxacin) and rifampin (if the isolate is susceptible

to each agent) reach therapeutic levels in the cerebrospinal fluid. i

Intrathecal

gentamicin (2–10 mg/d) if high-level resistance is not detected. Intraventricular

daptomycin has been used in two cases of meningitis j

Intrathecal Q/D (1–5 mg/d)

has been used in combination with Q/D systemic therapy in meningitis. If Q/D is

chosen, simultaneous use of both systemic and intrathecal therapy is suggested.

k

Approved by the FDA only for uncomplicated urinary tract infections caused by

vancomycin-susceptible E. faecalis. l

Concentrations of amoxicillin and ampicillin

in urine far exceed those in serum and may be potentially effective even against

isolates with high MICs. Doses up to 12 g/d are suggested for isolates with MICs of

≥64 μg/mL.

CHOICE OF ANTIMICROBIAL AGENTS

Among the β-lactams, the most active are the aminopenicillins

(ampicillin, amoxicillin) and ureidopenicillins (i.e., piperacillin);

next most active are penicillin G and imipenem. Cephalosporins,

with the possible exception of ceftaroline, are not active as monotherapy. For E. faecium, a combination of high-dose ampicillin (up

to 30 g/d) plus an aminoglycoside has been suggested—even for

ampicillin-resistant strains if the MIC is ≤64 μg/mL—since a plasma

ampicillin concentration higher than this value can be achieved at

high doses. The only two aminoglycosides recommended for synergistic therapy in severe enterococcal infections are gentamicin and

streptomycin. This is because the most common acquired enzyme

conferring high-level resistance to gentamicin also is active against

tobramycin and amikacin but not streptomycin, and the resistance

mechanisms causing streptomycin high-level resistance do not

1202 PART 5 Infectious Diseases

affect gentamicin. The use of amikacin is strongly discouraged

because it is infrequently active tobramycin should never be used

for the treatment of E. faecium infections due to the presence of

a chromosomally encoded, species-specific, tobramycin-modifying

enzyme and aminoglycoside monotherapy should not be employed.

Vancomycin is an alternative to β-lactam drugs for the treatment

of E. faecalis infections but is less useful against E. faecium because

resistance is common.

As mentioned above, use of the aminoglycoside–ampicillin combination for E. faecalis infections has become increasingly problematic because of toxicity in critically ill patients and increased rates

of high-level resistance to aminoglycosides. An observational, nonrandomized, comparative study encompassing a multicenter cohort

was conducted in 17 Spanish hospitals and one Italian hospital; the

results indicated that a 6-week course of ampicillin plus ceftriaxone

is as effective as ampicillin plus gentamicin in the treatment of E.

faecalis endocarditis, with less risk of toxicity. Therefore, this regimen should be considered in patients at risk for aminoglycoside

toxicity or those with isolates displaying high-level resistance to

aminoglycosides, and it is now recommended as first-line therapy

for E. faecalis endocarditis. Use of dual β-lactam regimens for

ampicillin-susceptible isolates of E. faecium has not been studied

in the clinical setting. Limited in vitro data suggest that synergism

between ampicillin and ceftriaxone is not reliably active against

these isolates.

Linezolid is the only agent approved by the U.S. Food and

Drug Administration (FDA) for the treatment of VRE infections

(Table 149-2). (A prior approval for quinupristin/dalfopristin has

been withdrawn.) Linezolid is not bactericidal, and its use in severe

endovascular infections has produced mixed results; therefore, it is

recommended only as an alternative to other agents for such infections. In addition, linezolid may cause significant toxicities (thrombocytopenia, peripheral neuropathy, optic neuritis, and lactic

acidosis) when used in regimens given for >2 weeks. Nonetheless,

linezolid may play a role in the treatment of enterococcal meningitis

and other CNS infections, although clinical data are limited.

The lipopeptide daptomycin is a bactericidal antibiotic with

potent in vitro activity against all enterococci. Although daptomycin is not approved by the FDA for the treatment of VRE or E.

faecium infections, it has been used alone (at high dosage) or in

combination with other agents (ampicillin, ceftaroline, and tigecycline) with apparent success against multidrug-resistant enterococcal infections (Tables 149-1 and 149-2). The main adverse reactions

to daptomycin are elevated creatine phosphokinase levels and

eosinophilic pneumonitis (rare). Daptomycin is not useful against

pulmonary infections because the pulmonary surfactant inhibits its

antibacterial activity.

Several meta-analyses have examined the question of which

agent should be preferred for VRE bacteremia—linezolid or daptomycin. These studies concluded either no difference between

the two drugs or favored linezolid due to lower all-cause and

infection-related mortality, but were limited by small patient numbers and heterogenous outcomes. A subsequent large retrospective

observational study from the Veterans Affairs database reported

lower rates of all-cause mortality at 30 days and less microbiologic

failure (i.e., positive cultures despite therapy) with daptomycin

as compared to linezolid. One important observation from these

investigations is that the efficacy of daptomycin is dependent on

the dose, with improved outcomes seen with high-dose daptomycin therapy (≥10 mg/kg) as compared to standard-dose therapy

(6 mg/kg). Genome sequencing of clinical isolates has revealed

that mutations in genes associated with daptomycin resistance are

not uncommon (see “Antimicrobial Resistance,” below) and were

associated with the emergence of resistance to daptomycin at lower

simulated dosing regimens (6 mg/kg) in experimental models of

infection. These data led the Clinical Laboratory and Standards

Institute (CLSI) to change the daptomycin breakpoints in 2019.

For E. faecium, all isolates with an MIC of ≤4 mg/L are placed in a

“susceptible dose-dependent” category based on a dosing regimen

of 8–12 mg/kg, while those with an MIC ≥8 mg/L are considered

resistant. For all other enterococci, isolates are considered susceptible with an MIC of ≤2 mg/L, intermediate with an MIC of 4 mg/L,

and resistant with an MIC ≥8 mg/L.

The glycylcycline drug tigecycline is active in vitro against all

enterococci, regardless of the isolates’ vancomycin susceptibility.

However, its use as monotherapy for endovascular or severe enterococcal infections is not recommended because of low attainable

blood levels. Newer generation tetracyclines, such as eravacycline

and omadacycline, also display in vitro activity, but their role in the

treatment of enterococcal infections remains to be evaluated.

Telavancin, a lipoglycopeptide approved by the FDA for the

treatment of skin and soft tissue infections as well as hospitalassociated pneumonia, is active against vancomycin-susceptible

enterococci but not VRE. Likewise, dalbavancin, a lipoglycopeptide

antibiotic with a long terminal half-life, has FDA approval for skin

and soft tissue infections due to susceptible strains of E. faecalis,

but no activity against VRE. Oritavancin, a novel glycopeptide

with activity against VRE, has been approved for the treatment of

acute bacterial skin and soft tissue infections caused by susceptible

organisms, including vancomycin-susceptible E. faecalis. The MICs

of oritavancin against VRE are low, and this compound may be a

promising drug for VRE treatment in the future.

Lastly, tedizolid—a new oxazolidinone now available for clinical

use—is approved only for the treatment of E. faecalis infections.

Tedizolid is more potent than linezolid in vitro against VRE strains;

however, its role in severe VRE infections remains to be determined.

ANTIMICROBIAL RESISTANCE

Resistance to β-lactam agents continues to be observed only infrequently in E. faecalis but is characteristic of E. faecium. The

mechanism of ampicillin resistance in E. faecium is related to a

penicillin-binding protein (PBP) designated PBP5, which is the

critical target of β-lactam antibiotics. PBP5 exhibits low affinity for

ampicillin and can synthesize cell wall in the presence of this antibiotic, even when other PBPs are inhibited. The version of this protein

found in ampicillin-resistant hospital-associated strains has multiple amino-acid differences that even further decrease the affinity of

PBP5 for ampicillin; these changes and/or increased production of

PBP5 are the two most common mechanisms of high-level ampicillin resistance (e.g., MIC >32 μg/mL) in clinical strains.

Vancomycin is a glycopeptide antibiotic that inhibits cell-wall

peptidoglycan synthesis in susceptible enterococci and has been

widely used against enterococcal infections in clinical practice

when the utility of β-lactams is limited by resistance, allergy, or

adverse reactions. This effect is mediated by binding of the antibiotic to peptidoglycan precursors (UDP-MurNAc-pentapeptides)

upon their exit from the bacterial cell cytoplasm. The interaction of

vancomycin with the peptidoglycan is specific and involves the last

two d-alanine residues of the precursor. The first isolates of VRE

were documented in 1986, and vancomycin resistance (particularly

in E. faecium) has since increased considerably around the world.

The mechanism involves the replacement of the last d-alanine

residue of peptidoglycan precursors with d-lactate (e.g., VanA

and VanB) or d-serine (e.g., VanC), with consequent high- and

low-level resistance, respectively. There is significant heterogeneity

among isolates, but either substitution substantially decreases the

affinity of vancomycin for the peptidoglycan; with the d-lactate

substitution, the affinity for binding to the pentapeptide precursor

is decreased by ~1000-fold. Vancomycin-resistant organisms also

produce enzymes that destroy the d-alanine-d-alanine ending precursors, ensuring that additional binding sites for vancomycin are

not available.

The genes encoding the machinery responsible for vancomycin

resistance are located in the van operon and likely originated in

soil bacteria. Several variants of the operon have been described,

but VanA is the most common in clinical isolates in the United

States, Latin America, and Europe, whereas VanB isolates are more

frequent in Australia. Two enterococcal species, E. gallinarum and