# 36 - 154 Enterococcal Infections

### 154 Enterococcal Infections

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■FURTHER READING
Bruckner L, Gigliotti F: Viridans group streptococcal infections 
among children with cancer and the importance of emerging antibi­
otic resistance. Semin Pediatr Infect Dis 17:153, 2006.
Parks T et al: Polyspecific intravenous immunoglobulin in clindamy­
cin-treated patients with streptococcal toxic shock syndrome: A 
systematic review and meta-analysis. Clin Infect Dis 67:1434, 2018.
Raabe V, Shane A: Group B Streptococcus (Streptococcus agalactiae), 
in Gram-Positive Pathogens, 3rd ed, Fischetti V et al (eds). Washing­
ton, DC, ASM Press, 2019, pp 228–238.
Shulman ST et al: Clinical practice guideline for the diagnosis and 
management of group A streptococcal pharyngitis: 2012 update by 
the Infectious Diseases Society of America. Clin Infect Dis 55:1279, 
2012.
Stevens DL, Bryant AE: Necrotizing soft tissue infections. N Engl J 
Med 377:2253, 2017.
Xie O et al: Inter-species gene flow drives ongoing evolution of Strepto­
coccus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. Nat 
Commun 15:2286, 2024.
William R. Miller, Cesar A. Arias, 

Barbara E. Murray*

Enterococcal Infections
Enterococci have been recognized as potential human pathogens for 
well over a century, but only in recent years have these organisms 
acquired prominence as important causes of nosocomial infections. 
The ability of enterococci to survive and/or disseminate in the hospital 
environment and to acquire antibiotic resistance determinants makes 
the treatment of some enterococcal infections in critically ill patients 
a difficult challenge. Enterococci were first mentioned in the French 
literature in 1899; the “entérocoque” was found in the human gastro­
intestinal tract. The first pathologic description of an enterococcal 
infection dates to the same year. A clinical isolate from a patient who 
died as a consequence of endocarditis was initially designated Micro­
coccus zymogenes, was later named Streptococcus faecalis subspecies 
zymogenes, and would now be classified as Enterococcus faecalis. The 
ability of this isolate to cause severe disease in both rabbits and mice 
illustrated its potential lethality in the appropriate settings.
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■MICROBIOLOGY AND TAXONOMY
Enterococci are gram-positive organisms. In clinical specimens, they 
are usually observed as single cells, diplococci, or short chains 
(Fig. 154-1), although long chains are noted with some strains. 
Enterococci were originally classified as streptococci because organ­
isms of the two genera share many morphologic and phenotypic char­
acteristics, including a generally negative catalase reaction. Only DNA 
hybridization studies and later 16S rRNA sequencing clearly demon­
strated that enterococci should be grouped as a genus distinct from the 
streptococci. Unlike the majority of streptococci, enterococci hydrolyze 
esculin in the presence of 40% bile salts and grow at high salt concen­
trations (e.g., 6.5%) and at high temperatures (46°C). Enterococci are 
usually reported by the clinical laboratory to be nonhemolytic on the 
basis of their inability to lyse the ovine or bovine red blood cells (RBCs) 
commonly used in agar plates; however, some strains of E. faecalis do 
lyse RBCs from humans, horses, and rabbits due to the presence of an 
acquired hemolysin/cytolysin gene. The majority of clinically relevant 
enterococcal species hydrolyze pyrrolidonyl-β-naphthylamide (PYR); 
*Deceased.

FIGURE 154-1  Gram’s stain of cultured blood from a patient with enterococcal 
bacteremia. Oval gram-positive bacterial cells are arranged as diplococci and short 
chains. (Courtesy of Audrey Wanger, PhD.)
CHAPTER 154
this characteristic is helpful in differentiating enterococci from organ­
isms of the Streptococcus gallolyticus group (formerly known as S. bovis, 
which includes S. gallolyticus, S. pasteurianus, and S. infantarius) and 
from Leuconostoc species. Although many species of enterococci have 
been isolated from human infections, the overwhelming majority of 
cases are caused by two species, E. faecalis and E. faecium. Less fre­
quently isolated species include Enterococcus gallinarum, E. durans, E. 
hirae, and E. avium.
Enterococcal Infections
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■PATHOGENESIS
Enterococci are normal inhabitants of the large bowel of human adults, 
although they usually make up <1% of the culturable intestinal micro­
biota. In the healthy human host, enterococci are typical symbionts 
that coexist with other gastrointestinal bacteria; in fact, the utility of 
certain enterococcal strains as probiotics in the treatment of diarrhea 
suggests their possible role in maintaining the homeostatic equilibrium 
of the bowel. These commensals play a role in colonization resistance, or 
the ability of a healthy gastrointestinal microbiota to impede the establish­
ment of a population of drug-resistant bacteria such as vancomycinresistant enterococci (VRE). Colonization resistance arises from a 
complex set of metabolic and immunologic interactions between the 
host, pathogen, and intestinal microbiota, many of which are disrupted 
in hospitalized or chronically ill patients.
Several studies have shown that a higher level of gastrointestinal 
colonization is a critical factor in the pathogenesis of enterococcal 
infections. Physical factors, such as stomach pH and the mucin layer 
on the interior of the intestinal lumen, provide a barrier and limit 
pathogen access to the intestinal epithelium. In the hospital setting, 
administration of medications that suppress stomach acid secretion, 
or degradation of the mucin layer by gut commensals during periods 
of decreased oral intake, can disrupt these protective layers. The avail­
ability of specific carbon sources also has been shown to influence the 
ability of enterococci to colonize the intestine. Depletion of fructose 
by members of the genus Olsenella leads to impaired growth and a 
decrease in the enteric burden of VRE in a mouse-colonization model, 
while the presence of lactose favors the outgrowth of enterococci. Fur­
ther, enterococci may potentiate the fitness and virulence of pathogens 
such as Clostridioides difficile by altering the availability of fermentable 
amino acids, by promoting C. difficile fitness, and by depletion of argi­
nine, which leads to increased C. difficile toxin production.

One of the most important factors that promotes increased gastro­
intestinal colonization by enterococci is the administration of antimi­
crobial agents since enterococci are intrinsically resistant to a variety 
of commonly used antibacterial drugs. In particular, antibiotics that 
are excreted in the bile and have broad-spectrum activity (e.g., certain 
cephalosporins and antimicrobials with anaerobic activity) are usually 
associated with the recovery of higher numbers of enterococci from 
feces. However, the increased colonization by hospital-associated strains 
of E. faecium in the presence of antimicrobial agents appears to be due 
to more than the simple filling of a “biologic niche.” Studies of coloniza­
tion dynamics in mouse intestines suggest host-derived antimicrobial 
peptides produced by the innate immune system (such as the lectin 
RegIIIγ) and compounds such as lantibiotics or bacteriocins produced 
by members of the microbiota itself are important mediators of coloni­
zation resistance. Activation of Toll-like receptors by lipopolysaccharide 
(an important component of the gram-negative cell envelope) leads, in 
mice, to increased production of RegIIIγ, and loss of this stimulation by 
antibiotic-induced disruptions of commensal gram-negative bacteria 
impairs clearance of VRE from the intestines. Similarly, antimicrobial 
lantibiotics produced by commensal bacteria (such as Blautia pro­
ducta) are active against VRE in vitro, but this organism may require 
a cooperative partnership with other members of the microbiota to 
effectively provide colonization resistance. Disruption of these partner­
ships by antibiotic administration can lead to an environment where 
VRE can flourish. Another factor that may contribute to enterococcal 
survival in the gastrointestinal tract is the production of bacteriocins 
(molecules that kill competing bacteria). Strains of E. faecalis harboring 
pheromone-producing plasmids that code for bacteriocins are capable 
of outcompeting enterococci lacking such plasmids, and conjugative 
transfer of these elements enhances the survival of recipient enterococci. 
In the absence of antibiotics, hospital-associated lineages of E. faecium 
seem to be less adapted for survival in the gastrointestinal tract than are 
commensal E. faecium strains. Studies examining the rate of carriage of 
VRE in patients after discharge from the hospital document a median 
time to clearance between 2 and 4 months in patients without ongoing 
risk factors, such as continued antibiotic use, residence in a long-term 
care facility, or need for hemodialysis.

PART 5
Infectious Diseases
Colonization by enterococci may also have important effects on 
the treatment of noninfectious syndromes. In hematopoietic stem cell 
transplant patients, domination of the gastrointestinal tract by entero­
cocci is associated with increased inflammation and a greater severity 
of illness and mortality in graft-versus-host disease. Certain enterococ­
cal species, such as E. faecium, E. durans, and E. hirae, modulate the 
host immune response and can potentiate the activity of anti-PD-L1 
immune checkpoint inhibitor therapy. This effect is mediated by the 
presence of salA, a gene which encodes a peptidoglycan hydrolase 
with D,L-endopeptidase activity. The muropeptides generated by SalA 
induce host activation of NF-κB via NOD2, leading to an enhanced 
antitumor immune response.
Several vertebrate, worm, and insect models have been developed to 
study the role of possible pathogenic determinants in both E. faecalis 
and E. faecium. Three main groups of virulence factors may increase 
the ability of enterococci to colonize the gastrointestinal tract and/or 
cause disease. The first group, enterococcal secreted factors, are mol­
ecules released outside the bacterial cell that contribute to the process 
of infection. The best studied of these molecules include enterococ­
cal hemolysin/cytolysin and two enterococcal proteases (gelatinase 
and serine protease). Enterococcal cytolysin is a heterodimeric toxin 
produced by some strains of E. faecalis that is capable of lysing human 
(as well as equine but not ovine) RBCs as well as polymorphonuclear 
leukocytes and macrophages. A newly described pore-forming toxin, 
Epx, specifically targets human leukocyte antigen type 1, and has been 
shown to be active against peripheral blood mononuclear cells and 
intestinal organoids in vitro. E. faecalis gelatinase and serine protease 
are thought to mediate virulence by several mechanisms, including the 
degradation of host tissues and the modification of critical components 
of the immune system. Mutants lacking the genes corresponding to 
these proteins are highly attenuated in experimental animal models of 
peritonitis, endocarditis, and endophthalmitis.

A second group of virulence factors, enterococcal surface components, 
includes adhesins and is thought to contribute to bacterial attachment 
to extracellular matrix molecules in the human host. Several molecules 
on the surface of enterococci have been characterized and shown to 
play a role in the pathogenesis of enterococcal infections. Among the 
characterized adhesins is aggregation substance of E. faecalis, which 
mediates the attachment of bacterial cells to each other, thereby 
facilitating conjugative plasmid exchange. Several lines of evidence 
indicate that aggregation substance and enterococcal cytolysin act 
synergistically to increase the virulence potential of E. faecalis strains 
in experimental endocarditis. The surface protein adhesin of collagen 
of E. faecalis (Ace) and its E. faecium homologue (Acm) are microbial 
surface components adhering to matrix molecules (MSCRAMMs); 
they recognize adhesive matrix molecules involved in bacterial attach­
ment to host proteins such as collagen, fibronectin, and fibrinogen. 
Both Ace and Acm are collagen adhesins that are important in the 
pathogenesis of experimental endocarditis. Pili of both E. faecalis and 
E. faecium are important mediators of attachment to and invasion of 
host tissues. Mutants of E. faecalis lacking pili are attenuated in biofilm 
production, experimental endocarditis, and urinary tract infections 
(UTIs). Other surface proteins that share structural homology with 
MSCRAMMs and appear to play a role in enterococcal attachment to 
the host and in virulence include the E. faecalis surface protein Esp 
and its E. faecium homologue Espfm, the second collagen adhesin of E. 
faecium (Scm), the surface proteins of E. faecium (Fms), SgrA (which 
binds to components of the basal lamina), and EcbA (which binds 
to collagen type V). Additional surface components apparently asso­
ciated with pathogenicity include the Erl protein (a protein from the 
WxL family) and polysaccharides, which are thought to interfere with 
phagocytosis of the organism by host immune cells. Teichoic acids on 
the enterococcal surface appear to be immunogenic, and antibodies to 
these molecules are protective in some animal models.
The third group of virulence factors has not been well character­
ized but includes the E. faecalis stress protein Gls24, which has been 
associated with enterococcal resistance to bile salts and appears to be 
important in the pathogenesis of endocarditis, and the hylEfm-containing 
plasmids of E. faecium, which are transferable between strains and 
increase gastrointestinal colonization by E. faecium. In mouse peritoni­
tis, acquisition of these plasmids increased the lethality of a commensal 
strain of E. faecium and enhanced colonization of the uroepithelium. A 
gene encoding a regulator of oxidative stress (AsrR) has been identified 
as an important virulence factor of E. faecium.
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■EPIDEMIOLOGY
According to data collected from 2018 to 2021 by the National Health­
care Safety Network of the Centers for Disease Control and Prevention, 
enterococci are the third most common isolates (after Escherichia 
coli and staphylococci) from hospital-associated infections in the 
United States. Although E. faecalis remains the predominant species 
recovered from nosocomial infections, the isolation of E. faecium has 
increased substantially in the past 20 years and accounts for approxi­
mately one-third of all enterococcal infections identified to the species 
level. This point is important, since E. faecium is by far the most resis­
tant and challenging enterococcal species to treat. More than 90% of E. 
faecium isolates are resistant to ampicillin (historically the most effec­
tive β-lactam agent against enterococci), while ampicillin resistance in 
E. faecalis is uncommon. Vancomycin resistance in E. faecium isolates 
ranges from 50–70% in acute care hospitals in the United States to up to 
80% in long-term care facilities. Resistance to vancomycin in E. faecalis 
isolates is less common, with a higher prevalence in long-term care 
facilities (10–12%) than in acute care hospitals (2–5%).
The dynamics of enterococcal transmission and dissemination in 
the hospital environment have been extensively studied, with a focus 
on VRE. These studies have revealed that VRE colonization of the 
gastrointestinal tract is a critical step in the development of enterococ­
cal disease and that a substantial proportion of patients colonized with 
VRE remain colonized for prolonged periods (sometimes >1 year) and 
are more likely than patients without VRE colonization to develop 
an Enterococcus-related illness (e.g., bacteremia). Important factors

associated with VRE colonization and persistence in the gut include 
prolonged hospitalization; long courses of antibiotic therapy; hospi­
talization in long-term care facilities, surgical units, and/or intensive 
care units; organ transplantation; renal failure (particularly in patients 
undergoing hemodialysis) and/or diabetes; high APACHE (Acute 
Physiology and Chronic Health Evaluation) scores; and physical prox­
imity to patients infected or colonized with VRE or these patients’ 
rooms. Once a patient becomes colonized with VRE, several key factors 
are involved in the organisms’ dissemination in the hospital environ­
ment. VRE can survive exposure to heat and certain disinfectants 
and have been found on numerous inanimate objects in the hospital, 
including bed rails, medical equipment, doorknobs, gloves, telephones, 
and computer keyboards. Thus, health care workers and the environ­
ment play pivotal roles in enterococcal transmission from patient to 
patient, and infection control measures are crucial in breaking the 
chain of transmission. Moreover, two meta-analyses have found that, 
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, from 8.1% in 2012 to 17.6% in 2022. 
Furthermore, there are important regional differences in rates of van­
comycin resistance among E. faecium, with rates below 5–10% in most 
of western Europe and Scandinavia, and 25–50% across much of south­
ern and eastern Europe. Despite regional differences, Europe has seen a 
general trend of increasing rates of VRE over the past decade, although 
these rates continue to be much lower than in the United States. The 
reasons are not totally understood, but 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 entero­
coccal 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. Ongoing collection of 
enterococcal isolates as a part of epidemiologic surveillance 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 transi­
tion, including the ability to recombine large portions of chromosomal 
DNA from the core genome and a malleable accessory genome consist­
ing 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 vancomycin-

resistant strains. The population can be divided into two large groups, 
or clades, of organisms: a hospital-associated clade A and a commu­
nity-associated clade B. The hospital-associated clade appears to be 
evolving rapidly via a series of historic and ongoing recombination 
events. Certain regions of the chromosome show a convergence of 
genomic diversity both within and between clades, suggesting there 
are several “hot spots” for recombination. Importantly, these regions 
contain the polysaccharide biosynthesis cluster, which has been impli­
cated in altering the antigenic capsular polysaccharide in streptococci, 

and the LiaFSR locus, a major cell envelope stress system that medi­
ates resistance to membrane-active antibiotics and host antimicrobial 
peptides. 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 sus­
ceptible 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 pro­
vide a genome defense for bacteria to protect them from foreign DNA, 
such as phages, but they also serve to reduce the frequency of acquisi­
tion 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 phenomenon suggests that 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.
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■CLINICAL SYNDROMES
CHAPTER 154
Urinary Tract Infection and Prostatitis 
Enterococci are wellknown causes of nosocomial UTI—the most common infection caused 
by these organisms (Chap. 140). Enterococcal UTIs are usually associ­
ated 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 midstream 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 pros­
tatic tissue poorly. Chronic prostatic infection can be a source of recur­
rent enterococcal bacteremia.
Enterococcal Infections
Bacteremia and Endocarditis 
Bacteremia without endocarditis 
is another frequently encountered presentation of enterococcal dis­
ease. Intravascular catheters and other devices are commonly associ­
ated with these bacteremic episodes (Chap. 147). Other well-known 
sources of enterococcal bacteremia include the gastrointestinal and 
hepatobiliary tracts; pelvic and intraabdominal foci; and, less fre­
quently, 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, and recent studies have implicated E. faecalis as the 
leading cause of endocarditis after transcatheter aortic valve implan­
tation (TAVI). 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. 
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 abnormali­
ties. 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 spondy­
lodiscitis). 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, particu­
larly when multidrug-resistant organisms or major complications are 
involved. A clinical scoring system (DENOVA) has been proposed to 
help differentiate enterococcal bacteremia from true endocarditis and 
determine the need for echocardiography. The duration of therapy is 
usually 4–6 weeks, with more prolonged courses suggested for multi­
drug-resistant isolates in the absence of valvular replacement. Risk of 
relapse for endocarditis due to E. faecalis varies across studies, but it is 
higher in patients who are treated with antibiotics alone (2–11%) than 
in those who undergo surgery (0–3%); relapse may occur out to 1-year 
post-treatment.
Meningitis 
Enterococcal meningitis is an uncommon disease 
(accounting for only ~4% of meningitis cases) that is usually associ­
ated 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 organ­
ism 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 associa­
tion with Strongyloides hyperinfection also has been documented.
Intraabdominal, Pelvic, and Soft Tissue Infections 
As men­
tioned above, 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. 137). These organisms are commonly found 
(usually along with other bacteria, including enteric gram-negative 
species and anaerobes) in clinical samples from intraabdominal and 
PART 5
Infectious Diseases

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 intraabdomi­
nal infections originating in the community and involving previously 
healthy patients is minor since surgery and broad-spectrum antimi­
crobial 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 infec­
tions 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 com­
plications and death among patients with intraabdominal infections. 
Thus, anti-enterococcal therapy is recommended for nosocomial peri­
tonitis 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. 134), particularly those involving surgical wounds (Chap. 147). 
In fact, these organisms rank third as agents of nosocomial surgical-site 
infections, with E. faecalis the most frequently isolated species. The clini­
cal relevance of enterococci in some of these infections—as in intraab­
dominal 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 etio­
logic agents of bone and joint infections, including vertebral osteomy­
elitis, 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 reconstruc­
tion 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 chal­
lenging, 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 con­
centration [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, combina­
tion 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 bacte­
rial cell, presumably as a result of cell-wall alterations produced 
by the β-lactam (or glycopeptide). Nonetheless, attaining syner­
gistic 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 154-1 and 154-2), mainly because of differences in 
resistance profiles (see below). For example, resistance to ampicil­
lin 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 limi­
tations 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 antimicro­
bial therapy. 
CHOICE OF ANTIMICROBIAL AGENTS
Among the β-lactams, the most active are the aminopenicillins 
(ampicillin, amoxicillin); next most active are penicillin G, imipe­
nem, and ureidopenicillins (i.e., piperacillin). Cephalosporins are 
not active as monotherapy. The only two aminoglycosides recom­
mended 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 streptomy­
cin, and the resistance mechanisms causing high-level resistance 
to streptomycin do not affect gentamicin. The use of amikacin is 
strongly discouraged because it is infrequently active, and tobramy­
cin should never be used for the treatment of E. faecium infections 
due to the presence of a chromosomally encoded, species-specific, 
tobramycin-modifying enzyme. 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 com­
bination for E. faecalis infections has become increasingly prob­
lematic 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 1 Italian hospital; 
the results indicated that a 6-week course of ampicillin plus ceftri­
axone 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 
154-2). Linezolid is not bactericidal, and its use in severe endovas­
cular infections has produced mixed results; therefore, it is recom­
mended only as an alternative to other agents for such infections. In 
addition, linezolid may cause significant toxicities (thrombocytope­
nia, 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 
in vitro activity against all enterococci. Although daptomycin is 
not approved by the FDA for the treatment of VRE or E. faecium 

TABLE 154-1  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
• Ampicillinb (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) ± 
CHAPTER 154
another active agentf
Urinary tract 
infections 
(uncomplicated)
• Amoxicillin (500 mg PO q8h)  
• Fosfomycin (3 g PO, one dose)i
• Ampicillin (500 mg IV or PO q6h)
• Nitrofurantoin (100 mg PO q6h)
Enterococcal Infections
aAuthors’ preferences are underlined for each category; many of the regimens are 
off-label. bIn 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. If choosing a β-lactam other than ampicillin for an invasive infection, 
susceptibility testing for penicillin should be performed to identify penicillin-resistant, 
ampicillin-susceptible (PRASEF) isolates. Limited in vitro data suggest that synergistic 
killing by dual β-lactams (i.e., ampicillin and ceftriaxone) may be compromised in 
PRASEF isolates. Some suggest caution with the combination of ampicillin and 
ceftriaxone in PRASEF isolates and would consider an alternate therapy (such as 
daptomycin plus ampicillin) guided by susceptibility testing in cases of persistent 
bacteremia or signs of clinical failure. cOnly if the organism does not exhibit high-level 
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. 
dVancomycin 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. Vancomycin-resistant strains of E. faecalis have been reported. 
eConsider doses of 10–12 mg/kg once daily, adjusted for renal function. Monitoring of 
creatine phosphokinase levels is recommended throughout therapy because of possible 
rhabdomyolysis. fPotentially active agents may include an aminoglycoside (if HLR is not 
detected), ampicillin, ceftaroline, tigecycline, eravacycline, 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. gIn 
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. 
hThe 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. iApproved by the U.S. Food and Drug Administration only for uncomplicated 
urinary tract infections caused by vancomycin-susceptible E. faecalis.

TABLE 154-2  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
Nonendovascular 
bacteremiae
• High-dose daptomycinb ± another agentc ± an 
aminoglycosided 
• Linezolid (600 mg IV q12h)
Meningitis
• Linezolid (600 mg IV q12h) ± another 

CSF-penetrating active agentf 
• High-dose daptomycinb (plus intraventricular 
daptomycin) ± another CSF-penetrating active 
agentf,g
Urinary tract infections
• Fosfomycin (3 g PO, one dose)h 
• Nitrofurantoin (100 mg PO q6h)
• Ampicillin or amoxicillin (2 g IV/PO q4–6h)i
aAuthors’ preferences are underlined for each category; many of these regimens 
are off-label. bDaptomycin 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. cPotentially active agents 
may include ampicillin or ceftaroline (even if the infecting strain is resistant in vitro), 
tigecycline, eravacycline, or a fluroquinolone. 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. The authors prefer use of 
combination therapy for all endovascular infections or for bacteremic patients in 
whom source control cannot be achieved, as in vitro data suggest combination 
therapy may prevent or delay the emergence of daptomycin resistance. dOnly if 
the organism does not exhibit high-level resistance to aminoglycosides (see Table 
154-1, footnote c). eIn 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. 
fFluoroquinolones (e.g., moxifloxacin) and rifampin (if the isolate is susceptible 
to each agent) reach therapeutic levels in the cerebrospinal fluid. gIntrathecal 
gentamicin (2–10 mg/d) if high-level resistance is not detected. Intraventricular 
daptomycin has been used in two cases of meningitis. hApproved by the U.S. Food 
and Drug Administration (FDA) only for uncomplicated urinary tract infections 
caused by vancomycin-susceptible E. faecalis. iConcentrations 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. Of note, quinupristin-dalfopristin (Q-D) lost FDA approval for 
infections due to vancomycin-resistant Enterococcus, and it was discontinued by 
the manufacturer in 2022.
PART 5
Infectious Diseases
infections, it has been used alone (at high dosage) or in combina­
tion with other agents (ampicillin, ceftaroline, and tigecycline) 
with apparent success against multidrug-resistant enterococcal 
infections (Tables 154-1 and 154-2). 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 dap­
tomycin. These studies concluded either no difference between the 
two drugs or favored linezolid due to lower all-cause and infectionrelated mortality, but they were limited by small patient num­
bers 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 
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 dapto­
mycin therapy (≥10 mg/kg) 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 suscep­
tible 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 entero­
coccal 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 infre­
quently 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; recent structural work has demon­
strated that these changes lead to a more dynamic binding pocket 
with an increase in the hydrolysis of ampicillin at the active site, 
thus allowing for increased turnover of the enzyme. Increased pro­
duction of PBP5 is also seen in high-level ampicillin-resistant (e.g., 
MIC >32 μg/mL) clinical strains. In E. faecalis, ampicillin resistance 
is extremely rare; however, an emerging phenotype of penicillinresistant but ampicillin-susceptible E. faecalis (PRASEF) has been 
described. Similar to E. faecium, changes in the promoter of PBP4 
(the E. faecalis homologue of PBP5) or the amino-acid sequence of 
the enzyme itself are associated with increases in the MIC of ampi­
cillin (although still below the susceptible breakpoint), penicillin, 
piperacillin, and imipenem; in vitro data suggest that these changes 
may also impair the synergistic activity of ampicillin and ceftriax­
one against some PRASEF isolates.
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 anti­
biotic 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.