1. Optimizing Therapy for Vancomycin-
Resistant Enterococci (VRE)
Peter K. Linden, M.D.1
ABSTRACT
Enterococci are gram-positive, facultative bacteria with low intrinsic virulence but
capable of causing a diverse variety of infections such as bacteremia with or without
endocarditis, and intra-abdominal, wound, and genitourinary infection. During the past
2 decades the incidence of hospital-acquired enterococcal infection has significantly risen
and is increasingly due to multidrug-resistant strains, primarily to the coacquisition
of genetic determinants that encode for the stable expression of high-level b-lactam,
aminoglycoside, and glycopeptide resistance.
Because enterococci constitute part of the normal colonizing flora, careful clinical
interpretation of cultures that grow enterococci is paramount to avoid unnecessary and
potentially deleterious antimicrobial therapy. Traditional antimicrobial treatment for
ampicillin- and glycopeptide-susceptible enterococcal infection remains a penicillin-,
ampicillin-, semisynthetic penicillin–based regimen, or vancomycin in a penicillin-intol-
erant individual. The need for a bactericidal combination with a cell-wall active agent
combined with an aminoglycoside is most supported for native- or prosthetic valve
endocarditis but is unproven for the majority of infections due to enterococci. The
emergence of vancomycin-resistant enterococci prompted the clinical development of
several novel and modified antimicrobial compounds approved for VRE infection (quinu-
pristin-dalfopristin, linezolid) and several approved for non-VRE indications (daptomycin,
tigecycline).
There is a paucity of comparative clinical trial data with these new agents,
although linezolid, based upon its efficacy and tolerability, appears to be the cornerstone
of current treatment approaches. Despite a relatively short period of clinical use, enter-
ococcal resistance has now been described for quinupristin-dalfopristin and linezolid and
more recently even for daptomycin and tigecycline. Moreover, the optimal treatment of
endocarditis due to VRE strains is unknown because, with the exception of daptomycin,
current treatment options only yield bacteriostasis. Nonantimicrobial measures to treat
VRE infection, such as foreign body removal and percutaneous or surgical drainage of
close-spaced infection, reduce both the need for and the duration of anti-enterococcal
treatment and the emergence of resistance to the newer antimicrobials.
KEYWORDS: Enterococcus, vancomycin, linezolid, antimicrobial resistance,
nosocomial infection
1
Department of Critical Care Medicine, University of Pittsburgh Optimizing Antimicrobial Therapy for Serious Infections in the
Medical Center, Pittsburgh, Pennsylvania. Critically Ill; Guest Editor, David L. Paterson, M.D., Ph.D.
Address for correspondence and reprint requests: Peter K. Linden, Semin Respir Crit Care Med 2007;28:632–645. Copyright # 2007
M.D., Department of Critical Care Medicine, University of Pittsburgh by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
Medical Center, 602 A Scaife Hall, 3550 Terrace St., Pittsburgh, PA NY 10001, USA. Tel: +1(212) 584-4662.
15261 (e-mail: lindenpk@ccm.upmc.edu). DOI 10.1055/s-2007-996410. ISSN 1069-3424.
632

2. OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 633
INCIDENCE OF ENTEROCOCCAL sporins) is expressed in all enterococci due to the
INFECTION AND RESISTANCE TRENDS expression of inner-cell-wall penicillin-binding proteins
Enterococci have become more common and problematic (PBPs) with low affinity for these compounds.3 Expo-
pathogens over the past 2 decades, with a rise in both the sure of such enterococcal strains to an effective b-lactam
overall incidence of enterococcal infection and multidrug results in inhibitory but not bactericidal activity as
resistance. In a nationwide surveillance study [Surveil- measured by time-killing kinetic curves.4
lance and Control of Pathogens of Epidemiological Low-level resistance to aminoglycosides is secon-
Importance (SCOPE)] between 1995 and 2002, enter- dary to their low penetrability through the outer-perim-
ococci were the third most frequent cause of nosocomial eter envelope of the organism, a property that can be
bloodstream infection, and high-level vancomycin- overcome with the synergistic activity of an effective cell
resistance was present in 60% of Enterococcus faecium wall active agent such as a penicillin or vancomycin.5
strains but only 2% of E. faecalis strains.1 A Centers for Although the majority of enterococci exhibit in vitro
Disease Control and Prevention (CDC) surveillance susceptibility to trimethoprim/sulfamethoxasole their
program during the same time period showed that VRE ability to utilize exogenous folate in vivo precludes
accounted for 27.5% of intensive care unit (ICU) noso- the clinical utility of trimethoprim-sulfamethoxazole
comial bacteremic and nonbacteremic infections.2 The (TMP/SMX) and other agents that impair folate syn-
vast majority of E. faecium strains are multidrug resistant thesis.6 A significant percentage of enterococci may also
with high-level resistance to penicillin and ampicillin possess constitutive resistance to macrolides (erythromy-
(MIC > 128 mg/mL) and high-level resistance to cin, azithromycin) and lincosamides (clindamycin) pri-
gentamicin (MIC > 1000 mg/mL), which eliminates marily mediated by modification of the ribosomal
the potential for bactericidal ‘‘synergistic’’ treatment. attachment site.7
The forces behind this important trend include the
increased prevalence and greater longevity of immuno-
compromised hosts due to native or iatrogenic immuno- Acquired Resistance Mechanisms
suppression, the increased use of antimicrobials that There are few other species of bacteria that have the
are devoid of enterococcal activity (cephalosporins, proclivity and efficiency of the Enterococcus to acquire
quinolones) and thus selective for more resistant pheno- new and multiple antimicrobial resistance mechanisms3,4
types, and, most importantly, the appearance of new (Table 2). The genomic elements that encode for resist-
resistance mechanisms (i.e., high-level vancomycin ance are carried on plasmid or larger transposon elements,
resistance), which confer resistance to previously effective are stable, and often carry multiple resistance determi-
antimicrobial classes. nants that culminate in multidrug-resistant strains. Enter-
ococci acquire resistance to chloramphenicol (mediated by
chloramphenicol acetyltransferase), quinolones (by gyrase
ANTIMICROBIAL RESISTANCE mutations), rifampin (by mutation of the gene that enc-
MECHANISMS AMONG ENTEROCCI odes for RNA polymerase), and tetracyclines (by a variety
of mechanisms).8 However, the most clinically important
Intrinsic Resistance Mechanisms antimicrobials to which enterococci have acquired resist-
Enterococci possess several constitutive, nontransferable ance are discussed in more detail following here.
resistance mechanisms against a variety of antimicro-
bials, which limits therapeutic options even for vanco-
mycin-susceptible enterococci and magnifies the effect High-Level b-Lactam Resistance
of superimposed intrinsic resistance traits (Table 1). Overproduction and/or mutation of the penicillin-
Relative or absolute resistance to the b-lactams (pen- binding protein 5 receptor leading to diminished affinity
icillin, ampicillin, antipseudomonal penicillins, cephalo- for b-lactams has increased dramatically in E. faecium
Table 1 Intrinsic Resistance Mechanisms among Enterococci
Antimicrobial Mechanism(s) Comments
Ampicillin, penicillin Altered binding protein
Aminoglycosides (LL) Decreased permeability Altered High-level gentamicin strains may be
ribosomal binding susceptible to high-level streptomycin
Clindamycin Altered ribosomal binding
Erythromycin Altered ribosomal binding
Tetracyclines Efflux pump
Trimethoprim-sulfamethoxasole Utilize exogenous folate
LL, low level.

3. 634 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007
Table 2 Acquired Resistance Mechanisms among Enterococci
Antimicrobial Mechanism(s) Comments
Ampicillin, penicillin (HL) Mutation of pbp-5 95% of E. faecium < 5% E. faecalis
Aminoglycoside (HL) Enzyme modification Plasmid mediated Some HL-gentamicin
R strains may be streptomycin S
Quinolones DNA gyrase mutation
Chloramphenicol Efflux pump
Glycopeptide Altered cell wall binding Transposon 1546
Quinupristin/dalfopristin Ribosomal modification Efflux pump ermB gene vatd, vate gene
Linezolid Single point mutation G2476U mutation
Daptomycin Unknown Described in E. faecalis, E. faecium,
and E. durans
HL, high level.
but remains uncommon (< 5%) among E. faecalis England in 1986 was a major watershed mark in the
strains.9,10 This property is expressed constitutively and evolution of enterococcal antimicrobial resistance and
carried by resistance genes located on chromosomal ele- the final step toward the subsequent establishment of
ments. E. faecium strains with acquired high-level ampi- endemic multidrug-resistant enterococci.15,16 VRE
cillin resistance have ampicillin MICs > 128 mg/mL and strains did not first appear in the United States until
are neither inhibited nor killed by ampicillin, penicillin, 1989, but thereafter their incidence rapidly increased
or other b-lactams. The ubiquity of high-level ampicillin from 0.3% of all enterococci in 1989 to 7.9% in 1993.17
resistance has been a major step toward the eventual During this early period the majority of reported VRE
evolution of multidrug resistance among E. faecium as isolates were almost exclusively E. faecium, were mono-
the superimposition of other resistance traits have or pauciclonal in origin, and predominantly originated
appeared in such strains. from ICU patients in tertiary care centers, particularly in
the northeastern United States, where both vanA and
vanB genotype outbreaks were observed; however, there
High-Level Aminoglycoside Resistance was no discernible epidemiologic or clinical differentia-
The first reports of high-level gentamicin resistant tion between the two types. Local enhancement of
(HLGR) strains in the United States were in 1979, contact precautions usually aborted or significantly
appearing in both E. faecalis and E. faecium.11 More recent modified such outbreaks.
surveillance data from the SCOPE program between the A more contemporaneous surveillance study of
years 1997 and 1999 showed 69 to 71% of all U.S. bloodstream isolates has shown a steady decrease in
enterococcal strains were HLGR and 40% of all tested vancomycin susceptibility among E. faecium strains
vancomycin-resistant enterococci (VRE) strains.12 Enter- from 60% in 1997 to only 39.1% in 2002, whereas the
ococci acquire resistance to aminoglycosides via (1) vast majority (96.1 to 99.4%) of E. faecalis strains
changes in the ribosomal attachment sites; (2) diminished continue to remain vancomycin susceptible over this
aminoglycoside transport into the cell; and (3) 5-year period.18 The incidence of VRE remains highest
aminoglycoside-modifying enzymes (adenyltransferase, in the intensive care unit setting. It has increased to a
phosphotransferase, and bifunctional acetyl-phospho- greater relative extent on hospital floors and parahospital
transferase). Although the majority of HLGR strains centers such as long-term acute care (LTAC) facilities
also exhibit high-level streptomycin resistance, a minority and skilled-care nursing facilities, which often receive
retain sensitivity to streptomycin; thus susceptibility test- patients from hospitals with endemic VRE epidemi-
ing to high-level streptomycin is worthwhile in HLGR ology.19
strains.13 No reliable bactericidal activity can be achieved
with any antimicrobial combination against strains with
high-level aminoglycoside resistance.14 Genetic Basis of Vancomycin Resistance
Six distinct glycopeptide resistance phenotypes have
been discovered: VanA, VanB, VanC, VanD, VanE,
VANCOMYCIN AND OTHER and VanG, distinguished based upon gene content,
GLYCOPEPTIDE RESISTANCE glycopeptide minimum inhibitory concentrations
(MICs), and inducibility and transferability properties20
Epidemiology (Table 3). The vanA and vanB phenotypes uniformly
Without question, the appearance of E. faecium strains confer high-level vancomycin resistance (MIC > 64 mg/
with high-level vancomycin resistance in France and mL) and have the highest prevalence and clinical

4. OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 635
Table 3 Level and Type of Vancomycin Resistance in Enterococci
Acquired Resistance Level, Type Intrinsic Resistance.
Low Level Type
Strain High, Variable, Moderate, Low VanC1/C2/C3
Characteristic VanA VanB VanD
VanG VanE
MIC, mg/L
Vancomycin 64–1000 4–1000 64–128 16 8–32 2–32
Teicoplanin 16–512 0.5–1 4–64 0.5 0.5 0.5-1
Conjugation Positive Positive Negative Positive Negative Negative
Mobile element Tn1546 Tn1547 or Tn1549
Expression Inducible Inducible Constitutive Inducible Inducible Constititive
Inducible
Location Plasmid Plasmid Choromosome Choromosome Choromosome Choromosome
choromosome choromosome
Modified target D-Ala-D--Lac D--Ala-D--Lac D--Ala-D--Lac D--Ala-D--Ser D--Ala-D--Ser D--Ala-D--Ser
D-Ala-D-Lac, D-alanine-D-lactate; D-Ala-D-ser, D-alanine-D-serine; MIC, minimum inhibitory concentration.
(With permission from Couvalin.20)
importance. Although vanB strains retain susceptibility antibiotic-induced mutation. (2) Amplification of the
to teicoplanin, this agent was never commercially avail- VRE inoculum within the gastrointestinal reservoir
able in the United States, and rapid resistance has been usually due to antimicrobial selective pressures. Prior
described when VanB strains undergo teicoplanin ex- or ongoing antimicrobials may also enhance the risk of
posure.21 Transposon 1546 (Tn1546) contains the vanA VRE colonization by reducing naturally competing gut
gene complex which encodes for an eight-peptide se- flora. (3) Natural- or iatrogenic anatomical or immune
quence culminating in ligase-mediated modification of defects that lead to bloodstream or nonbloodstream
the cell wall target for vancomycin from a high affinity (tissue) invasion. Perirectal, rectal, or, preferentially,
D-alanine-D-alanine linkage to a low affinity D-ala-
nine-D-lactate linkage on the cell wall peptidoglycan
terminus.22 The vanB gene cluster has partial DNA
homology with the vanA gene cluster and similarly
encodes for ligase modification of the vancomycin target.
The vanA gene has been shown to be transferable in
vitro to Staphylococcus aureus, and naturally occurring
vanA gene–mediated vancomycin resistance, probably
due to horizontal transposon transmission, has been
reported in four methicillin-resistant S. aureus (MRSA)
strains in three patients with protracted vancomycin
exposure for MRSA infection and a fourth patient
without prior vancomycin exposure.23–28
Dynamics and Risk Factors for VRE Colonization
and Infection
Colonization with VRE is a necessary prerequisite for
VRE superinfection, which will arise only when ana-
tomical or other predisposing factors become manifest.
Similar to the more susceptible enterococcal strains, the
natural colonizing reservoir for VRE is the intestinal
tract, with secondary contiguous reservoirs on the skin,
genitourinary tract, and oropharynx.29,30 There are three
sequential processes leading to detectable VRE coloni-
zation and potential subsequent infection with multiple
modifiers (Fig. 1): (1) Exposure to enterococci contain-
ing the vancomycin-resistant genome via contact with an
Figure 1 Sequence of vancomycin-resistant enterococci (VRE)
animate or inanimate source. It should be emphasized exposure and antimicrobial amplification leading to VRE super-
that the vanA gene does not arise from a spontaneous or infection and increased VRE transmission.

5. 636 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007
stool cultures have been the traditional sites to detect Table 4 Clinical and Epidemiological Clues That MDR
VRE colonization.31,32 The duration of VRE intestinal Enterococcal Infection Is Present
colonization is variable, can last for months to years, and Significant and recent antimicrobial exposure
may be indefinite, in part subject to the inoculum- Multiple agents
detection threshold of the surveillance testing method Third-generation cephalosporins
employed.33–35 Spontaneous clearance of intestinal col- Antianaerobic antimicrobials
onization only occurs in the minority of patients in Vancomycin
several studies analyzing serial cultures in both antimi- Positive rectal-fecal surveillance culture or vancomycin-resistant
crobial- and nonantimicrobial-exposed patients. enterococci from a prior clinical site
Multiple case control and cohort studies have Intra-abdominal infection (abscess, peritonitis, cholangitis)
analyzed risk factors for either VRE colonization, Indwelling catheters in place (bladder, intravascular)
VRE superinfection, or both.36–39 Two fundamental High incidence of MDR enterococci in unit, hospital
risk factor categories are demographic/illness severity Prior liver transplant, neutropenia, chemotherapy-related
variables and the type, intensity, and duration of recent mucositis
antimicrobial exposure. Demographic risks include du- MDR, multidrug-resistant.
ration of hospital- and ICU length of stay, physical
proximity to VRE-colonized patients in the same unit, gens, a careful clinical assessment of whether the re-
and hospitalization in units with a high prevalence of ported isolate is a likely cause of the patient’s clinical
VRE, ‘‘colonization pressure.’’ Prior administration of syndrome that merits specific treatment is always war-
multiple antibiotics, third-generation cephalosporins, ranted. Realistically, however, it may be difficult to make
antimicrobials with anaerobic spectrums (metronidazole, this distinction, particularly in patients who have major
clindamycin), and parenteral vancomycin have been comorbid conditions or critical illness that is naturally
implicated in case-control analyses of colonization or coupled with colonization or infection due to multidrug-
superinfection. Such antimicrobials probably exert a resistant enterococcal strains. Although enterococci are
selective effect and amplify otherwise undetectable or of low virulence, it bears emphasis that they are also
smaller VRE inocula in the intestines and other secon- quite capable of promulgating the systemic inflammatory
dary reservoirs. Donskey and colleagues have demon- response syndrome (SIRS), severe sepsis, and septic
strated that the density of VRE as measured by serial shock and have been a frequent inciting blood pathogen
quantitative stool cultures increased significantly when in recent prospective, randomized sepsis trials.42
patients received ! 1 antianaerobic antimicrobial, Abundant and recent observational studies sup-
whereas this effect was not seen in patients receiving port the association between appropriate empirical
antimicrobials with minimal antianaerobic activity.40 antimicrobial therapy and survival.43–45 Thus, for the
Interestingly, parenteral vancomycin administration re- severe end of the clinical spectrum, strong consideration
sulted in no increase in the stool VRE density. More- should be given to empirical antienterococcal therapy for
over, patients with high VRE density coupled with fecal patients whose demographic features and clinical pre-
incontinence were also more likely to have positive sentation place them at high risk for enterococcal in-
environmental cultures for VRE. The ‘‘VRE-selective’’ fection or sepsis. Clearly a major part of this decision also
effects of antimicrobials and other risk factors become includes estimating the likelihood that the enterococcal
relatively diminished when the proportion of patients strain could be a multidrug-resistant strain. Such epi-
already colonized with VRE is 50% or greater, which demiological and clinical clues, which might prompt
may explain some studies where newly introduced anti- empirical enterococcal therapy, are summarized in
biotic control measures may only yield modest reduc- Table 4.
tions in VRE colonization and infection rates in
hyperendemic settings.41 Patients with comorbidities,
including oncologic conditions, especially neutropenia, Does the Enterococcus in the Culture Result
and prior solid organ transplantation, especially liver Require Antimicrobial Treatment?
transplantation, appear to have the highest rates of Microbiological culture data that report the presence of
VRE bacteremia and poorest outcomes. enterococci always require some level of clinical discrim-
ination to determine whether they merit treatment.
Enterococcal isolates from a respiratory specimen (spu-
GENERAL ISSUES IN THE TREATMENT OF tum, endotracheal aspirate, bronchoalveolar lavage), and
ENTEROCOCCAL INFECTION skin, wound, or mucosal surfaces almost always represent
The treatment of serious enterococcal infection is chal- colonization. Urine cultures obtained via indwelling
lenging from several aspects. Because enterococci may bladder (Foley) catheters often represent asymptomatic
colonize skin, wound, and mucosal surfaces and their bacteriuria. Wound and intra-abdominal drains often
isolation is often accompanied by more virulent patho- become colonized with skin flora, including enterococci.

6. OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 637
However, such isolates may be significant when the Table 5 Nonantimicrobial Interventions for
character of the drainage fluid reveals evidence of Vancomycin-Resistant Enterococcal Infections
inflammatory response (i.e., pyuria or purulence). Site of Infection Nonantimicrobial Intervention
Although enterococci may be blood culture contami-
Bloodstream Catheter removal
nants, particularly when specimens are obtained from
Consider endovascular infection if
indwelling intravascular catheters, the appropriate clin-
no primary source obvious or
ical bias should be that such cultures represent true
patient with risk factors for
pathogens in most instances. Finally, simple nonantimi-
endocarditis or other endovascular
crobial interventions may obviate the need for antienter-
material
ococcal therapy, such as removal of intravascular or
Closed-space Consider percutaneous or surgical
bladder catheters or superficial wound debridement.46,47
infection drainage, e.g., cholangitis—
percutaneous transhepatic
drainage or endoscopic retrograde
Is Bactericidal Therapy Required?
cholangiopancreatography for
The majority of enterococcal infections are not proven to
stent placement
require bactericidal treatment and can be managed
Urinary tract infection Removal of bladder catheter
successfully with a single effective agent.48,49 Either
or bacteriuria
native- or prosthetic-valve endocarditis is the prototyp-
Superficial wound Incision and drainage or debridement
ical enterococcal infection for which bactericidal anti-
infection
microbial therapy is required, usually achieved with the
Suspected foreign May require removal if refractory
combination of a cell wall–active agent such as ampicil-
body infection to antimicrobial therapy
lin, penicillin, or vancomycin combined with an amino-
or adjacent to devitalized tissue
glycoside such as gentamicin or streptomycin. Other
sites of infection for which bactericidal treatment is
probably merited include enterococcal meningitis and considerations is summarized in Table 5. It also bears
enterococcemia in a neutropenic host. emphasis that the inability to address the nonantimicro-
However, a bactericidal combination is not pos- bial considerations of such complex VRE infections has
sible to achieve with enterococci exhibiting high-level been the principal cofactor leading to the development of
aminoglycoside resistance and almost all strains of VRE strains that have evolved resistance to the recently
E. faecium strains with high-level vancomycin resistance. approved VRE antimicrobials, quinupristin-dalfopristin
Uncommon exceptions are vancomycin-resistant E. and linezolid.
faecalis strains, which retain ampicillin and high-level
gentamicin susceptibility. Successful treatment of such
cases has been reported with ampicillin and gentamicin, Specific Antimicrobials for the Treatment of
ampicillin þ ofloxacin, penicillin þ streptomycin, and Vancomycin-Resistant Enterococcal Infection
linezolid þ gentamicin.50 Limited clinical experience Despite the established high prevalence of multidrug-
is available for the treatment of vancomycin-resistant resistant enterococcal strains with high-level vancomy-
enterococcal endocarditis with the newer agents (see cin-resistance there is a remarkable paucity of controlled,
later discussion). comparative trial data on its antimicrobial treatment.
Major obstacles have been the slow development of
novel agents with VRE activity, high levels of comor-
Nonantimicrobial Treatment of VRE Infection bidity that confound outcome interpretation, complex
Many VRE infections may be partially or completely surgical infection for which antimicrobial therapy alone
cured with conservative or aggressive nonantimicrobial is not curative, and the polymicrobial nature of many
interventions. Less serious infections such as bladder VRE infections, particularly those occurring in the
catheter–associated bacteriuria and urinary tract infec- abdomen. Both approved and nonapproved treatment
tion may be adequately treated simply with catheter options for VRE are summarized in Table 6. At present
removal. Postoperative superficial wound infections there are only two U.S. Food and Drug Administration
may also respond to opening the incision and simple (FDA)-approved treatments for VRE (E. faecium) in-
drainage or debridement. Closed-space infection such as fection: quinupristin/dalfopristin (Q/D, Synercid, King
intra-abdominal abscesses, cholangitis due to biliary Pharmaceuticals, Inc., Bristol, TN) and linezolid (Zyvox,
obstruction, devitalized tissue, or infected foreign bodies Pfizer, New York, NY) and two other approved agents
(intravascular catheters, synthetic graft or mesh material, that have in vitro activity against VRE but are not
prosthetics) are not infrequently the primary source of approved for VRE infection; daptomycin (Cubicin,
VRE bacteremic or nonbacteremic infection. The treat- Cubist Pharmaceuticals, Lexington, MA), which is ap-
ment implications for infections with such anatomical proved for complicated skin–skin structure infection,

7. 638 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007
Table 6 Therapeutic Antimicrobial Options for VRE Infection
Antimicrobial(s) Reported Evidence Comments
High-dose ampicillin or Case reports May be effective with VRE strains
ampicillin-sulbactam with ampicillin MIC 32–64 mg/mL
Chloramphenicol Case series Resistance reported
Tetracycline, doxycycline Case reports Æ rifampin or ciprofloxacin
Novobiocin Anecdotal No longer manufactured
Nitrofurantoin Small case series Only for urinary tract infections
Teicoplanin Case reports Not active against VanAResistance in VanB reported
Quinupristin/dalfopristin Large case series but noncomparative Bacteriostatic
Not active against E. faecalis
Resistance reported
Linezolid 1. Dose comparative trial Bacteriostatic
2. Large compassionate use series Resistance reported
Daptomycin 1. Case report þ series Bactericidal
Resistance reported
Tigecycline In vitro data only Bacteriostatic
Dalbavancin In vitro data only VanA strains resistant
Telavancin In vitro data only
Oritavancin In vitro data only
MIC, minimum inhibitory concentration.
and S. aureus bacteremia and tigecycline (Tygacil, Wyeth been reported with the use of tetracycline, doxycycline,
Pharmaceuticals, Inc., Philadelphia, PA), which is ap- and oral novobiocin combined with either ciprofloxacin or
proved for complicated skin–skin structure and intra- doxycycline; however, such experience has never been rep-
abdominal infection. roduced in larger clinical series of prospective trials.55–58
Prior to the availability of Q/D and linezolid Teicoplanin, a glycopeptide not commercially
approval several centers published their experience with available in the United States, does have in vitro activity
a variety of available agents or combinations that dem- versus VanB phenotypic enterococci. In a European
onstrated in vitro activity. Clinical success was described study of 63 patients with vancomycin-susceptible enter-
with high parenteral dosages of ampicillin or ampicillin/ ococcal infection, clinical and microbiological responses
sulbactam (18 to 24 g/day), even including endocarditis. were observed in 84% and 87% of cases, respectively.59
Such a strategy appears limited to those uncommon VRE This agent remains unstudied for VanB enterococcal
strains with ampicillin MICs of 32 to 64 mg/mL, a target infection, perhaps in part due to the development of
range for which plasma ampicillin levels can be achieved teicoplanin resistance among VanB E. faecalis during
with high dose therapy.50–52 Because no b-lactamase teicoplanin therapy.60,61
elaboration occurs with VRE, the mechanism of sulbac- Nitrofurantoin has in vitro activity against both
tam activity is not known, although a plausible explan- VanA and VanB enterococci.62 Due to its ability to
ation is its intrinsic penicillin-binding protein properties. achieve high urinary concentrations nitrofurantoin has
Chloramphenicol has bacteriostatic activity against been shown to be effective in VRE urinary tract
enterococci and VRE strains; however, its in vivo efficacy infection.46,63 Nitrofurantoin cannot be employed for
was never established. In a retrospective study of 80 cases VRE outside the urinary tract and in patients with a
of VRE bacteremia, 51 patients were treated with chlor- creatinine clearance < 30 mL/min because elevated
amphenicol from which 22/36 (61%) evaluable patients blood concentrations are associated with hepatic, pul-
demonstrated a clinical response.53 A microbiological monary, hematologic, and other toxicities.
response was also observed in 33/43 (77%) of the micro-
biologically evaluable patients. No survival benefit was QUINUPRISTIN/DALFOPRISTIN
observed compared with VRE bacteremic patients in the Quinupristin/dalfopristin (Q/D) is a semisynthetic
study cohort who did not receive chloramphenicol. Sub- parenteral streptogramin compound, which is derived
sequently at the same center, the prevalence of chloram- from its parent natural compound pristinamycin, a
phenicol resistance among VRE strains over a 10-year product of Streptomyces pristinaspiralis, an oral and top-
period (1991 to 2000) were observed to increase from 0 to ical antistaphylococcal agent that has been in clinical use
11%, a trend that correlated significantly with prior in Europe since the 1980s. The major properties of this
chloramphenicol or quinolone exposure.54 Isolated re- compound are summarized in Table 7. This antimicro-
ports of favorable outcome for VRE infection have also bial is a 30:70 mixture of quinupristin and dalfopristin,

8. OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 639
Table 7 Major Features of Quinupristin/Dalfopristin and Linezolid
Feature Quinupristin/ Dalfopristin Linezolid
Antimicrobial class Streptogramn Oxazolidinone
Peak serum concentrations (mg/L) 10-12 15.1
Elimination half-life (h) 0.8 (Q) , 0.6 (D) 5.5
Major metabolic routes Hepatobiliary Peripheral nonoxidative
Major elimination routes Faecal (70-75%) Nonrenal (65%)
Urinary (19%) Urinary (30%)
Protein binding (%) 30 (Q) 70 (D) 31
Mechanism of action Protein synthesis inhibition Protein synthesis inhibition
Site of action 50S ribosome 70S initiation complex
Postantibiotic effect (h) 6–8 1
Bactericidal (vs VRE) No No
Cytochrome P-450 inhibition Yes No
Formulations Parenteral Parenteral þ oral
Dose and administration 5–7.5 mg/kg q 8–12h 600 mg q12 h
Dosage adjustment None None
Approved indications VRE VRE
Complicated SSSI Complicated SSSI
Nosocomial pneumonia Nosocomial pneumonia
Major adverse effects Phlebitis (peripheral) Myelosuppression
Myalgia/arthralgia
Cost ($US per day; 2000 values) $300-350 $115 (parenteral)
$80 (oral)
D, dalfopristin; Q, quinupristin; qXh, every X hours; SSSI, skin and skin structure infection; VRE, vancomycin-resistant enterocooci.
(With permission from Linden.42)
which are derivatives of streptogramin types B and A, Clinical interest in the utility of Q/D for serious
respectively. It is a unique antimicrobial because it acts VRE infection began in the mid-1990s with a large-
through sequential ribosomal binding and is internally scale, noncomparative, open-label, emergency use
synergistic to produce a bactericidal effect. Dalfopristin program for multiresistant gram-positive infection, prin-
initially binds to the 50S bacterial ribosome, which in- cipally vancomycin-resistant E. faecium and MRSA in-
duces a permanent conformational change that acceler- fection refractory or intolerant to vancomycin.66,67 The
ates quinupristin ribosomal binding.64 Protein synthesis patient populations in both series had a high prevalence
is impaired via both the interruption of peptide chain of acute and chronic comorbidities, including diabetes,
elongation and the inhibition of formed peptide extru- oncologic conditions, chronic liver disease, dialysis me-
sion. SSuch synergism results in bactericidal activity chanical ventilation, and prior organ transplantation.
against some important gram-positive species, including Q/D was administered at 7.5 mg/kg intravenously every
Streptococcus pneumoniae, Streptococcus agalacticae, and 8 hours to patients with documented VRE bacteremia or
some strains of Staphylococcus aureus. However, only nonbacteremic VRE infection, with the duration of
bacteriostatic activity is present for the majority of E. treatment determined by the primary treating physi-
faecium strains by time–killing curve studies. This effect is cians. The overall success rate defined as both clinical
primarily mediated by 23S ribosomal modification success and bacteriologic eradication was 65.8% in the
encoded for by the ermB gene (erythromycin methylase), initial study and 65.6% in the follow-up study. There
which reduces quinupristin affinity for its ribosomal have been several reports of clinical cure combining Q/D
binding site and thus limits activity to only the dalfopris- with doxycycline or high-dose ampicillin in endocarditis;
tin moiety. Such strains are termed MLSb (macrolide- however, no larger-scale experience has been per-
lincosamide-streptogramin) phenotypes.65 Erythromycin formed.68–70
resistance serves as an excellent surrogate marker for the As Q/D usage increased both before and after its
presence of the MLSb phenotype among enterococci. regulatory approval in 1999, several important clinical
Q/D is also unique as an antienterococcal agent based limitations became apparent. Peripheral intravenous
upon its marked disparity in in vitro susceptibility be- administration was associated with a high rate of
tween E. faecium (MIC90 ¼ 1 to 2 mg/mL) and E. faecalis phlebitis necessitating central venous administration.
(MIC90 ¼ 8 to 16 mg/mL). This disparity is most likely Myalgia and arthralgia unassociated with objective
due to altered ribosomal binding or presence of an active inflammatory signs were observed in 7 to 10% of patients
efflux pump. in the emergency use program, with much higher rates in

9. 640 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007
oncologic patients and liver transplant recipients.71,72 infection.77 Among 549 cases of VRE infection, there
Although the precise reason for this toxicity is unknown was an 81.4% clinical cure rate at end-of-therapy.
a neuropathic cause is suspected. Its higher incidence in Because linezolid is a bacteriostatic agent that displays
populations with diminished metabolism and excretion no synergistic activity with other agents its efficacy in
suggest it is due to either native drug or metabolite VRE native- or prosthetic-valve endocarditis remains
accumulation. Phenotypic resistance to Q/D among questionable. Both clinical success and failure have been
E. faecium (MIC ! 4 mg/mL) was observed in six reported when linezolid has been used as a first-line
(1.8%) and five (1.3%) of VRE cases, either during or therapy or salvage treatment; however, no large-scale
after treatment, from both published emergency use randomized trial experience is yet available.78–80 In
series.71,72 Clonal dissemination of Q/D-resistant recent years, linezolid has become the dominant agent
strains despite the absence of Q/D or other streptogra- for the treatment of serious VRE infection. Multiple
min exposure has been described among pediatric pa- cases report of linezolid-resistance (MIC ! 8 mg/mL)
tients.73 Three fundamental resistance mechanisms have occurring in VRE (E. faecium) and vancomycin-suscep-
been discovered: enzymatic modification (acetylation) of tible E. faecalis strains that were susceptible (MIC 1 to
dalfopristin encoded by the vatD or vatE genes, active 2 mg/mL) at baseline but developed a fourfold or greater
efflux by an adenosine triphosphate (ATP)-binding rise in MIC to 8 to 32 mg/mL.81–85 Common to most
protein encoded by the msrC or lsa genes, and alteration cases where linezolid-resistance appeared has been a
of the ribosomal target site encoded for by the erm protracted length of therapy (> 28 days) associated
genes.70 Because phenotypic resistance requires the with retained foci of VRE infection such as abscesses,
presence of resistance mechanisms to both the quinu- devitalized tissue, or foreign materials. The majority of
pristin and the dalfopristin components, at least two or linezolid-resistant isolates contain a single base-pair
more resistance genes are present. Several surveillance mutation in the genome encoding for domain V of the
studies have uncovered large Q/D resistance reservoirs 23S ribosomal binding site (G2476U mutation). The
among E. faecium isolated from both domestic poultry phenotypic level of resistance as determined by elevation
and livestock in the United States, which may relate to in MIC level has been shown to correlate with the ‘‘gene
the use of virginiamycin as a growth-promoting food dose’’ or number of copies of 23S rDNA containing the
additive in domestic poultry.74 G2466U mutation.86 Notably this mutation was pre-
dicted by earlier in vitro spiral plate serial passage
LINEZOLID experiments with linezolid.87 Horizontal cross trans-
Linezolid is an oxazolidinone compound, a novel syn- mission of an identical clone of linezolid-resistant
thetic class that inhibits bacterial protein synthesis in a E. faecium among linezolid-naive patients within the
unique fashion via inhibiting the formation of the 70S same ICU or hospital center have also been de-
initiation complex (50S and 30S ribosomes, mRNA, scribed.88,89 A case- controlled analysis revealed that a
initiation factors 2 and 3, and fMet-tRNA).75 The major longer course of linezolid (38 days vs 11 days) and
properties of linezolid are summarized in Table 6. Line- linezolid exposure prior to hospitalization were risk
zolid exhibits a broad gram-positive spectrum but has factors for the emergence of linezolid-resistant VRE.90
only bacteriostatic activity against vancomycin-resistant Thus repeat linezolid susceptibility testing is advisable in
or susceptible enterococci with an MIC90 of 2 mg/mL, patients who have had prior linezolid exposure or per-
which is right at the susceptibility breakpoint. FDA sistent isolation of a VRE strain on therapy or in patients
approval was granted in 2000 for vancomycin-resistant treated in a nosocomial setting with prior linezolid
E. faecium infection in addition for other indications, resistance. Although gastrointestinal symptoms are the
including community-acquired and nosocomial pneu- most common reported toxicity, reversible myelosup-
monia and complicated skin and skin structure infection. pression (thrombocytopenia, leukopenia, and/or anemia)
Due to the lack of an approved comparator agent, has been the most important treatment-limiting side
linezolid was evaluated for patients with clinical and effect with higher rates observed than the original regis-
microbiological evidence of serious VRE infection in a tration studies. Bone marrow examination has shown
blinded, parenteral, dose-comparative trial comparing changes similar to those observed with reversible chlor-
66 patients randomized to 200 mg q 12 hours to amphenicol toxicity.91,92 Such toxicity is usually observed
79 patients treated with 600 mg q 12 hours.76 Among only with sustained linezolid treatment that exceeds
evaluable patients at end-of-treatment, a modest dose 2 weeks. Other reported toxicities of note include
response was observed, with 67% and 52% response rates gastrointestinal upset, rare cases of serotonin syndrome,
seen in the high-dose and low-dose groups, respectively. optic- and peripheral neuropathy, and lactic acidosis.93–96
In addition, efficacy and safety were also demonstrated
in a large study (n ¼ 796 patients) emergency-use DAPTOMYCIN
program for resistant, or treatment-refractory, or treat- Daptomycin is a novel cyclic lipopeptide compound with
ment-intolerant patients with serious gram-positive a broad gram-positive spectrum and rapid bactericidal

10. OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 641
activity that is currently approved for complicated tee for Clinical Laboratory Standards (NCCLS) break-
skin–skin structure infection and S. aureus bacteremia, points for vancomycin-resistant E. faecium strains are not
including right-sided endocarditis.97 Its apparent yet established.108,109 Although clinical experience with
mechanism of action includes attachment to the exterior tigecycline for VRE infection is not yet available
of the bacterial cytoplasmic membrane with membrane it appears to be a promising option, particularly for
penetration of a lipophilic tail with disruption of the intra-abdominal sites, where it has shown comparable
transmembrane potential due to ion efflux, an effect that efficacy to meropenem in non-VRE monomicrobial and
is both concentration- and calcium ion–dependent and polymicrobial infection.
leads to nonlytic bacterial cell death. In vitro studies
have shown nearly uniform activity against vancomycin- NOVEL GLYCOPEPTIDES (ORITAVANCIN, DALBAVANCIN,
resistant E. faecium and E. faecalis strains with an MIC TELAVANCIN)
90 of 2–4 mg/mL.98,99 In one recent study examining Several new glycopeptide derivatives have in vitro bac-
only VRE strains that were either linezolid- or Q/D- tericidal activity against VRE. Dalbavancin is a long-
resistant, daptomycin demonstrated susceptibility using acting (half-life 7 to 10 days) derivative of teicoplanin,
a 4 mg/mL provisional breakpoint.100 The MIC break- which has received approval for the treatment of com-
point is 4 mg/mL for vancomycin-susceptible E. faecalis; plicated skin–skin structure infection; however, similarly
however, there is no established breakpoint for vanco- to teicoplanin, this agent lacks in vitro activity against
mycin-susceptible or -resistant E. faecium. Regardless the more prevalent VanA enterococcal strains.110
of the testing method (E-test, disk diffusion, or broth Oritavancin is a semisynthetic glycopeptide that blocks
dilution) the zone size or MIC result can be signifi- peptidoglycan synthesis and exerts bactericidal activity
cantly elevated by a two- to eightfold magnitude with across a broad gram-positive spectrum.111 It has superior
inadequate calcium supplementation. To the present activity against vanA and vanB enterococci compared
time, clinical experience with daptomycin for serious with dalbavancin and telavancin, with concentration-
VRE infection remains quite limited. The optimal dependent bactericidal activity against both E. faecium
dosing for enterococcal infection is not yet established; and E. faecalis strains (MIC90 ¼ 1 to 2 mg/mL) and is
however, daily dosing at 6 mg/kg in the absence of renal synergistic with ampicillin against the majority of iso-
insufficiency has been the most common dosing scheme. lates.112 This agent has completed phase 3 trials in cSSSI
A randomized phase 3 trial versus linezolid in VRE (complicated skin-skin structure infection); however,
infection was aborted due to enrollment difficulties. concerns pertaining to its long half-life, high protein
In a study of nine neutropenic patients with VRE binding, and reports of spontaneous resistance may
bacteremia treated with daptomycin at 4 mg/kg/day limit its development.
or 6 mg/kg/day, a clinical and/or microbiological re- Telavancin, a long-acting lipoglycopeptide with
sponse was observed in only 4/9 (44%).101 In a second multiple sites of action at the cell membrane and cell
report a similar response rate of 5/11 (45%) was wall has shown noninferiority versus standard therapy in
observed in patients with VRE bacteremia and endo- gram-positive cSSSI, including MRSA; however, clin-
carditis treated with 6 mg/kg/day of daptomycin.102 ical data for VRE are not yet available.113,114
Unfortunately, daptomycin resistance has been re-
ported during treatment for vancomycin-resistant
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