Vancomycin-Resistant Enterococci

Vancomycin-Resistant Enterococci
Yesim Cetinkaya, Pamela Falk and C. Glen Mayhall

Clin. Microbiol. Rev. 2000, 13(4):686. DOI:
10.1128/CMR.13.4.686-707.2000.
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CLINICAL MICROBIOLOGY REVIEWS, Oct. 2000, p. 686–707 Vol. 13, No. 4
0893-8512/00/$04.00⫹0
Copyright © 2000, American Society for Microbiology. All Rights Reserved.
Vancomycin-Resistant Enterococci
YESIM CETINKAYA, PAMELA FALK, AND C. GLEN MAYHALL*
Department of Healthcare Epidemiology and Division of Infectious Diseases, University of Texas
Medical Branch at Galveston, Galveston, Texas 77555-0835
INTRODUCTION .......................................................................................................................................................686
MECHANISMS OF RESISTANCE..........................................................................................................................687
␤-Lactam Resistance ..............................................................................................................................................687
Aminoglycoside Resistance ....................................................................................................................................687
Vancomycin Resistance ..........................................................................................................................................687
Phenotypic description .......................................................................................................................................687

Genotypic classification and resistance mechanisms ....................................................................................688
(i) Action of vancomycin on peptidoglycan synthesis ................................................................................688
(ii) VanA glycopeptide resistance .................................................................................................................688
(iii) VanB glycopeptide resistance ................................................................................................................689
(iv) VanC glycopeptide resistance ................................................................................................................689
(v) VanD glycopeptide resistance .................................................................................................................689
(vi) VanE glycopeptide resistance.................................................................................................................689
(vii) Other resistance classes and organisms .............................................................................................689
(viii) Vancomycin-dependent enterococci ....................................................................................................690
EPIDEMIOLOGY AND CONTROL........................................................................................................................690
Geographic Distribution and Spread within Hospitals.....................................................................................690
VRE in Long-Term-Care Facilities.......................................................................................................................690
VRE in the Community..........................................................................................................................................690
Risk Factors.............................................................................................................................................................691
Colonization and Infection ....................................................................................................................................692
Reservoirs.................................................................................................................................................................692
Modes of Transmission..........................................................................................................................................693
Prevention and Control Measures........................................................................................................................693
Prudent use of vancomycin................................................................................................................................694
Education programs ...........................................................................................................................................695
Role of the microbiology laboratory in the detection, reporting, and control of VRE .............................695
Implementation of infection control measures ...............................................................................................696
Control of VRE in long-term-care facilities ....................................................................................................697
Surveillance cultures ..........................................................................................................................................698
Attempts to eradicate gastrointestinal colonization ......................................................................................698
TREATMENT..............................................................................................................................................................698
REFERENCES ............................................................................................................................................................702
INTRODUCTION designations such as faecalis, faecium, durans, and so forth

were retained but were preceded by the genus name Entero-
Enterococci were originally classified as enteric gram-posi-
coccus in place of Streptococcus. Although a dozen Enterococ-
tive cocci and later included in the genus Streptococcus (185).
In the 1930s, with the establishment of the Lancefield serolog- cus species have been identified, only two are responsible for
ical typing system, enterococci were classified as group D strep- the majority of human infections. Until recently, E. faecalis had
tococci and were differentiated from the nonenterococcal been the predominant enterococcal species, accounting for 80
group D streptococci such as Streptococcus bovis by distinctive to 90% of all clinical isolates, and E. faecium had accounted for
biochemical characteristics (149). Sherman further recom- 5 to 15% (110, 158, 173, 204, 219). Other Enterococcus species
mended that the term “enterococcus” should be used specifi- (E. gallinarum, E. casseliflavus, E. durans, E. avium, and E.
cally for streptococci that grow at both 10 and 45°C, at pH 9.6, raffinosis) are isolated much less frequently and account for
and in 6.5% NaCl and survive at 60°C for 30 min (232). These less than 5% of clinical isolates (110, 158, 173, 204, 219).
organisms were also noted to hydrolyze esculin in the presence Enterococci have been recognized as an important cause of
of bile. In the 1980s, based on genetic differences, enterococci endocarditis for almost a century. In addition to this long-
were removed from the genus Streptococcus and placed in their established role, enterococci began to be recognized as com-
own genus, Enterococcus (228). The previously used species mon causes of hospital-acquired infections in the middle to
late 1970s. This was coincident with and probably related to the
increasing use of third-generation cephalosporins to which en-
* Corresponding author. Mailing address: Division of Infectious
Diseases, Route 0835, Sealy Smith Building, University of Texas Med-
terococci are naturally resistant (185). Enterococci are cur-
ical Branch, 301 University Blvd., Galveston, TX 77555-0835. Phone: rently ascendant nosocomial pathogens, having become the
(409) 747 0228. Fax: (409) 772 2337 or (409) 772 6527. E-mail: second most common organisms recovered from nosocomial
[email protected]. urinary tract and wound infections and the third most common
686
VOL. 13, 2000 VANCOMYCIN-RESISTANT ENTEROCOCCI 687
TABLE 1. Intrinsic and acquired antimicrobial drug resistance been used extensively for the treatment of Clostridium difficile
in enterococcia enterocolitis.
Intrinsic resistance
In 1988, Uttley et al. were the first to report the isolation of
␤-Lactams (particularly cephalosporins and penicillinase-resistant vancomycin-resistant E. faecalis and E. faecium in England
penicillins) (248). Shortly after the first isolates of vancomycin-resistant
Low concentrations of aminoglycosides enterococci (VRE) were reported by investigators in the
Clindamycin United Kingdom and France (155, 248), similar strains were
Fluoroquinolones detected in hospitals located in the eastern half of the United
Trimethoprim-sulfamethoxazole States (104). Subsequently, VRE have spread with unantici-
pated rapidity and are now encountered by hospitals in most
Acquired resistance states (31, 43, 134).
High concentrations of ␤-lactams, through alteration of PBPs or
production of ␤-lactamase
High concentrations of aminoglycosides MECHANISMS OF RESISTANCE
Glycopeptides (vancomycin, teicoplanin)
Tetracycline ␤-Lactam Resistance
Erythromycin

Fluoroquinolones Complete or relative resistance to ␤-lactams is a character-
Rifampin istic feature of the genus Enterococcus. E. faecalis is typically 10
Chloramphenicol to 100 times less susceptible to penicillin than are most strep-
Fusidic acid tococci, while E. faecium is at least 4 to 16 times less suscep-
Nitrofurantoin tible than E. faecalis (185). While most isolates of E. faecalis
a
Adapted in 2000 from reference 109 with permission; original version Copy- are inhibited by concentrations of penicillin or ampicillin (1 to
right @ 1996, Massachusetts Medical Society (all rights reserved). 8 ␮g/ml) easily achievable in humans, isolates of E. faecium
usually require an average of 16 to 64 ␮g/ml to inhibit growth,
although some isolates are even more resistant (186). An ad-
ditional problem with enterococci is that they are typically
cause of nosocomial bacteremia in the United States (227). tolerant to ␤-lactams (i.e., MBC/MIC of ⬎32). The major
One of the major reasons why these organisms have survived in mechanism underlying this resistance has been the production
the hospital environment is their intrinsic resistance to several of low-affinity PBP (95). Penicillin resistance is directly pro-
commonly used antibiotics and, perhaps more important, their portional to the amount of PBP5 (a specific PBP) produced
ability to acquire resistance to all currently available antibiot- (259). Fontana et al. showed that loss of the ability of a strain
ics, either by mutation or by receipt of foreign genetic material of E. faecium to produce PBP5 caused this highly penicillin-
through the transfer of plasmids and transposons (Table 1) resistant strain to become hypersusceptible to penicillin (97).
(53). Therapeutic difficulties presented by enterococci were ␤-Lactamase-producing enterococci are infrequently isolated
well recognized as early as the 1950s, when response rates of (182). Unlike most staphylococci, where ␤-lactamase produc-
enterococcal endocarditis to penicillin used alone were found tion is inducible, ␤-lactamase production in enterococci is con-
to be markedly lower than those of streptococcal endocarditis stitutive, low level, and inoculum dependent (127, 182).
(73, 77). Because most enterococci are tolerant to the bacte-
ricidal activity of ␤-lactam and glycopeptide antibiotics, bac- Aminoglycoside Resistance
tericidal synergy between one of these antibiotics and an ami- Early studies demonstrated that two types of streptomycin
noglycoside is needed to treat most serious enterococcal resistance occur in enterococci: (i) moderate-level resistance
infections such as endocarditis and meningitis (144, 175). Since (MIC, 62 to 500 ␮g/ml), because of low permeability, which
the duration of therapy is longer and the toxicity of the com- can be overcome with a penicillin (which increases the cellular
bination regimens is increased compared to those used for uptake of the aminoglycoside); and (ii) high-level resistance
streptococcal endocarditis, enterococci are considered prob- (MIC, ⱖ2,000 ␮g/ml), which is either ribosomally mediated or
lem organisms with respect to antimicrobial therapy (186). The due to the production of aminoglycoside-inactivating enzymes
synergistic bactericidal effect between aminoglycosides and (171). Since enterococcal resistance to gentamicin and strep-
␤-lactam or glycopeptide antibiotics is lost if there is high-level tomycin occur by different mechanisms, it is important to test
resistance to either class of drug. Resistance to high concen- susceptibilities to both agents. Gentamicin resistance is pre-
trations of aminoglycoside antibiotics is usually mediated by dominantly the result of the presence of the inactivating enzyme
aminoglycoside-modifying enzymes, and it is widespread 2⬙-phosphotransferase-6⬘-acetyltransferase conferring resistance
among enterococci (more than 50% of isolates in some centers to gentamicin, tobramycin, netilmicin, amikacin, and kanamy-
show this resistance) (267). Also, many isolates of E. faecium cin. Hence, gentamicin resistance is a good predictor of resis-
are highly resistant to penicillins, because their penicillin bind- tance to other aminoglycosides except streptomycin. Strepto-
ing proteins (PBP) have low affinity for penicillins (113). Until mycin resistance is encountered mainly in enterococcal strains
recently, vancomycin was virtually the only drug that could be that produce streptomycin adenyltransferase; these strains
consistently relied on for the treatment of infections caused by remain susceptible to gentamicin (127). Penicillin-aminoglyco-
multidrug-resistant enterococci. side synergy does not occur in high-level aminoglycoside-resis-
Vancomycin had been in clinical use for more than 30 years tant enterococci (streptomycin MIC, ⱖ2,000 ␮g/ml: gentami-
without the emergence of marked resistance (129). Teicopla- cin MIC, ⱖ500 ␮g/ml).
nin is another glycopeptide antibiotic; it is not available in the
United States but has been used in Europe. Because of their
activity against methicillin-resistant staphylococci and other Vancomycin Resistance
gram-positive bacteria, these drugs have been widely used for Phenotypic description. There are five recognized pheno-
therapy and prophylaxis against infections due to these organ- types of vancomycin resistance, VanA, VanB, VanC, VanD,
isms (109). Oral vancomycin, which is poorly absorbed, has and VanE (7, 94, 206). Two of these (VanA and VanB) are
688 CETINKAYA ET AL. CLIN. MICROBIOL. REV.
TABLE 2. Characteristics of phenotypes of glycopeptide-resistant enterococcia

Phenotype
Characteristic
VanA VanB VanC VanD VanE
Vancomycin MIC (␮g/ml) 64–⬎1,000 4–1,024 2–32 128 16

Teicoplanin MIC (␮g/ml) 16–512 ⱕ0.5 ⱕ0.5 4 0.5
Most frequent enterococcal E. faecium, E. faecalis E. faecium, E. faecalis E. gallinarum, E. casseliflavus, E. faecium E. faecalis
species E. flavescens
Genetic determinant Acquired Acquired Intrinsic Acquired Acquired
Transferable Yes Yes No No No
a
Adapted in 2000 from reference 109 with permission; original version Copyright @ 1996, Massachusetts Medical Society (all rights reserved).
mediated by newly acquired gene clusters not previously found resistance (vanR, vanS, vanH, vanX, and vanZ) are located on
in enterococci. VanA and VanB resistance phenotypes were a 10,581-bp transposon (Tn1546) of E. faecium, which often

described primarily in E. faecalis and E. faecium. VanA-resis- resides on a plasmid (11). Expression of these genes results in
tant strains possess inducible, high-level resistance to vanco- the synthesis of abnormal peptidoglycan precursors terminat-
mycin (MICs, ⱖ64 ␮g/ml) and teicoplanin (MICs, ⱖ16 ␮g/ml) ing in D-Ala–D-lactate instead of D-Ala–D-Ala. Vancomycin
(Table 2) (7). Resistance can be induced by glycopeptides binds to D-Ala–D-Lac with markedly lower affinity than it does
(vancomycin, teicoplanin, avoparcin, and ristocetin) and by to the normal dipeptide product (37). The core protein func-
nonglycopeptide agents such as bacitracin, polymyxin B, and tions favoring synthesis of pentadepsipeptide terminating in
robenidine, a drug used to treat coccidial infections in poultry D-Ala–D-Lac are as follows. (i) VanA protein is a ligase of
(146). The details of vancomycin resistance have been best altered substrate specificity which produces D-Ala–D-Lac in
documented with the vanA gene cluster found on the transpo- preference to D-Ala–D-Ala (36). (ii) VanH protein is a D-
son, or “jumping” genetic element, Tn1546 (7, 11). VanB iso- hydroxy acid dehydrogenase which creates a pool of D-lactate
lates were initially believed to be inducibly resistant to more for use in the above reaction (12). (iii) VanX protein is a
modest levels of vancomycin (MICs, 32 to 64 ␮g/ml) but are D,D-dipeptidase lacking activity against D-Ala–D-Lac. This en-
susceptible to teicoplanin. It is now known that levels of van- zyme reduces pools of D-Ala–D-Ala produced by the native
comycin resistance among VanB isolates may range from 4 to enterococcal ligase, thereby minimizing the competing synthe-
ⱖ1,000 ␮g/ml whereas susceptibility to teicoplanin is retained. sis of normal pentapeptide (215, 262).
VanB resistance determinants also reside on large mobile el- VanA alone cannot confer resistance to vancomycin, prob-
ements that can be transferred from one strain of enterococcus ably because D-hydroxy acids such as D-Lac are neither natural
to another (212, 213). The VanC resistance phenotype was products present in the environment of enterococci nor nor-
described in E. casseliflavus and E. gallinarum, which demon- mally produced by enterococci (154). Thus, to synthesize D-
strate intrinsic, low-level resistance to vancomycin (MICs, 4 to lactate, enterococci must acquire the gene(s) within the vanA
32 ␮g/ml) and are susceptible to teicoplanin. operon required to produce the substrate for VanA. VanH is
Certain limitations of this classification method have be- responsible for the synthesis of D-lactate.
come evident over time. For example, the genetic determinants VanR and VanS proteins constitute a two-component reg-
of the VanA phenotype have now appeared in E. gallinarum ulatory system that regulates the transcription of the vanHAX
and other enterococcal species (68). In a strain of E. avium, the gene cluster (8). VanS apparently functions as a sensor to
VanA resistance determinants conferred a typical level of re- detect the presence of vancomycin (7, 11) or, more likely, some
sistance to teicoplanin but low-level resistance to vancomycin early effect of vancomycin on cell wall synthesis (117). VanS
(MIC, 16 ␮g/ml) (218). Additionally, mutants derived from then signals VanR, the response regulator, which results in
VanB strains may exhibit resistance to teicoplanin and thus be activation, or turning on, of the synthesis of some other pro-
phenotypically indistinguishable from VanA strains (126). teins (VanH, VanA, and VanX) involved in resistance. In
Nevertheless, this phenotypic classification scheme is still use- VanA phenotype strains, either vancomycin or teicoplanin can
ful, because it usually corresponds well to the genotypic clas- induce the transcription, but the precise signals are still un-
sification and utilizes information that can be derived simply known (15). vanY and vanZ may contribute to but are not
and inexpensively in a laboratory (80). essential for resistance. VanY protein is a D,D-carboxypepti-
Genotypic classification and resistance mechanisms. (i) Ac- dase that cleaves the D-Ala terminal peptide from any normal
tion of vancomycin on peptidoglycan synthesis. Under normal peptide that may have been made, contributing modestly to
conditions of peptidoglycan synthesis in enterococci, two mol- resistance levels (53). VanZ modestly increases the MICs of
ecules of D-alanine are joined by a ligase enzyme to form teicoplanin but not of vancomycin, through mechanisms that
D-Ala–D-Ala, which is then added to UDP-N-acetylmuramyl- have not yet been elucidated. It is not essential to the expres-
tripeptide to form the UDP-N-acetylmuramyl-pentapeptide. sion of the VanA phenotype.
The UDP-N-acetylmuramyl-pentapeptide, when incorporated Mapping of the vanA gene cluster from several U.S. isolates
into the nascent peptidoglycan (transglycosylation), permits revealed some heterogeneity in organization (122, 123).
the formation of cross-bridges (transpeptidation) and contrib- Tn1546 existed intact in some strains but had insertion-like
utes to the strength of the peptidoglycan layer (80). Vancomy- sequences between vanS and vanH in others. These vancomy-
cin binds with high affinity to the D-Ala–D-Ala termini of the cin resistance gene clusters may be incorporated into even
pentapeptide precursor units, blocking their addition to the larger mobile elements containing additional insertion-like el-
growing peptidoglycan chain and preventing subsequent cross- ements (122, 123).
linking (262, 265). Cross-linking of the precursors to the growing peptidoglycan
(ii) VanA glycopeptide resistance. The vanA gene and other is processed in bacteria by the PBPs, with PBP5 being used in
genes involved in the regulation and expression of vancomycin enterococci (96). The replacement of D-Ala by D-Lac does not
impair cross-linking of the modified precursors to the growing (iv) VanC glycopeptide resistance. Low-level resistance to
peptidoglycan chain. However, PBPs other than PBP5, which vancomycin is typical of E. gallinarum, E. casseliflavus, and E.
are so far not known to play a role in cell wall synthesis, are flavescens. The nucleotide sequences of the vanC-1 gene in E.
probably required for processing of the altered precursors (6). gallinarum, the vanC-2 gene in E. casseliflavus, and the vanC-3
These high-molecular-weight PBPs display a higher affinity for gene in E. flavescens have been reported, although there is
␤-lactams. Since VanA resistance is inducible, a shift in the some disagreement about whether E. flavescens is a legitimate
PBPs occurs only in the presence of vancomycin and results in enterococcal species (52). VanC ligase of E. gallinarum favors
␤-lactam hypersusceptibility. This effect explains the synergy the production of a pentapeptide terminating in D-Ala–D-Ser.
displayed by the combination of the two classes of drugs Substitution of D-Ser for D-Ala is presumed to weaken the
against vancomycin-resistant strains. binding of vancomycin to the novel pentapeptide. Insertional
(iii) VanB glycopeptide resistance. VanB glycopeptide resis- inactivation of vanC-1 unmasks the concomitant production of
tance in enterococci is mediated by an abnormal ligase (VanB) the D-Ala–D-Ala pentapeptide in E. gallinarum (216). D,D-
that is structurally related to VanA ligase (76% amino acid Dipeptidase and D,D-carboxypeptidase activities analogous to
identity). VanB protein also favors the production of the pen- those of VanA and VanB strains have been described. It is
tadepsipeptide terminating in D-Ala–D-Lac (87). Genes anal- presumed that the level of resistance expressed represents the
ogous to their class A resistance counterparts are designated balance achieved between normal and abnormal peptidoglycan

vanHB, vanXB, vanYB, vanRB, and vanSB (15). Levels of D,D- synthesis (80). The presence of variable amounts of D-Ala–D-
dipeptidase activity (VanXB) correlate with levels of vancomy- Ala relative to D-Ala–D-Ser could account for the variable
cin resistance (10). There is a high degree of sequence identity levels of vancomycin resistance observed among isolates of
(approximately 70%) between VanHAX and VanHBBXB but VRE carrying the VanC phenotype (186). That is, lower MICs
considerably less homology (25 to 35% sequence homology) could be explained by the presence of larger amounts of D-
between the RS and Y proteins of VanA and VanB VRE (10, Ala–D-Ala, which enables vancomycin to inhibit cell wall syn-
86). There is no gene counterpart of vanZ in these organisms. thesis, and higher MICs could be explained by a higher pro-
vanYB is not found in all strains, and its position in the gene portion of D-Ala–D-Ser. Resistance may be inducible or
clusters differs from that of vanY in Tn1546 (9, 86). Recent constitutive (221). The vanC-2 gene of E. casseliflavus demon-
reports have shown DNA sequence heterogeneity, suggesting strates approximately 66% nucleotide sequence similarity to
three subtypes of the vanB ligase gene: vanB-1, vanB-2, and vanC-1. Like E. gallinarum, these strains also possess an addi-
vanB-3 (60, 203, 208). The regulatory system in class B strains tional native ligase (189). There is extensive homology (98%)
appears insensitive to induction by teicoplanin (10, 53). Teico- between the gene sequences of vanC2 and vanC3 (52). vanA
genes have recently been identified in strains of E. gallinarum
planin induces the synthesis of VanA-related proteins but does
and E. casseliflavus, conferring higher levels of resistance to
not induce the production of VanB-related proteins. On the
vancomycin (MIC, ⬎256 ␮g/ml) in these species than normally
other hand, vancomycin induces the synthesis of the resistance
anticipated and also resulting in resistance to teicoplanin (68).
proteins of both systems, and in fact, if a teicoplanin-suscepti-
(v) VanD glycopeptide resistance. A novel vancomycin re-
ble enterococcus with the vanB gene cluster is preexposed to
sistance gene designated vanD was first described in a New
vancomycin, the strain then tests teicoplanin resistant as well.
York Hospital in 1991 (206). The strain carrying this resistance
In addition, teicoplanin-resistant mutants can be derived from trait was an E. faecium strain that was inhibited by vancomycin
teicoplanin-susceptible, vanB-containing enterococci when at 64 ␮g/ml and teicoplanin at 4 ␮g/ml. Partial sequencing of
these organisms are plated onto teicoplanin-containing agar. the ligase gene showed that it was distinct from but similar to
Such mutants can also arise in vivo during therapy (186). Pos- the vanA and vanB ligase genes. Recently, three clinical iso-
sible mechanisms for teicoplanin resistance of these mutants lates of vancomycin-resistant E. faecium carrying the VanD
include the loss of their requirement for an inducer (that is, if resistance trait were found in Boston (199), and the deduced
they constitutively produce high levels of the vancomycin re- amino acid sequence of VanD showed 67% identity to those of
sistance proteins) and the ability of teicoplanin to act as an VanA and VanB. VanD appears to be located on the chromo-
inducer. some and is not transferable to other enterococci.
Another difference between VanA- and VanB-type resis- (vi) VanE glycopeptide resistance. The vanE vancomycin
tance is that VanA is more widely distributed. It is by far the resistance gene has recently been described in E. faecalis
predominant type of resistance reported in Europe. While BM4405, which is resistant to low levels of vancomycin (MIC,
VanB strains are fairly common in the United States, with 16 ␮g/ml) and susceptible to teicoplanin (MIC, 0.5 ␮g/ml) (94).
some hospitals reporting VanB exclusively, VanA still predom- This new resistance phenotype has similarities to the intrinsic
inates (51). The vanA ligase gene, has also been found in a VanC type of resistance. The deduced amino acid sequence
wider range of enterococcal species as well as in Corynebacte- has a greater identity to VanC (55%) than to VanA (45%),
rium spp., Arcanobacterium haemolyticum, and Lactococcus VanB (43%), or VanD (44%) (94).
spp., while vanB has been found primarily in E. faecium and E. (vii) Other resistance classes and organisms. Lactobacillus
faecalis. The difference in the dissemination of these resistance casei , Pediococcus pentosaceus, and Leuconostoc mesenteroides
traits may be related to the observation that the vanA gene are naturally resistant to glycopeptides. Although the terminus
cluster is often located on a transposon similar to Tn1546, appears to be the same (D-Ala–D-Lac), as found in VRE with
which, in turn, can be a part of a conjugative (transferable) VanA or VanB phenotypes (24, 120), DNA from these organ-
plasmid (11, 119, 122, 123). Such a genetic arrangement is an isms does not hybridize with resistance gene probes prepared
excellent avenue for the dissemination of these genes. The from VRE (24, 120).
vanB cluster is often located on the host chromosome and In the laboratory, conjugal transfer of VanA-type vancomy-
initially was thought not to be transferable to other bacteria. cin resistance genes from enterococci to other gram-positive
However, it can also occur on plasmids, and, even when it is cocci has been accomplished. Recipient organisms in success-
chromosomal, this gene cluster has been transferable as part of ful transfers have included group A and viridans group strep-
large mobile elements, perhaps related to large conjugative tococci, Listeria monocytogenes, and Staphylococcus aureus (57,
transposons (212). 189). Transfer of resistance genes to S. aureus, resulting in high
levels of resistance to vancomycin, was demonstrated both in included a number of different species such as E. faecalis,
vitro and on the skin of mice. This gives rise to concern that E. faecium, E. gallinarum, E. casseliflavus, E. avium, and E.
such transfer in humans under natural conditions indeed might mundtii (19). Fortunately, rates of stool colonization with VRE
be feasible (193). Vancomycin resistance genes have already among hospitalized patients far exceed infection rates with
been found in human isolates of nonenterococcal organisms. A these organisms (147, 176). Gastrointestinal tract colonization
vanB-related gene sequence (designated vanB3) has been with VRE may persist for weeks or months, and single negative
found in Streptococcus bovis (208). cultures may be intermixed with positive cultures over time
(viii) Vancomycin-dependent enterococci. An interesting (176). During outbreaks, environmental cultures in hospital
phenomenon that has developed in some strains of VanA- and rooms have yielded VRE (29, 167, 235).
VanB-type VRE is that of vancomycin dependence (64, 261).
These enterococci are not just resistant to vancomycin but now VRE in Long-Term-Care Facilities
require it for growth. Vancomycin-dependent enterococci have
The role of long-term-care facilities (LTCFs) in the epide-
been recovered from apparently culture-negative clinical sam-
miology of VRE has not been well defined. In a study per-
ples by plating them onto vancomycin-containing agar, such as
formed in Chicago, where VRE have been endemic for several
that used for isolation of Campylobacter or gonococci. A likely
years, it was found that 47% of patients admitted to a hospital
explanation for the phenomenon of vancomycin dependence is

from LTCFs were colonized with VRE (M. L. Elizaga, D.
that these enterococci turn off their normal production of
Beezhold, M. K. Hayden, et al., Abstract, Clin. Infect. Dis.
D-Ala–D-Ala and then can grow only if a substitute dipeptide-
23:925, 1996). The prevalence of VRE among LTCF residents,
like structure is made. With most VanA- and VanB-type en-
however, varies considerably by geographic area (32). Several
terococci, this occurs only in the presence of vancomycin,
preliminary reports emphasized that 10 to 16% of patients
which induces the synthesis of associated dehydrogenase
admitted to the hospital from nursing homes were colonized
(VanH) and ligase (VanA or VanB) that make D-Ala–D-Lac.
with VRE (M. P. Revuelta, J. A. Nord, R. L. Yarrish, et al.,
The reason for the cell turning off the synthesis of D-Ala–D-Ala
Abstract, Clin. Infect. Dis. 21:730, 1995; S. J. Sargent, V. S.
is that as long as vancomycin is present, D-Ala–D-Ala is not
Baselski, L. D. Reed, et al., Abstract, Clin. Infect. Dis. 21:729,
necessary for cell wall synthesis by VRE (186). Indeed, it is
1995). In two reports, most or all nursing-home residents who
being destroyed by the action of VanX. Once the vancomycin
were colonized with VRE had been hospitalized in an acute-
is removed, D-Ala–D-Lac is no longer synthesized, and without
care hospital within the preceding 3 months (29; J. Quale, K.
either D-Ala–D-Ala or D-Ala–D-Lac, the cell cannot continue to
Patel, M. Zaman, et al., Abstract, Clin. Infect. Dis. 21:733,
grow or replicate. Reversion to vancomycin independence has
1995). Bonilla et al. reported that VRE colonization of resi-
been observed; it probably occurs by either a mutation that
dents in a Veterans’ Affairs (VA) LTCF in Michigan ranged
leads to constitutive production of D-Ala–D-Lac or one that
from 9% (in December 1994) to 19% (in January 1996) (27).
restores the synthesis of D-Ala–D-Ala.
During the same periods, 47 and 33% of residents’ rooms were
contaminated with VRE, respectively. Transmission between
EPIDEMIOLOGY AND CONTROL roommates was not observed. During the surveys, it was found
that 26 to 41% of health care workers carried VRE on their
Geographic Distribution and Spread within Hospitals hands. In another recent study in a VA LTCF in Pittsburgh,
vancomycin-resistant E. faecium was identified in 24 of the 36
Since their initial recovery from patients in the United King-
patients at the time of transfer from an acute-care facility (35).
dom and France, VRE have been found in many other coun-
VRE in these patients persisted for a median of 67 days after
tries, including Australia, Belgium, Canada, Denmark, Ger-
identification. Treatment of VRE colonization with antimicro-
many, Italy, Malaysia, The Netherlands, Spain, Sweden, and
bials prolonged colonization. Serial surveillance of the 34-bed
the United States (261).
ward showed that the rates of colonization were stable, with
From 1989 through 1993, the percentage of nosocomial en-
only three documented instances of VRE acquisition. The
terococcal infections reported to the Centers for Disease Con-
authors of this report also noted that during 2.5 years of sur-
trol and Prevention’s National Nosocomial Infections Surveil-
veillance for infection, a single case of bacteremia occurred in
lance system that were due to VRE increased from 0.3 to 7.9%
a patient in whom colonization with VRE could not be dem-
(43). The increase was mainly due to the 34-fold rise (from 0.4
onstrated by rectal swab culture and no infections occurred in
to 13.6%) of VRE infections in intensive care unit (ICU)
patients colonized with VRE. These studies indicate that col-
patients, although a trend toward increased VRE infections
onized residents of LTCFs may serve as a reservoir for VRE
also was noted in non-ICU patients (43).
for acute-care hospitals, just as patients from acute-care hos-
Hospital outbreaks of infection or colonization have been
pitals may reintroduce VRE to an LTCF continually.
reported with both VanA and VanB isolates (29). Such out-
breaks may involve clonal dissemination of strains indistin-
guishable by pulsed-field gel electrophoresis (PFGE), not only VRE in the Community
within hospitals but also among several local hospitals (180). In the United States, attention has focused on the epidemi-
Multiple clones are often encountered, and sporadic isolates of ology of VRE mainly in hospitals, and there is little evidence to
unrelated strains may coexist with a predominant clone sus- suggest that transmission of VRE to healthy adults occurs to
pected of institutional spread (30, 147). In hospitals in which any significant extent in the community (B. E. Murray, Edito-
VRE outbreaks have been detected at an early stage, cases rial response, Clin. Infect. Dis. 20:1134–1136, 1995). In a study
often have been caused by a single strain (29, 30, 51, 121, 164, in Texas, investigators failed to find any VRE in the feces or
176). When VRE have been present in a hospital or commu- carcasses of chickens (186; Murray, Editorial response). In
nity for months or years, molecular typing of isolates often addition, VRE could not be isolated from healthy volunteers in
reveals that vancomycin resistance has spread by plasmids or two studies (186, 252; Murray, Editorial response). Two cases
transposons to many different clones (51, 122, 167, 181, 235). of apparent community-acquired VRE urinary tract infections
Patients may be colonized simultaneously with more than in New York City have been reported (104). In another case,
one strain of VRE (167, 252). Stool isolates of VRE have the husband caregiver of an elderly woman colonized with
TABLE 3. Summary of data from case-control studies in patients infected with VREa
Source of VRE isolates Resistance phenotype and Statistical
Reference Ward type Risk factors
(no. of cases) species (no.) analysis used
164 Medical-surgical/ICU Blood (4), urine (2), VanA, E. faecium (9) Univariate Duration of ceftazidime treatment,
stools (3) no. of days in ICU
69 Oncology Blood (11) VanA, E. faecium (11) Univariate Intestinal colonization with VRE,
use of antibiotics active against
anaerobes
180 Variousb Various (colonization ⫹ VanA, E. faecium (6) Univariate Previous exposure to antibiotics,
infection) (41) use of third-generation
cephalosporins, use of
parenteral vancomycin
181 Various Various (20) VanB, E. faecium (35) Multivariate Use of multiple antibiotics
(ciprofloxacin, aztreonam,
vancomycin), severity of illness
230 Various (mainly Blood (46) E. faecium (40, Multivariate Hematological malignancy, use of

oncology- including 38 VanA) vancomycin, severity of illnessc
hematology, AIDS, E. faecalis (2)
surgical, ICU)
252 Hepatology (included Various (colonization ⫹ NAd Multivariate Length of hospital stay
transplant infection) (38)
recipients)
161 Liver transplantation Blood (54) VanA (54) Multivariate Length of hospital stay
a
Reprinted with modification from reference 154 with permission from the publisher.
b
Seven hospitals including both primary and tertiary care centers.
c
Based on APACHE II score.
d
NA, not available.
VRE developed urinary retention and urinary tract infection organ transplant recipients, and patients who experience pro-
with a VRE strain that was found to be indistinguishable from longed hospitalization (30, 43, 71, 114, 135, 137, 164, 247, 248).
the woman’s isolate by PFGE (231). Thus, as colonized pa- Several studies have used case-control methods and multivar-
tients leave the hospital environment, the possibility that trans- iate analysis to examine the risk factors for VRE infection
mission might occur in the community cannot be discounted. among hospitalized individuals (Table 3). Among the risk fac-
The situation in Europe is quite different from that in the tors that have emerged are longer duration of hospitalization
United States. In Europe, VRE have been isolated from sew- (181, 235, 247), longer lengths of stay in ICU (176, 201), the
age and various animal sources (19, 139). It has been suggested need for intrahospital transfer to another ward (247), the need
that the use of glycopeptide-containing animal feeds in some for surgical reexploration following liver transplantation (201),
regions of Europe may have contributed to such differences and the use of enteral tube feedings or sucralfate (235). While
(184). In one study, VanA-resistant E. faecium was isolated gastrointestinal tract colonization may precede infection in
from frozen poultry and pork and from the feces of 12 of 100 many patients, in one study stool surveillance culture positivity
nonhospitalized inhabitants in a rural area (139). VanA VRE antedated infection in only half of the cases (255). This may in
have also been found in the feces or intestines of other farm part reflect the limitations of surveillance cultures in detecting
animals or pets, including horses, dogs, chickens, and pigs (65). low densities of microorganisms. Occasionally, VRE will be
These observations suggest a potential for VRE or the resis- detected in surveillance cultures of nose, throat, or mouth
tance genes of VRE to reach humans through the food chain
specimens in the absence of detectable rectal or perineal col-
or through contact with domesticated animals.
onization. Other risk factors that have been associated with
Colonization of healthy individuals with VRE does not nec-
colonization or infection include previous antimicrobial ther-
essarily indicate a risk of infection with these organisms. In
a point-prevalence culture survey at one Belgian hospital in apy, exposure to contaminated medical equipment such as
1993, 3.5% of patient stool isolates were positive for VRE; electronic thermometers, proximity to a previously known
however, to that point, no infections due to VRE had been VRE patient, and exposure to a nurse who was assigned on the
encountered at that institution (111). Van der Auwera et al. same shift to another known patient (30, 137, 164). Risk factors
reported that stool cultures from 11 (28%) of 40 healthy vol- specifically associated with VRE infections such as bacteremia
unteers who were not health care workers and who had not include malignancy, increased Acute Physiology and Chronic
taken antibiotics in the preceding year yielded a heterogeneous Health Evaluation (APACHE) II score, neutropenia, pro-
collection of isolates of vancomycin-resistant E. faecium (249). longed hospital stay, antibiotic therapy and preceding therapy
The same group also detected VRE in the stools of up to 64% with agents active against anaerobes, mean number of days on
of volunteers who had received oral glycopeptides in previous antibiotic therapy, renal insufficiency, and hospitalization on a
studies (249). hematologic malignancy/bone marrow transplantation service
(30, 71, 121, 152, 179, 230). Parenteral vancomycin use and
Risk Factors receipt of third-generation cephalosporins have been cited by
others as risk factors for colonization or infection with VRE
Early studies dealing with the emergence of VRE in the (61, 180, 181, 247). In a recent prospective cohort study using
United States revealed that most patients with VRE were in logistic regression, VRE colonization at the time of ICU ad-
ICUs (51). However, VRE are now being seen with increasing mission was found to be associated with second- and third-
frequency among patients with chronic renal failure or cancer, generation cephalosporins, length of stay prior to surgical ICU
admission, more than one prior ICU stay, and history of solid- VRE bacteremia may reach 60 to 70% (70, 71, 247). Approx-
organ transplantation (198). imately half of these deaths may be attributable directly to the
Oral vancomycin use may also be a risk factor for VRE infection. Papanicolaou et al. found VRE infection to be a
colonization (29, 147, 165), and this has led to recommenda- strong predictor of mortality in liver transplant patients (201).
tions discouraging the use of this agent for the primary treat- Linden et al. reported that enterococcal infection-related mor-
ment of antibiotic-associated diarrhea (44). However, there is tality was 46% in liver transplant recipients with VRE bacte-
also recent evidence that metronidazole may not be a micro- remia, which was significantly greater than the 25% mortality
biologically innocuous alternative to oral vancomycin for the observed in patients with vancomycin-susceptible enterococcal
treatment of antibiotic-associated diarrhea. The use of oral or bacteremia (161). Patients with neutropenia, chronic renal fail-
parenteral metronidazole (or other agents with significant an- ure, or other serious conditions and liver transplant recipients
tianaerobic activity) was noted as a risk factor for VRE bac- seem to be the most likely to experience prolonged bacteremia
teremia in one study (71), while others have suggested that or to die as a result of VRE (179).
metronidazole or clindamycin exposure is a risk factor for In other studies, comparison of patients with VRE and van-
VRE acquisition (176). comycin-susceptible enterococcal bacteremias revealed no sig-
Vancomycin most probably predisposes patients to coloni- nificant differences in mortality, especially after controlling for
zation and infection with VRE by inhibiting the growth of the factors such as age and APACHE II score (30, 247, 255). There

normal gram-positive bowel flora and by providing a selective is no evidence that VRE are more virulent than vancomycin-
advantage for VRE that may be present in small numbers in susceptible strains of the same enterococcal species.
the individual’s bowel (249; Murray, Editorial response). For Although many nosocomial enterococcal bacteremias are
example, Van der Auwera et al. found that administration of polymicrobial, 80 to 90% of VRE bacteremias have been mo-
oral vancomycin or teicoplanin to individuals whose baseline nomicrobial in some series (70, 161). These studies have re-
stool specimens contained few or no detectable VRE led to vealed that some enterococcal bacteremias are associated with
recovery of VRE in large numbers, sometimes as much as 106 refractory hypotension (161) or hypotension with clinically sig-
to 108 CFU/g of stool (249). The selective pressure exerted by nificant hypoperfusion and organ dysfunction (70). Hypoten-
the increasing use of vancomycin in the United States during sion has also accompanied E. faecalis bacteremic superinfec-
the last 10 to 15 years has been extraordinary. For example, the tion observed during the treatment of E. faecium infection with
amount of vancomycin used at one university hospital in- dalfopristin-quinupristin (49).
creased 20-fold from 1981 to 1991 (83). In addition to bloodstream infections, which are often cath-
Beezhold et al. reported a high prevalence of skin coloniza- eter related, VRE may be isolated from urine, intra-abdominal
tion with VRE (86%) among hospitalized patients with VRE abscesses or surgical site infections, and various tubes and
bacteremia (21). Skin colonization with VRE was found to be drains relating to infections within the abdomen. VRE are
associated with diarrhea (prior or present) or fecal inconti- occasionally isolated from pleural fluid and rarely isolated
nence in two studies (21, 263). The high prevalence of skin from cerebrospinal fluid; generally this occurs following sur-
colonization might explain the importance of VRE as a cause gery or other instrumentation (80).
of catheter-related sepsis. It may also increase the risk of It is not always easy to assess the clinical significance of VRE
cross-infection or blood culture contamination, which may also in routine cultures or to differentiate colonization from infec-
explain the frequent spontaneous resolution of bacteremia due tion. This is especially true for urine or when VRE are part of
to VRE (21). a polymicrobial infection. In some cases, attempts at treatment
are not indicated. The extent to which VRE causes morbidity
Colonization and Infection and mortality is often difficult to determine, because most
affected patients have serious underlying diseases that cause
The emergence of vancomycin resistance in enterococci in substantial morbidity and death and because VRE are often
addition to the increasing incidence of high-level enterococcal recovered in mixed cultures with other potential pathogens (32).
resistance to penicillin and aminoglycosides presents a serious
challenge for physicians treating patients with infections due to Reservoirs
these microorganisms (43, 121). Treatment options are often
limited to combinations of antimicrobials or experimental Although much has been learned about the epidemiology of
compounds with unproven efficacy (125, 174). Resistance to VRE in recent years, a consensus regarding the most impor-
cephalosporins and clindamycin occurs almost without excep- tant reservoirs of VRE has not been reached. In 1993, Bates et
tion. Few isolates are susceptible to currently available macro- al. noted that several hospitalized VRE patients in the United
lides, and resistance to fluoroquinolones is now common (78). Kingdom had had little or no previous contact with medical
Once VRE are established in the hospital environment, their institutions (J. Bates, Z. Jordens, and J. B. Selkon, Letter,
frequent resistance to multiple antibiotics makes it difficult to Lancet 342:490–491, 1993). Subsequent investigations revealed
avoid further selective pressure in their favor (156). that several of these patients resided on farms and that chick-
In many affected institutions, most patients from whom ens and swine present on the farms were colonized with van-
VRE are recovered are colonized rather than infected with the comycin-resistant E. faecium. VRE has subsequently been re-
organism (30, 135, 156, 176). The ratio of colonized to infected covered from various animal sources in different European
patients may reach as high as 10:1 at hospitals in which peri- countries (processed chickens, chicken carcasses, pork meat)
rectal or rectal swab specimens from high-risk patients are (140; Bates et al., Letter). The occurrence of VRE in such
screened for VRE (135, 176). In one study, 40% of organisms animals could be related to the fact that avoparcin (a glyco-
colonizing the gastrointestinal tract were E. gallinarum, but no peptide) has been available as a feed additive for more than 15
infections were caused by this species (156). Infections caused years in the United Kingdom and other European countries (1,
by VRE often involve intra-abdominal sites, the urinary tract, 260). It has been fed to broiler chickens, swine, and cattle
the bloodstream, surgical sites, and vascular catheter sites. (270). These findings suggest that contaminated food products
VRE infections tend to occur in more debilitated or seri- may serve as a reservoir from which nonhospitalized individu-
ously ill hospitalized patients. Mortality rates in patients with als can acquire VRE.
In the United States, avoparcin is not a licensed feed addi- VRE culture positive for as long as 1 year have been reported
tive for animals, and culture surveys of a limited number of (30). According to the study of Montecalvo et al., some pa-
chickens in several cities have failed to detect VRE (T. S. tients were persistently colonized with the same VRE strain, as
Harrison, S. Qaiyumi, J. G. Morris, Jr., and R. S. Schwalbe, demonstrated by PFGE, whereas others were positive for more
Program Abstr. 35th Intersci. Conf. Antimicrob. Agents Che- than one strain during the follow-up period (176). Because
mother., abstr. J78, 1995; Murray, Editorial response). Further persistently colonized patients may reintroduce VRE into a
studies of animal-based food products are needed to deter- facility on multiple occasions, hospitals should develop means
mine if food items represent a community reservoir for VRE in of prompt identification of such patients at the time of read-
this country. mission so that they can be placed in isolation pending repeat
At present, hospitalized patients with gastrointestinal car- surveillance cultures (30, 44).
riage of VRE appear to be the major reservoir of the organism
in the United States. Because most colonized patients are Modes of Transmission
asymptomatic, this reservoir can easily go unnoticed unless
Transmission of VRE by health care workers whose hands
surveillance culture specimens are obtained from patients at
become transiently contaminated with the organism while car-
risk (32). The gastrointestinal tract is undoubtedly the major
ing for affected patients is probably the most common mode of
reservoir for E. faecium, but positive clinical specimens in the

nosocomial transmission. This concept is supported by the
absence of fecal carriage provide evidence for direct exogenous
recovery of VRE and other resistant enterococci from cultures
acquisition rather than gastrointestinal colonization and sub-
of specimens from the hands of health care workers (247, 267).
sequent endogenous infection (252). In one study, 33% of very
Transmission of VRE may also occur by way of contami-
ill liver patients who acquired vancomycin-resistant E. faecium
nated medical equipment, although this is probably much less
had positive throat swabs (252). Colonization at this site may
important than transmission by the hands of personnel. Elec-
follow contamination by staff hands during mouth, tracheos-
tronic thermometers contaminated with the outbreak strain
tomy, or endotracheal tube care. Oropharyngeal colonization
were epidemiologically implicated in an outbreak described by
may provide a source for cross-colonization, particularly if staff
Livornese et al. (164). The spread of VRE via bedpan washer
consider such manipulations to be “clean” and do not subse-
machines has also been reported (P. R. Chadwick and B. A.
quently wash their hands. In another study, however, vanco-
Openheim, Letter, Lancet 344:685, 1994). Nosocomial trans-
mycin-resistant E. faecium was not isolated from throat swabs
mission of VRE has been attributed to the use of fluidized
of any patients known to be infected or colonized at other sites
microsphere beds from which multiply resistant strains were
(121).
recovered despite repeated attempts at decontamination by
Environmental surfaces and medical equipment items in the
the manufacturers (100). Enterococci have been recovered
patient’s room frequently become contaminated with VRE and
from 7 to 30% of environmental cultures during several out-
may also serve as a reservoir for the organism in the hospital.
breaks (30, 71, 137, 181, 263, 267). Since enterococci may
Examples of items that may be contaminated include patient
remain viable for several days to weeks on dry surfaces, it
gowns and linen, beds, bedside rails, overbed tables, floors,
seems plausible that contaminated surfaces may act as a source
doorknobs, washbasins, glucose meters, blood pressure cuffs,
from which personnel may contaminate their hands or clothing
electronic thermometers, electocardiogram monitors, electro-
(30). However, further studies are necessary to determine the
cardiograph wires, intravenous fluid pumps, and commodes
extent to which these items contribute to the transmission of
(29, 30, 112, 137, 164, 167, 181, 235). Widespread environmen-
VRE (32).
tal contamination by VRE is especially likely to occur in the
Disposable cover gowns worn by personnel who care for
rooms of patients who have diarrhea (30). In some studies,
VRE patients have also been shown to be contaminated with
isolates from contaminated surfaces and from affected patients
the patient’s organism (29). Presumably, the clothing of the
in the room have been shown to represent the same strains of
personnel who do not wear cover gowns may also become
VRE (29, 235). VRE may remain viable on such surfaces for
contaminated with VRE. However, at present there is no con-
days or weeks because the organisms are resistant to desicca-
clusive proof that VRE are spread by contaminated clothing.
tion and extreme temperatures (30, 101, 138, 195). For exam-
There is no proof that enterococci, including VRE, are spread
ple, VRE may survive for 5 to 7 days on countertops and have
by the airborne route. Recovery of VRE from animal sources
been recovered 24 h or more after experimental contamination
in parts of Europe suggests that food-borne transmission may
of bedrails, telephone handpieces, or stethoscope diaphragms
occur in certain geographic areas (260; Bates et al., Letter).
(195). Vancomycin-resistant E. faecium has also been isolated
However, conclusive proof of food-borne transmission of VRE
from a tourniquet 4 days after discharge of a colonized patient
in Europe (or other areas) is not yet available.
and from intravascular monitoring equipment after several
days in storage (30, 161, 176). VRE have been recovered from
the hands of personnel by some investigators (250) but not by Prevention and Control Measures
others (30, 181, 252). In a few instances, health care workers The epidemiology of VRE has not been elucidated com-
have been found to have gastrointestinal colonization with pletely; however, as mentioned above, certain patient popula-
VRE, but the epidemiologic significance of this finding is un- tions are at increased risk for VRE infection or colonization.
clear (121, 135). These include critically ill patients or those with severe under-
Montecalvo et al. emphasized that patients may remain col- lying disease or immunosuppression, such as ICU patients or
onized with VRE for weeks or months and are often still patients in oncology or transplantation wards, those who have
colonized at the time of readmission to the hospital (176). had an intra-abdominal or cardiothoracic surgical procedure,
Their findings support earlier reports of persistent VRE colo- those with an indwelling urinary or central venous catheter,
nization among high-risk patients (30, 114, 164). Green et al. and those who have had a prolonged hospital stay or received
reported that nearly 60% of liver transplant patients with VRE multiple antimicrobial agents (30, 33, 43, 104, 121, 137, 177).
remained colonized for 12 weeks or more (115), and Livornese Because enterococci are part of the normal flora of the gas-
et al. found that a majority of patients remained colonized for trointestinal tract and the female genital tract, most infections
more than 3 months (164). Occasional patients who remained with these organisms have been attributed to the patient’s
TABLE 4. Measures for reducing nosocomial transmission of VREa

Control measures Hospitals without VRE Hospitals with low prevalence of VRE Hospitals with high prevalence of VRE
Reduce excessive use of antibiotics Strongly Strongly recommended Strongly recommended

recommended
Educational programs for personnel Strongly Strongly recommended Strongly recommended
recommended
Surveillance
Test all enterococcal isolates for Periodically Routinely Routinely
resistance to vancomycin
Point prevalence culture surveys Not applicable Culture roommates or, Perform periodic surveys in high-
on affected wards preferably, all patients on ward risk units; consider screening
when new case occurs patients on admission to high-
risk units
Identify patients with VRE at the Not applicable When possible, use computerized Desirable, but may not be
time of readmission demographic file to detect practical in all facilities with
VRE patients on admission high prevalence of VRE

Placement of patients with VRE Not applicable Place colonized or infected Isolate or cohort VRE patients in
patients in a private room high-risk unit
Gloves Standard precautionsb Wear gloves when entering Wear gloves when entering rooms
rooms of VRE patients of VRE patients and consider
wearing gloves to care for all
patients in high-risk units
Gowns Standard precautionsb Wear gown if substantial contact Routine wearing of gowns, in
with patient or environment is addition to gloves, may have
anticipated little added benefit
Hand washing and hand hygiene Standard precautionsb After removing gloves, wash After removing gloves, wash
hands with antiseptic soap or hands with antiseptic soap or
use waterless antiseptic agent use waterless antiseptic agent
Noncritical patient care equipment Standard precautionsb Dedicate noncritical items to a Dedicate noncritical items to a
items (e.g., stethoscopes, single patient or cohort of single patient or cohort of
sphygmomanometers) patients patients
Discontinuing barrier precautions Not applicable Require 3 consecutive negative Require 3 consecutive negative
cultures for VRE from stool or cultures for VRE from stool or
rectal swab specimens and rectal swab specimens and from
from other body sites colonized other body sites colonized with
with VRE taken 1 wk or more VRE taken 1 wk or more apart
apart
Housekeeping Use standard cleaning Emphasize the importance of Consider obtaining cultures before
and disinfection cleaning and disinfection and after cleaning to ensure the
procedures procedures efficacy of procedures used
a
Reprinted with modification from reference 32 with permission from the publisher.
b
Standard precautions, as defined by the CDC HICPAC recommendations (107).
endogenous flora (185). However, recent reports have demon- To minimize nosocomial transmission of VRE, hospitals
strated that enterococci, including VRE, can be spread by must use a multidisciplinary approach that requires participa-
direct patient-to-patient contact or indirectly via transient car- tion by a variety of departments and personnel (Table 4) (32,
riage on the hands of personnel (30), contaminated environ- 44).
mental surfaces (30, 137), or patient care equipment (164). Prudent use of vancomycin. Efforts to control antibiotic-
In addition to the existing problem with VRE, the potential resistant organisms generally focus on decreasing the use of
emergence of vancomycin resistance in clinical isolates of S. antibiotics and decreasing the opportunities for the spread of
aureus or S. epidermidis is a serious public health concern. The organisms between individuals. The logic behind efforts to
vanA gene, which is frequently plasmid borne, can be trans- decrease antibiotic use is that the presence of an antibiotic
ferred in vitro from enterococci to a variety of gram-positive provides a tremendous advantage to a resistant organism and
microorganisms including S. aureus (193). can increase the number of resistant bacteria manyfold (186).
In response to the dramatic increase in vancomycin resis- The greater the number of resistant bacteria in a given clinical
tance in enterococci, the Subcommittee on Prevention and sample, the easier it is for that resistant organism to be trans-
Control of Antimicrobial-Resistant Microorganisms in Hospi- mitted to another person. This makes efforts at decreasing
tals of the CDC Hospital Infection Control Practices Advisory transmission more important but also more difficult.
Committee (HICPAC) had several meetings in 1993 and 1994. Vancomycin use has been reported consistently as a risk
In an effort to control the nosocomial transmission of VRE, factor for colonization and infection with VRE (30, 121, 164,
HICPAC published recommendations in February 1995 (44). 177) and may increase the possibility of the emergence of
These recommendations mainly focused on (i) prudent use of vancomycin-resistant S. aureus or S. epidermidis. Encouraging
vancomycin, (ii) education of hospital staff, (iii) effective use of the appropriate use of oral and parenteral vancomycin is an
the microbiology laboratory, and (iv) implementation of infec- important component of HICPAC recommendations. In an
tion control measures (including the use of gloves and gowns effort to bring about more prudent use of antibiotics, HICPAC
and isolation or cohorting of patients, as appropriate to specific emphasizes the importance of education of medical staff and
conditions). students about the situations in which the use of vancomycin is
considered appropriate. It also gives a long list of situations in a selective advantage for VRE and enhance their survival
which vancomycin use should be discouraged. According to (186). The use of third-generation cephalosporins has long
HICPAC recommendations, situations in which the use of been recognized as a risk factor for enterococcal infections in
vancomycin is appropriate or acceptable are as follows (44): (i) general. Several studies have shown that receipt of third-gen-
for treatment of serious infections due to ␤-lactam-resistant eration cephalosporins and use of agents with significant anti-
gram-positive microorganisms; (ii) for treatment of infections anaerobic activity are risk factors for colonization or infection
due to gram-positive microorganisms in patients with serious with VRE (71, 176, 180, 181, 247). Other measures that have
allergy to ␤-lactam antimicrobials; (iii) when antibiotic-associ- been suggested for the control of VRE outbreaks include for-
ated colitis fails to respond to metronidazole therapy or is mulary policies discouraging the use of third-generation ceph-
severe and potentially life-threatening; (iv) prophylaxis, as rec- alosporins and agents most likely to cause C. difficile colitis
ommended by the American Heart Association, for endocar- (209).
ditis following certain procedures in patients at high risk for Education programs. Continuing educational programs for
endocarditis; and (v) prophylaxis of major surgical procedures hospital staff (including attending and consulting physicians,
involving the implantation of prosthetic materials or devices, medical residents, students, pharmacy personnel, nurses, lab-
e.g., cardiac and vascular procedures and total hip placement, oratory personnel, and other direct patient caregivers) should
at institutions with a high rate of infections due to methicillin- include information about the epidemiology of VRE and the

resistant S. aureus (MRSA) or methicillin-resistant S. epider- potential impact of this pathogen on the cost and outcome of
midis (MRSE). A single dose administered immediately before patient care (44). Because detection and containment of VRE
surgery is sufficient unless the procedure lasts more than 6 h, in require a very aggressive approach and high performance stan-
which case the dose should be repeated. Prophylaxis should be dards for hospital personnel, special awareness and educa-
discontinued after a maximum of two doses. tional sessions may be indicated.
Situations in which the use of vancomycin should be discour- Role of the microbiology laboratory in the detection, report-
aged include the following: (i) routine surgical prophylaxis ing, and control of VRE. Early detection of patients colonized
other than in a patient with life-threatening allergy to ␤-lactam or infected with VRE is an essential component of any hospital
antibiotics; (ii) empirical antimicrobial therapy for a febrile program designed to prevent nosocomial transmission of VRE
neutropenic patient, unless there is strong evidence at the (32). Once the prevalence of VRE reaches high levels within
outset that the patient has an infection due to gram-positive an institution, prevention of transmission is more difficult. The
microorganisms (e.g., inflamed exit site of a Hickman catheter) microbiology laboratory is the first line of defense against the
and the prevalence of infections due to MRSA in the hospital spread of VRE in the hospital. The ability of the laboratory to
is substantial; (iii) treatment in response to a single blood identify enterococci and to detect vancomycin resistance
culture positive for coagulase-negative staphylococci, if other promptly and accurately is essential in recognizing VRE colo-
blood cultures drawn in the same time frame are negative, i.e., nization and infection and avoiding complex, costly contain-
if contamination of the blood culture is likely (because con- ment efforts that are required when recognition of the problem
tamination of blood cultures with members of the skin flora, is delayed (44). In addition, cooperation and communication
e.g., S. epidermidis, may cause vancomycin to be administered between the laboratory and the infection control program will
to patients inappropriately, phlebotomists and other personnel facilitate control efforts substantially. In many hospitals, the
who obtain blood cultures should be trained properly to min- first cases of VRE have been detected by isolating VRE from
imize microbial contamination of specimens); (iv) continued clinical specimens submitted to the laboratory for clinical pur-
empirical use for presumed infections in patients whose cul- poses (104, 137). Although some hospital laboratories continue
tures are negative for ␤-lactam-resistant gram-positive micro- to perform antimicrobial susceptibility testing only on entero-
organisms; (v) systemic oral or local (e.g., antibiotic lock) pro- cocci recovered from normally sterile body sites such as blood
phylaxis of infection or colonization of indwelling central or or urine, this practice is no longer appropriate for areas in
peripheral vascular catheters; (vi) selective decontamination of which VRE have been encountered (44; Murray, Editorial
the digestive tract; (vii) eradication of MRSA colonization; response). Only 45 to 50% of VRE isolated from clinical spec-
(viii) primary treatment of antibiotic-associated colitis; (ix) imens during VRE outbreaks have been recovered from blood
routine prophylaxis in very low-birth-weight infants; (x) routine or urine specimens. Accordingly, once VRE have been de-
prophylaxis in patients on continuous ambulatory peritoneal tected in a hospital, enterococci recovered from all body sites
dialysis or hemodialysis; (xi) treatment (chosen for dosing con- should be tested for susceptibility to vancomycin (44; Murray,
venience) of infections due to ␤-lactam-susceptible gram-pos- Editorial response). Hospitals that have not yet detected VRE
itive microorganisms in patients with renal failure; and (xii) use but are located in (or receive patients from) geographic areas
of vancomycin solution for topical application or irrigation. where VRE have been encountered should strongly consider
Vancomycin use in hospitals increased significantly over the performing susceptibility tests on all enterococcal isolates (Ta-
1980s (165). As noted above, there is some evidence that re- ble 4) (44).
stricting the use of this agent may assist in the control of VRE Susceptibility tests that detect vancomycin resistance accu-
outbreaks. Further study is required to determine the most rately must be used, or the prevalence of VRE may be under-
effective methods for influencing the prescribing practices of estimated (188, 241, 242, 244). Laboratories using disk diffu-
physicians, although a variety of techniques may be useful (85, sion should incubate plates for 24 h and read zones of
237, 238). In addition, key parameters of vancomycin use can inhibition under transmitted light (188, 242). MICs can be
be monitored through the hospital’s quality assurance and im- determined by agar dilution, agar gradient dilution, broth ma-
provement process or as a part of the drug utilization review of crodilution, or manual broth microdilution (188, 242). These
the pharmacy and therapeutics committee and the medical systems should also be incubated for 24 h. Some of the fully
staff. automated methods of testing enterococci for resistance to
A factor that may complicate our ability to reduce or elim- vancomycin are unreliable, especially in detecting VRE iso-
inate VRE by decreasing vancomycin use is that VRE are lates containing the VanB resistant determinant. In a recent
often resistant to multiple other antimicrobial agents as well. study evaluating the accuracy of eight currently available sus-
Administration of any of these agents could potentially provide ceptibility test methods (agar dilution, disk diffusion, E-test,
agar screen plate, Vitek GPS-TA and GPS-101, and MicroScan (iii) Wear a clean nonsterile gown when entering the room
overnight and rapid panels), it was shown that vanA VRE were of a VRE-infected or -colonized patient if substantial contact
detected by all methods but vanB VRE were often not de- with the patient or environmental surfaces in the patient’s
tected by Vitek GPS-TA and MicroScan rapid (sensitivities, 47 room is anticipated or if the patient is incontinent or has
and 53% respectively) (84). All methods except the E-test and diarrhea, an ileostomy, a colostomy, or wound drainage not
the agar screen continue to show problems in the detection of contained by a dressing (30).
VanC1 and VanC2 VRE. The agar screen appears to be the (iv) Remove gloves and gowns before leaving the patient’s
most reliable and easy method for routine screening, if detec- room, and wash hands immediately with an antiseptic soap or
tion of VanA-, VanB-, VanC1-, and VanC2-mediated resis- use a waterless antiseptic agent (66, 133, 192). Hands can be
tance in enterococci is required. The new Vitek GPS-101 contaminated via glove leaks or during glove removal, and
shows improved sensitivity compared to the Vitek GPS-TA bland soap is relatively ineffective in removing VRE from the
without significant loss of specificity (84). When VRE are iso- hands (40, 63, 141, 143, 205).
lated from a clinical specimen, vancomycin resistance should (v) Ensure that after glove and gown removal and hand-
be confirmed by repeating antimicrobial susceptibility testing washing, clothing and hands do not contact environmental
by any of these recommended methods, especially if VRE surfaces potentially contaminated with VRE (e.g., door knob
isolates are unusual in the hospital. While performing confir- or curtain) in the patient’s room (30, 137).

matory susceptibility tests, the patient’s primary caregiver, pa- Although it is not recommended by HICPAC, some hospi-
tient care personnel on the ward on which the patient is hos- tals require that gowns and gloves be worn routinely by all
pitalized, and infection control personnel must be immediately personnel entering a VRE patient’s room (30, 121). Anecdotal
notified about the presumptive identification of VRE, so that experience in an ICU in which outbreaks caused by a single
the patient can be placed on appropriate isolation precautions clone of VRE occurred revealed that routinely wearing gowns
promptly (44). This preliminary report must be followed by the and gloves before entering the rooms of patients, combined
(final) result of the confirmatory test. with other infection control measures, was effective in termi-
Enterococci may also be tested for vancomycin resistance by nating the outbreaks (29, 30). Handwerger et al. also reported
using PCR assays designed to detect the genes responsible for that the use of gowns in addition to the other infection control
glycopeptide resistance in these organisms (51, 242). Such tests procedures terminated the outbreak (121). A recent prospec-
may be particularly helpful in detecting VanB- or VanC-con- tive study conducted in an ICU in which multiple strains of
taining strains with low-level resistance to vancomycin (242). VRE were highly endemic, however, found that routine use of
Testing VRE isolates for susceptibility to teicoplanin by using gloves and gowns was no more effective in interrupting trans-
simple disk diffusion tests will differentiate between VanA mission than was universal use of gloves alone (235). The fact
(teicoplanin-resistant) and VanB (teicoplanin-susceptible) that routine use of gowns did not seem to provide additional
strains in most instances. However, occasional teicoplanin-re- protection against VRE transmission in the latter study may
sistant VanB-type strains have been reported. Surveillance cul- have been caused partially by the fact that heavy environmen-
tures for VRE are time-consuming and expensive for the lab- tal contamination did not occur during the study period. Fur-
oratory to perform. Recently, it has been reported that PCR ther studies are needed to establish the circumstances in which
may be a cost-effective alternative to surveillance cultures for routine use of gowns by personnel provides additional protec-
VRE in some hospitals (226). However, in using the alterna- tion against the spread of VRE.
tive, the laboratory may lose the ability to perform strain- In addition to these isolation precautions, the use of non-
typing studies with the organisms in their institutions (226). critical items such as stethoscopes, sphygmomanometers, or
It is important to establish whether the emergence of VRE rectal thermometers should be dedicated to a single patient or
in a hospital has been caused by the spread of a single strain or cohort of patients infected or colonized with VRE (164). If
by the simultaneous appearance of several different clones, such devices are to be used on other patients, they should first
because this can affect the control measures that may be given be adequately cleaned and disinfected (251). Culture of stools
priority (32). Since most strains of VRE are resistant to mul- or rectal swabs of roommates of patients newly found to be
tiple drugs, antimicrobial susceptibility patterns lack discrimi- infected or colonized with VRE must be performed to deter-
natory power. A variety of molecular typing methods have mine the colonization status and to see whether isolation pre-
been used to establish the degree of clonal relatedness of cautions are necessary. Additional screening of patients on the
VRE, including ribotyping, plasmid analysis, PFGE, arbitrarily ward can be performed at the discretion of the infection con-
primed PCR, and examination of hybridization patterns ob- trol staff. A policy deciding when patients infected and/or col-
tained with probes, such as insertion sequences (IS6770) or onized with VRE can be removed from isolation precautions
vanA and vanB gene probes (16, 19, 30, 51, 69, 104, 164, 167). should be adopted. The optimal requirements remain un-
A combination of genotypic methods such as PFGE plus plas- known. However, since VRE colonization may persist indefi-
mid analysis is likely to yield the most accurate information nitely, stringent criteria may be appropriate, e.g., VRE-
about the number of strains present in an institution and the negative cultures on at least three consecutive occasions, 1
patterns of transmission (51, 167). week or more apart, for all cultures from multiple body sites
Implementation of infection control measures. The current (including stool, rectal swab, perineal area, axilla or umbilicus,
isolation precautions recommended by HICPAC to prevent and wound, Foley catheter, and/or colostomy sites if present)
patient-to-patient transmission of VRE are as follows. (121). A system of highlighting the records of infected or col-
onized patients should be established so that they can be rec-
(i) Place VRE-infected or -colonized patients in single ognized and placed on isolation precautions promptly upon
rooms or in the same room as other patients with VRE (30). readmission to the hospital, because patients with VRE may
(ii) Wear clean nonsterile gloves when entering the room of remain colonized for long periods following discharge from the
a VRE-infected or -colonized patient (30, 137, 164). During hospital. Ideally, this information should be computerized so
the course of caring for a patient, a change of gloves may be that placement of colonized patients will not be delayed due to
necessary after contact with material that may contain high unavailability of the patients’ medical records. Local and state
concentrations of VRE (e.g., stool). health departments should be consulted in developing a plan
for the discharge of VRE-infected or colonized patients to optimal (89, 151, 181, 235). Accordingly, hospitals that expe-
nursing homes, other hospitals, or home health care as part of rience difficulties in controlling the nosocomial transmission of
a larger strategy for handling patients with resolving infections VRE should consider developing systems for monitoring and
and patients colonized with antimicrobial-resistant microor- improving the compliance of personnel with recommended
ganisms. barrier precautions.
The HICPAC has some additional recommendations for Control of VRE in long-term-care facilities. There are a few
hospitals with endemic VRE or continued VRE transmission studies indicating that colonized residents of LTCFs may serve
despite the implementation of measures (44). These are as as a reservoir for acute-care hospitals (27, 35; Elizaga et al.,
follows. Abstract; Quale et al., Abstract; Revuelta et al., Abstract; Sar-
gent et al., Abstract). These studies suggest that VRE may not
(i) Control efforts should initially be focused in ICUs and on be a frequent cause of infection in residents of LTCFs (58).
areas where the VRE transmission rate is highest (121). Such The cost of control measures that are recommended for acute
units may serve as a reservoir for VRE, from which VRE care may be prohibitive in LTCFs, and these measures are
spreads to other wards when patients are well enough to be impractical for use in LTCFs. VRE have not yet been reported
transferred. to be a cause of serious illness in LTCF patients. It is known
(ii) Where feasible, staff who provide regular care to pa- that highly compromised patients are potential candidates for

tients should be cohorted to minimize the movement of health serious VRE infection. This is not likely to be true of the vast
care givers between VRE-positive and VRE-negative patients. majority of LTCF residents. Based on these observations, The
(iii) In conjunction with careful epidemiologic studies and Society for Healthcare Epidemiology of America Committee
upon the direction of the infection control staff, personnel on Long-Term Care decided to develop a position document
should be examined for chronic skin and nail problems. Hand about VRE in LTCFs. This document was recently published
and rectal swab cultures should be performed on specimens (58).
obtained from them. VRE-positive personnel epidemiologi- The Committee believes that patients who are infected or
cally linked to VRE transmission should be removed from the colonized with VRE may be cared for safely in an LTCF with
care of VRE-negative patients until their carrier state has been minimal risk of development of nosocomial infection in other
eradicated. patients and that the task of carrier identification and proper
(iv) The results of several enterococcal outbreak investiga- isolation probably is borne most appropriately by acute-care
tions suggest a potential role for the environment in the trans- institutions (58). According to the recommendations of the
mission of enterococci (30, 164, 267). Institutions experiencing Committee, the general approach to the control of VRE in
ongoing VRE transmission should verify that the hospital has LTCFs is summarized as follows (58).
adequate procedures for the routine care, cleaning, and disin-
fection of environmental surfaces (e.g., bedrails, charts, carts, (i) Employee education about basic infection control and
doorknobs, faucet handles, and bedside commodes) and that VRE is essential to any effort to control these organisms.
these procedures are being followed by housekeeping person- (ii) If an outbreak of infection appears to be under way,
nel. Some hospitals may elect to perform focused environmen- surveillance cultures of swabs of the rectum or perirectal area
tal cultures before and after cleaning rooms housing patients and wounds for VRE may be appropriate. Otherwise, they are
with VRE to verify the efficacy of hospital policies and proce- unlikely to be cost-effective and are not recommended.
dures. All environmental culturing should be approved and (iii) When a patient infected or colonized with VRE is
supervised by the infection control program in collaboration transferred from an LTCF to an acute-care facility, this infor-
with the clinical laboratory (30, 164, 267). mation should be provided to the receiving institution.
(v) Representative VRE isolates should be sent to refer- (iv) As an initial recommendation, the Committee advises
ence laboratories for strain typing by PFGE or other suitable continuing VRE isolation until at least two rectal cultures (or
techniques to aid in defining reservoirs and patterns of trans- wound cultures) taken on separate days are found to be neg-
mission. ative for the organism.
(v) If possible, patients infected or colonized with VRE
Some hospitals have been slow to implement the new should be placed in private rooms. If the patient must share a
HICPAC recommendations for isolation of patients with VRE room, a roommate colonized with the same organism is pre-
and continue to use more traditional isolation systems such as ferred. If there is no private room available, a patient with
“contact isolation” (initially described in 1983) or “body sub- VRE (who is continent of stool, does not have diarrhea, and
stance isolation” (106). Unfortunately, a number VRE out- does not have an open wound infected or colonized with VRE)
breaks have continued despite the use of these policies (30, can be placed in the same room with another patient. Although
137, 177, 181, 224, 247). Therefore, hospitals that have not no data are available, it would be appropriate that the other
already implemented barrier precautions recommended by patient not be severely immunocompromised (i.e., not have
HICPAC should strongly consider doing so. had organ transplantation, not be neutropenic, not be suffering
Strict implementation of infection control measures has con- from severe acute or chronic illness, and not have been treated
tributed to the control of VRE outbreaks (29, 209). Other recently with multiple or broad-spectrum antibiotics), not have
authors have been less impressed with the value of contact open wounds, not be receiving antibiotics, and not have an
precautions in reducing the rates of VRE acquisition in insti- indwelling catheter or other drainage device. Similar precau-
tutions where VRE colonization is endemic (145, 176, 181, tions would be appropriate if an infected or colonized patient
255). Even skeptics agree, however, that rates might have been must share a bathroom with another patient. Careful hand-
increased further in the absence of infection control efforts. washing is necessary, and caring for the noncolonized room-
Unfortunately, breaches in infection control protocols occur mate before contact with the VRE-colonized patient or his
commonly. In one study, breaks in protocol were noted in 72% environment would be appropriate.
of monitored patient interactions (30). A number of other (vi) Gloves (clean and nonsterile) are required before con-
studies have demonstrated that compliance of health care tact with a colonized or infected patient, his or her secretions,
workers with recommended barrier precautions is often sub- and inanimate environment within the room. Gloves should be
changed after contact with materials that have a high concen- onized patients, and (iii) to reduce the reservoir of VRE in the
tration of microorganisms (e.g., stool) and before contact with institutional environment.
the roommate or his or her immediate environment. Hands Combinations of novobiocin with doxycycline or tetracycline
should be washed with an antiseptic agent containing chlor- failed to eradicate VRE from the stools of seven of eight
hexidine or alcohol after the gloves are removed. treated patients (178). Two groups reported more promising
(vii) Gowns are required if it is expected that the health care results with oral bacitracin. In one study, treatment cleared
worker’s clothing will have material contact with the patient, VRE from stools in six of eight patients, with one relapse; in
patient’s secretions, or environmental surfaces. Gowns are es- the other study, bacitracin cleared VRE in eight of eight pa-
pecially important if a patient has diarrhea or a wound with tients, with two recurrences (47, 197). In another study, how-
drainage not contained in a dressing. Care must be taken to ever, while combination therapy with bacitracin plus doxy-
avoid environmental contact by clothing after the gown is re- cycline initially cleared VRE from the stools of all treated
moved. Gowns must be disposed of in a way that will minimize patients, with longer follow-up only 33% remained free of
contamination of the environment. detectable VRE, a proportion comparable to that in an un-
(viii) Patient transport should be limited to situations re- treated control group (M. R. Weinstein, J. Brunton, I. Camp-
quired for medical care, and precautions must be continued, to bell, et al., Program Abstr. 36th Intersci. Conf. Antimicrob.
prevent transmission to other patients and to prevent contam- Agents Chemother., abstr. J10, 1996). Although some patients

ination of environmental surfaces. Room restrictions probably appear to have responded to these attempts at decolonization,
are appropriate only for patients with wound drainage not no regimen has been uniformly effective in eradicating VRE
contained in a dressing or for those who are incontinent or who from the gastrointestinal tract (32). Determination of whether
have diarrhea. VRE can be eradicated from the gastrointestinal tract by an-
(ix) Patient care equipment should, if possible, be dedicated timicrobial chemotherapy will require prolonged observation
to a single patient. If this is impossible, appropriate cleaning and use of enrichment techniques, or possibly even glycopep-
and disinfection should be done between patients. The use of tide challenge, to detect low densities of VRE remaining in the
individual thermometers is strongly encouraged. Areas that the stool before any regimen can be considered effective.
patient may contaminate (e.g., bedrails, bedside tables, com-
modes, soap dispensers, faucets, door handles, etc.) should be TREATMENT
cleaned frequently (at least daily) with an appropriate disin-
fectant. Serious enterococcal infections (e.g., bacteremia and endo-
(x) Recommendations for prudent vancomycin use should carditis) require treatment with a bactericidal combination of
be followed. antibiotics that should include a penicillin (e.g., ampicillin or
penicillin G) to which the Enterococcus isolate is susceptible
Surveillance cultures. Performing special surveillance cul- and an aminoglycoside (e.g., gentamicin or streptomycin) to
tures of patients to detect gastrointestinal colonization not which the Enterococcus isolate does not exhibit high-level re-
identified by clinical cultures has often proved useful during sistance (127). Vancomycin in combination with an aminogly-
outbreaks and should be considered an essential component of coside has demonstrated synergistic activity against entero-
successful VRE control programs (29, 30, 44, 71, 137, 164, 181, cocci both in vitro and in vivo (256), and it is recommended as
247). Failure to perform periodic prevalence surveys may re- the drug of choice in patients with serious penicillin allergy or
sult in poor control of VRE in hospitals. Prevalence surveys in the treatment of ampicillin- and penicillin-resistant strains
may be limited (culturing samples only from roommates of of bacteria (127). However, enterococci are becoming increas-
known VRE cases) or more comprehensive (culturing samples ingly resistant to traditional antibiotic therapy. In addition to
from all patients on a ward in which a newly discovered case high-level aminoglycoside resistance and ampicillin resistance,
has occurred or obtaining periodic samples for culture from rapid spread of vancomycin resistance has resulted in limited
high-risk patients such as those in ICUs, hematology-oncology therapeutic alternatives (182, 185).
wards, or transplantation units) (9, 29, 144, 189). During out- Treatment of infections due to VRE, especially E. faecium,
breaks, more comprehensive studies are desirable. Other strat- is extremely problematic, because these organisms are resistant
egies to identify colonized patients include screening stool to multiple antibiotics. Penicillin or ampicillin with or without
specimens submitted for C. difficile toxin assays for VRE and a synergizing aminoglycoside would be a reasonable choice in
screening rectal or perirectal swab specimens obtained from the nonallergic patient infected with vancomycin-resistant E.
patients admitted from high-risk institutions (hospitals and faecalis. Almost all E. faecalis strains are at least moderately
LTCFs in which VRE are endemic). Perirectal cultures seem susceptible to ampicillin. Therefore, if vancomycin resistance
to have a sensitivity similar to rectal cultures for detecting emerged predominantly in E. faecalis, the treatment of most of
colonized individuals (253). these infections could be relatively easy. Unfortunately, van-
Surveillance cultures of stool, rectal, or perirectal specimens comycin resistance has preferentially appeared in E. faecium,
should be inoculated onto selective media containing vanco- which is inherently more resistant to penicillin and ampicillin.
mycin (64, 121, 135, 181, 247, 253). Although brain heart in- However, it should be remembered that many E. faecium
fusion agar plates containing vancomycin are useful for con- strains are only moderately resistant to ampicillin. Routine
firming vancomycin resistance when testing isolated colonies of testing by the clinical laboratory will classify an E. faecium
enterococci, they are not appropriate for screening stool spec- strain as ampicillin resistant if it is able to grow in 16 ␮g of
imens for VRE, because they support the growth of many ampicillin per ml. Higher concentrations are not routinely
other organisms. tested. However, if the organism can be inhibited by 32 ␮g of
Attempts to eradicate gastrointestinal colonization. There ampicillin per ml, it may be worthwhile to use ampicillin, since
has been interest in eradication of gastrointestinal colonization it should be possible to exceed this concentration severalfold in
with VRE for the following reasons (80): (i) to decrease the vivo with high doses (186). Therefore, when faced with an
subsequent risk of infection in the individual patient, (ii) to infection by a strain of E. faecium that is resistant to both
minimize inconvenience to the patient and costs to the hospital ampicillin and vancomycin, it would be appropriate to ask the
associated with infection control procedures applicable to col- laboratory to perform additional susceptibility tests to deter-
mine the MIC of ampicillin. While the level of resistance at sistant. However, Hayden et al. described the in vivo develop-
which no benefit will be derived has not been established, ment of teicoplanin resistance in a VanB E. faecium isolate
based on the half-life and peak drug levels, it will likely be (126). This finding has raised concern about this treatment
difficult to exceed a concentration of ⱖ128 ␮g/ml of ampicillin option and has limited the therapeutic efficacy of this agent.
in serum for a protracted period (186). Strains for which the A number of new approaches to the treatment of VRE
ampicillin MICs are ⬎100 ␮g/ml are now common, and this infections including ␤-lactam–␤-lactam, ␤-lactam–glycopep-
concentration is close to the limit of concentrations achievable tide, and ␤-lactam–fluoroquinolone combinations have been
in the serum. Mekonen et al. described the failure of ampicillin explored in experimental animal models (34, 42, 265). Each
at a total dose of 20 g/day (mean level in serum, 103 ␮g/ml) approach has limitations. The combination of a glycopeptide
combined with gentamicin to clear VRE bacteremia in a liver and a ␤-lactam is an interesting one whose use derives from the
transplant patient. Substitution of ampicillin-sulbactam at 30 observation that some strains of E. faecium, although resistant
g/day (equivalent to 20 g of ampicillin; mean ampicillin level in to ampicillin and vancomycin, are still inhibited by the combi-
serum, 130 ␮g/ml) led to clearing of the bacteremia (168). The nation of the two. For such strains, the MIC of ampicillin
authors attributed this success to the slightly better activity of decreases in the presence of vancomycin. This is possibly be-
ampicillin combined with sulbactam compared with that of cause the cell, in order to use the vancomycin-induced D-Ala–
ampicillin alone against the clinical isolate of E. faecium (MIC, D-Lac-containing precursor, must shift to using a different cell

32 and 64 ␮g/ml, respectively). In this case, ␤-lactamase pro- wall synthesis enzyme (high-molecular-weight PBPs as de-
duction was not an issue. It is known that some strains are scribed above). If this enzyme is more easily inhibited by am-
approximately one dilution more susceptible to ampicillin picillin, the MIC of ampicillin would decrease (186). The lab-
when tested in the combination (80). However, it seems doubt- oratory can predict which strains will show this interaction by
ful whether this approach would have predictable utility in comparing the results of ampicillin disk susceptibility using
general. If the infecting VRE is highly resistant to ampicillin, agar plates with and without vancomycin or by determining the
there are few treatment options and one should ask the labo- susceptibility to ampicillin using broth with and without van-
ratory to test various other antimicrobials including tetracy- comycin. Unfortunately, many ampicillin-resistant, vancomy-
clines, erythromycin, chloramphenicol, high levels of amino- cin-resistant E. faecium strains do not show this phenomenon;
glycosides, rifampin, fluoroquinolones, novobiocin, and, for even with those that do, subpopulations resistant to the com-
urinary tract infection, nitrofurantoin (186). When enterococci bination usually exist and can be preferentially selected after
have high-level resistance to both gentamicin and streptomy- exposure to the combination (186). The combination of ceftri-
cin, no regimen currently available is likely to produce a reli- axone, vancomycin, and gentamicin was reported to be signif-
able bactericidal effect. Inconsistent results have been reported icantly more effective than either penicillin-vancomycin-genta-
with high-dose ampicillin alone, vancomycin, teicoplanin, or micin or penicillin-teicoplanin-gentamicin in the treatment of
ciprofloxacin, either alone or in combination with a penicillin experimental penicillin- and glycopeptide-resistant E. faecium
or daptomycin (76, 127, 246). Currently, it is not known what endocarditis (42). The authors postulated that ceftriaxone,
constitutes the best therapy for enterococcal endocarditis due which is normally ineffective against enterococci, must have
to strains with high-level resistance to all aminoglycosides. A some affinity for PBPs that become essential due to the induc-
reasonable approach would be continuous infusion of a high tion of glycopeptide resistance. In all these cases, the strains
dose of ampicillin, probably for longer than the usual 6 weeks expressed low-level aminoglycoside resistance; similar results
(73, 183). Valvular replacement may play a role in treating may not be obtained with strains exhibiting high-level amino-
relapsing or intractable disease (93). Treatment options for glycoside resistance, since the addition of an aminoglycoside
multiple-drug-resistant enterococci are extremely limited, and remains necessary for bacteriocidal activity. Other investiga-
agents to which they may appear susceptible are at best bac- tors did not obtain synergy with these regimens, leading to the
teristatic, of unproven efficacy, or associated with toxicity conclusion that the phenomenon is strain dependent (45, 98,
(200). Thus, optimal therapy for these patients remains un- 118). Combinations involving double ␤-lactams have also been
known. examined, and the combination of ampicillin and imipenem
Chloramphenicol is one of the few agents that retains in appeared to have a positive interaction in an experimental
vitro activity against many strains of multiple-drug-resistant E. model of endocarditis in rabbits (34).
faecium. This agent has been used with limited (no reduction in Ciprofloxacin and other quinolones introduced in the same
mortality) or modest success in the treatment of VRE infec- period (ofloxacin, norfloxacin, and enoxacin) have only modest
tions (200, 201). This was illustrated in a retrospective review activity against enterococci. A bactericidal effect is inoculum
of 16 patients with serious VRE infections (e.g., bacteremias dependent and may be seen only at concentrations unattain-
and abscesses) who were treated with chloramphenicol at a able systemically in clinical use (92, 222). Effectively, their use
university teaching institution (194). All the isolates were re- is limited to the treatment of urinary tract infections (183, 185).
sistant to several antibiotics but were susceptible to chloram- In a rat model of endocarditis, synergy with ciprofloxacin plus
phenicol. Although 8 of 14 evaluable patients had some clinical either gentamicin or rifampin or both was shown in vitro and
response, 3 were classified as microbiological failures despite in vivo against strains of vancomycin-resistant E. faecium lack-
achieving drug levels in serum in the therapeutic range. One ing resistance to each antibiotic. Triple therapy (ciprofloxacin-
death was attributed to overwhelming sepsis due to VRE. The rifampin-gentamicin) was the most effective at sterilizing vege-
specific contribution of chloramphenicol to patient outcome tations (257). Although ciprofloxacin in high persistent
could not be determined, since the response rate to therapy concentrations may be effective in treating enterococcal endo-
was confounded by numerous medical problems and multiple carditis in the rat model, concentrations attainable in serum in
concomitant antimicrobials and interventions (e.g., drainage humans have not yielded satisfactory results (73, 76, 92). In
and debridement). time-kill studies using strains of E. faecium with high-level
Teicoplanin is another glycopeptide that is active in vitro resistance to ampicillin, vancomycin, and aminoglycosides, the
against most VanB-type enterococci. It has shown some effi- combination of ampicillin at 40 ␮g/ml plus ciprofloxacin at 3
cacy in animal models of endocarditis when combined with an ␮g/ml was bactericidal for all strains with ciprofloxacin MIC of
aminoglycoside to which the infecting strain is not highly re- 8 ␮g/ml or below. Unfortunately, regimens containing lower
concentrations of either antibiotic alone were not effective groups, quinupristin-dalfopristin therapy was associated with a
(150). significantly lower incidence of vancomycin-resistant E. fae-
Newer fluoroquinolone antibiotics with greater activity cium-associated mortality. On the other hand, frank clinical
against gram-positive bacteria have been created (207), and failure was seen in five quinupristin-dalfopristin-treated pa-
while enterococci remain among the least susceptible gram- tients. One failure occurred in a patient with refractory neu-
positive bacteria (with E. faecium in general being less suscep- tropenia following drug-induced bone marrow suppression.
tible than E. faecalis), some compounds at 1 ␮g/ml or less The lack of bactericidal activity of quinupristin-dalfopristin
inhibit 90% of strains (207). Clinafloxacin is the most active may compromise its clinical and bacteriological efficacy in neu-
agent against enterococci among these new fluoroquinolones. tropenia and other conditions where bactericidal activity is
The combination of ampicillin at 20 ␮g/ml with clinafloxacin at required for eradication (174). However, satisfactory outcomes
1 ␮g/ml also had bactericidal activity against similar strains have been reported in other challenging clinical conditions.
when the drugs were present in serum at concentrations that Quinupristin-dalfopristin therapy achieved microbiological
are easily attainable (38). and clinical cure in a patient with vancomycin-resistant E.
Novobiocin is an older DNA gyrase inhibitor with gram- faecium prosthetic valve endocarditis, in an 8-month-old infant
positive activity. Clinical application of novobiocin was aban- with ventriculitis due to a vancomycin-resistant E. faecium-
doned due to the emergence of resistance in staphylococci and infected central nervous system shunt and in three cases of

the availability of newer, less toxic agents (200). In vitro data vancomycin-resistant E. faecium peritonitis due to peritoneal
suggest that novobiocin is very active against VanA- or VanB- dialysis catheter-associated infection (166, 187; W. B. Furlong
type vancomycin-resistant E. faecium strains, even if these and F. Bompart, Program Abstr. 34th Intersci. Conf. Antimi-
strains are concomittantly resistant to penicillin and ampicillin crob. Agents Chemother., abstr. M66, 1994). Superinfection
(103). Novobiocin plus ciprofloxacin was found to be effective with E. faecalis has been observed during therapy of E. faecium
in a rabbit model of endocarditis (211). The combination of infection with this agent (49). De novo resistance to quinupris-
fluoroquinolones with novobiocin has also been investigated in tin-dalfopristin among E. faecium strains has been reported
other studies (103, 150, 211). Novobiocin was not bactericidal previously (55), and the rise in MICs of quinupristin-dalfopris-
alone; however, upon addition of a fluoroquinolone, the com- tin to 1 to 2 ␮g/ml in the study by Linden et al. raises the
bination was additive and bactericidal. The use of novobiocin possibility that frank resistance to quinupristin-dalfopristin
combined with ciprofloxacin has been reported, with high re- could develop in some strains. An increase in the MIC of the
lapse rates occurring after treatment (161). Resistance to quin- drug associated with relapse after therapy has also been ob-
olones, which is now common, would render such combina- served (50, 161).
tions ineffective because of the expected rapid emergence of There has been a considerable effort to develop alternative
resistance to novobiocin when used as a single agent. Nitro- agents in the same group, either as totally new compounds or
furantoin is active against many isolates of VRE and might be as modifications of vancomycin or teicoplanin. Daptomycin
an alternative for the treatment of urinary tract infections (LY146032), an acidic lipopeptide, gave promising results in
caused by VRE. vitro. Its MICs were low in most investigations (26, 48, 170,
Treatment of multidrug-resistant enterococci that are resis- 234), with strains of all species of Enterococcus being inhibited
tant to penicillin, aminoglycosides, and glycopeptides is exper- by 8 ␮g/ml and MICs at which 90% of isolates were inhibited
imental at best (41, 128; B. M. Willey, D. Degani, and A. (MIC90s) being recorded up to 4 ␮g/ml; glycopeptide-resistant
McGreer, Program Abstr. 33rd Intersci. Conf. Antimicrob. E. faecium strains were included (25, 166). The inoculum effect
Agents Chemother., abstr. 119, 1993). Currently, no prospec- was small, the agent was effectively bactericidal alone (unlike
tive studies evaluating the efficacy of alternative drug regimens teicoplanin and vancomycin) (25, 261), and there was no cross-
in infected patients have been published, although numerous resistance with vancomycin and teicoplanin. Addition of serum
investigators have studied various drugs and combinations to the medium impaired the in vitro activity (25, 157, 170, 240).
both in vitro and in animal models. Dalfopristin-quinupristin Variable but quite encouraging results were obtained in animal
(RP 59500) is a streptogramin antibiotic that has been studied models. Although daptomycin was well tolerated, the early
in the treatment of infections due to vancomycin-resistant E. results in clinical trials were disappointing; the drug was inef-
faecium. It has bacteristatic activity against strains of this spe- fective for the treatment of staphylococcal septicemia (108).
cies but is inactive against E. faecalis. It does not exhibit cross- This may have been the result of the very high (⬎90%) plasma
resistance with any existing antibiotics (131, 250). In vitro stud- protein binding, and a higher dosage might have provided
ies have demonstrated increased activity of RP 59500 when effective therapy (148, 220). Unfortunately, higher-dosage reg-
combined with vancomycin against MRSA (136). However, no imens were associated with toxicity in humans, and the drug
synergy was found against VRE when the drug was combined was withdrawn in 1990 (18).
with ampicillin, ciprofloxacin, gentamicin, rifampin, streptomy- Ramoplanin, a lipoglycodepsipeptide, is even more active.
cin, teicoplanin, or vancomycin (L. B. Rice and L. L. Carias, In all investigations, all strains of all species, including vanco-
Program Abstr. 34th Intersci. Conf. Antimicrob. Agents Che- mycin-resistant E. faecalis and E. faecium, were inhibited by 8
mother., abstr. E100, 1994). RP 59500 was first made available ␮g/ml and the MIC90s (in all but one study) ranged from ⱕ0.25
for use under an investigator-sponsored investigational new- to 1.6 ␮g/ml (18, 54, 132, 170, 234). Ramoplanin is also bac-
drug program for treatment of patients with life-threatening tericidal for enterococci, with the MBCs being only fourfold
infection due to vancomycin-resistant E. faecium (194). It is the higher than the MICs (132). Ramoplanin inhibits cell wall
first antibiotic approved for the treatment of patients with synthesis by acting at the level of lipid-intermediate formation,
serious or life-threatening infections associated with vancomy- whereas vancomycin and daptomycin interfere with pepti-
cin-resistant E. faecium bacteremia. In a recent review, Linden doglycan synthesis by preventing transglycosylation (223). Ad-
et al. compared the clinical and bacteriological outcomes of 20 dition of human serum results in fourfold increase in the MIC.
patients with vancomycin-resistant E. faecium bacteremia In preliminary studies, ramoplanin has been poorly tolerated
treated with RP 59500 with a historical cohort of 42 patients following intravenous or intramuscular injection, and it seems
with VRE bacteremia treated with other agents (162). They unsuitable for systemic use because of its toxicity; however, it
found that despite the high overall mortality rates in both is being developed for topical use (261). It has been suggested
that ramoplanin could be used for the clearance of glycopep- planin, LY264826, and other glycopeptides with increased
tide-resistant enterococci from the gastrointestinal tract (132), antienterococcal activity (39, 190, 191, 224, 236, 264). Some of
and it might well be used to eradicate C. difficile without a risk them are not bactericidal, some show cross-resistance with
of colonization by glycopeptide-resistant enterococci (22). teicoplanin- and vancomycin-resistant strains, and they are still
One of the most active agents against VRE is a semisyn- at early stages of development. It is clear that before this group
thetic glycopeptide designated LY333328, which demonstrates of antimicrobial agents can offer new treatment possibilities for
bactericidal as well as bacteristatic activity against enterococci these infections, further work is needed to produce a satisfac-
(229). LY333328 is an investigational N-alkyl semisynthetic tory bactericidal glycopeptide that is effective and nontoxic in
derivative of the naturally occurring glycopeptide LY264826 systemic use and lacks cross-resistance with vancomycin and
(56). Its mechanism of action is still unknown but is thought to teicoplanin (91).
be similar to that of vancomycin. The primary mechanism Other investigational agents with activity in vitro against
appears to be the inhibition of cell wall synthesis and assembly VRE include glycylcyclines, oxazolidinones, and ketolides.
by complexing with the D-alanyl–D-alanine precursor. It might Some isolates of VRE are susceptible to tetracyclines. Doxy-
also impair RNA synthesis (90, 171). Several studies have cycline and minocycline have been used in the treatment of
shown that LY 333328 exhibits bactericidal activity against VRE infections, often with other agents. While successes have
VRE (202; S. Zelenitsky, J. Karlowsky, D. Hoban, et al., Pro- been described, it is difficult to assess their overall effectiveness

gram Abstr. 36th Intersci. Conf. Antimicrob. Agents Che- (47, 176). The high rate of tetracycline resistance, especially
mother., abstr. F200, 1996). The reported MIC90s for different among clinically important gram-positive cocci, has limited its
strains of MRSA and VRE (VanA and VanB strains) are ⱕ1 effectiveness (77, 239). Tetracycline derivatives known as gly-
␮g/ml. Overall, LY333328 has been reported to exhibit a cylcyclines have excellent activity against enterococci includ-
higher rate of killing and a higher concentration-dependent ing multidrug-resistant strains. The glycylcyclines CL329,998
killing effect against both staphylococci and enterococci (M. S. (DMG-MINO) and CL331,002 (DMG-DMDOT) are N,N-
Barret, M. E. Erwin, and R. N. Jones, Program Abstr. 36th dimethylglycylamido derivatives of 9-aminominocycline and
Intersci. Conf. Antimicrob. Agents Chemother., abstr. F203, 9-amino-6-demethyl-6-deoxytetracycline, respectively. These
1996; S. Donabedian, M. B. Perri, L. A. Thal, and M. J. Zervos, compounds were developed to overcome the three types of
Program Abstr. 36th Intersci. Conf. Antimicrob. Agents Che- resistance mechanisms exhibited by many clinically important
mother., abstr. F204, 1996; Zelenitsky et al., 36th ICAAC). bacteria and to restore a broader range of activity to the tet-
Concentration-dependent killing is a unique finding, since it racycline class. DMG-MINO and DMG-DMDOT show excel-
has not been previously reported for glycopeptides (13, 90, lent activity against strains resistant to tetracycline due to a
169). This effect is significant, because LY333328 is affected by ribosomal protection mechanism and to the production of ef-
proteins and inoculum and so a slight increase in drug concen- flux pumps (245). Thus, modification at position 9 overcomes
tration can easily compensate for these effects. The lack of data two distinct resistance mechanisms. These drugs show activity
regarding the pharmacokinetics in humans and the toxicity of against most enterococcal strains, including those resistant to
LY333328 creates uncertainties about whether it is possible to parent drugs or to other antimicrobial agents (74). Their ac-
achieve the desired concentrations in humans that would com- tivity remains bacteristatic. Preclinical toxicological studies
pensate for the inoculum effect and protein binding without have shown qualitatively similar profiles to those noted with
causing serious side effects (169). Such a problem has been minocycline and tetracycline (243). If they are effective clini-
described in the past with daptomycin. The excellent inhibitory cally, the glycylcyclines will be important drugs for the treat-
and bactericidal activities of LY333328 suggest that it could be ment of infections caused by resistant gram-positive bacteria,
a clinically useful alternative for the treatment of severe infec- but they are still a long way from being marketed (99, 243).
tions caused by gram-positive pathogens (including VRE), par- Ketolides are a new class of macrolide derivatives with good
ticularly those resistant or not fully susceptible to the available gram-positive activity (C. Agouridas, Y. Beneditti, A. Bonne-
glycopeptides (23). In preliminary in vivo studies, LY333328 foy, et al., Program Abstr. 3rd Int. Conf. Macrolides Azalides
has been reported to have a considerable advantage over van- Streptogramins, abstr. F14.10, 1996; C. Agouridas, A. Bonne-
comycin in terms of its pharmacokinetics, with apparently a foy, and J. F. Chantot, Program Abstr. 35th Intersci. Conf.
much longer half-life in rats (Y. Lin, R. E. Stratford, L. L. Antimicrob. Agents Chemother., abstr. F158, 1995). Instead of
Zornes et al., Program Abstr. 35th Intersci. Conf. Antimicrob. the cladinose moiety, these agents have a 2-keto structure,
Agents Chemother., abstr. F254, 1995). In two recent studies, which appears to increase their stability in a weakly acidic
it was found that the postantibiotic effect for LY333328 was environment (Agouridas et al., 3rd Int. Conf.). Their mecha-
prolonged (18.7 h at 10 times the MIC and 7.4 ⫾ 2.2 h at 10 nism of action is similar to that of macrolides or macrolide-
times the MBC) (14; A. Novelli, T. Mazzei, S. Fallani, et al., lincosamide-streptogramin compounds, which consists of bind-
Program Abstr. 37th Intersci. Conf. Antimicrob. Agents Che- ing to the 50S ribosomal subunit and inhibition of bacterial
mother., abstr. F-16, p. 148, 1997). In one of these studies, it protein synthesis (C. Agouridas, A. Bonnefoy, K. Braham, et
was also shown that the presence of ampicillin (10 times the al., Program Abstr. 35th Intersci. Conf. Antimicrob. Agents
MIC) increased the PAE to 23 h and that ampicillin, quini- Chemother., abstr. F175, 1995). They also penetrate well into
pristin-dalfopristin, and gentamicin exhibited bacteriostatic phagocytes (C. Agouridas, P. Coletto, P. Mauvais, and J. F.
synergy with LY333328 (14). However, 50% serum decreased Chantot, Program Abstr. 35th Intersci. Conf. Antimicrob.
the postantibiotic effect by 30 to 50%. These data also indicate Agents Chemother., abstr. F170, 1995). Ketolides show in vitro
the persistence of the effect of LY333328 for many hours and activity against multidrug-resistant gram-positive organisms,
therefore the possibility that therapy may require infrequent including staphylococci, enterococci and pneumococci (L. M.
dosing. Ednie, S. K. Spaangler, M. R. Jacobs, and P. C. Appelbaum,
Other peptide antimicrobial agents have been investigated Program Abstr. 3rd Int. Conf. Macrolides Azalides Strepto-
for activity against enterococci. Derivatives of vancomycin may gramins, abstr. F3.19, 1996; A. Fremaux, G. Sissia, J. F. Chan-
show increased activity against enterococci, including glyco- tot, and P. Geslin, Program Abstr. 35th Intersci. Conf. Anti-
peptide-resistant strains (191), but development of these com- microb. Agents Chemother., abstr. F160, 1995). RU-64004 is a
pounds is at an early stage. There are also derivatives of teico- novel ketolide. For vancomycin-resistant E. faecium strains,
the potential spectrum of RP 59500 was found to be equal or related elements in the absence of induction. J. Bacteriol. 179:97–106.
superior to that of RU-64004 (130; Ednie et al., 3rd Int. Conf.; 9. Arthur, M., F. Depardieu, C. Molinas, P. Reynolds, and P. Courvalin. 1995.
The vanZ gene of Tn1546 from Enterococcus BM4147 confers resistance to
Fremaux et al., 35th ICAAC). In vivo studies with animal teicoplanin. Gene 154:87–92.
models have shown quite promising results, especially against 10. Arthur, M., F. Depardieu, P. Reynolds, and P. Courvalin. 1996. Quantita-
infections caused by macrolide-resistant strains of gram-positive analysis of the metabolism of soluble cytoplasmic peptidoglycan pre-
tive bacteria, although there are at present few data on their cursors of glycopeptide resistance enterococci. Mol. Microbiol. 21:33–44.
11. Arthur, M., C. Molinas, F. Depardieu, and P. Courvalin. 1993. Character-
antienterococcal activity (Agouridas et al., 35th ICAAC, abstr. ization of Tn1546, a Tn3-related transposon conferring glycopeptide resis-
F158). Results with another ketolide, RU-66647, are similar to tance by synthesis of depsipeptide peptidoglycan precursors in Enterococcus
earlier data reported for RU-64004 (130; Agouridas et al., 3rd faecium BM4147. J. Bacteriol. 175:117–127.
Int. Conf.; Agouridas et al., 35th ICAAC, abstr. F175 and 12. Arthur, M., C. Molinas, S. Dutka-Malen, and P. Courvalin. 1991. Structural
relationship between the vancomycin resistance protein VanH and 2-hy-
F170; H. Dabernat, M. Seguy, and C. Delmas, Program Abstr. droxycarboxylic acid dehydrogenases. Gene 103:133–134.
35th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 13. Bailey, E. M., M. J. Rybak, and G. W. Kaatz. 1991. Comparative effect of
F161, 1995; Ednie et al., 3rd Int. Conf.; R. Fabre, J. D. Cavallo, protein binding on the killing activities of teicoplanin and vancomycin.
J. C. Chapalain, and M. Meyron, Program Abstr. 35th Intersci. Antimicrob. Agents. Chemother. 35:1089–1092.
14. Baltch, A., R. P. Smith, and L. H. Bopp. 1998. Comparison of inhibitory and
Conf. Antimicrob. Agents Chemother., abstr. F164, 1995; bactericidal activities and postantibiotic effects of LY333328 and ampicillin
Fremaux et al., 35th ICAAC).

used singly and in combination against vancomycin-resistant Enterococcus
The oxazolidinones are a new class of synthetic antibiotics faecium. Antimicrob. Agents Chemother. 42:2564–2568.
with good antienterococcal activity and are different from any 15. Baptista, M., F. Depardieu, P. Courvalin, and M. Arthur. 1996. Specificity
of induction of glycopeptide resistance genes in Enterococcus faecalis. An-
other class (75). The mechanism of activity demonstrated has timicrob. Agents Chemother. 40:2291–2295.
been the inhibition of protein synthesis leading to a bacteri- 16. Barbier, N., P. Saulnier, E. Chachaty, S. Dumontier, and A. Andremont.
static effect against most species (62). The oxazolidinones in- 1996. Random amplified polymorphic DNA typing versus pulsed-field gel
hibit bacterial translocation at the initiation of protein synthe- electrophoresis for epidemiological typing of vancomycin-resistant entero-
cocci. J. Clin. Microbiol. 34:1096–1099.
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Mechanisms of resistance that affect antibiotics in current clin- In vitro activity of vancomycin, teicoplanin, daptomycin, MDL 62873 and
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linezolid are two investigational oxazolidinone agents which reservoir for vancomycin-resistant enterococcal infection in man. Antimi-
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Rifampin alone has very limited usefulness in the treatment ramoplanin and four glycopeptide antibiotics against clinical isolates of
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Vancomycin-Resistant Enterococci

Yesim Cetinkaya, Pamela Falk and C. Glen Mayhall

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INTRODUCTION designations such as faecalis, faecium, durans, and so forth

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TABLE 2. Characteristics of phenotypes of glycopeptide-resistant enterococcia

Vancomycin MIC (␮g/ml) 64–⬎1,000 4–1,024 2–32 128 16

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TABLE 4. Measures for reducing nosocomial transmission of VREa

Reduce excessive use of antibiotics Strongly Strongly recommended Strongly recommended

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