Resistance Mechanisms, Epidemiology, and Approaches to Screeningfor Vancomycin-Resistant Enterococcus in the Health Care Setting

Matthew L. Faron,a Nathan A. Ledeboer,a,b Blake W. Buchana,b

Medical College of Wisconsin, Milwaukee, Wisconsin, USAa; Wisconsin Diagnostic Laboratories, Milwaukee, Wisconsin, USAb

Infections attributable to vancomycin-resistant Enterococcus (VRE) strains have become increasingly prevalent over the pastdecade. Prompt identification of colonized patients combined with effective multifaceted infection control practices can reducethe transmission of VRE and aid in the prevention of hospital-acquired infections (HAIs). Increasingly, the clinical microbiologylaboratory is being asked to support infection control efforts through the early identification of potential patient or environmen-tal reservoirs. This review discusses the factors that contribute to the rise of VRE as an important health care-associated patho-gen, the utility of laboratory screening and various infection control strategies, and the available laboratory methods to identifyVRE in clinical specimens.

Hospital-acquired infections (HAIs) are a serious threat forpatient care and carry a significant cost to hospitals, since

treatment of these infections is no longer reimbursable. In addi-tion, regulations requiring hospitals to report HAIs creates furtherpressure to reduce incidence rates. Screening patients at admis-sion for methicillin-resistant Staphylococcus aureus (MRSA) hasbeen a successful approach in reducing MRSA HAIs in somehealth care systems and may be a successful strategy for control-ling other health care-associated pathogens, including Clostrid-ium difficile, carbapenem-resistant Enterobacteriaceae (CRE), andvancomycin-resistant Enterococcus (VRE) (1). However, there isdebate about the optimal approach to screening and infectioncontrol, which may differ between pathogens of interest.

Members of the genus Enterococcus are well-documentedpathogens associated with various clinical manifestations, includ-ing bacteremia, infective endocarditis, intra-abdominal and pelvicinfections, urinary tract infections, and, in rare cases, central ner-vous system infections (2–4). Infection with vancomycin-resis-tant Enterococcus is associated with an increased mortality rate,illustrated by a 2.5-fold increase in mortality for patients sufferingfrom VRE bacteremia (5). Vancomycin resistance in Enterococcusspp. has been increasing in prevalence since it was first encoun-tered in 1986 (6, 7). Currently, 30% of Enterococcus species isolatesfrom the United States are vancomycin resistant, and infectionwith these organisms causes an estimated 1,300 deaths each year(8). The majority of VRE are associated with the species E. faecium(77%) and E. faecalis (9%), with the remaining 14% of isolatesrepresenting species less frequently implicated in serious infec-tions, including E. gallinarum, E. casseliflavus, E. avium, and E.raffinosus (8).

The optimal approach to reducing VRE infections is multifac-torial, requiring antimicrobial stewardship to reduce the selectionof VRE in colonized patients, appropriate infection control prac-tices to reduce transmission, and reliable sensitive laboratorymethods for the detection of VRE in a timely manner.

ANTIMICROBIAL RESISTANCE MECHANISMS ANDAPPROACHES TO THERAPY

Understanding the mechanism behind resistance is essential toreducing empirical antibiotic therapies that select resistant patho-gens. Elimination of normal gut flora by commonly used broad-

spectrum antibiotics (vancomycin, cephalosporins, and metroni-dazole) encourages the selective proliferation of VRE (9). Thisincreases the likelihood of resulting infections with these bacteriaor leaves patients more susceptible to colonization by resistantstrains encountered in the environment or health care setting.Treatment of infections due to Enterococcus spp. can be challeng-ing, since enterococci are intrinsically resistant to several classes ofantibiotics, including �-lactams and aminoglycosides, and can ac-quire resistance to other classes, including quinolones, tetracy-clines, and glycopeptides (e.g., vancomycin). Resistance to glyco-peptides may be encoded chromosomally or extrachromosomallyon plasmids. Often, these genes are located within transposons orother mobile elements, which can serve as a reservoir for the trans-mission of resistance to other organisms (10). The choice of ther-apy for infections due to Enterococcus spp. depends largely on thesite of infection (e.g., urinary versus nonurinary) and the antimi-crobial susceptibility profile of the isolate. In some scenarios, suchas infective endocarditis, multiple antibiotics may be used toachieve a synergistic effect. This may include antibiotics to whichthe organism is considered intrinsically resistant, such as genta-micin or ceftriaxone, when used singly (11). Therefore, combina-tion therapy requires an understanding of the intrinsic and ac-quired resistance mechanisms that contribute to therapy successor failure.

Aminoglycoside resistance. Enterococcus spp. may demon-strate moderate-level (MIC, 62 to 500 �g/ml) or high-level (MIC,�2,000 �g/ml) resistance (HLR) to aminoglycosides (12). Mod-erate resistance is conferred by an intrinsic mechanism attributedto low permeability of the cell wall to the large aminoglycosidemolecules (13). A study including 2,507 E. faecalis and 469 E.faecium isolates from clinical specimens in France found the prev-

Accepted manuscript posted online 4 May 2016

Citation Faron ML, Ledeboer NA, Buchan BW. 2016. Resistance mechanisms,epidemiology, and approaches to screening for vancomycin-resistantEnterococcus in the health care setting. J Clin Microbiol 54:2436 –2447.doi:10.1128/JCM.00211-16.

Editor: C. S. Kraft, Emory University

Address correspondence to Blake W. Buchan, bbuchan@mcw.edu.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

crossmark

2436 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

alence of moderate resistance to be 8.9% and 49.2%, respectively(14). HLR to aminoglycosides is mediated through modificationof the ribosomal attachment sites or the production of aminogly-coside-modifying enzymes (12). Both mechanisms are encodedby specific genes and are typically plasmid borne. The prevalenceof HLR to aminoglycosides can vary from 40 to 68% among En-terococcus species isolates, depending on geographical location,and differs between E. faecalis and E. faecium (15, 16). Intrinsicresistance may be overcome using a combination treatment with a�-lactam and an aminoglycoside, also referred to as a synergytherapy approach. Synergy therapy is based on the principle that�-lactams will disrupt the cell wall, thereby facilitating increasedcellular penetration by the aminoglycoside to reach a concentra-tion sufficient for the inhibition of protein synthesis. This ap-proach is effective in treating infections caused by organisms withmoderate-level resistance to aminoglycosides; however, synergy islost in strains with HLR to aminoglycosides, because the increasein intracellular aminoglycoside concentration cannot overcomethe presence of specific aminoglycoside-modifying enzymes.Therefore, accurate differentiation between the moderate-levelresistance (MLR) and HLR phenotypes is important when consid-ering synergistic antibiotic therapies for serious infections (17).Laboratories can determine HLR by performing a high-level ami-noglycoside test according to the CLSI guidelines.

�-Lactam resistance. Intrinsic resistance to �-lactams ismaintained in enterococci through the overproduction of penicil-lin binding proteins (PBPs) with low binding affinity for �-lac-tams, most notably PBP 4 and PBP 5 (18–21). The level of resis-tance differs between E. faecalis and E. faecium, with E. faecalisbeing 10- to 100-fold less susceptible to penicillin than strepto-cocci and E. faecium being at least 4- to 16-fold less susceptiblethan E. faecalis (22). Despite reduced susceptibility to penicillin,the majority of E. faecalis isolates (�99%) remain susceptible toampicillin, while �20% of E. faecium isolates demonstrate ampi-cillin susceptibility (23). Importantly, neither penicillin nor ampi-cillin susceptibility is indicative of susceptibility to cephalosporins.For patients who are aminoglycoside intolerant, combination treat-ment with ampicillin and ceftriaxone was observed to be as effec-tive as ampicillin and gentamicin in treating VRE with the genta-micin HLR phenotype (24). These therapies are most useful intreating severe infections, such as endocarditis and meningitis(25).

Glycopeptide resistance. Glycoproteins are bactericidal drugsthat function by binding to the terminal D-Ala-D-Ala in the pen-tapeptide portion of the N-acetylglucosamine (NAG)–N-acetyl-muramic acid (NAM) peptidoglycan (PG) cell wall precursor (Fig.1). Binding blocks transpeptide linkage of cell wall components,resulting in reduced integrity and, ultimately, cell death. Resis-tance to glycopeptides in Enterococcus spp. is mediated by the van-comycin resistance (Van) operon. This operon may be carriedchromosomally or extrachromosomally on a plasmid. The Vanoperon consists of vanS-vanR, a response regulator; vanH, a D-lac-tate dehydrogenase gene, vanX, a D-Ala-D-Ala dipeptidase gene;and a variable ligase in which 9 variant genes have been identified(vanA, vanB, vanC, vanD, vanE, vanG, vanL, vanM, and vanN)(26). Expression is inducible by the two-component systemVanS/R, which senses disruptions in the cellular membranecaused by glycopeptides, as well as cell wall damage caused bybacitracin or polymyxin B (27). The variable ligase gene is centralin determining the level of vancomycin resistance (low, medium,

or high), with the most commonly identified genes being vanA,vanB, and vanC. VanA is plasmid borne, confers high-level resis-tance (MIC, �256 �g/ml) to vancomycin, and is most commonlyassociated with E. faecium and E. faecalis, while chromosomallyencoded VanC confers low-level resistance (MIC, 8 to 32 �g/ml)to vancomycin and is almost exclusively found in E. gallinarum, E.casseliflavus, and E. flavescens (11).

VanA resistance. Enterococcus spp. carrying vanA are highlyresistant to glycopeptides and are the dominant VRE variants of E.faecium and E. faecalis globally. Resistance is mediated by substi-tuting the high-affinity terminal D-Ala-D-Ala peptide on NAMsubunits with D-Ala-D-Lac. This amino acid substitution causes a1,000-fold decrease in the affinity of the pentapeptide for vanco-mycin (Fig. 1) (11). Incorporation of NAM subunits containingthe substituted D-Ala-D-Lac peptide into the peptidoglycan layerrequires PBPs other than PBP 4 and PBP 5. In the presence ofvancomycin, these alternative PBPs become the dominant pro-teins for cell wall synthesis. The alternative PBPs used during thepresence of vancomycin have enhanced binding to �-lactams,which when used together can allow synergistic treatment (28).VanA-expressing strains are also resistant to the glycopeptide tei-coplanin (Te) due to the presence of an additional gene present onthe vanA operon, vanZ, which confers resistance by an unknownmechanism (29).

VanB resistance. Isolates carrying vanB are less prevalent thanvanA-carrying strains but can be found throughout the world andare commonly identified in Australia, where the majority of E.faecium VRE isolates carry vanB (30, 31). As with to vanA, resis-tance in vanB is mediated by converting D-Ala-D-Ala to D-Ala-D-Lac (11). However, vanB confers varied resistance to vancomycin,ranging from moderate- to high-level resistance (MIC range, 4 to�256 �g/ml) (11). The mechanism for the lower-level resistancecompared to that of vanA is not well defined but is likely the resultof a lower proportion of D-Ala-D-Lac substitution in the cell wallof strains carrying vanB. Resistance to vancomycin is proportionalto the percent composition of D-Ala-D-Lac to D-Ala-D-Ala (32).Smaller amounts of D-Ala-D-Lac incorporation might result fromreduced expression of the vanB operon, a reduction in VanX orVanB enzymatic activity, or a combination of minor mechanisticchanges. Te resistance is not observed in vanB-carrying isolates, asvanZ is not encoded in this operon.

Risk of vancomycin resistance transmission to other patho-gens. Vancomycin is one of the few antibiotics that can be used totreat infections resulting from Gram-positive multidrug-resistantorganisms (MDRO), such as MRSA; therefore, transmission ofvancomycin resistance from enterococci to MRSA is of major con-cern. Horizontal gene transfer has been shown to be a mechanismof transmission between enterococci, and in vitro studies havedemonstrated that transfer between Enterococcus and S. aureus canoccur (33). In 2002, the first case of vancomycin-resistant S. au-reus (VRSA) was isolated from a 40-year-old diabetic patient un-dergoing dialysis and was obtained from a dialysis catheter cul-tured from both the exit site and catheter tip. A week later, theVRSA isolate was isolated from a diabetic foot ulcer. MIC testingand DNA sequence analysis conducted by the CDC confirmed theisolate as VRSA (34). To date, 14 cases of VRSA have been re-ported in the United States; however, the presumably frequentinteraction between VRE and MRSA (cocultured, with the twoorganisms recovered from the same source) and rare incidence ofVRSA isolation suggest that in vivo transfer of vancomycin resis-

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2437Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

tance between these species occurs at an extremely low frequency(35). If a laboratory expects a potential VRSA isolate (vancomycinMIC, �16 �g/ml), local infection control at the hospital should benotified of the possible result, and the laboratory should workwith local and state departments of public health to have the iso-late tested for confirmation.

Horizontal gene transfer of the van operon between Enterococ-cus spp. and other organisms also appears to occur at a very lowfrequency. In a study that performed mating experiments betweenEnterococcus species and Gram-positive gut flora (Lactococcus spp.and Bifidobacterium spp.), no transfer of vanA between genera wasobserved (36). Interestingly, the authors observed that interspe-cies transmission within the Enterococcus genus, e.g., E. faecium toE. faecalis, occurred at a much lower frequency (1/108 per donor/

recipient) than intraspecies transmission (1/106 per donor/recip-ient). This may explain the higher prevalence of vanA within E.faecium isolates, as transmission occurs between E. faecium iso-lates, but not between E. faecium and other Enterococcus species, athigh frequencies. Infection control and antimicrobial stewardshipprograms that aim to reduce acquisition (i.e., colonization and/orinfection) of VRE and MRSA infections may aid in reducing thepossible transmission of glycopeptide resistance to S. aureus byminimizing coinfection with VRE and MRSA.

ENTEROCOCCUS SPP. IN THE HEALTH CARE SETTINGEpidemiology. Enterococcus spp. are normal colonizers of the hu-man gastrointestinal (GI) tract but can be recovered from the skin,genitourinary (GU) tract, and the oral cavity. Surveillance studies

FIG 1 Vancomycin acts by binding to D-Ala-D-Ala pentapeptides blocking cell wall biosynthesis. Resistance to vancomycin is conferred by the van operon, whichconsists of a two-component regulatory system (vanS-vanR) that responds to either vancomycin, disruption at the cell membrane, or both. Detection of stimulusthen activates downstream genes vanH, vanA or vanB and vanX. VanX is a D,D-dipeptidase that cleaves D-Ala-D-Ala repeats, both depleting the pool ofD-Ala-D-Ala and supplying the bacteria with a free D-Ala for Van(A/B). VanH is a D-hydroxyacid dehydrogenase that reduces pyruvate to D-Lac for the ligaseVan(A/B). Van(A/B) then ligates D-Ala-D-Lac, allowing for the production of D-Ala-D-Lac pentapeptides that have low affinity for vancomycin. In addition,VanY is a D,D-carboxypeptidase that cleaves the D-Ala terminal peptide to further reduce pools of pentapeptides that have high affinity to vancomycin. Finally,VanZ, which is present on vanA-carrying strains, confers modest resistance to teicoplanin through an unknown mechanism. Differences in the level of resistanceare likely a result of pentapeptide composition, as the ratio between pentapeptides consisting of high affinity to low affinity to vancomycin correlate with theisolate MICs. High-level resistance (HLR) occurs when pentapeptides are mostly composed of low-affinity molecules, and moderate-level resistance (MLR)involves more-heterogeneous pools of high- and low-affinity pentapeptides.

Minireview

2438 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

conducted by the European Antimicrobial Resistance SurveillanceSystem and National Healthcare Safety Network (NHSN) reportvaried rates of colonization, depending on geographical locationand immune status of the patient population. Generally speaking,colonization rates for inpatients range from as low as �2% inFinland to as high as 34% in Ireland and 33% in intensive care unit(ICU) patients in the United States (37). Asymptomatic coloniza-tion is typically transient but can persist from months to years;decolonization is not recommended, since it can contribute to theaccelerated development of resistance (38). Colonized patients area potential risk to health care facilities, serving as a source of fortransmission via shedding of VRE into the surrounding environ-ment and onto health care workers (11, 39).

Hospital rooms housing patients infected or colonized withVRE are quickly contaminated and can also serve as a reservoir fortransmission. Environmental sampling studies have isolated VREfrom most surfaces found in rooms that previously housed in-fected patients, such as patient gowns, bedside rails, floors, door-knobs, and blood pressure cuffs (12). Enterococcus has been shownto persist for as long as 4 months on surfaces, and in a clinicalsetting, VRE was shown to persist through an average of 2.8 stan-dard room cleanings, thereby acting as a continual source for pos-sible transmission (40, 41). Recent studies involving environmen-tal surveillance suggest that admission to a room previouslyoccupied by a patient with VRE infection was associated with asignificant increased risk for VRE acquisition by subsequent pa-tients (hazard ratio, 4.4) (42).

Health care workers may also serve as vectors for the transmis-sion of VRE between patients in different rooms or wards. With-out proper hand hygiene, VRE can persist for up to 60 min on ahealth care worker (HCW)’s skin (11). Once hands are contami-nated, hand hygiene plays a major role in reducing transmissionrates; however, compliance is generally low. In a systematic reviewfrom 2010 to 2014 of several hand hygiene intervention studies, itwas found that compliance ranged from 23 to 69% (43). Further-more, it is important to educate HCWs about the possibility ofcontact with environmental services to ensure understanding thathand contamination can occur without specific contact with thepatient, and precaution should be applied even in the absence ofpatient interaction.

APPROACHES TO SCREENING AND IMPACT FOR CONTROLOF VRE

Both the CDC and the Society for Healthcare Epidemiology ofAmerica (SHEA) have released guidelines that recommend activescreening of patients for VRE colonization in hospitals and long-term-care facilities (44–46); however, many hospitals have notincorporated these recommendations. This is likely the result oflimited evidence from outcome studies demonstrating significantbenefit from laboratory screening for VRE and a lack of evidencesuggesting which patients should be screened to maximize thecost-to-benefit ratio. Accumulating evidence highlights severalspecific risk factors that can be used to determine which patientsare at highest risk and may benefit from screening efforts. The riskfactors include length of hospital stay, recent or current use ofantibiotics, patients whom are immunosuppressed, patients withprior hospital visits, and patients transferred from long-term-carefacilities (47).

Passive or active screening. Guidelines to control MDRO bythe CDC recommend that all hospitals adopt active rather than

passive screening approaches. In the case of VRE, passive screen-ing refers to the detection of VRE from clinical specimens submit-ted for routine culture (i.e., not specifically submitted for detec-tion of VRE). Patients are only isolated after laboratory detection(culture or molecular) or if previously positive for VRE on a prioradmission. Because the ratio of VRE-infected to -colonized pa-tients is 1:10, a passive screening approach may not adequatelyidentify a sufficient proportion of colonized patients to effectivelyreduce VRE transmission (12). Modeling of screening strategiesusing data from a 10-bed ICU at the University of Maryland Med-ical Center estimated that passive screening would reduce VREinfection by only 4.2% compared with no screening or isolationpractices (48).

Active screening is less well defined but can include the collec-tion of specimens specifically for VRE screening or screening ofstools collected for other purposes (e.g., for C. difficile testing).There are no specific recommended practices, but studies report-ing on the utility of screening often include testing upon hospitaladmission for patients with specific risk factors (e.g., those whoare immunosuppressed or have a history of broad-spectrum anti-biotic usage) and patients received from long-term-care facilities.Additionally, continued periodic screening 1 to 2 times a weekduring hospital admission and a screen at discharge may be em-ployed. In hospitals that do not perform specific screening forVRE colonization, reflex testing of C. difficile specimens for VREcan help determine the relative prevalence of VRE colonization ina patient population and can aid in early detection of outbreaks(49). Routine screening of patients at admission is effective inhospital settings with higher prevalence, but the cost of intensivescreening may not be justified in hospitals with a low prevalence ofVRE or in hospitals without high-risk patient populations. Imple-mentation of active screening for all ICU patients at admissionmay reduce VRE infections by up to 39% compared with noscreening (48). Another approach to reducing the spread of VREwithin the hospital setting is to cohort patients by VRE coloniza-tion status, as determined by laboratory screening result, and ded-icate specific HCWs to each cohort. This method may be difficult tocoordinate, requires adequate hospital beds for cohorting, and islikely not practical for the majority of hospitals; however, reducedHCW contact between colonized and noncolonized patients has thepotential to reduce the spread of VRE in the hospital (50).

Outcome studies of active screening. Estimating the real-world effect and benefits gained by implementation of routinescreening strategies can be difficult, and clinical outcome studiesare not without limitations. A lack of proper case controls or im-plementation of multiple variables at one time to provide optimalpatient care may obscure the independent contribution of anysingle screening or infection control measure. In addition, resultsmay be dependent upon site-specific factors, such as organismprevalence and compliance of HCWs, which vary from facility tofacility. Further, infection control practices often differ betweenstudies, and the materials and methods may not be adequate togenerate optimal comparisons across studies. A summary of sev-eral studies that performed analyses of active screening is pre-sented in Table 1.

Several studies have shown that active surveillance of stool orrectal swabs has a positive effect in reducing the burden of VREand related infections in hospitals. A retrospective comparisonbetween two urban hospitals in the United States demonstrated a2.1-fold lower rate of VRE bacteremia in the hospital performing

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2439Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

TA

BLE

1Su

mm

ary

ofst

udi

esob

serv

ing

the

clin

ical

impa

ctan

dco

stof

acti

veV

RE

scre

enin

g

Sett

ing/

regi

on(r

efer

ence

)E

xper

imen

tald

esig

n

Spec

imen

type

/det

ecti

onm

eth

od(n

)St

udy

inte

rven

tion

Res

ult

sC

ost

anal

ysis

Com

men

ts

30fa

cilit

ies

inSi

ouxl

and

regi

on,

USA

( 78)

Com

pari

son

ofpr

eval

ence

ofpr

e-/

post

impl

emen

tati

onst

rate

gy

Per

ian

alsw

abpl

ated

tobi

lees

culin

agar

(3,7

74)

Scre

enin

gon

adm

issi

on,

coh

orti

ng

pati

ents

,ba

rrie

rpr

ecau

tion

s,ed

uca

tion

,an

dh

and

hyg

ien

e

Pre

vale

nce

ofco

lon

izat

ion

redu

ced

from

2.2%

to0.

5%

NA

aR

equ

ired

colla

bora

tion

of32

hea

lth

care

faci

litie

s,in

clu

din

gbo

thac

ute

-car

ean

dlo

ng-

term

-car

efa

cilit

ies,

alon

gw

ith

mu

ltip

leim

plem

enta

tion

stra

tegi

es65

0-be

dh

ospi

tal,

NY

,USA

( 56)

Com

pari

son

ofV

RE

BSI

rate

san

dco

stan

alys

isP

eria

nal

swab

sin

ocu

late

dto

En

tero

cocc

osel

brot

h

15-c

ompo

nen

tin

fect

ion

con

trol

targ

etin

gle

uke

mia

,lym

phom

a,an

dso

lid-t

um

orpa

tien

ts

Con

trol

stra

tegi

esre

duce

dra

tes

ofV

RE

BSI

from

2.1

pati

ents

to0.

45pa

tien

ts/1

,000

days

Cos

tof

stra

tegy

for

1/yr

tota

led

$116

,515

,w

ith

anes

tim

ated

stu

dyn

etsa

vin

gsof

$189

,318

;cos

tbe

nefi

cial

for

faci

litie

sth

ath

ave

6–9

VR

EB

SIpe

ryr

Cos

tan

alys

isba

sed

onle

ngt

hof

stay

betw

een

tim

epe

riod

s,w

hic

hco

uld

infl

ate

savi

ngs

;h

owev

er,a

con

serv

ativ

ees

tim

ate

of13

.7da

ysst

ayfo

rV

RE

BSI

(19

inot

her

stu

dies

)m

ayu

nde

rest

imat

eco

stof

VR

EB

SI2

un

iver

sity

hos

pita

ls,

Ch

arlo

ttes

ville

,VA

,USA

( 77)

Com

pari

son

oftw

ore

gion

alh

ospi

tals

wh

ere

scre

enin

gw

asim

plem

ente

dat

1of

2h

ospi

tals

Per

irec

tal

swab

s/cu

ltu

re(u

nkn

own

agar

)(1

0,40

0)

Wee

kly

scre

enin

gof

inpa

tien

tsde

emed

hig

hri

sk

193

(0.3

8%)

cult

ure

posi

tive

wit

h1

VR

EB

SIco

mpa

red

to29

VR

EB

SIat

aco

mpa

riso

nh

ospi

talt

hat

does

not

scre

en

Cos

tof

scre

enw

as$2

53,0

99;e

stim

ated

cost

of29

VR

EB

SIw

as$7

61,3

20

Com

pari

son

betw

een

2di

ffer

ent

regi

onal

hos

pita

ls,s

ofa

ctor

s,su

chas

staf

fco

mpe

ten

cyan

din

fect

ion

con

trol

proc

edu

res,

may

affe

ctre

sult

s2,

700-

bed

hos

pita

ls,C

hic

ago,

IL,U

SA( 5

1)R

etro

spec

tive

stu

dyco

mpa

rin

gV

RE

BSI

rate

sbe

twee

na

hos

pita

lth

atsc

reen

sco

mpa

red

ton

onsc

reen

ing

hos

pita

l

Rec

tals

wab

spl

ated

tose

lect

ive

med

ium

Wee

kly

rect

alsw

abs

inh

igh

-ris

ku

nit

sR

ate

ofV

RE

BSI

was

2.1-

fold

hig

her

inh

ospi

tal

that

does

not

scre

en;4

clon

esw

ere

resp

onsi

ble

for

�75

%of

VR

EB

SIat

hos

pita

lth

atdo

esn

otsc

reen

vs4

clon

esco

nsi

stin

gof

37%

ofal

lin

fect

ion

sat

scre

enin

gh

ospi

tal

NA

Com

pari

son

betw

een

2di

ffer

ent

regi

onal

hos

pita

ls,s

ofa

ctor

s,su

chas

staf

fco

mpe

ten

cyan

din

fect

ion

con

trol

proc

edu

res,

may

affe

ctre

sult

s;re

tros

pect

ive

stu

dy

19-b

edIC

U,S

t.Lo

uis

,MO

,U

SA( 5

5)C

ompa

red

dete

ctio

nra

tefr

omac

tive

scre

enin

gof

ICU

pati

ents

vssc

reen

ing

ofC

.dif

ficile

stoo

ls

Rec

tals

wab

s/cu

ltu

re(u

nkn

own

agar

)(1

,872

)

Swab

colle

cted

atad

mis

sion

,dis

char

ge,

and

ever

y7

days

280

dete

ctio

ns

atad

mis

sion

wit

hac

tive

scre

enin

gco

mpa

red

to25

pati

ents

dete

cted

byC

.dif

ficile

test

ing,

3of

wh

ich

wer

en

otde

tect

edby

swab

scre

enin

g

Act

ive

scre

enin

gco

stw

as$1

,913

/mo;

esti

mat

edco

stof

HA

colo

niz

atio

nof

$3,0

65–$

9,97

0pe

rpa

tien

t;es

tim

ated

cost

ofV

RE

BSI

was

$17,

143–

$36,

380

apa

tien

t

Rat

eof

VR

Eco

lon

izat

ion

was

not

dete

rmin

ed,a

nd

savi

ngs

wer

eba

sed

ontr

ansm

issi

ondy

nam

ic

Minireview

2440 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

ICU

s,U

SA(5

4)C

lust

erra

ndo

miz

edtr

ial

com

pari

ng

ICU

sw

ith

and

wit

hou

tco

nta

ctpr

ecau

tion

saf

ter

posi

tive

scre

en

Rec

talo

rst

ools

ampl

ew

ith

in2

days

ofad

mis

sion

enri

ched

inbi

lees

culin

azid

ebr

oth

and

plat

edto

bile

escu

linag

ar(9

,139

)

Con

tact

and

expa

nde

dba

rrie

rpr

ecau

tion

sim

plem

ente

daf

ter

posi

tive

cult

ure

un

til

disc

har

ge

No

sign

ifica

nt

diff

eren

cew

asob

serv

edbe

twee

nin

terv

enti

onan

dco

ntr

olIC

Us

for

inci

den

cera

tes

ofco

lon

izat

ion

orin

fect

ion

NA

Del

ayin

resu

lts

assw

abs

wer

esh

ippe

dto

are

fere

nce

site

;m

onit

orin

gob

serv

edle

ss-t

han

-ide

alco

mpl

ian

cein

barr

ier

prot

ecti

onu

sed

byH

CW

s,es

peci

ally

wh

enin

tera

ctin

gw

ith

envi

ron

men

tK

yoto

Japa

n( 5

2)C

ompa

riso

nof

pre-

and

post

con

trol

prog

ram

for

VR

Eou

tbre

ak

Stoo

lspe

cim

ens

colle

cted

for

any

reas

onan

dac

tive

surv

eilla

nce

for

tran

sfer

/sel

ecti

veV

RE

agar

Adh

ered

togu

idel

ines

that

con

sist

edof

good

han

dh

ygie

ne,

good

barr

ier

prot

ecti

on,

and

adm

issi

onsc

reen

ing

Init

iali

ncr

ease

from

0.71

%de

tect

ion

to1.

2%de

tect

ion

but

then

fell

to0.

17%

afte

r4

yrof

inte

rven

tion

NA

An

nu

alsu

rvei

llan

cew

aslik

ely

inad

equ

ate,

asde

tect

ion

was

incr

ease

daf

ter

guid

elin

esw

ere

impl

emen

ted

St.L

ouis

,MO

,USA

( 49)

Com

pari

son

ofdi

scon

tin

uat

ion

ofre

flex

ing

stoo

lssu

bmit

ted

for

C.

diffi

cile

test

ing

No

scre

enin

gR

emov

alof

scre

enin

gas

acl

inic

alpr

acti

ceV

RE

BSI

incr

ease

dfr

om2.

1to

3.6

per

10,0

00pa

tien

t-da

ys

Yea

rly

cost

ofsc

reen

ing

and

isol

atio

npr

oced

ure

sw

as$1

16,7

08co

mpa

red

toes

tim

ated

cost

of$1

39,2

86fo

rth

e14

extr

aV

RE

BSI

No

eval

uat

ion

sof

pati

ent

popu

lati

ons

wer

epe

rfor

med

tode

term

ine

ifth

ere

wer

em

ore

at-r

isk

pati

ents

inei

ther

pre-

orpo

stdi

scon

tin

uat

ion

13E

uro

pean

ICU

s( 7

9)C

ompa

red

3ph

ases

con

sist

ing

ofba

selin

e,u

niv

ersa

lch

lorh

exid

ine

was

hin

g,an

dsc

reen

ing

ofpa

tien

ts

Rec

tals

wab

sw

ere

plat

edto

chro

mog

enic

agar

wit

hin

2da

ysof

adm

issi

onan

dth

en2�

aw

eek

(14,

390)

Han

dh

ygie

ne

and

chlo

rhex

idin

ecl

ean

ing

and

con

tact

prec

auti

ons

for

posi

tive

scre

ens

Ch

lorh

exid

ine

was

hin

gsre

duce

dM

RSA

but

not

VR

Eac

quis

itio

n;n

odi

ffer

ence

sin

MD

RO

BSI

inal

lth

ree

phas

es

NA

Han

dh

ygie

ne

rose

from

52%

to69

%an

d77

%in

phas

es2

and

3,re

spec

tive

ly;

chlo

rhex

idin

ew

ash

ing

was

still

perf

orm

edin

phas

e3

Sin

gapo

re,C

hin

a( 5

3)C

ompa

repr

e-an

dpo

stin

terv

enti

onof

aV

RE

bun

dle

prog

ram

Not

desc

ribe

d,bu

tP

CR

con

firm

edva

nAan

dva

nB

VR

Ebu

ndl

ebR

edu

ctio

nin

VR

Ede

tect

ion

from

1.5/

1,00

0to

0.5/

1,00

0

NA

6%ca

ses

occu

rred

wit

hin

firs

t48

hof

hos

pita

lizat

ion

;bu

ndl

eim

plem

enta

tion

mak

esit

diffi

cult

toas

sess

wh

ich

impl

emen

tati

onw

asm

ost

ben

efici

ala

NA

,not

appl

icab

le.

bB

un

dle

incl

ude

dac

tive

surv

eilla

nce

,en

han

ced

prec

auti

ons

sign

age,

auto

mat

edsy

stem

for

VR

Eid

enti

fica

tion

ofkn

own

carr

iers

onad

mis

sion

,hyg

ien

eed

uca

tion

,hyd

roge

npe

roxi

deva

por

(HP

V)

clea

nin

gof

disc

har

ged

VR

Epa

tien

ts,

chan

gein

blea

chcl

ean

ing

solu

tion

,an

dcl

ean

ing

audi

ts.

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2441Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

weekly active surveillance on all inpatients (51). Strain typing of allbloodstream infection (BSI) isolates revealed that 4 clones wereresponsible for more than 75% of all Enterococcus species BSI atthe hospital that did not actively screen for VRE, compared to 37%at the hospital with active screening. These data suggest that hos-pital transmission may be significantly more frequent at hospitalsthat are unaware of patient colonization status. Similarly, imple-mentation of routine screening of stool specimens coupled withhand hygiene and barrier protection for positive patients (in ac-cordance with 2003 SHEA guidelines) reduced the rate of patientcolonization by more than 80% (1.2% versus 0.17%) in just 3years (52). A comparable reduction in VRE colonization wasachieved by combining active screening and hand hygiene withtracking of previous carriers and environmental cleaning of colo-nized patients’ rooms after discharge (53). Following implemen-tation of this bundle strategy, the rate of VRE detection reducedfrom 1.5 to 0.5 per 1,000 admissions.

Counter to studies demonstrating measureable benefit, thereare also reports in the literature that suggest that active screeningof patients does not reduce the prevalence of VRE in a health caresetting. One cluster randomized trial included multiple hospitalICUs across the United States. Screening for VRE was on all ad-missions, and ICUs were randomly assigned to one of two groups,(i) an intervention group (n � 10), which was given the result ofscreening and implemented barrier precautions for positive pa-tients; or (ii) a control group (n � 8), which was blinded to thescreening result and so no intervention was implemented (54).After adjustment for baseline characteristics, the incidence of col-onization was not significantly different between the interventionand control groups (40.4 3.3 and 35.6 3.7, respectively, P �0.35). Unfortunately, this study had several limiting factors, in-cluding a 3-day delay between the collection of specimens andreporting of results. This delay may reduce the impact of interven-tional practices, since VRE transmission from colonized patientsmay have occurred in the 3 days prior to the implementation ofbarrier precautions. In addition, adherence to barrier precautionswas monitored and found to be suboptimal, with a median of 77to 82% of HCWs using gloves or gowns, and only 69% compliancewith hand hygiene after contact with colonized patients. Com-bined, these factors may have contributed to decreasing the po-tential impact of screening and infection control efforts. Impor-tantly, this highlights the real-world difficulty in implementing aneffective screening and infection control program and under-scores the fact that laboratory screening alone is insufficient tosignificantly impact the rate of HAIs.

Cost analysis of active screening. Active screening for VREcan carry a substantial monetary burden for the laboratory, in-cluding the cost of materials and labor, that may be difficult topredict prior to implementation. The total cost of screening isdependent upon several factors, including the patient populationthat is screened (hospital wide versus select ICU populations), themethod of screening (culture based versus molecular) and otherfactors, including the potential for automation. One laboratorysupporting a 19-bed ICU performing rectal swabs on all patientsat admission, weekly during hospital stay, and at discharge deter-mined that the active screening cost to their laboratory was $30.66per patient or $22,956 per year ($29,570 in 2015 using the Con-sumer Price Index), inclusive of labor, laboratory supplies for cul-ture, specimen collection supplies, and processing costs (55). Im-plementation of additional infection control practices based on a

positive screen result increases the overall cost to the hospital aswell. In one study, this cost was estimated at $116,515 ($224/pa-tient) annually for additional infection control measures in a 22-bed adult oncology unit (56). However, implementation of thisprogram resulted in a net savings of $189,318 annually ($294,433in 2015), based on a reduction in VRE BSI from 2.1/1,000 patient-days to 0.45/1,000 patient-days (estimated $123,081), reducedVRE colonization (estimated $2,755), and reductions in antimi-crobial use (estimated $179,997). Compared with the previousreports, active screening alone is cost-effective if it reduces 1 to 2VRE BSI events a year, whereas larger infection control programsmay need to prevent multiple infections a year to be cost-effective.Long-term costs of specialized chromogenic VRE screening mediacan be offset if the laboratory adopts automated systems that canplate, incubate, and analyze media by reducing the cost of tech-nologists’ time (57).

LABORATORY CONSIDERATIONS FOR VRE SCREENINGOptimal specimen collection. When screening patients for a spe-cific pathogen, it is essential that the optimal specimen is collectedto achieve maximum sensitivity. The CDC recommends screeningfor VRE using either rectal swabs or stool specimens. The use ofstool specimens submitted to the laboratory for C. difficile detec-tion provides a noninvasive specimen and targets patients withfactors that also predispose them to a higher VRE colonizationrate. In one study, stools submitted for C. difficile testing had aVRE positivity rate of 10.4%, compared with 9.7% positivity forrectal swabs collected from high-risk (e.g., bone marrow and solidorgan transplant and surgical ICU) patients based on culture us-ing selective media (58). Other studies suggest that stool speci-mens may be superior to rectal swab specimens for recovery ofVRE. A direct comparison of paired stool specimens and rectalswabs cultured using Enterococcosel agar (BD, Franklin Lakes,NJ) demonstrated a sensitivity of only 58% for rectal swab speci-mens compared to stool specimens (59). Enrollment for this studywas low (n � 35 positive specimens), but additional dilution ex-periments found that rectal swabs collected from patients with�4.5 log10 CFU of VRE/g of stool were unlikely to be detected byplating to selective media. Although potentially more sensitive,the clinical significance of these findings is unknown, since therehave been no studies establishing the relative risk of transmissionby patients harboring lower concentrations of VRE.

Culture-based screening methods. Laboratories that chooseto offer screening for VRE need to consider test sensitivity, com-plexity, turnaround time, and cost. Chromogenic agars are rela-tively inexpensive and provide a valuable tool for the laboratory.These agars and have been successfully used to screen for MRSAcolonization as a component of infection prevention efforts (60,61). Several VRE chromogenic agars that can identify VRE fromstool specimens are currently FDA cleared and commerciallyavailable. These media may also differentiate between E. faeciumand E. faecalis. In general, chromogenic agars have superior sen-sitivity, ranging from 90 to 99%, compared to bile esculin azideagar containing vancomycin (BEAV), which is approximately85% sensitive (62, 63). The specificity of chromogenic agars is alsosuperior to BEAV, which can be as low as 70 to 75%. A summaryof the performance of these agars can be found in Table 2 (62–68).False-positive results due to breakthrough growth of non-E. faeca-lis, non-E. faecium isolates are less common on chromogenic me-dia than on BEAV, which frequently supports the growth E. cas-

Minireview

2442 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

seliflavus, E. gallinarum, Leuconostoc spp., and Pediococcus species.These species harbor low-level vancomycin resistance and are alsoesculin positive, making them difficult to distinguish from E.faecalis and E. faecium. In a study comparing 5 chromogenic agars,non-VRE isolates were recovered from 16.5% of specimens usingBEAV, whereas isolation of non-VRE organisms on chromogenicagar ranged from 0.9% to 5.6% of the specimens tested (62). Thesedifferences are likely due to the lower concentration of vancomy-cin used by BEAV, 6 �g/ml, versus 8 to 10 �g/ml used in chromo-genic media, as well as the specific colony color imparted by thechromogens used. While more sensitive than BEAV, chromogenicagar still requires 18 to 24 h of incubation, which can delay theimplementation of infection control measures.

Molecular screening methods. Nucleic acid amplificationtests (NAATs) have been applied tor VRE screening and detectionusing both stool and rectal swab specimens. Among these assaysare both laboratory-developed tests (LDTs) and commercially de-veloped assays, such as the Roche LightCycler VRE (vanA andvanB) detection assay, the Cepheid Xpert vanA and vanB assay,and the Cepheid Xpert vanA assay. The Cepheid Xpert vanA assayis FDA cleared, and the Xpert vanA and vanB assay is CE marked.Currently, the Roche LightCycler VRE detection kit is marketed asresearch use only (RUO).

The performance of molecular assays is varied, with sensitivityranging from 61.5 to 100% and specificity ranging from 14.7 to99.5% (69, 70). The wide difference in assay performance is due toseveral factors, including the gold-standard method used for cul-ture comparison and the prevalence of VRE in the study popula-tion. The Roche LightCycler VRE detection kit demonstrated ahigh negative predictive value (NPV) of 99.9% for VRE but suf-fered low positive predictive values (PPV) of 1.4% for vanB and68.5% vanA when results were compared to direct culture usingEnterococcosel agar (68). A significantly higher PPV of 92.0% was

reported using the Cepheid Xpert vanA and vanB assay, but refer-ence culture was performed using a broth enrichment step prior toplating, which may increase the recovery of VRE in culture (71).Interestingly, a similar study evaluating the Xpert vanA and vanBassay using broth-enriched culture reported a PPV of only 32%(72). These data suggest that the reference culture method canaffect assay performance data, but additional factors also contrib-ute to the poor PPV commonly observed with these assays.

A major factor impacting PPV and NPV calculations is thepretest probability or prevalence of a given target, in this case VRE,in the population being studied. In the two studies that reported aPPV greater than 90%, VRE prevalence was 30% and 47% amongthe specimens tested, whereas both studies reporting low PPVs of1.4% and 2.6% had VRE prevalence of 1.3% and 1.4%, respec-tively (68, 69, 71, 73). These data suggest that the utility of molec-ular assays to serve as a “rule-in” test is limited; however, theseassays can still be effectively used to identify noncolonized pa-tients with a high NPV. An obvious advantage of molecular assaysis the potential to reduce turnaround time (TAT) by 18 to 72 hcompared with culture, thereby enabling rapid screening to ruleout VRE. The short TAT may be especially beneficial for facilitiesthat implement strategies where all new or returning high-riskpatients are treated as VRE patients until a screen returns negative.However, the additional cost of primary screening using compar-atively expensive molecular assays must be weighed against thecost of unnecessary isolation measures, which may include gowns,gloves, and private rooms.

Another factor contributing to the reported low specificity andPPV of NAATs is the presence of vanA and vanB in multiple bac-terial species other than Enterococcus spp., including Streptococcusmitis, Streptococcus bovis, Eubacterium lenta, Ruminococcus spp.,Lactococcus spp., Leuconostoc spp., and some Clostridium species(68, 74). Many of these organisms are ubiquitous colonizers of the

TABLE 2 Summary of published performance data on FDA-cleared chromogenic agar for VRE

Detection methoda Sensitivity (%) Specificity (%)Time toresult (h) Notes Reference(s)

BEAVb 84.8–87.6 73–100 48–72 Breakthrough of nonpathogenic E. gallinarumand E. casseliflavus due to intrinsic resistance.False-positive results if Leuconostoc orPediococcus spp. are present in specimen

58–61

ChromogenicchromID VRE 86.3–98.2 97.5–100 48 (read at 24

and 48)Differentiates E. faecalis from E. faecium by color 58, 61, 62

VRESelect 91.9–98.7 99.0–99.7 24–28 Differentiates E. faecalis from E. faecium by color 58, 59Spectra VRE 93.9–98.2 99.–99.7 24 Uses -galactosidase to differentiate E. faecium

from E. faecalis58, 60

CHROMagar 98.2–98.6 96.5–99.1 24 Differentiates pathogenic vs nonpathogenicEnterococcus by color

58, 62

Nucleic acid amplificationtest

Non-Enterococcus strains can carry vanA or vanB

BD GeneOhm 91.8 93.6 12 Positive predictive value, 66.6% 63Roche LightCycler

detection kitc

73.3, 85.4 99.6, 83.9 �4 Positive predictive value, 68.5% and 1.42% 64

Cepheid Xpert 61–100 69.3–99.5 1 Positive predictive values range from 2–32% forvanB and 66–92% for vanA

71–73, 75

a Gold standard used to confirm VRE was Gram stain, followed by catalase and pyrrolidonyl arylamidase (PYR) tests. Etests were used to confirm vancomycin resistance.b BEAV, bile esculin azide agar containing vancomycin.c Values for Roche LightCycler are for for vanA and vanB isolates, respectively.

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2443Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

human gastrointestinal (GI) tract, and vanB carriage can be highin both healthy and sick individuals. Graham et al. observed highrates of nonenterococcal vanB carriage in community adults(63%), children (27%), and hemodialysis patients (27%) (75).Currently available molecular tests do not link the van genes toEnterococcus; therefore, they cannot differentiate between vanAand vanB carried by Enterococcus versus other bacterial species.This shortcoming can be minimized through the use of an assaytargeting only vanA, provided it is used in a geographic regionwith a low prevalence of Enterococcus spp. harboring vanB. Alter-natively, preenrichment of specimens for 16 to 24 h in selectivebroth containing 16 mg/liter amoxicillin, 20 mg/liter amphoteri-cin B, 20 mg/liter aztreonam, and 20 mg/liter colistin significantlyincreased Xpert vanA and vanB assay specificity when coupledwith a reduced cycle threshold (CT) for calling positive results(76). Following selective broth enrichment, a CT of �25 demon-strated a sensitivity, specificity, PPV, and NPV of 97%, 100%,100%, and 99.5%, respectively. This is compared to values of100%, 77.3%, 41%, and 100%, respectively, for nonenriched sam-ples using the assay default of CT �35 for calling a positive result.Importantly, broth-enriched specimens with a CT of �30 werereliably reported as true negative; however, specimens with CT

values of 25 to 30 were variable and required culture confirmationbefore reporting. In addition to requiring independent validationof modified specimen and CT thresholds, broth enrichment alsodelays the reporting of results by 18 to 24 h. This delay abrogatesone of the key advantages of molecular assays, namely, rapid TAT,and mirrors the time to result using chromogenic agars, which, ingeneral, are less expensive per specimen than molecular assays.Finally, the use of NAAT as a primary screen for VRE means thatorganisms are not recovered and therefore are not available forstrain typing to aid in outbreak epidemiology.

Conclusion. Reducing the total prevalence of VRE and VREinfections in individual hospital settings requires multiple strate-gies, including antimicrobial stewardship, active screening of at-risk patients, strict adherence to hand hygiene, and effective roomcleaning after discharge. Laboratories considering implementa-tion of the CDC recommendations to perform active screeningshould look at several factors to ensure that implementationwould be beneficial and cost-effective. Hospital settings that havea high prevalence of VRE infection have the potential to achievethe most dramatic reductions in VRE HAIs and associated totalcost of care per patient. For hospitals with a low prevalence ofVRE, the cost of additional screening and infection control mea-sures needs to be weighed against the risk and frequency of VREinfections. However, because the cost of BSI can be $20,000 to$30,000 per patient, the prevention of a single VRE BSI per year mayoffset the cost of screening and infection control measures (77).

The choice of screening methodology can impact the success ofinfection control measures and the total cost of the program. Thelow PPV of molecular testing methods and comparatively highcost may make it difficult to justify NAAT-based primary screen-ing for all hospital admissions. Conversely, culture is relativelyinexpensive but delays results by at least 18 h, which in turn canreduce the effectiveness of infection control measures. One possi-ble solution is to reserve NAATs for an initial admission screen ofpatients at highest risk for infection (ICUs and transplant wards),with subsequent weekly surveillance conducted by culture. Thisworkflow removes the initial 18- to 24-h window for transmissionwhen using culture and allows for the immediate isolation of patients

with a positive result until culture confirmation is available. However,this method may be costly for hospitals with a large number of high-risk admissions and may be impractical for hospitals with limitedspace dedicated for single-patient isolation rooms.

Regardless of screening methodology (culture versus NAAT)or approach (targeted versus universal, active versus passive), it isessential to ensure communication between the laboratory, pri-mary care providers, and infection control practitioners to ensureappropriate implementation of infection control programs fol-lowing a positive laboratory result. Inadequate or delayed inter-ventional measures or lack of adherence to these programs willresult in a failure of infection control efforts and adds unnecessarycost to patient care without providing added value.

REFERENCES1. Köck R, Becker K, Cookson B, van Gemert-Pijnen JE, Harbarth S,

Kluytmans J, Mielke M, Peters G, Skov RL, Struelens MJ, Tacconelli E,Witte W, Friedrich AW. 2014. Systematic literature analysis and review oftargeted preventive measures to limit healthcare-associated infections bymeticillin-resistant Staphylococcus aureus. Euro Surveill 19:pii�20860.http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId�20860.

2. Sievert DM, Ricks P, Edwards JR, Schneider A, Patel J, Srinivasan A,Kallen A, Limbago B, Fridkin S, National Healthcare Safety Network(NHSN) Team and Participating NHSN Families. 2013. Antimicrobial-resistant pathogens associated with healthcare-associated infections: sum-mary of data reported to the National Healthcare Safety Network at theCenters for Disease Control and Prevention, 2009 –2010. Infect ControlHosp Epidemiol 34:1–14. http://dx.doi.org/10.1086/668770.

3. Hill EE, Herijgers P, Claus P, Vanderschueren S, Herregods MC,Peetermans WE. 2007. Infective endocarditis: changing epidemiologyand predictors of 6-month mortality: a prospective cohort study. EurHeart J 28:196 –203.

4. Wang JS, Muzevich K, Edmond MB, Bearman G, Stevens MP. 2014.Central nervous system infections due to vancomycin-resistant entero-cocci: case series and review of the literature. Int J Infect Dis 25:26 –31.http://dx.doi.org/10.1016/j.ijid.2014.01.009.

5. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. 2005. Compar-ison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin In-fect Dis 41:327–333. http://dx.doi.org/10.1086/430909.

6. Leclercq R, Derlot E, Duval J, Courvalin P. 1988. Plasmid-mediatedresistance to vancomycin and teicoplanin in Enterococcus faecium. N EnglJ Med 319:157–161. http://dx.doi.org/10.1056/NEJM198807213190307.

7. Frieden TR, Munsiff SS, Low DE, Willey BM, Williams G, Faur Y,Eisner W, Warren S, Kreiswirth B. 1993. Emergence of vancomycin-resistant enterococci in New York City. Lancet 342:76 –79. http://dx.doi.org/10.1016/0140-6736(93)91285-T.

8. Centers for Disease Control and Prevention. 2013. Antibiotic resistancethreats in the United States, 2013. Centers for Disease Control and Pre-vention, Atlanta, GA. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

9. Stiefel U, Nerandzic MM, Pultz MJ, Donskey CJ. 2014. Gastrointestinalcolonization with a cephalosporinase-producing Bacteroides species pre-serves colonization resistance against vancomycin-resistant Enterococcusand Clostridium difficile in cephalosporin-treated mice. Antimicrob AgentsChemother 58:4535–4542. http://dx.doi.org/10.1128/AAC.02782-14.

10. Leavis HL, Willems RJ, van Wamel WJ, Schuren FH, Caspers MP,Bonten MJ. 2007. Insertion sequence-driven diversification creates aglobally dispersed emerging multiresistant subspecies of E. faecium. PLoSPathog 3:e7. http://dx.doi.org/10.1371/journal.ppat.0030007.

11. O’Driscoll T, Crank CW. 2015. Vancomycin-resistant enterococcal in-fections: epidemiology, clinical manifestations, and optimal management.Infect Drug Resist 8:217–230.

12. Cetinkaya Y, Falk P, Mayhall CG. 2000. Vancomycin-resistant entero-cocci. Clin Microbiol Rev 13:686 –707. http://dx.doi.org/10.1128/CMR.13.4.686-707.2000.

13. Aslangul E, Massias L, Meulemans A, Chau F, Andremont A, CourvalinP, Fantin B, Ruimy R. 2006. Acquired gentamicin resistance by perme-ability impairment in Enterococcus faecalis. Antimicrob Agents Che-mother 50:3615–3621. http://dx.doi.org/10.1128/AAC.00390-06.

Minireview

2444 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

14. Abat C, Raoult D, Rolain JM. 2016. Low level of resistance in enterococciisolated in four hospitals, Marseille, France. Microb Drug Resist 22:218–222.

15. Dadfarma N, Imani Fooladi AA, Oskoui M, Mahmoodzadeh HosseiniH. 2013. High level of gentamicin resistance (HLGR) among Enterococcusstrains isolated from clinical specimens. J Infect Public Health 6:202–208.http://dx.doi.org/10.1016/j.jiph.2013.01.001.

16. Parameswarappa J, Basavaraj VP, Basavaraj CM. 2013. Isolation, iden-tification, and antibiogram of enterococci isolated from patients with uri-nary tract infection. Ann Afr Med 12:176 –181. http://dx.doi.org/10.4103/1596-3519.117629.

17. Moellering RC, Jr, Wennersten C, Weinberg AN. 1971. Studies onantibiotic synergism against enterococci. I. Bacteriologic studies. J LabClin Med 77:821– 828.

18. Williamson R, Calderwood SB, Moellering RC, Jr, Tomasz A. 1983.Studies on the mechanism of intrinsic resistance to beta-lactam antibioticsin group D streptococci. J Gen Microbiol 129:813– 822.

19. Hollenbeck BL, Rice LB. 2012. Intrinsic and acquired resistance mecha-nisms in Enterococcus. Virulence 3:421– 433. http://dx.doi.org/10.4161/viru.21282.

20. Fontana R, Grossato A, Rossi L, Cheng YR, Satta G. 1985. Transitionfrom resistance to hypersusceptibility to beta-lactam antibiotics associ-ated with loss of a low-affinity penicillin-binding protein in a Streptococcusfaecium mutant highly resistant to penicillin. Antimicrob Agents Che-mother 28:678 – 683. http://dx.doi.org/10.1128/AAC.28.5.678.

21. Duez C, Zorzi W, Sapunaric F, Amoroso A, Thamm I, Coyette J. 2001.The penicillin resistance of Enterococcus faecalis JH2-2r results from anoverproduction of the low-affinity penicillin-binding protein PBP4 anddoes not involve a psr-like gene. Microbiology 147:2561–2569. http://dx.doi.org/10.1099/00221287-147-9-2561.

22. Murray BE. 1997. Vancomycin-resistant enterococci. Am J Med 102:284 –293. http://dx.doi.org/10.1016/S0002-9343(99)80270-8.

23. Protonotariou E, Dimitroulia E, Pournaras S, Pitiriga V, Sofianou D,Tsakris A. 2010. Trends in antimicrobial resistance of clinical isolates of En-terococcus faecalis and Enterococcus faecium in Greece between 2002 and2007. J Hosp Infect 75:225–227. http://dx.doi.org/10.1016/j.jhin.2009.12.007.

24. Fernández-Hidalgo N, Almirante B, Gavalda J, Gurgui M, Pena C, deAlarcon A, Ruiz J, Vilacosta I, Montejo M, Vallejo N, Lopez-MedranoF, Plata A, Lopez J, Hidalgo-Tenorio C, Galvez J, Saez C, Lomas JM,Falcone M, de la Torre J, Martinez-Lacasa X, Pahissa A. 2013. Ampi-cillin plus ceftriaxone is as effective as ampicillin plus gentamicin for treat-ing Enterococcus faecalis infective endocarditis. Clin Infect Dis 56:1261–1268. http://dx.doi.org/10.1093/cid/cit052.

25. Leone S, Noviello S, Esposito S. 2016. Combination antibiotic therapyfor the treatment of infective endocarditis due to enterococci. Infection44:273–281.

26. Walsh CT, Fisher SL, Park IS, Prahalad M, Wu Z. 1996. Bacterialresistance to vancomycin: five genes and one missing hydrogen bond tellthe story. Chem Biol 3:21–28.

27. Lai MH, Kirsch DR. 1996. Induction signals for vancomycin resistanceencoded by the vanA gene cluster in Enterococcus faecium. AntimicrobAgents Chemother 40:1645–1648.

28. al-Obeid S, Billot-Klein D, van Heijenoort J, Collatz E, Gutmann L.1992. Replacement of the essential penicillin-binding protein 5 by high-molecular mass PBPs may explain vancomycin-beta-lactam synergy inlow-level vancomycin-resistant Enterococcus faecium D366. FEMS Micro-biol Lett 70:79 – 84.

29. Arthur M, Depardieu F, Molinas C, Reynolds P, Courvalin P. 1995. ThevanZ gene of Tn1546 from Enterococcus faecium BM4147 confers resis-tance to teicoplanin. Gene 154:87–92. http://dx.doi.org/10.1016/0378-1119(94)00851-I.

30. Coombs GW, Pearson JC, Daley DA, Le T, Robinson OJ, Gottlieb T,Howden BP, Johnson PD, Bennett CM, Stinear TP, Turnidge JD,Australian Group on Antimicrobial Resistance. 2014. Molecular epide-miology of enterococcal bacteremia in Australia. J Clin Microbiol 52:897–905. http://dx.doi.org/10.1128/JCM.03286-13.

31. Schouten MA, Hoogkamp-Korstanje JA, Meis JF, Voss A, EuropeanVRE Study Group. 2000. Prevalence of vancomycin-resistant enterococciin Europe. Eur J Clin Microbiol Infect Dis 19:816 – 822. http://dx.doi.org/10.1007/s100960000390.

32. Arthur M, Depardieu F, Reynolds P, Courvalin P. 1996. Quantitativeanalysis of the metabolism of soluble cytoplasmic peptidoglycan precur-sors of glycopeptide-resistant enterococci. Mol Microbiol 21:33– 44. http://dx.doi.org/10.1046/j.1365-2958.1996.00617.x.

33. de Niederhäusern S, Bondi M, Messi P, Iseppi R, Sabia C, Manicardi G,Anacarso I. 2011. Vancomycin-resistance transferability from VanA en-terococci to Staphylococcus aureus. Curr Microbiol 62:1363–1367. http://dx.doi.org/10.1007/s00284-011-9868-6.

34. Centers for Disease Control and Prevention. 2002. Staphylococcus aureusresistant to vancomycin–United States, 2002. MMWR Morb Mortal WklyRep 51:565–567.

35. Walters MS, Eggers P, Albrecht V, Travis T, Lonsway D, Hovan G,Taylor D, Rasheed K, Limbago B, Kallen A. 2015. Vancomycin-ResistantStaphylococcus aureus–Delaware, 2015. MMWR Morb Mortal Wkly Rep64:1056. http://dx.doi.org/10.15585/mmwr.mm6437a6.

36. Werner G, Freitas AR, Coque TM, Sollid JE, Lester C, Hammerum AM,Garcia-Migura L, Jensen LB, Francia MV, Witte W, Willems RJ, Sunds-fjord A. 2011. Host range of enterococcal vanA plasmids among Gram-positive intestinal bacteria. J Antimicrob Chemother 66:273–282. http://dx.doi.org/10.1093/jac/dkq455.

37. Orsi GB, Ciorba V. 2013. Vancomycin resistant enterococci healthcareassociated infections. Ann Ig 25:485– 492.

38. Bonten MJ, Hayden MK, Nathan C, Rice TW, Weinstein RA. 1998.Stability of vancomycin-resistant enterococcal genotypes isolated fromlong-term-colonized patients. J Infect Dis 177:378 –382. http://dx.doi.org/10.1086/514196.

39. Ford CD, Lopansri BK, Gazdik MA, Snow GL, Webb BJ, Konopa KL,Petersen FB. 2015. The clinical impact of vancomycin-resistant Entero-coccus colonization and bloodstream infection in patients undergoing au-tologous transplantation. Transpl Infect Dis 17:688 – 694. http://dx.doi.org/10.1111/tid.12433.

40. Kramer A, Schwebke I, Kampf G. 2006. How long do nosocomial patho-gens persist on inanimate surfaces? A systematic review. BMC Infect Dis6:130. http://dx.doi.org/10.1186/1471-2334-6-130.

41. Byers KE, Durbin LJ, Simonton BM, Anglim AM, Adal KA, Farr BM.1998. Disinfection of hospital rooms contaminated with vancomycin-resistant Enterococcus faecium. Infect Control Hosp Epidemiol 19:261–264. http://dx.doi.org/10.2307/30142418.

42. Drees M, Snydman DR, Schmid CH, Barefoot L, Hansjosten K, VuePM, Cronin M, Nasraway SA, Golan Y. 2008. Prior environmentalcontamination increases the risk of acquisition of vancomycin-resistant enterococci. Clin Infect Dis 46:678 – 685. http://dx.doi.org/10.1086/527394.

43. Kingston L, O’Connell NH, Dunne CP. 2015. Hand hygiene-relatedclinical trials reported since 2010: a systematic review. J Hosp Infect 92:309 –320.

44. Smith PW, Bennett G, Bradley S, Drinka P, Lautenbach E, Marx J,Mody L, Nicolle L, Stevenson K, Society for Healthcare Epidemiologyof America (SHEA), Association for Professionals in Infection Controland Epidemiology. 2008. SHEA/APIC guideline: infection preventionand control in the long-term care facility. Am J Infect Control 36:504 –535.http://dx.doi.org/10.1016/j.ajic.2008.06.001.

45. Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare InfectionControl Practices Advisory Committee. 2007. Management of multi-drug-resistant organisms in health care settings, 2006. Am J Infect Control35:S165–193. http://dx.doi.org/10.1016/j.ajic.2007.10.006.

46. Shay DK, Goldmann DA, Jarvis WR. 1995. Reducing the spread ofantimicrobial-resistant microorganisms. Control of vancomycin-resistant enterococci. Pediatr Clin North Am 42:703–716. http://dx.doi.org/10.1016/S0031-3955(16)38986-6.

47. Hayden MK, Bonten MJ, Blom DW, Lyle EA, van de Vijver DA,Weinstein RA. 2006. Reduction in acquisition of vancomycin-resistantEnterococcus after enforcement of routine environmental cleaning mea-sures. Clin Infect Dis 42:1552–1560. http://dx.doi.org/10.1086/503845.

48. Perencevich EN, Fisman DN, Lipsitch M, Harris AD, Morris JG, Jr,Smith DL. 2004. Projected benefits of active surveillance for vancomycin-resistant enterococci in intensive care units. Clin Infect Dis 38:1108 –1115.http://dx.doi.org/10.1086/382886.

49. Bodily M, McMullen KM, Russo AJ, Kittur ND, Hoppe-Bauer J, War-ren DK. 2013. Discontinuation of reflex testing of stool samples for van-comycin-resistant enterococci resulted in increased prevalence. InfectionControl Hosp Epidemiol 34:838 – 840. http://dx.doi.org/10.1086/671276.

50. Armeanu E, Bonten MJ. 2005. Control of vancomycin-resistant entero-cocci: one size fits all? Clin Infect Dis 41:210 –216. http://dx.doi.org/10.1086/431206.

51. Price CS, Paule S, Noskin GA, Peterson LR. 2003. Active surveillance

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2445Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

reduces the incidence of vancomycin-resistant enterococcal bacteremia.Clin Infect Dis 37:921–928. http://dx.doi.org/10.1086/377733.

52. Matsushima A, Takakura S, Yamamoto M, Matsumura Y, Shirano M,Nagao M, Ito Y, Iinuma Y, Shimizu T, Fujita N, Ichiyama S. 2012.Regional spread and control of vancomycin-resistant Enterococcus faeciumand Enterococcus faecalis in Kyoto, Japan. Eur J Clin Microbiol Infect Dis31:1095–1100. http://dx.doi.org/10.1007/s10096-011-1412-x.

53. Fisher D, Pang L, Salmon S, Lin RT, Teo C, Tambyah P, Jureen R, CookAR, Otter JA. 2016. A successful vancomycin-resistant enterococci reduc-tion bundle at a Singapore hospital. Infection Control Hosp Epidemiol37:107–109. http://dx.doi.org/10.1017/ice.2015.251.

54. Huskins WC, Huckabee CM, O’Grady NP, Murray P, Kopetskie H,Zimmer L, Walker ME, Sinkowitz-Cochran RL, Jernigan JA, Samore M,Wallace D, Goldmann DA, STAR*ICU Trial Investigators. 2011. Inter-vention to reduce transmission of resistant bacteria in intensive care. NEngl J Med 364:1407–1418. http://dx.doi.org/10.1056/NEJMoa1000373.

55. Shadel BN, Puzniak LA, Gillespie KN, Lawrence SJ, Kollef M, MundyLM. 2006. Surveillance for vancomycin-resistant enterococci: type, rates,costs, and implications. Infection Control Hosp Epidemiol 27:1068 –1075.http://dx.doi.org/10.1086/507960.

56. Montecalvo MA, Jarvis WR, Uman J, Shay DK, Petrullo C, HorowitzHW, Wormser GP. 2001. Costs and savings associated with infectioncontrol measures that reduced transmission of vancomycin-resistant en-terococci in an endemic setting. Infection Control Hosp Epidemiol 22:437– 442. http://dx.doi.org/10.1086/501931.

57. Faron ML, Buchan BW, Vismara C, Lacchini C, Bielli A, Gesu G, LiebregtsT, van Bree A, Jansz A, Soucy G, Korver J, Ledeboer NA. 2015. Automatedscoring of chromogenic media for the detection of MRSA using the WASPLabimage analysis software. J Clin Microbiol 54:620–624.

58. Hacek DM, Bednarz P, Noskin GA, Zembower T, Peterson LR. 2001.Yield of vancomycin-resistant enterococci and multidrug-resistant Enter-obacteriaceae from stools submitted for Clostridium difficile testing com-pared to results from a focused surveillance program. J Clin Microbiol39:1152–1154. http://dx.doi.org/10.1128/JCM.39.3.1152-1154.2001.

59. D’Agata EM, Gautam S, Green WK, Tang YW. 2002. High rate offalse-negative results of the rectal swab culture method in detection ofgastrointestinal colonization with vancomycin-resistant enterococci. ClinInfect Dis 34:167–172. http://dx.doi.org/10.1086/338234.

60. Robotham JV, Graves N, Cookson BD, Barnett AG, Wilson JA, Edge-worth JD, Batra R, Cuthbertson BH, Cooper BS. 2011. Screening,isolation, and decolonisation strategies in the control of meticillin resis-tant Staphylococcus aureus in intensive care units: cost effectiveness eval-uation. BMJ 343:d5694. http://dx.doi.org/10.1136/bmj.d5694.

61. Das S, Harazin M, Wright MO, Dusich I, Robicsek A, Peterson LR.2014. Active surveillance and decolonization without isolation is effectivein preventing methicillin-resistance Staphylococcus aureus transmission inthe psychiatry units. Open Forum Infect Dis 1:ofu067. http://dx.doi.org/10.1093/ofid/ofu067.

62. Suwantarat N, Roberts A, Prestridge J, Seeley R, Speser S, Harmon C,Zhang C, Henciak S, Stamper PD, Ross T, Carroll KC. 2014. Compar-ison of five chromogenic media for recovery of vancomycin-resistant en-terococci from fecal samples. J Clin Microbiol 52:4039 – 4042. http://dx.doi.org/10.1128/JCM.00151-14.

63. Anderson NW, Buchan BW, Young CL, Newton DW, Brenke C, Laps-ley L, Granato PA, Ledeboer NA. 2013. Multicenter clinical evaluation ofVRESelect agar for identification of vancomycin-resistant Enterococcusfaecalis and Enterococcus faecium. J Clin Microbiol 51:2758 –2760. http://dx.doi.org/10.1128/JCM.00979-13.

64. Peterson JF, Doern CD, Kallstrom G, Riebe KM, Sander T, Dunne WM,Jr, Ledeboer NA. 2010. Evaluation of Spectra VRE, a new chromogenicagar medium designed to screen for vancomycin-resistant Enterococcusfaecalis and Enterococcus faecium. J Clin Microbiol 48:4627– 4629. http://dx.doi.org/10.1128/JCM.01676-10.

65. Ledeboer NA, Tibbetts RJ, Dunne WM. 2007. A new chromogenic agarmedium, chromID VRE, to screen for vancomycin-resistant Enterococcusfaecium and Enterococcus faecalis. Diagn Microbiol Infect Dis 59:477– 479.http://dx.doi.org/10.1016/j.diagmicrobio.2007.06.018.

66. Peltroche-Llacsahuanga H, Top J, Weber-Heynemann J, Lutticken R,Haase G. 2009. Comparison of two chromogenic media for selective iso-

lation of vancomycin-resistant enterococci from stool specimens. J ClinMicrobiol 47:4113– 4116. http://dx.doi.org/10.1128/JCM.00882-09.

67. Devrim F, Gulfidan G, Gozmen S, Demirag B, Oymak Y, Yaman Y,Oruc Y, Yasar N, Apa H, Bayram N, Vergin C, Devrim I. 2015.Comparison of the BD GeneOhm VanR assay and a chromogenic agar-based culture method in screening for vancomycin-resistant enterococciin rectal specimens of pediatric hematology-oncology patients. Turk JPediatr 57:161–166.

68. Mak A, Miller MA, Chong G, Monczak Y. 2009. Comparison of PCR andculture for screening of vancomycin-resistant enterococci: highly dispa-rate results for vanA and vanB. J Clin Microbiol 47:4136 – 4137. http://dx.doi.org/10.1128/JCM.01547-09.

69. Babady NE, Gilhuley K, Cianciminio-Bordelon D, Tang YW. 2012.Performance characteristics of the Cepheid Xpert vanA assay for rapididentification of patients at high risk for carriage of vancomycin-resistantenterococci. J Clin Microbiol 50:3659 –3663. http://dx.doi.org/10.1128/JCM.01776-12.

70. Gazin M, Lammens C, Goossens H, Malhotra-Kumar S, MOSAR WP2Study Team. 2012. Evaluation of GeneOhm VanR and Xpert vanA/vanBmolecular assays for the rapid detection of vancomycin-resistant entero-cocci. Eur J Clin Microbiol Infect Dis 31:273–276. http://dx.doi.org/10.1007/s10096-011-1306-y.

71. Marner ES, Wolk DM, Carr J, Hewitt C, Dominguez LL, Kovacs T,Johnson DR, Hayden RT. 2011. Diagnostic accuracy of the CepheidGeneXpert vanA/vanB assay ver. 1.0 to detect the vanA and vanB vanco-mycin resistance genes in Enterococcus from perianal specimens. DiagnMicrobiol Infect Dis 69:382–389. http://dx.doi.org/10.1016/j.diagmicrobio.2010.11.005.

72. Sloan LM, Uhl JR, Vetter EA, Schleck CD, Harmsen WS, Manahan J,Thompson RL, Rosenblatt JE, Cockerill FR, III. 2004. Comparison ofthe Roche LightCycler vanA/vanB detection assay and culture for detec-tion of vancomycin-resistant enterococci from perianal swabs. J Clin Mi-crobiol 42:2636 –2643. http://dx.doi.org/10.1128/JCM.42.6.2636-2643.2004.

73. Bourdon N, Berenger R, Lepoultier R, Mouet A, Lesteven C, Borgey F,Fines-Guyon M, Leclercq R, Cattoir V. 2010. Rapid detection of vanco-mycin-resistant enterococci from rectal swabs by the Cepheid Xpert vanA/vanB assay. Diagn Microbiol Infect Dis 67:291–293. http://dx.doi.org/10.1016/j.diagmicrobio.2010.02.009.

74. Domingo MC, Huletsky A, Giroux R, Boissinot K, Picard FJ, Lebel P,Ferraro MJ, Bergeron MG. 2005. High prevalence of glycopeptide resis-tance genes vanB, vanD, and vanG not associated with enterococci inhuman fecal flora. Antimicrob Agents Chemother 49:4784 – 4786. http://dx.doi.org/10.1128/AAC.49.11.4784-4786.2005.

75. Graham M, Ballard SA, Grabsch EA, Johnson PD, Grayson ML. 2008.High rates of fecal carriage of nonenterococcal vanB in both children andadults. Antimicrob Agents Chemother 52:1195–1197. http://dx.doi.org/10.1128/AAC.00531-07.

76. Zhou X, Arends JP, Kampinga GA, Ahmad HM, Dijkhuizen B, vanBarneveld P, Rossen JW, Friedrich AW. 2014. Evaluation of the XpertvanA/vanB assay using enriched inoculated broths for direct detection ofvanB vancomycin-resistant enterococci. J Clin Microbiol 52:4293– 4297.http://dx.doi.org/10.1128/JCM.01125-14.

77. Muto CA, Giannetta ET, Durbin LJ, Simonton BM, Farr BM. 2002.Cost-effectiveness of perirectal surveillance cultures for controlling van-comycin-resistant Enterococcus. Infection Control Hosp Epidemiol 23:429 – 435. http://dx.doi.org/10.1086/502080.

78. Ostrowsky BE, Trick WE, Sohn AH, Quirk SB, Holt S, Carson LA, HillBC, Arduino MJ, Kuehnert MJ, Jarvis WR. 2001. Control of vancomy-cin-resistant Enterococcus in health care facilities in a region. N Engl J Med344:1427–1433. http://dx.doi.org/10.1056/NEJM200105103441903.

79. Derde LP, Cooper BS, Goossens H, Malhotra-Kumar S, Willems RJ,Gniadkowski M, Hryniewicz W, Empel J, Dautzenberg MJ, Annane D,Aragao I, Chalfine A, Dumpis U, Esteves F, Giamarellou H, Muzlovic I,Nardi G, Petrikkos GL, Tomic V, Marti AT, Stammet P, Brun-BuissonC, Bonten MJ, MOSAR WP3 Study Team. 2014. Interventions to reducecolonisation and transmission of antimicrobial-resistant bacteria in inten-sive care units: an interrupted time series study and cluster randomisedtrial. Lancet Infect Dis 14:31–39. http://dx.doi.org/10.1016/S1473-3099(13)70295-0.

Minireview

2446 jcm.asm.org October 2016 Volume 54 Number 10Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from

Blake W. Buchan, Ph.D., D(ABMM), is an As-sistant Professor of Pathology at the MedicalCollege of Wisconsin and Associate Director ofMicrobiology at Wisconsin Diagnostic Labora-tories, Milwaukee, WI. He was awarded a Ph.D.in microbiology from the University of Iowa in2009 for his work elucidating regulatory mech-anisms for the expression of virulence factors inFrancisella tularensis and completed postdoc-toral training in Clinical Microbiology at theMedical College of Wisconsin in 2011. Dr. Bu-chan’s interests include matrix-assisted laser desorption ionization–time offlight mass spectrometry (MALDI-TOF MS), PCR, and microarray-baseddiagnostics for the detection of bacterial, viral, and fungal pathogens, and hehas served as Principal Investigator for numerous clinical trials evaluatingnovel diagnostic assays. Dr. Buchan is involved with several professionalsocieties, including ASM and SCACM, and is a member of the editorialboard for the Journal of Clinical Microbiology. Dr. Buchan has a strong recordof publication in peer-reviewed journals and has presented at numerousscientific meetings, including ASM, ECCMID, CVS, IDSA, SCACM, andICAAC.

Minireview

October 2016 Volume 54 Number 10 jcm.asm.org 2447Journal of Clinical Microbiology

on March 26, 2020 by guest

http://jcm.asm

.org/D

ownloaded from