www.elsevier.es/medintensiva
CONSENSUS
STATEMENT
Diagnosis
and
treatment
of
catheter-related
bloodstream
infection:
Clinical
guidelines
of
the
Spanish
Society
of
Infectious
Diseases
and
Clinical
Microbiology
and
(SEIMC)
and
the
Spanish
Society
of
Spanish
Society
of
Intensive
and
Critical
Care
Medicine
and
Coronary
Units
(SEMICYUC)
!
F.
Chaves
a,
J.
Garnacho-Montero
b,∗,
J.L.
del
Pozo
(Coordinators)
c,
Authors:
E.
Bouza
d,
J.A.
Capdevila
e,
M.
de
Cueto
f,
M.Á.
Domínguez
g,
J.
Esteban
h,
N.
Fernández-Hidalgo
i,
M.
Fernández
Sampedro
j,
J.
Fortún
k,
M.
Guembe
l,
L.
Lorente
m,
J.R.
Pa˜no
n,
P.
Ramírez
o,
M.
Salavert
p,
M.
Sánchez
q,
J.
Vallés
raServiciodeMicrobiología,HospitalUniversitario12deOctubre,Madrid,Spain
bUnidadClínicadeCuidadosIntensivos,HospitalUniversitarioVirgenMacarena,Sevilla,Spain
cÁreadeEnfermedadesInfecciosas,ServiciodeMicrobiología,ClínicaUniversidaddeNavarra,Pamplona,Spain
dServiciodeMicrobiologíaClínicayEnfermedadesInfecciosas,HospitalGeneralUniversitarioGregorioMara˜nón,Madrid;
InstitutodeInvestigaciónSanitariaGregorioMara˜nón,Madrid;CIBERdeEnfermedadesRespiratorias,CibeRes,InstitutodeSalud CarlosIII,Madrid;DepartamentodeMedicina,FacultaddeMedicina,UniversidadComplutensedeMadrid,Madrid,Spain
eServiciodeMedicinaInterna,HospitaldeMataró,Mataró,Barcelona,Spain
fUnidaddeEnfermedadesInfecciosasyMicrobiología,HospitalUniversitarioVirgenMacarena,Sevilla,Spain gServiciodeMicrobiología,HospitalUniversitarideBellvitge,IDIBELL,L’HospitaletdeLlobregat,Barcelona,Spain hDepartamentodeMicrobiologíaClínica,FundaciónJiménezDíaz,UniversidadAutónomadeMadrid,Madrid,Spain iServeideMalaltiesInfeccioses,HospitalUniversitariValld’Hebron,UniversitatAutònomadeBarcelona,Barcelona,Spain jServiciodeEnfermedadesInfecciosas,HospitalUniversitarioMarquésdeValdecilla,Santander,Spain
kUnidaddeEnfermedadesInfecciosas,HospitalUniversitarioRamónyCajal,Madrid,Spain
lUnidaddeEnfermedadesInfecciosasyMicrobiologíaClínica,HospitalGeneralUniversitarioGregorioMara˜nón,Instituto
deInvestigaciónSanitariaGregorioMara˜nón,Madrid,Spain
mUnidaddeCuidadosIntensivos,HospitalUniversitariodeCanarias,SantaCruzdeTenerife,Spain
nUnidaddeEnfermedadesInfecciosas,HospitalClínicoUniversitarioLozanoBlesa,InstitutodeInvestigaciónSanitariaAragón(IIS
Aragón),Zaragoza,Spain
oUnidaddeCuidadosIntensivos,HospitalUniversitariiPolitècnicLaFe,Valencia;CIBERdeEnfermedadesRespiratorias
(CibeRes),InstitutodeSaludCarlosIII,Madrid,Spain
! Thecompleteconsensusstatementhasalsobeenpublishedin:EnfermInfeccMicrobiolClin.2017.http://dx.doi.org/10.1016/j.eimc. 2017.10.019
∗Correspondingauthor.
E-mailaddress:jgarnachom@gmail.com(J.Garnacho-Montero). https://doi.org/10.1016/j.medin.2017.09.012
pUnidaddeEnfermedadesInfecciosas,HospitalUniversitariiPolitècnicLaFe,Valencia,Spain
qServiciodeMedicinaIntensiva,HospitalClínicoSanCarlos,DepartamentodeMedicina,FacultaddeMedicina,Universidad
ComplutensedeMadrid,Madrid,Spain
rUnidaddeCuidadosIntensivos,HospitalUniversitariParcTaulí,Sabadell,Barcelona;CIBERdeEnfermedadesRespiratorias,
InstitutodeSaludCarlosIII,Madrid,Spain
Received21July2017;accepted29September2017
KEYWORDS Catheter-related bloodstream infection; Guidelines; Bacteremia; Bloodcultures; Antibiotic
Abstract: Catheter-relatedbloodstreaminfections (CRBSI)constituteanimportantcause of hospital-acquired infectionassociatedwithmorbidity,mortality,andcost.The aimofthese guidelinesistoprovideupdatedrecommendationsforthediagnosisandmanagementofCRBSIin adults.PreventionofCRBSIisexcluded.Expertsinthefieldweredesignatedbythetwo partici-patingSocieties(theSpanishSocietyofInfectiousDiseasesandClinicalMicrobiologyand[SEIMC] andtheSpanish SocietyofSpanishSocietyofIntensiveandCriticalCareMedicineand Coro-naryUnits[SEMICYUC]).Short-termperipheralvenouscatheters,non-tunneledandlong-term centralvenouscatheters,tunneledcathetersandhemodialysiscathetersarecoveredbythese guidelines.Thepanelidentified39keytopicsthatwereformulatedinaccordancewiththePICO format.Thestrengthoftherecommendationsandqualityoftheevidenceweregradedin accor-dancewithESCMIDguidelines.RecommendationsaremadeforthediagnosisofCRBSIwithand withoutcatheterremovalandoftunnelinfection.Thedocumentestablishestheclinical situa-tionsinwhichaconservativediagnosisofCRBSI(diagnosiswithoutcatheterremoval)isfeasible. Recommendations arealso made regarding empirical therapy, pathogen-specific treatment (coagulase-negativestaphylococci,Staphylococcusaureus,Enterococcusspp.,Gram-negative bacilli,andCandidaspp.),antibioticlocktherapy,diagnosisandmanagementofsuppurative thrombophlebitisandlocalcomplications.
©2017ElsevierEspa˜na,S.L.U.ySEMICYUC.Allrightsreserved.
PALABRASCLAVE Bacteriemia relacionadacon catéter; Guíadepráctica clínica; Bacteriemia; Hemocultivos; Antibioticoterapia
Diagnósticoytratamientodelabacteriemiarelacionadaconcatéter:guíadepráctica clínicadelaSociedadEspa˜noladeEnfermedadesInfecciosasyMicrobiologíaClínica (SEIMC)ydelaSociedadEspa˜noladeMedicinaIntensiva,CríticayUnidades
Coronarias(SEMICYUC)
Resumen Labacteriemiarelacionadaconcatéteres(BRC)esunacausaimportantede infec-ciónhospitalariayseasociaconelevadosmorbilidad,mortalidadycostes.Elobjetivodeesta guíadeprácticaclínicaesproporcionarrecomendacionesactualizadaspara eldiagnóstico y tratamiento de la BRC en pacientesadultos. De este documento se excluye la prevención de la BRC. Expertos en la materia fueron designados por lasdos Sociedades participantes (SociedadEspa˜noladeEnfermedadesInfecciosasyMicrobiologíaClínica ySociedadEspa˜nola de Medicina Intensiva, Crítica y Unidades Coronarias). Los catéteres venosos periféricos a corto plazo, loscatéteres venososcentrales notunelizados y de largoplazo, loscatéteres tunelizados y los catéteres dehemodiálisis están incluidos en estasguías. Elpanel identi-ficó 39 temas clave quefueron formulados de acuerdocon elformato PICO. La fuerza de lasrecomendacionesylacalidaddelaevidenciaseclasificarondeacuerdoconlasdirectrices delaESCMID.SedanrecomendacionesparaeldiagnósticodeBRCconextraccióndecatéter y sinél,y dela infección entúnel.Eldocumento establecelassituacionesclínicas enque es factibleun diagnósticoconservador deCRBSI(diagnóstico sinretiradade catéter). Tam-biénsedanrecomendacionesrespectoalaterapiaempírica,eltratamientoespecíficosegúnel patógenoidentificado(estafilococoscoagulasa-negativos,Staphylococcusaureus,Enterococcus spp.,bacilosgramnegativosyCandidaspp.),laterapiaconselladodelcatéteryeldiagnóstico, asícomotratamientodelatromboflebitissupurativaylascomplicacioneslocales.
Introduction:
justification
and
aims
Intravasculardeviceshavebecomeanessentialcomponent of modernmedicine for theadministrationof intravenous fluids, medication, blood products and parenteral nutri-tionandfor monitoringhemodynamicstatusandproviding hemodialysis. According to national data supplied by the study of the prevalence of nosocomial infections in Spain (EPINE), itis estimatedthat about70% of patients admit-ted to Spanish hospitals will wear one of these devices at some point during their stay.1 Local or systemic
infec-tionsrepresentoneofthemainassociatedcomplications.2
Theincidenceofcatheter-relatedinfectionsvaries
consid-erablydependingonthetypeandintendeduse,theinsertion
site, the experience and training of the individual who
placesthecatheter,thefrequencywithwhichthecatheter
is accessed, duration of catheter placement, the
charac-teristics of thepatient,and theuse ofproven prevention
strategies. Catheter-related bloodstream infections
(CRB-SIs) are among the most frequent infections acquired in
hospital.Currentestimatesarethatbetween15%and30%
ofallnosocomialbacteremiasarecatheter-related.3CRBSIs
have significantassociatedmorbidity,incur increased
hos-pitalcosts,4 estimated at approximately18,000 eurosper
episode,andlengthofstay.5 Attributablemortalityranges
between 12%and 25%.6 Inrecent years,therehasbeen a
remarkableincreaseinourknowledgeoftheepidemiology
of CRBSI and of the most appropriate methodologies for
diagnosis, management and prevention. The vast amount
ofinformationaccumulatedandtheinherentcomplexityof
this type of infection make it necessary tosort and
ana-lyzetheavailableinformation.Atthesametime,thereare
fewcurrentguidelinesavailableonthistopic.Thelast
Span-ishcatheter-relatedinfectionsguidelineswerepublishedin
2004.7Theaimofthisnewguideistoupdate
recommenda-tionsforthediagnosisandmanagementofcatheter-related
bloodstreaminfections.Thisdocumenttargetsonly
microbi-ologicaldiagnosisandantimicrobialtherapy;otheraspects
of infection management and prevention are therefore
excluded.Onlyadultpatientswiththeseinfectionsare
cov-ered.
Methods
The two participating Societies (the Sociedad Espa˜nola
de Enfermedades Infecciosas y Microbiología Clínica and
the Sociedad Espa˜nola de Medicina Intensiva, Crítica y
Unidades Coronarias) nominated three coordinators for
this project (FC, JGM and JLdP: a microbiologist, an
intensivist,andaninfectiousdiseasephysician).This
coor-dinating group selected the rest of the members of the
panel,includingmicrobiologists,intensivists,andinfectious
diseasephysicians.TheScientificCommitteesofboth
Soci-etiesapprovedtheirproposal. Thepresent Statementwas
writtenfollowingtheSEIMCguidelinesforconsensus
state-ments(www.seimc.org)aswellastherecommendationsof
the Agree Collaboration (www.agreecollaboration.org) for
evaluating the methodological qualityof clinical practice
guidelines.Thestrengthoftherecommendationsand
qual-ityoftheevidenceweregradedinaccordancewithESCMID
guidelines(Table1).
Thecoordinatinggroupidentified39keytopicsthatwere
formulated in accordance with the PICO format defining
thepopulation,intervention, comparator,and outcomeof
interest.Thesekeyquestionswereapprovedbythe
Scien-tificCommitteesofboth Societies andthendistributed to
thedifferentmembersofthepanel(2or3questionseach)
forfurtherdevelopment.Thecoordinatinggroupwrotethe
firstdraftbasedonthesectionssubmittedbyeach
partici-pant,whichwasthensent tothepanelforcriticalreview.
Beforeits final approval,the document waspublished on
theintranetofbothSocietiesandleftopentosuggestions
andcommentsfrommembers.Allauthorsandcoordinators
oftheStatementhaveagreedthecontentsofthedocument
and thefinal recommendations. Asummary of these
rec-ommendationsisavailableintheSupplementaryElectronic
Material.
Catheter-related
bloodstream
infection
diagnosis
(
Table
2
)
Generalaspects
Whenshouldcatheter-relatedbloodstreaminfectionbe sus-pected?
CRBSI shouldbe clinically suspectedif the patienthas
fever, chills or hypotension with signs of infection
proxi-maltoinsertionsitesof peripheralvenous cannulaeor on
the skin overlying the subcutaneous tunnel of a tunneled
catheter.8 Severalcircumstances shouldincrease suspicion
thatagivenepisodeofbacteremiaiscatheter-related.The
mostobviousoneisapatientwithlocalsignsofinfectionat
thecatheter.Inaddition,bloodstreaminfectionsareoften
caused by microorganismsthat colonize the skin, such as
Staphylococcus aureus, coagulase-negative staphylococci, Corynebacteriumspp.,Bacillusspp.,Candidaspp.,among
others.CRBSIshouldalsobeconsideredinsettingsof
persis-tentorrecurrentbloodculturesforgivenmicroorganisms.8
ClinicalsuspicionofCRBSIshouldalsoariseinpatientswith
intravenouscatheterswhohavefocalinfectionsknowntobe
causedbythehematogenousspreadofbacteria(i.e.,
sep-ticemboli);thisisthecase inendocarditisor suppurative
thrombophlebitis,particularlyifcausedbyStaphylococcus
spp.orCandidaspp.inpatientswithvenouscatheters.
Sep-ticembolisecondarytoaCRBSIaremorefrequentlyfound
inthelungs,9althoughvirtuallyanyorgancanbeaffected
bysepticmetastasisarisingfromaninfectedcatheter.10,11
RECOMMENDATIONS
1. CRBSIshouldbesuspectedinpatientswithintravenous
cathetersandfever,chillsorothersignsofsepsis,even
intheabsenceoflocalsignsofinfection,andespecially
ifnoalternativesourceisidentified(A-III).
2. Clinicalsuspicionof CRBSIshouldalsoariseinpatients
with intravenous catheters with metastatic infections
causedbyhematogenousspreadofmicroorganisms(i.e.,
septicemboli)(A-III).
3. Persistent or recurrent bacteremia caused by
microor-ganisms that colonize the skin in patients with
intravenouscathetersshouldleadtoCRBSIsuspicion
Table1 Strengthofrecommendationandqualityofevidence. Category/gradingDefinition
Strengthofrecommendations
A Stronglysupportsarecommendationforuse B Moderatelysupportsarecommendationforuse C Marginallysupportsarecommendationforuse D Supportsarecommendationagainstuse Qualityofevidence
I Evidencefromatleastoneproperlydesignedrandomized,controlledtrial
II Evidencefromatleastonewell-designedclinicaltrial,withoutrandomization;fromcohortorcase-controlled analyticstudies(preferablyfrom1center);frommultipletimeseries;orfromdramaticresultsof
uncontrolledexperiments
III Evidencefromopinionsofrespectedauthorities,basedonclinicalexperience,descriptivecasestudies
Howiscomplicatedcatheter-relatedbloodstream infec-tiondefined?
Thereareseveralfactorsassociatedwithworseoutcomes in patients with CRBSI and identifying these risk factors canhelpinthemanagementofthosepatients.Thereisno universallyaccepteddefinitionofcomplicatedCRBSI. Endo-carditisisoneof themain CRBSI-associatedcomplications witha prolongedtherapy that requires catheterremoval. Suppurative thrombophlebitis also makes CRBSI compli-cated, as do metastatic foci of infection, which usually require prolonged therapy and catheter removal. Local complications,such astunnelinfectionor a port abscess, even in the absence of septic thrombophlebitis, require catheterremovalandsocomplicateaCRBSI.10,11 Systemic
severity(septicshock) inpatientswithsuspectedCRBSIis
anothercircumstancethatshouldleadtopromptcatheter
removal.Non-resolvingfeverorbacteremia(≥72h)should
leadtoa detailedreassessmentofthepatientinorderto
rule out local or distant infectious complications and so
shouldbeconsideredcomplicatedCRBSI.Itisveryimportant
tocloselymonitorimmunocompromisedhostswithCRBSIfor
possibletreatmentfailure.
RECOMMENDATIONS
1. Patients diagnosed with CRBSI and with endocarditis,
suppurativethrombophlebitis,septicmetastasis,
extra-luminalinfections,septicshock,non-resolvingCRBSI,or
immunocompromisedpatientsshouldbecategorizedas
complicatedCRBSI(A-III).
2. Non-resolvingfeverorbacteremia(≥72h)shouldleadto
adetailedreassessmentofthepatientinordertoruleout
localordistantinfectiouscomplicationsandsoshouldbe
consideredcomplicatedCRBSI(A-III).
Diagnosis
without
catheter
withdrawal
(conservative
diagnosis)
Howshouldbloodculturesbetaken?
Because the aim of a blood culture is to detect true
bacteremiaandavoidcontaminationleadingtounnecessary
treatment,aproperdiagnosticmethodologyisneeded.This
isparticularlyimportantwhencatheter-relatedbacteremia
issuspected,becausethecommonetiologicagentsarealso
themostfrequentcontaminants.
Conventional blood cultures are currently performed
using commercial systems with automated detection of
growth.Thesesystemsconsistofanaerobicandan
anaero-bicbottle,consideredasonebloodcultureset.Somestudies
showasensitivityof<80%foronebloodculturesetand>99%
for3ormoreculturesets.12---14Toensureoptimaldetection
of bacteremia, the volume of blood is the essential
fac-tor. The ClinicalandLaboratory Standards Institute(CLSI)
recommendsthereforethatabloodvolumeofatleast20ml
beinoculatedintoeachof2bloodculturesets(twobottles
perset)takenfromdifferentvenipuncturesites.15
Bloodmustbeobtainedusinganasepticmethodologyto
reduce theriskofcontamination16---18 tolessthan3%ofall
bloodculturesets,19 whichisconsideredtobethe
accept-able range. The venipuncture should be performed after
disinfecting the skin. The three key factors when
choos-ing theantisepticare:antimicrobialspectrum, methodof
application,anddurationofantimicrobialeffect.Themost
commonly used disinfectants are alcohol-,
chlorhexidine-and iodine-based products.20---24 A recent meta-analysis of
6 randomized control trials concluded that: (1) overall,
alcohol-based products seemed to be superior to
non-alcohol-based solutions, and (2) solutions containing a
combination of alcohol and chlorhexidine showed
signifi-cant reductions in contaminatedblood culturescompared
with aqueous povidone-iodine.23 The most widely studied
concentration is 2% chlorhexidine gluconate in isopropyl
alcohol. On the other hand, a recent study showed that
choice of antiseptic agent did not impact contamination
rates when the blood cultures were collected by a
phle-botomyteam.Perhapsthesinglemostimportantaspectis
theuseofpropertechnique,whichincludestimerequired
toperformtheprocedureandallowingenoughtimeforthe
disinfectant toexert itsantimicrobial effect.Alcohol and
chlorhexidineproductsrequire30stodry,whereaspovidone
iodinepreparationsrequire1.5---2min.Nostudieshave
eval-uatedtheeffectofdisinfectingcatheteraccesshubsbefore
drawingthebloodsamples,16althoughitseemstobea
ratio-nalinterventionaimedatminimizingriskofcontamination.
Thetimingofbloodculturecollectionmayvary.Although
mostbloodculturesystemshavedifferentmethodsof
Table2 Summaryofmaindiagnosticmethodsforcatheter-relatedbloodstreaminfections. Criteriafor
positivity
Interpretation Comments Recommendation
Diagnosiswithoutcatheterwithdrawal Pairedquantitative
bloodcultures
Ratio≥3:1 Bothsetsarepositiveforthe samemicroorganismandthe setobtainedthroughthe catheterhas≥3:1fold-higher colonycountthanthe peripheralculture
Sensitivity≈79% Specificity≈99%
Laborintensiveandexpensive A-II
Pairedbloodcultures fordifferentialtime topositivity(DTP)
≥120min Bothsetsarepositiveforthe samemicroorganismandthe setobtainedthroughthe catheterbecomespositive ≥120minearlier
Sensitivity:72%to96% Specificity:90%to95% Lessspecificityforlong-term catheters
TheinterpretationofDTP shouldtakeintoaccount adherencetothetechnical procedureandthetype ofmicroorganism
A-II
Endoluminalbrushing >100CFU IndicativeofCRBSI Sensitivity:95%to100% Specificity:84%to89% ItmayunderestimateCRBSI inshort-termcatheters Riskofpathogendissemination andthromboticcomplications
C-III
Superficialcultures (semiquantitative culturesofskin surroundingthe portalentryand catheterhubs)
≥15CFU perplate
IndicativeofCRBSI Sensitivity:78% Specificity:92% Mustbecombinedwith peripheralbloodculture
B-II Gramstain-acridine orangeleukocyte cytospinofcatheter blood Presenceofany microorganisms inaminimum of100 high-powered fields
IndicativeofCRBSI Sensitivity≈79% Specificity≈87%
Thetechniqueissimpleand rapid,butrequirescytospin technology
B-II
Diagnosiswithcatheterwithdrawal Semiquantitative
catheterculture ≥15
CFU Thesamemicroorganisminat leastonepercutaneousblood cultureandcathetertip culture
Sensitivity≈84% Specificity≈86%
Thismethodmainlydetects colonizationontheexternal surface A-II Quantitativecatheter segmentculture (vortexingorflushing internalsurface)
≥103CFU Thesamemicroorganisminat leastonepercutaneousblood cultureandcathetertip culture
Sensitivity≈83% Specificity≈91%
Allquantitativemethodsare timeconsuming
A-II
Quantitativecatheter segmentculture (sonication)
≥102CFU Thesamemicroorganisminat leastonepercutaneousblood cultureandcathetertip culture
Sensitivity≈83% Specificity≈91%
Allquantitativemethodsare timeconsuming
A-II
beobtained,ifatallpossible,beforeantibiotictherapy is started.16,25---27 Blood cultures obtained from intravascular
catheters areassociatedwithhigher sensitivityand
nega-tivepredictive values.17 InpatientswithsuspectedCRBSI,
two sets of blood cultures should be taken, one from a
peripheral vein andthe other fromthecatheter hub.For
multiple-lumen venous catheters, several studies suggest
thatbloodculturesbedrawnfromalllumens(i.e.,thesame
volumefromeachlumen)toestablishadiagnosisofCRBSI.
Omittingaculture ofsamplesfromoneor morelumensis
associatedwithfailingtodetect aconsiderablenumberof
Once drawn, the blood should be immediately
inocu-latedintotheblood culturebottles,whichshouldthen be
appropriatelymarked(peripheralvein,catheter,etc.) and
promptlyand simultaneously incubated in the automated
machine,in ordertointerpret the results onthebasis of
timeto positivity of each blood culture set. Becausethe
rubbercapsarenotsterile,theyareusuallydisinfectedwith
analcoholsolution,whichmustbedriedbeforeinoculation.
Sincetheincidenceoftrueanaerobicbacteremiaislow,31it
maybepreferabletoinoculatetheoptimalvolumeofblood
intotheaerobicbottlefirst,andthentheremainingvolume
intotheanaerobicbottle.
RECOMMENDATIONS
1. Bloodculturesshouldbeobtainedusinganaseptic
tech-niqueandbeforetheinitiationofantimicrobialtherapy
(A-I).
2. Skin preparation for obtaining blood samples drawn
percutaneouslyshouldbeperformed withproper
tech-niques, including the time to perform the procedure
andleavingadequatetimefor thedisinfectanttotake
effect(A-I).Alcohol-containingproductsareassociated
withlow ratesof contamination.Alcohol-chlorhexidine
solutionsreducebloodculturecontaminationmore
effi-cientlythanaqueouspovidone-iodine(A-I).
3. Twopairsofbloodculturesshouldbedrawninpatients
withsuspectedCRBSI,onefromaperipheralveinandthe
otherfromthecatheter(A-I).
4. Formultiple-lumenvenouscatheters,samplesshouldbe
obtainedfromalllumens(A-II).
Howshouldconventionalbloodculturesbeinterpreted?
Identificationofthemicroorganismisconsideredcrucial
for interpreting the significance of the result.
Propioni-bacterium spp., Bacillusspp., andmost Corynebacterium
spp.almostalwaysmeancontamination.16,26,32
Contamina-tionis definedas the isolation of an organism in a blood
culturethatis notpresent inthepatient’sbloodstream.19
Unfortunately,someofthemicroorganismsthatfrequently
contaminate blood cultures are also common causes of
CRBSI,such ascoagulase-negative staphylococci, which is
theleadingcauseofCRBSI.Otherorganismsthatcause
bac-teremia,suchasS.aureusandEnterococcusspp.,canalso
bedetectedascontaminants,albeitinalowpercentageof
cases.33Inthecaseofskincommensals,atleast2positive
bloodcultureswithanidenticalstrainarerequiredforthem
tobeconsideredacauseofbacteremia.25
Matrix-assistedlaserdesorption/ionizationtime-of-flight
mass spectrometry (MALDI-TOF MS) is one of the most
widely evaluated new technologies for the rapid
micro-bial identification of blood culture isolates.34---40 Although
the performance of MALDI-TOF-based identification varies
depending on the enrichment and purification methods
used,thistechnologyhasshownhighsensitivityand
speci-ficityfor rapididentification ofmicrobes inpositiveblood
cultures.34---40 MALDI-TOF has some limitations associated
withtheidentificationof someGram-positive
microorgan-isms(Streptococcusspp.),non-fermentingGram-negatives,
and non-albicans Candida species,39 although its use in
theclinicalsettingcouldimprovetimetoidentificationof
microorganisms,timetoeffectivetherapyandtimeto
opti-malantimicrobialtherapy.41
Detecting the actual time to positivity of each blood
cultureisconsideredcriticaltothediagnosisofCRBSI.
Sev-eralstudieshaveconfirmedthatmeasuringthedifferential
timetopositivity(DTP)of bloodculturesobtainedfroma
centralvenouscatheterandaperipheralveinishighly
diag-nosticforsuspectedCRBSI.42,43Blotetal.44,45reportedthat
a DTPcut-off limitof120minhad94% sensitivityand94%
specificityfor catheter-relatedinfection,and96.4%
sensi-tivityand100%specificityforcatheter-relatedsepsis.Other
studies showedsimilarresults for thesame cut-off value,
withsensitivities rangingfrom72% to96.4% and
specifici-tiesbetween90.3%and95%.42,43Raadetal.46 showedthat
aDTPof≥120minwasassociatedwitha81%sensitivityand
92%specificityforshort-termcatheters(<30days)and93%
sensitivityand75%specificityforlong-termcatheters(>30
days). Althoughthisdiagnostictesthasbeenimplemented
in routine clinical practice, some authors have reported
that DTP is not useful for diagnosis of CRBSI in medical
surgical intensive care units.47 These differences can be
attributedtothedefinitionofCRBSIused48 ortothetype
of microorganism causing the CRBSI.49---51 A recent report
suggested thataDTPof≥120min wastheoptimal cut-off
point for diagnosis of Candida spp. CRBSI (85% sensitivity
and 82% specificity),except for Candidaglabrata.51
How-ever,inastudyofcatheter-relatedcandidaemia(CRC)that
included mainly Candida albicans and Candida
parapsilo-sis, Bouzaetal.49 found thata DTPof≥120minhad high
sensitivity(94.7%)butlowspecificity(40%).Ingeneral,the
accuracy of the DTP methodrequires accurately tracking
howlongittakesthebloodculturesfromthesource
(cen-tralvenouscathetervs.peripheralvein)tobecomepositive.
Themethodalsoreliesontheculturesbeingplacedinthe
automatedmachineatthesametime.46
ForsuspectedCRBSI,detectionoftheidentical
microor-ganisminbloodculturesobtainedviaperipheral
venipunc-ture and the suspected catheter was recently evaluated
asameansof diagnosingCRBSIwithout catheterremoval.
Althoughmostlaboratoriesuseantimicrobialsusceptibility
testing andbiochemicalidentificationtoestablishidentity
withoutusingmoleculartechniques,whichseemstobethe
most practical waytocompare isolates,the possibilityof
polyclonal infection should always be considered, as
sev-eral studies have demonstratedthat polyclonal infections
areprobablymorecommonthanpreviouslysuspected.52---54
RECOMMENDATIONS
1. Positivityofbloodculturesobtainedthroughthecatheter
≥120minbeforethoseobtainedfromaperipheralvein
with the same microorganism is highly suggestive of
CRBSI. An optimal DTP cut-off for the diagnosis of
catheter-related candidemia has not been established
(A-II).
2. TheinterpretationofDTPshouldconsideradherenceto
theproceduraltechniqueusedandthetypeof
microor-ganism(A-II).
3. Rapidmicrobial identification by MALDI-TOFMS froma
positivebloodculturesignificantlyreducestimeto
iden-tification ofmicroorganismsand hasclinicalimpacton
themanagementofpatientswithsuspectedbloodstream
How should quantitative blood cultures be taken and interpreted?
The quantitative methodology is based on lysing red
blood cellswithdifferentdetergents,centrifugation(i.e.,
lysis-centrifugation)andinoculatingthesedimentinto
dif-ferentculturemediaandindifferentatmospheres.55,56This
systemhasshownbetterresultsthanconventionalmethods
in terms of detection times and specificity, but is
rela-tively complex and the sample must beprocessed within
20---30min of inoculation of the blood into the tube.26,27
There are no specific guidelines for the procedure of
obtainingbloodcultures,sothattherecommendationsfor
conventional blood culturesabovealso applyto
quantita-tive blood cultures,15,16,25---27,32 except for inoculation into
thebottle.Inthelysis-centrifugationsystem,10mlofblood
is inoculated into the lysis tube, which contains the
spe-cificamountofdetergentforthisvolume.Afterinoculation,
thebloodanddetergentshouldbegentlymixedbefore
cen-trifugationisperformed.Anothercurrentlyusedmethodfor
diagnosing CRBSI is the pour plate method.57 Briefly, for
each quantitativeblood culture, 1---3ml of bloodis mixed
with20mlofpreviouslymeltedbrainheartinfusionagarat
∼56◦CinPetriplates,thentheplatesareincubated
aero-bicallyfor4daysat35---37◦C.
The number of blood cultures required is similar to
conventionalbloodcultures.FordiagnosisofCRBSI,several
authors have demonstrated that a differential colony
count that is (5---10 times) greater for the intravascular
catheterblood culture thanthe peripheralvein culture is
indicativeofCRBSI.42,58---61Inameta-analysisperformedby
Safdar etal.,62 the differentialquantitativeblood culture
(DQBC)wasthebestapproachfordiagnosingCRBSIwithout
catheterremoval,withapooledsensitivityof0.79(95%CI:
0.74, 0.84), and pooled specificity of 0.99 (95% CI: 0.98,
1.0). There is some controversy about the cut-off point
of DQBC. A study that evaluated different cut-off points
for paired quantitativeblood culturesforthe diagnosis of
CRBSIshowedthattheDQBCwasnotusefulwithshort-term
central venous catheters (CVCs), although in long-term
CVCs, DQBCs of 2:1 or greater, or 5:1 or greater were
sensitive, but associated withlow specificity and positive
predictive values.61 Quantitative blood cultures are labor
intensiveandexpensive,whichmakesthemlesspracticable
forroutineuse.
RECOMMENDATION
1. Aquantitativebloodculturewithacolonycount3times
greaterinasampledrawnthroughacatheterthanfrom
theperipheralveinsupportsadiagnosisofCRBSI(A-II).
What particular aspects should be considered for the diagnosisofCRBSIinpatientsonhemodialysis?
Forpatientswithoutafunctioningvascularaccess,
cen-tral venous catheters (CVC) have become an acceptable
means of vascular access for hemodialysis (HD),although
their clinical usefulness is severely limited by potential
infectiouscomplications.63---65TherelativeriskofaCVC
caus-ingCRBSIinHDpatientsisestimatedtobeapproximately10
timeshigherthantheriskofbacteremiainpatientswithan
arteriovenousfistulaorgraft.63,65,66
InHDpatients,particularlyintheoutpatientsetting,it
isdifficulttomeetthestandardmicrobiologicalcriteria of
pairedquantitativebloodculturesanddifferentialtimeto
positivitytoconfirm diagnosisofCRBSI.The limitationsof
thestandard diagnostic criteria for CRBSIinclude the
fol-lowing:
1. Obtaining peripheral blood culturesmay beimpossible
inupto40%ofHDpatients,eitherbecausetheir
periph-eralveinshavebeenexhausted orbecauseoftheneed
to avoidvenipuncture in veinsintended for the future
creationofadialysisfistulaorgraft.25,66---69
2. If blood cultures are drawn during the dialysissession
whensystemicbloodiscirculatingthroughthecatheter,
thereisnosignificantdifferencebetweenperipheraland
catheterbloodcultureresults,sothatperipheral
samp-lingcanbeomitted.67---69
3. In the absence of concurrent blood cultures from the
catheterandaperipheralvein,thereisariskthata
pos-itivebloodculturecorrespondstoasourceofinfection
otherthanthecatheter.67,68
4. In theoutpatient setting, longer preincubation due to
excessive timefor transportation may leadto a
false-negativeDTP.25,69
RECOMMENDATIONS
1. Wheneverpossible,pairedblood samplesfromtheCVC
andaperipheralveinshouldbeobtainedforCRBSI
diag-nosisinhemodialysispatients(A-II).
2. Peripheralbloodsamplesshouldbeobtainedfromveins
thatarenotintendedforfuturecreationofdialysis
fis-tulaeorgrafts.Theveinsofthehandforoutpatientsand
hand orfemoralveinsforhospitalinpatients shouldbe
usedtoobtainperipheralbloodcultures(A-III).
3. Ifabloodsamplecannotbedrawnfromaperipheralvein,
twoseparatesamplesshouldbedrawn,10---15minapart,
throughtheCVCorthedialysiscircuitconnectedtothe
catheter(B-II).
What other conservative techniques may be used for diagnosisofCRBSI?
ConservativemethodsforthediagnosisofCRBSIinclude
endoluminalbrushing,superficialculturesoftheskinaround
theinsertionsiteandcatheterhubs,andtheGramstainwith
acridine orange leukocyte cytospin (AOLC) test.42,43,70---72
Endoluminal brushing, a method of sampling the internal
surfaceofthecatheter,showedhighsensitivity(95---100%)
and specificity (84---89%) in two studies7,2,73 although the
procedure is impractical and unreliable and major
side-effectshavebeenreported,suchascardiacarrhythmiasand
embolizationwithsubsequentbacteremia.56Superficial
cul-tures(semiquantitativeculturesofskinaroundthecatheter
insertionsiteandcatheterhubs)havealsobeenproposedfor
thediagnosis ofCRBSI,43 basedonasensitivityand
speci-ficity of78% and 92%, respectively. Ithas been suggested
thatsuperficialandperipheralbloodculturesbecombined
toscreenforCRBSI,reservingDQBCasamorespecific
tech-nique for confirmation. Other authors have also reported
onthe Gramstain-AOLC test asa rapid method for
diag-nosis of CRBSI.70 The methodrequires two50!Lsamples
ofcatheterblood.Afterseveralsteps,includingtheuseof
cytospintechnology,amonolayerofleukocytesand
acridine orange or Gram stain, and viewedby ultraviolet
andlightmicroscopy,respectively.The authorsreporteda
96%sensitivityand92%specificity.70Inthemeta-analysisby
Safdaretal.,62 theoverallsensitivityandspecificityofthe
AOLCtestwere72%and91%,respectively.Generally
speak-ing,thesemethodshavenotbeenvalidatedbyotherauthors
andarenotwidelyusedinclinicallaboratories.Table2gives
abriefsummaryof theseconservativemethods andthose
requiringcatheterremoval.
RECOMMENDATIONS
1. Endoluminal brushing of the internal surface of the
cathetermaybeusefulfordiagnosisofCRBSI.However,
theprocedureisimpracticalandmajorside-effectshave
beenreported(C-III).
2. Semiquantitative cultures of skin around the catheter
insertionsite and catheterhubs with≥15CFU may be
indicativeforCRBSI.Theseproceduresmustbecombined
withperipheralbloodculture(B-II).
3. Gramstain-acridineorangeleukocytecytospin(AOLC)of
catheterbloodmaybeusedasarapidmethodfor
diag-nosisofCRBSI.Thepresenceofanymicroorganismsina
minimumof100high-powered fieldsmaybeindicative
ofCRBSI(B-II).
Whatisthevalueofmoleculartechniquesforthe diag-nosisofCRBSI?
Mostmolecular techniquesfor diagnosis of CRBSI
with-out catheterwithdrawal areperformed directly on blood
samplesdrawnthroughcatheters.Variousmolecular
meth-ods have been applied to different patient populations.
A 16S rDNA analysis of blood drawn through vascular
accessdevicesinpatientswithhematologicdisordershada
100%positivepredictivevalueforCRBSI.74,75Otherauthors
used pulsed-field gel electrophoresis (PFGE) to confirm
CRBSIcausedbycoagulase-negativestaphylococci(CoNS)in
patientswithneutropenia.76Moststudiesarebasedon
real-timePCR, suchasLightCycler® SeptiFastor Gene Xpert®,
which are demonstrated to be a useful complementary
diagnostic tool for blood cultures, especially in patients
receivingantibiotics.77---80Thereisverylittledataaboutthe
useofmoleculartechniqueswithsamplesotherthanblood
toconfirmaCRBSIepisode.81
Although direct molecular detection techniques for
detecting microorganismsin the blood andother samples
areapromisingapproachforimprovingpatientmanagement
andoutcomebystreamliningthediagnosisofCRBSI,theyare
stillcurrentlyunabletoreplacethetraditionalcultureand
remainexpensiveandtime-consuming.82,83
RECOMMENDATION
1. Thereis notenough informationtorecommend
imple-menting molecular techniques in clinical practice for
CRBSIdiagnosis(C-II).
Diagnosis
of
CRBSI
with
catheter
withdrawal
Whenshouldacathetertipbesentforculture?
Diagnosis of CRBSI requires establishing the presence
ofa bloodstreaminfection(see sectionHow should blood
cultures be taken?) and demonstrating that the infection
is related tothe catheter. As a generalrecommendation,
a catheter culture shouldonly be obtained whena CRBSI
issuspected,84 thusavoidingunnecessarycultures.Several
factorsshouldbetakenintoconsiderationwhen
determin-ing whetherthe cathetershouldberemoved: thetype of
catheter, ease of new catheterinsertion, immune status,
theseverityoftheunderlyingillnessofthepatient,andthe
presenceandseverityofsepsis.85---88
RECOMMENDATION
1. CatheterculturesshouldonlybeobtainedwhenCRBSIis
suspected(AII).
Howshouldacatheterbesenttoandprocessedin the MicrobiologyLaboratory?
Afterpullingthecatheter,itstipshouldbecuttoalength
of 5cmapproximately,understerileconditionsand
avoid-ing contact withthe patient’s skin, andthen placed in a
dry,sterilecontainerfortransport.Thecathetertipshould
be stored at 4---8◦C27 while transport tothe laboratory is
arranged.
Themostwidelyusedlaboratorytechniqueisthe
semi-quantitative method described by Maki, in which the
cathetersegmentisrolled acrossablood agarplateusing
sterile forceps. After overnight incubation, the number
of colony-forming units(CFU)is counted.89 Onelimitation
of this method is that it mainly detects colonization on
the external surface of the catheter. This is more of a
concernwithlong-termcatheters,whereluminal
coloniza-tion more frequently leads tobloodstream infections.56,90
In 1980, Cleri described a quantitativeculture methodto
improvethedetectionofmicroorganismsprogressinginside
thecatheterlumen.91 Quantitativeculturesofthe
endolu-menwereobtainedbyimmersingthecathetersegmentin
2---10ml of tryptic soy broth(TSB), then flushing it three
times with a syringe. The broth was serially diluted
100-fold.0.1mlofeachdilutionwasstreakedontosheepblood
agarandthenumberofCFUscountedafterincubation.91
Brun-Bruissonetal.92simplifiedCleri’stechniqueby
pla-cing the catheter segments into a test tube with1ml of
sterile distilledwater. Aftervortexing for 1min, 0.1ml of
thesuspensionisplatedontobloodagar.Othermodifications
ofquantitativeendoluminalculturesincludeaquantitative
sonicationtechnique,93inwhichthecathetertipisplacedin
10mlofTSBandsonicatedfor1min.0.1mlofboththe
soni-catedbrothanda1:100dilutionofthebrothareplatedonto
bloodagarandthenumberofcolony-formingunitscounted.
In order to distinguish between colonization on the
internal and external surfaces of the catheter, Li˜nares
etal.90usedthesemiquantitativemethodforculturingthe
catheters,89 thenamodifiedquantitativetechnique,
flush-ingeachcatheterlumenwith2mlof TSB,whichwasthen
seriallydilutedandplated.
Allquantitative methods are time-consuming,whereas
the simplicity of semiquantitative techniques has
con-tributed to their widespread use in clinical microbiology
laboratories.43,94Severalprospectivestudieshavecompared
Maki’ssemiquantitativetechniquewithquantitative
meth-ods (sonication and vortexing) for detection of CRBSIand
concludedthatthethreemethodsexhibitedsimilar
reliabil-ity,althoughMaki’ssemiquantitativetechniquewassimpler
Thepredictivevaluesofquantitativeorsemiquantitative
methods may varydepending onthetype andlocation of
thecatheter,theculturemethodologyused,andthesource
of catheter colonization.97 For example, skin-colonizing
microorganisms are more likely to colonize the external
surfaceofarecentlyinsertedcatheter,sothatMaki’s
semi-quantitativemethodwouldbeverysensitiveforidentifying
thiscolonization. Bycontrast,a catheterthathasbeen in
placeformorethanaweekcouldbecomecolonized
intralu-minally via the hub, rendering the roll plate method less
sensitive. In this case, methods that obtain samples for
culturefrombothinternal andexternalsurfacesaremore
sensitive.95
RECOMMENDATIONS
1. Themostreliablediagnosticmethodologiesforcatheters
sent toculturearethesemiquantitative(roll plate)or
quantitative(vortexorsonicationmethods)(A-II).
2. Qualitativecultures(cultureofthecathetertipbybroth
immersion) are unreliable for distinguishing between
contaminationandinfection,andarenottherefore
suit-ableforthediagnosisofCRBSI(A-II).
How should the results of catheter cultures be inter-preted?
A semiquantitative catheter cultures discriminate
between catheters as the cause of infection and
non-significantcolonization.Thecatheterisconsideredtobethe
sourceofinfectionifgrowthfromacultureofthecatheter
tipis≥15CFU,whereas<15CFUwithnoassociatedclinical
signsisconsideredtobecathetercolonization.89Thecut-off
point of ≥15CFU is significantly associated with clinical
signsandbacteremia,witha76%specificity.89 Subsequent
studies have validated the semiquantitativeculture
tech-niqueforevaluatingcatheter-relatedinfections.98,99 There
isnoestablishedcut-offpointformycobacteriaandfungi.
For quantitative catheter cultures (flushing the
inter-nal surface and vortexing), the cut-off point has been
establishedat103CFU/segment,basedagainonits
associ-ationwithbacteremiainCRBSI.Colonycountsoflessthan
103CFUare considered intermediate,possible
contamina-tion,ortheearlystagesofcolonization.91,92Forquantitative
cultures based on sonication, a cut-off point of >102CFU
wasestablishedtodiscriminatebetweencatheterinfection
and catheter colonization.93 In general, semiquantitative
andquantitativeculturesgivecomparableresults,although
the semiquantitative procedure is easier and faster in
practice.27,100
RECOMMENDATIONS
1. Thepresenceofmorethan14CFUperplateby
semiquan-titative culture (roll-plate) is indicative of significant
cathetercolonization(A-II).
2. A count of 103CFU/segment or more using
quantita-tiveculturemethodsbasedonvortexingorflushingthe
internalsurfacereflectssignificantcathetercolonization
(A-II).
3. Countsabove102CFU/segmentfor quantitativeculture
methods based on sonication indicate significant
cathetercolonization(A-II).
Howshouldasubcutaneousreservoirbeprocessed?
Venousaccessdevices(VADs) arewidelyusedfor
long-term access to the vascular system, mainly in cancer
patients. The diagnosis and management of CRBSI also
includesarecommendationtoperformaqualitativeculture
of the port reservoir contents as well as a
semiquantita-tivecultureofthecathetertipifVAD-relatedbloodstream
infection(VAD-RBSI)issuspected.Thishasbeenthoroughly
studiedin patientswithsuspectedVAD-RBSI by comparing
VADcultureswithblood culturesobtainedbeforeremoval.
In all studies, the catheter tip cultures failed to detect
severalVAD-RBSIepisodes,whereasculturesofthe
endolu-minalcontent(thromboticmaterial)hadbetterpredictive
value.101---104
Bouza et al. assessed the validity values of cultures
obtained from multiple sites of 223 VADs that had been
withdrawnforsomereasonandconfirmedthattherateof
VADcolonizationimprovedwhentheynotonlyobtained
cul-turesfromthecathetertipandtheinsideoftheport,but
alsofromthesonicationfluidusedtoobtainmicroorganisms
fromthe external surface of the port.105 In addition, del
Pozoetal.assessedtheyieldfromtheseptumof240VAPs
aftersonication.The latterprocedure showedthehighest
sensitivity and specificity (78% and 93%, respectively) for
diagnosingVADcolonizationwithacut-offof110CFU/ml.106
Theserecentfindingswillprobablyhaveanimpactonthe
routinelaboratoryprocessingofpulledVADs,since
confirma-tionofVAD-RBSIrequiresperformingculturesofthecatheter
tip,andtheinnerandouter surfacesoftheport.Thereis
noconsensusstatementforthresholdsforVADcultures.
RECOMMENDATION
1. Venous access devices removed for suspected CRBSI
should besent tothe microbiologylaboratory. Routine
processingshouldincludeacombinationofculturesfrom
different parts of the VAD, including a culture after
septumsonicationandsemiquantitativecathetertip
cul-tures(B-II).
Whatisthe presentvalueofmoleculartechniquesfor thediagnosisofCRBSIaftercatheterremoval?
Diagnosis of CRBSI requires confirmation that the
microorganismsisolated from blood and catheter tip
cul-tures are phenotypically identical. A recent study using
quantitativePCR forthedetectionofCoNSsuggestedthat
theroleofthecatheterasasourceofbacteremiamaybe
overestimated.107Indeed,theconventionalmicrobiological
proceduresusedtodiagnose CoNS CRBSI performed badly
when compared with an evaluation by PFGE of different
morphotypesofCoNS isolatedfromcathetertipandblood
cultures.108 By contrast,usingmicrosatellitemarkers, the
genotypesofCandidaisolatesrecoveredfrombloodcultures
andcathetertipswereamatchin91%ofpatientsstudied.109
Due to its low sensitivity, 16S rRNA polymerase chain
reaction(PCR)hasnotmanagedtoreplacetheconventional
cultureandthereareat presentnodata aboutthe
appli-cation of molecular methods to non-tunneled catheters.
Ontheother hand,the applicationof 16SrRNAPCR using
endoluminalsamplesincreaseddetectionofvenousaccess
device-relatedbloodstreaminfection(VAD-RBSI)inpatients
In summary, molecular methods have the potential to
improve diagnosis of CRBSIin patients undergoing
antibi-otic therapy, although these techniques have not been
standardized. RECOMMENDATION
1. 16SrRNAPCR couldbeperformed withseptum
sonica-tion fluid to rule out or confirm VAD-RBSI in patients
undergoingantibiotictherapy(C-III).
Diagnosis
of
local
signs
of
infection
Whatsamplesshouldbetakenandhowshouldtheybe inter-pretedwhenaninsertionsiteinfectionissuspected?
Insertion site infections are characterized by signs of
inflammation,includinginduration,erythema,warmth,and
painortendernesswithin2cmofthecatheterinsertionsite.
Theymayalsobeassociatedwithothersignsandsymptoms
ofinfection,suchasfever or purulentdischarge fromthe
insertionsite,withorwithout aconcomitant bloodstream
infection.6,111Amicrobiologicallydocumentedinsertionsite
infection is defined asexudate witha positive culture at
thecatheterinsertionsite.6,111Thesensitivityandpositive
predictivevalueof localinflammationfor thediagnosisof
CRBSIisshown tobeverylow.112 When catheterinfection
issuspectedandthereisexudateatthecatheterinsertion
site, the exudate should be sent for Gramstaining,
rou-tineculture, andadditional culturefor fungi asindicated
whenassessingimmunocompromisedpatients.25 Blood
cul-turesshouldalsobedrawn.6,111,112
In the absence of local signs of infection, the results
of several studies suggest that semi-quantitative cultures
of swabs of skin taken from around the insertion site
and surface cultures from the internal surface of the
catheterhubsmay beuseful for ruling outcatheter
colo-nizationandinfection,andsoavoidingunnecessarycatheter
withdrawals.43,81,113---115Forskinsamples,adrycottonswab
should be rubbed over a 2cm2 area aroundthe insertion
site. For hub samples a small alginate swab should be
introduced into each hub and rubbed repeatedly against
itsinnersurface.43,113Semi-quantitativegrowthof<15CFU
fromboththeinsertionsiteandthecatheterhubenables
CRBSItoberuled out,43,113 althoughsurfaceculturesshow
verylowspecificityandpositivepredictivevalue.
Combin-ing a semiquantitative culture of the subcutaneous tract
witha hub swabculture improves specificity andpositive
predictivevalues.116
VAD-related infectionshould be suspected if a patient
exhibitssignsofalocalinfection,suchaspainorerythemaat
theimplantsite.104Alocalcomplicatedinfectionisdefined
as infection of the tunnel or pocket, with extended
ery-themaorinduration(morethan2cm),purulentcollection,
skinnecrosisandspontaneousruptureanddrainage.Clinical
signs of local infection, such asredness or purulent
exu-date,havehighspecificitybutlowsensitivity.101,104Arecent
studyshowedthat23%ofpatientswithVAD-related
infec-tionhadlocalsignsofinfection.117 Insuchcases,aculture
ofpurulentfluidand/ornecrotictissuesurroundingtheport
isrequired.Bloodculturefromperipheralveinsshouldalso
beperformedinordertoruleoutCRBSI.
RECOMMENDATIONS
1. When there is exudate at the catheter insertion site,
it shouldbe sent for Gramstainingand culture.Blood
culturesshouldalsobedrawn(A-III).
2. Inpatientswithsuspectedcatheter-relatedinfectionbut
negative superficial cultures (growth of <15CFU from
both theinsertionsite andcatheterhubcultures),the
possibilityofinfectioncanreasonablyberuledout(B-II).
Catheter
related
bloodstream
infection
treatment
The main antimicrobial drug and dosage regimens that
shouldbeusedforCRBSIareshowninTable3.
Whencanacatheterberetaineduntilbloodculturesare available?
Twostudiesfoundnodifferencesinoutcomewhenearly
CVCremovalwascomparedwithawatchfulwaiting
strat-egy for suspected CRBSI in patients with non-tunneled
catheters.118---120 These studies excluded patients with
neutropenia,solidorganorhematologicmalignancy,
immu-nosuppressivedrugsorradiationtherapy,organtransplants,
intravascularforeignbodies,hemodynamicinstability,
sup-purationorfrankerythema/indurationattheinsertionsite,
aswellasbacteremiaorfungemia.OneoftheseICU
stud-ieswasarandomizedsingle-centerclinicaltrial118andthe
otherwasprospective,observational,andmulticenter.119In
themulticenterstudy,CRBSIwasconfirmedinonly 12%of
patientsandtherewasnodifferenceinmortalitybetween
immediateandlateremovalof theCVC.Another
random-izedtrialdemonstratedthat,withcriticallyillpatients,the
DTP method makes it possible to use a watchful waiting
strategyuptodefinitivediagnosisofCRBSI.121 Itshouldbe
notedthat catheterexchangeis notwithoutitsrisks,and
severecomplications,althoughfortunatelyuncommon,can
occur.122
RECOMMENDATION
1. Immediate removalof theCVC isnot routinely
recom-mended when CRBSI is suspected in patients who are
hemodynamically stable, without immunosuppressive
therapy, intravascular foreign bodies or organ
trans-plantation, no suppuration at the insertion site or
bacteremia/fungemia,(A-I).
Whenisitsafetoperformacatheterexchangeovera guidewire?
A CVC replacement can be inserted by percutaneous
venipuncture at a new site or by using the Seldinger
over-the-guidewire technique. A meta-analysis of 12
ran-domizedcontrolledtrials(RCT)123thatevaluatedguidewire
exchange versus new-site insertion found non-significant
differences betweenthetwofor theprevention ofCRBSI.
Guidewireexchangewasassociatedwithfewermechanical
complications (8 RCTs, relativerisk=0.48,95% confidence
interval=0.12---1.91) but also a higher rate of catheter
colonization (9 RCTs, relative risk=1.26, 95% confidence
interval=0.87---1.84),catheterexit-siteinfections (5RCTs,
Table3 Themainantimicrobialdruganddosageregimens thatshouldbeusedforcatheter-relatedinfections.
Antimicrobial Dosage
Antibacterials
Amikacin Loadingdose:25---30mg/kgIV, followedby15---20mg/kg/dIV Amoxicillin-clavulanate 2g/200---500mgevery6---8hIV Ampicillin 2gevery6---8hIV Aztreonam 1---2g/6---8hIV Cefazolin 2gevery8hIV Cefepime 2g/8---12hIV Ceftaroline 600mg/12hIV Ceftazidime 2g/8-12hIV Ceftriaxone 1gevery12h Cefotaxime 1---2g/6---8hIV Ciprofloxacin 500mg/12hIVVO Cloxacillin 2gevery4hIV
Colistin 7---9MUload,then4.5MU
every12hIV
Dalbavancin 1000mgIV,500mgIVoneweek apart Daptomycin 8---10mg/kg/dIV Ertapenem 1gevery24hIV Fosfomycin 4g/6---8hIV Gentamicin 5---7mg/kg/dIV Imipenem-cilastatin 500mgevery6hIV Levofloxacin 750mgdaily Linezolid 600mgevery12h Meropenem 1gevery8hIV Piperacillin-tazobactam 4/0.5gevery6---8h SMX-TMP 160---800mgbid 5---10mg/kg/dayofTMP Tedizolid 200mg/d Teicoplanin 6mg/kg/12h(3doses), 6mg/kg/dIV Tobramycin 5---7mg/kg/dIV
Vancomycin Loadingdose:25---30mg/kgIV, then15---20mg/kg/8---12hIV Antifungals
Anidulafungin 200mgloadingdose,100mg/d IV
Caspofungin 70mgloadingdose,50mg/k/d Fluconazole 800mgloadingdose,then
400mgdaily LiposomalamphotericinB 3---5mg/kg/d
Micafungin 100mg/dIV
Voriconazole 400mgbid×2doses,then 200mgevery12h6mg/kgIV every12hfor2doses,followed by4mg/kgIVevery12h Notethatdosesofthedrugsarenotadjustedforrenalorhepatic function.
and catheter-related bacteremia (9 RCTs, relative risk=1.72, 95% confidence interval=0.89---3.33).123 A
study of 1598 CVCs in critically ill patients showed that
over-the-guidewire exchange was associated with the
development of CRBSI.124 On the other hand, inserting
tunneled hemodialysis catheters using elective guidewire
exchangefromnon-tunneledcatheterswasnotassociated
withahigherincidenceofcatheterinfections,andvenous
accesswaspreservedinthesehigh-riskpatients.125
Guidewire exchange is not indicated for patients
with documented catheter infections or CRBSI.126 Using
guidewire-assisted exchange to replace a malfunctioning
catheteris an option if there is noevidence of infection
atthecathetersiteandnewpercutaneousvenipunctureis
notrecommendedbecauseof ahigh risk ofcomplications
(difficultvenousaccess,bleedingdiathesis).
RECOMMENDATIONS
1. Routine replacement of a CVC by guidewire exchange
isnotrecommendedbecausethisstrategyisassociated
withahigherriskofassociatedinfectiouscomplications.
(B-II)
2. Guidewire exchange of a CVC is contraindicated in
patients with documentedcatheter relatedinfections.
(A-II)
3. Guidewire exchange should be restricted to patients
withverydifficultvenousaccess(i.e.,extensive burns,
morbid obesity, or severe coagulopathy) and without
documented catheter infection (B-II). In this case, a
meticulous aseptic technique and a culture of the
cathetertiparemandatory.(A-III)
4. If the catheter tip culture is positive, the new line,
insertedoveraguidewire,shouldbere-placedviaanew
directvenipuncture.(C-III)
Whatshouldbedoneifthecathetertipcultureis posi-tive,butthebloodculturesarenegative?
Thereisverylimiteddataabouttheclinicalimplications
ofa positiveCVCtip culturewithnegativeblood cultures
takenatthetimeofcatheterremoval.
Two retrospective studies127,128 concluded that an
intravascular catheter colonized with S. aureus is a risk
factorforsubsequentS.aureusCRBSI.Antibiotictherapy
ini-tiatedwithin24hofcatheterremovalsignificantlyreduced
theriskforsubsequentS.aureusbacteremia(SAB).
Anotherretrospectivemulticenterstudyshowedalower
incidence of septic complications after the removal of a
colonized catheterin patients withearly antibiotic
treat-ment(13%vs.4%)(OR=4.2;95%CI=1.1---15.6).Inthatstudy,
exit-site infection wasalso a risk factor for the
develop-mentofS.aureusCRBSI(OR=3.39;95%CI=1.19---9.34).127A
meta-analysisoffourretrospectivestudiesyieldedapooled
ORof5.8(95%CI=2.6---13.2)forSABwhenantibiotic
ther-apy was not initiated. The number needed to treat to
prevent 1 episode of SAB was 7.4.129 Conversely, a more
recentretrospectivestudyconcludedthatadministrationof
earlyantistaphylococcaltherapyhadnoimpactonoutcome,
whichwasdefinedasS.aureusinfectionwithin3monthsof
catheterwithdrawal or deathwithno obviouscause. The
onlyfactorindependently associatedwithapooroutcome
wereclinical signsof sepsis atthe timethe catheterwas
removed(OR=20.8;95%CI=2.0---206.1).130,131
AretrospectivestudyofpatientswithCVCtipscolonized
withCandidaspp.observedthattheincidenceofsubsequent
candidemia(SC)wasonly1.7%andamultivariate analysis
of risk factors for poor prognosis showed that antifungal
therapy wasnot protective in this setting (OR=0.82;95%
CI=0.27---2.47).132Amorerecentstudyshowedthatthe
was not protective in 55% of patients.133 Another study
however showed that the risk of infectious complications
followingcatheterremovalwashigherwhenCandidaspp.
wereinvolved(7.7%)thaninthecaseofbacterialinfection
(1.8%)and initiating antifungaltherapy wassuggested for
allpatientswithpositivecathetertipculturesandnegative
bloodcultures.134
Noclearrecommendationscanbegivenifthecatheteris
colonizedwithothermicroorganisms.Thedecisionshouldbe
individualized,althoughantimicrobialtherapywouldbe
jus-tifiedonlyinpatientswithsepticshockandnootherobvious
explanationfortheclinicalpicture.
RECOMMENDATIONS
1. Antibiotictreatment(i.e.,5---7days)shouldbegivento
patientswithcathetertipculturespositiveforS.aureus
andnegativebloodculturesifthepatientshowssystemic
orlocalinfection(B-II).
2. In non-neutropenic patients or those without valvular
heart disease, the presence of a catheter tip culture
positive for Candida spp. and negative or unavailable
bloodculturesshouldbeassessedonanindividualbasis
before starting systematic antifungal treatment.
Anti-fungaltreatment shouldnotbeprescribedforpatients
withoutsystemicsignsofinfection(B-II).
3. No clear recommendations can be given for catheters
colonizedwithothermicroorganisms(C-III).
Empirical
antimicrobial
therapy
WhatistheempiricalantimicrobialtherapyforCRBSI?
The initial choice of antimicrobial should be based on
anassessmentoftheriskfactorsforinfection,theseverity
oftheclinical pictureandthelikelypathogens associated
withthespecificintravasculardevice.Fig.1summarizesthe
recommendedempiricalapproachforapatientwithahigh
indexofsuspicionforCRBSI.
Patients with S. aureus CRBSI are at high risk for
hematogenous metastasis, especially when the catheter
cannot be removed and/or antibiotic treatment is not
appropriate.135 As most CoNS are methicillin-resistant,
the choice of empirical therapy should include
antibi-otics with activity against these strains. Vancomycin is
the most commonly prescribed antimicrobial for CoNS
and methicillin-resistant S. aureus (MRSA) bacteremia in
recentdecades.Studies comparingtheefficacyandsafety
of glycopeptides (i.e., vancomycin vs. teicoplanin) for
Staphylococcusspp.(includingMRSA)bacteremiahave not observedsignificantdifferences,136,137althoughclinical
iso-lates of Staphylococcus epidermidis and Staphylococcus
haemolyticushavebeenreportedwithreduced susceptibil-itytoteicoplanin.138
Vancomycinisassociatedwithlowerclinicalsuccessrates
forMRSAbacteremia withMICs≥1.5mg/l(measuredby
E-test)139,140.Inacase---controlstudyfocusingoncasesofMRSA
bloodstream infection with a vancomycin MIC ≥1.5mg/l
(measured byE-test), ahigher survivalratewasobserved
inthepatientgrouptreatedwithdaptomycin.141
Multivari-ateanalysisconfirmedthatrenalimpairmentandprevious
therapywithvancomycinwereassociatedwithsignificantly
higherclinicalfailure.The impactontheoutcomeof
bac-teremia caused by CoNS with vancomycin MIC ≥1.5mg/l
(measuredbyE-test)isanunresolvedissue.
Previousstudieshaveindicatedthatvancomycinis
infe-rior to beta-lactams (i.e., cefazolin or oxacillin) for the
treatmentofmethicillin-susceptibleStaphylococcusaureus
(MSSA)bloodstreaminfections.142---144Thiswouldjustifythe
inclusionofabeta-lactamintheempiricaltreatmentofany
suspected case of CRBSI. A recent study compared
beta-lactamsandvancomycinforempiricalanddefinitivetherapy
of MSSAbloodstreaminfections among5787patientsfrom
122 hospitals.145 Patientswho received definitive therapy
with a beta-lactam had a 35% lower mortality compared
with patients who received vancomycin (HR=0.65; 95%
CI=0.52---0.80)aftercontrollingforotherfactors.145
Daptomycin is a lipopeptide antibiotic with in vitro
activity against Gram-positive bacteria and is also more
bactericidal than vancomycin.146,147 The only randomized
trial that has compared daptomycin with vancomycin or
a "-lactam concluded that daptomycin was noninferior
to vancomycin.148 In a recent cohort study including 579
episodes of bacteremia caused by MRSA, no significant
differences were observed in the mortality of patients
treated with vancomycin or daptomycin (OR=1.42 [95%
CI=0.83---2.44]).149 However, a recent study analyzing the
efficacy of daptomycin in 40 cancer patients treated for
Gram-positive CRBSI (including S. aureus) compared with
ahistoricalcontrolgroup of40patientstreatedwith
van-comycin confirmed faster bacteriological eradication and
clinicalresolutioninthedaptomycingroup.150
In a randomized clinical trial of skin-structure
infec-tion and CRBSI with S. aureus, including MRSA, linezolid
and its comparators showed similarefficacy for CRBSI.151
Ameta-analysisof 5randomizedcontrolledtrialsofMRSA
bacteremia observed that linezolid was noninferior to
vancomycin.152
RECOMMENDATIONS
1. If CRBSI is suspected, antimicrobial therapy should be
started as soon as possible with a bactericidal agent
activeagainstS. aureusandCoNS, especiallyif
associ-atedwithsepsisorsepticshock(B-II).
2. Vancomycin is recommended for empirical therapy in
patients withsuspected CRBSI(B-II).Teicoplaninis not
recommendedasempiricaltherapy,giventheexistence
of coagulase-negative staphylococci with reduced
sus-ceptibilitytoteicoplanin(C-III).
3. DaptomycincanbeadministeredforcasesofCRBSIwith
septicshock(C-III),acutekidneyinjury(B-III),topatients
with recent exposure to vancomycin (>1 week in the
past 3 months) (C-III) or if the local prevalence of S.
aureusisolateswithvancomycinMIC≥1.5!g/mlishigh
(C-III). The local prevalence of S. aureus isolateswith
vancomycinMIC≥1.5!g/mlsupportingroutineempirical
useofdaptomycinremainsundefined.
4. Linezolidshouldonlybeusedinpatientswith
contraindi-cationsforthepreviousagents(B-II).
WhenshouldempiricalcoverageofGram-negativebacilli orfungibeadded?
The incidence of Gram-negative bacilli (GN)-CRBSI is
reported to be 17---25% of all episodes of CRBSI.153,154
