Diagnóstico y tratamiento de la bacteriemia y endocarditis por Staphylococcus aureus. Guía clínica de la Sociedad Española de Microbiología Clínica y Enfermedades Infecciosas

EnfermInfeccMicrobiolClin.2015;33(9):626–632

ww w . e l s e v i e r . e s / e i m c

Consensus

statement

Executive

summary

of

the

diagnosis

and

treatment

of

bacteremia

and

endocarditis

due

to

Staphylococcus

aureus

.

A

clinical

guideline

from

the

Spanish

Society

of

Clinical

Microbiology

and

Infectious

Diseases

(SEIMC)

Francesc

Gudiol

_,

_José

_María

_Aguado

_,

_Benito

_Almirante

_,

_Emilio

_Bouza

_,

_Emilia

_Cercenado

_,

M.

Ángeles

Domínguez

_,

_Oriol

_Gasch

_,

_Jaime

_Lora-Tamayo

_,

_José

_M.

_Miró

_,

_Mercedes

_Palomar

_,

Alvaro

Pascual

_,

_Juan

_M.

_Pericas

_,

_Miquel

_Pujol

_,

_Jesús

_{Rodríguez-Ba ˜}

_no

_,

_Evelyn

_Shaw

_,

Alex

Soriano

_,

_Jordi

_Vallés

a_{ServiciodeEnfermedadesInfecciosas,IDIBELL,HospitalUniversitariodeBellvitge,Barcelona,Spain}

b_{UnidaddeEnfermedadesInfecciosas,InstitutodeInvestigacióni+12,HospitalUniversitario12deOctubre,Madrid,Spain}

c_{ServiciodeEnfermedadesInfecciosas,HospitalUniversitarioValledeHebrón,Barcelona,Spain}

d_{ServiciodeMicrobiologíayEnfermedadesInfecciosas,HospitalUniversitarioGregorioMara˜nón,Madrid,Spain} e_{ServiciodeMicrobiología,IDIBELL,HospitalUniversitariodeBellvitge,Barcelona,Spain}

f_{Departamentodepatologíayterapéuticaexperimental,UniversidaddeBarcelona,Spain}

g_{ServiciodeEnfermedadesInfecciosas,HospitalUniversitariParcTaulí,Sabadell,Spain}

h_{ServiciodeEnfermedadesInfecciosas,HospitalClínic–IDIBAPS,UniversidaddeBarcelona,Barcelona,Spain}

i_{ServiciodeMedicinaIntensiva,HospitalArnaudeVilanova,Lleida,Spain}

j_{UnidadClínicaIntercentrosdeEnfermedadesInfecciosas,MicrobiologíayMedicinaPreventiva,HospitalesUniversitariosVirgenMacarenayVirgendelRocío,Sevilla,Spain}

k_{DepartamentodeMicrobiología,UniversidaddeSevilla,Spain} l_{DepartamentodeMedicina,UniversidaddeSevilla,Spain}

m_{ServiciodeCuidadosIntensivos,HospitalUniversitariParcTaulí,Sabadell,Barcelona,Spain}

a

r

t

i

c

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e

i

n

f

o

Articlehistory: Received15March2015 Accepted16March2015

Keywords: Bacteremia Infectiveendocarditis Staphylococcusaureus Methicillin-resistant Methicillin-susceptible Clinicalguidelines

a

b

s

t

r

a

c

t

BacteremiaandinfectiveendocarditiscausedbyStaphylococcusaureusarecommonandseverediseases. Optimizationoftreatmentisfundamentalintheprognosisoftheseinfections.Thehighratesof treat-mentfailureandtheincreasinginterestintheinfluenceofvancomycinsusceptibilityintheoutcomeof infectionscausedbybothmethicillin-susceptibleand-resistantisolateshaveledtoresearchonnovel therapeuticschemes.Theinterestinthenewantimicrobialswithactivityagainstmethicillin-resistant staphylococcihasbeenextendedtosusceptiblestrains,whichstillcarrythemostimportantburden ofinfection.Newcombinationsofantimicrobialshavebeeninvestigatedinexperimentalandclinical studies,buttheirroleisstillbeingdebated.Also,theappropriatenessoftheinitialempiricaltherapy hasacquiredrelevanceinrecentyears.Theaimofthisguidelineistoupdatethe2009guidelinesandto provideanensembleofrecommendationsinordertoimprovethetreatmentofstaphylococcalbacteremia andinfectiveendocarditis,inaccordancewiththelatestpublishedevidence.

©2015ElsevierEspaña,S.L.U.andSociedadEspañoladeEnfermedadesInfecciosasyMicrobiología Clínica.Allrightsreserved.

∗ _{Correspondingauthor.}

E-mailaddress:[email protected](J.M.Aguado).

http://dx.doi.org/10.1016/j.eimc.2015.03.014

Palabrasclave: Bacteriemia Endocarditisinfecciosa Staphylococcusaureus Resistenteameticilina Sensibleameticilina Documentodeconsenso

Executive

summary

del

diagnóstico

y

el

tratamiento

de

la

bacteriemia

y

endocarditis

por

Staphylococcus

aureus

.

Una

guía

de

práctica

clínica

de

la

Sociedad

Espa ˜

nola

de

Microbiología

Clínica

y

Enfermedades

Infecciosas

(SEIMC)

r

e

s

u

m

e

n

LabacteriemiaylaendocarditisinfecciosacausadasporStaphylococcusaureussonenfermedades fre-cuentesygraves.Eltratamientoantibióticoesclaveeneléxitoterapéutico.Elrecientedescubrimiento delarelaciónentrelasusceptibilidadavancomicinayelpronósticodeestasinfecciones,tantocuando encepasresistentescomosensiblesameticilina,hallevadoalainvestigacióndenuevostratamientos.El interésporlosnuevosantibióticosconactividadfrenteacepasresistentesameticilinasehaextendidoa lascepassensibles,aúnresponsablesdelamayorpartedeinfecciones.Estudiosclínicosyexperimentales hanevaluadolaeficaciadenuevascombinacionesdeantimicrobianos,sibiensuindicaciónnohasido aúnestablecida.Tambiénlanecesidaddeuntratamientoinicialempíricocorrectohacobradorelevancia. Elobjetivodeestedocumentoesactualizareldocumentodeconsensodel2009yobtenerunconjuntode recomendacionesparamejorareltratamientodelabacteriemiayendocarditisestafilocócicas,deacuerdo alaúltimaevidenciacientíficapublicada.

©2015ElsevierEspaña,S.L.U.ySociedadEspañoladeEnfermedadesInfecciosasyMicrobiologíaClínica. Todoslosderechosreservados.

IthasonlybeensixyearssinceourpanelpublishedaClinical Guideline onthemanagementof methicillin-resistant

Staphylo-coccusaureusbacteremia (SAB) and infectiveendocarditis(IE).1

However,SABandIEcontinuetobeaclinicalproblemofparamount importance,andconsiderableevidencehasbeenpublishedduring thelastfewyears.Inadditiontosignificantadvancesintheresearch of methicillin-resistantS. aureus (MRSA) bloodstreaminfection, veryinterestingstudiesfocusingontheprognosisandclinical man-agementofmethicillin-susceptibleS.aureusbacteremiahavebeen performed.Indeed,methicillin-susceptiblestrainsactually carry themostimportantburdenofthisclinicalchallenge.New stud-iessuggestthatsomeaspectssuchasthevancomycinMICcould berelevant,alsointhesettingofmethicillin-susceptibleS.aureus. Also,wheninitiatingthetreatmentforSAB,somerelevant infor-mationisstilllacking,andthepossibilityofanunderlyingIEhas notbeenruled out.Thus, thereisaclinicalneedfor reconciling importantaspectsinthemanagementofSAB,suchastheempirical anddefinitivetreatment,thelengthoftherapy,ortheantimicrobial treatmentintegrationinawidercontextofmanagement optimiza-tion.Therefore,themainobjectiveofthisClinicalGuidelineisto provideanensembleofrecommendationsinordertoimprovethe treatmentofbacteremiaandIEcausedbyS.aureus,inaccordance tothelatestevidencepublished.

This Guideline will review important microbiological and geneticconceptsofSABpathogenesisandepidemics.Itwillalso analyzethemanagementofthreespecificclinicalscenarios: clini-calsuspicionofSAB;confirmednon-complicatedandcomplicated SAB;andinfectiveendocarditis.Themanagementofsecondary bac-teremiainspecificstaphylococcalinfectionsisbeyondthescopeof thisGuideline.Finally,theroleofcarebundlesthatmaycontribute toamelioratetheprognosisofSABwillbealsoanalyzed.Thewhole documentisavailableintheonlineversion.2

MicrobiologicalaspectsofSAB

Whataretheavailabletechniquestoidentify

methicillin-susceptibleS.aureus(MSSA)orMRSAinpositive

bloodcultures?

Recommendation

•Theimplementationof earlydetectionof S.aureusin positive blood cultures by matrix-assisted laser desorption ionization time-of-flight spectrometry (MALDI-TOF MS), or other rapid

techniques,combinedwiththedetectionofmethicillin suscep-tibilitybypolymerasechainreaction(PCR)basedmethodshas proventobeaconvenientcombinationfortheearlydiagnosisof

S.aureusbacteremiaandmethicillinsusceptibility(A-II).

Whatactionswouldimprovereportingofresultstotheclinician?

Recommendation

•Theactivenotificationofthemicrobiologicalresultsis recom-mended,aspartofabundleofinterventionsaimedtoimprove themanagementofpatientswithSAB(A-I).

Whataretherecommendedtechniquesfordeterminingthe

resistanceordiminishedsusceptibilityofS.aureus

toantimicrobialagents?

Recommendations

•TheEuropeanCommitteeofAntimicrobialSusceptibility Test-ing(EUCAST)specificmethodsforthedetectionofantimicrobial mechanisms of resistance of clinical and/or epidemiological importancearerecommended(B-III).

•For the detection of methicillin-resistance by disc diffusion, cefoxitinistheagentofchoice(B-III).

•Brothmicrodilutionisthegoldstandardmethodfordetermining vancomycinMIC,butitcanalsobedeterminedbystripmethods, agardilutionorautomatedsystems(B-III).

HowoftenthestudiesofsurveillanceofresistanceofS.aureus

shouldbeperformed?

Recommendations

•Theconstantchangesinthepatternofantimicrobialresistance

inS.aureusmustberegularlymonitored.Surveillancemustbe

performedona monthlybasis inhigh-riskunits,and at least onceperyearinawholeinstitution(B-III).

•Itisalsorecommendedtomonitortheevolutionofsusceptibility tovancomycin,daptomycinandlinezolidinsuccessiveisolates fromthesamepatient(B-III).

628 F.Gudioletal./EnfermInfeccMicrobiolClin.2015;33(9):626–632

EmpiricaltreatmentofaclinicalsuspicionofSAB

Whatistheimpactofanappropriateempiricaltreatmentinthe

prognosisofSAB?

Recommendation

•Withtheavailableevidence,itseemsreasonableprescribingearly appropriate treatmentto anypatient suspected to have SAB, althoughsomesubpopulationsmayhaveamoresignificant ben-efitascomparedtoothers(A-II).

Whoisathigherriskofpresentingwithbacteremiacaused

byMRSA?

Recommendations

•BacteremiabyMRSAshouldbesuspectedinthefollowing cir-cumstances:

(1)nosocomialepisodes,especially ifoccurringinwardswith highMRSAprevalence(dependingoneachcentre’slocal epi-demiology)(A-II);

(2)non-nosocomialepisodesinpatientspreviouslycolonizedby MRSA(A-II),comingfromnursinghomes(A-II)or hemodial-ysiscenters(B-II),withacentralvenouscatheter(CVC)(B-II) orchroniccutaneousulcers(B-II).

•IncludingantibioticswithactivityagainstMRSAin community-acquiredepisodeswithnoneoftheformerriskfactorsseemsto benotnecessary(B-II).

Whatisthemostappropriateempiricalantibiotictreatment

whensuspectingSAB?

Recommendations

•InasuspectedepisodeofSAB,atreatmentwithbactericidal activ-ityagainst S.aureus must bestarted, soeffectivebactericidal concentrationsareavailableassoonaspossible,especially for casespresentingwithseveresepsisorshock(C-III).

•Theempiricaltreatmentmustinclude,ifpossible,a penicillinase-stable␤-lactam(A-II).

•WhenthepresenceofMRSAseemslikely,asecondantibioticwith bactericidalactivityagainstMRSAshouldbeadded(C-III).The followingpossibilitieswouldbeadvisable:

oVancomycinincombinationwitha␤-lactam(B-III).

oIncasesofseveresepsisorshock(C-III),recentuse(previous 30days)ofvancomycin(C-III),ahigherlocalprevalenceofS.

aureusisolateswithvancomycinMIC≥1.5mg/L(measuredby

E-test)(C-III)and/orpreviousrenalimpairment(B-III)bythe useofdaptomycinincombinationwitha␤-lactamispreferred (C-III).

oAlternatively,patientsmaybetreatedwithdaptomycinalone atrecommendeddosesof10mg/kg(A-II)

Managementofnon-complicatedSAB

1Catheter-relatedbacteremia(CRB)

Inwhatcasesthecathetermustberemoved?

Recommendations

•Thepresenceofinflammatorysignsatthesiteofinsertionofany intravenouslineresponsibleforSABforcesthepromptremoval ofthecatheter.Cathetersshouldbealsoremovedifinfectionis suspected(presenceofcatheterandnootherobviousfocus)and catheteriseasilyreplaceable(A-II).

•AconservativeapproachtoCRBcausedbyS.aureusshouldbeonly attemptedinexceptionalcircumstances(e.g.absolute impossi-bilityofremovingthecatheterfortechnicalreasons),andtaking intoaccounttheclinicalandbaselinecharacteristicsofthepatient (B-II).Inthesecases,theantibioticlocktherapymustbe admin-isteredincombinationwithaneffectivesystemicantimicrobial treatment(B-II).Anyway,thepersistenceofbacteremiabeyond thefirst72hofaconservativemanagementwillleadtothe imme-diateremovalofthecatheter(B-II).

WhoshouldbescreenedforrulingoutcomplicationsofSAB

Recommendations

Acarefulevaluationofthepatient’ssymptomsandan exhaus-tiveclinicalexaminationareessentialincasesofcatheter-related SABinordertoruleoutpossiblesourcesoftheinfection.The pres-enceofeventualmetastaticsepticfocimustbeidentified(B-II).

•Bloodculturesmustbetakenafter72hoftheonsetofappropriate antimicrobialtherapyinordertoruleoutcomplicatedbacteremia (A-II).

•Systematically performing transesophageal echocardiography (TEE)toallpatientswithCRBbyS.aureusinordertodecidethe lengthoftherapyremainscontroversial.Theabsenceof valvu-larrisk(novalvulardisease,neitherpreviousnordiagnosedat the moment of SAB) along with a clinical and microbiologi-calresponsetotherapywithinthefirst72hafterthecatheter removalandonsetofadequateantibioticsareassociatedwitha favorableoutcome(absenceofcomplicationsorrelapse)inmore than95%ofpatientsthatreceivetreatmentforatleast14days afternegativebloodcultures(B-II).

•The length of therapy needs to be adapted to the findings of the TEE or central veins ultrasonography, when indicated (A-II).

•Theroleofnewimaging moleculartechniquesforthe diagno-sisofintracardiacdevice-associatedinfectionshasnotbeenfully elucidated(C-II).

Whatisthedefinitiveantibiotictreatmentofcatheter-related

bacteremia?

Recommendations

•ThetreatmentofchoiceforanepisodeofCRBcausedbyMSSAis cloxacillin(B-I).

•Alternatively,patientsmaybetreatedwithdaptomycin(A-I)or aglycopeptide(B-II).

•Thebestantimicrobialtreatmentinepisodescausedbyastrain ofMSSAwithlowsusceptibilitytovancomycin(MIC≥1.5mg/L measuredbyE-test)hasnotbeenelucidated.Thispanelsuggests touseacombinationofcloxacillinanddaptomycinwhenblood culturesremainpositiveand/orclinicalimprovementisnot evi-dentaftercatheterremoval(C-III).

•Inthecase of CRBcausedbyMRSA, vancomycinis the treat-mentofchoice(B-II).Itmaybecontinuedinstablepatientswith negativebloodculturesafter72hoftreatment,regardlessofthe susceptibilityofvancomycin(C-III).

•Alternatively,patientsmaybetreatedwithdaptomycin(A-I). •Linezolidshouldbeonlyusedinpatientswhocannottakethe

previousagents(B-II).

Whichclinical,biologicalormicrobiologicalparametersindicatea

favorableevolutionofpatientswithcatheter-relatedSAB?

Recommendation

AnepisodeofCRBcausedbyS.aureusmaybeconsideredas non-complicatedonthebasisofseveralcharacteristicsofthehost

(suchasabsenceofdiabetes,immunosuppressantconditionsand intravasculardevices),bytheclinicalpresentation,andbythe clin-icalandmicrobiologicalevolution(clearanceofbacteremiainless than3daysofadequatetreatment).

Forhowlongmustthepatientsbetreated?

Recommendations

•Systemicantibioticsincasesofnon-complicatedCRBcausedby

S.aureus mustbeadministered for a periodnot shorter than

14days(A-II).

•Inpatientswithfavorableclinicalandmicrobiologicalevolution, sequentialoralantibioticsmaybeconsidered(A-II).

2PrimarySAB

Whattestsshouldbeperformedinpatientswithapparently

primarySAB?

Recommendations

•Acarefulevaluationofthepatient’ssymptomsandanexhaustive clinicalexaminationareessentialincasesofprimarySABinorder toruleoutpossiblesourcesoftheinfection(C-I).

•Areliableechocardiographictestshouldbeperformedincarriers ofintracardiacdevicesandincasesofcommunity-acquiredSAB (A-II).

Whatisthelengthandtypeofdefinitiveantimicrobialtreatment?

Recommendations

•Recommendationsforthespecificdefinitiveantimicrobial treat-mentforprimarySABdonotdifferfromthoseofCRBbyS.aureus

(B-II).

•Thedurationofantibioticsshouldbenoshorter than14days (B-II).

•Inpatientscarryingintravascularprostheses,thelengthof ther-apywill depend on thefindings of thecomplementary tests performedtodiscardasecondaryinvolvementofthesedevices (C-I).

ManagementofcomplicatedSAB

Complicated SAB is defined as the persistence of positive blood cultures after three ormore days of adequate treatment (including catheter removal),and/or thedevelopmentof septic thromboflebitis,IEorothermetastaticdistantfoci.

Whichclinicalandmicrobiologicalevaluationmustbemade

inpatientswithcomplicatedSAB?

Recommendations

•Bloodculturesmustberepeatedevery72hinordertomonitor themicrobiologicalresponsetoantibiotictherapy(A-II). •Makeitsurethatanintravenouscatheterleftinplaceisnotthe

originofthepersistentbacteremia(A-II).

•Whenaforeignbody(i.e.prostheticjointsorprostheticvalves) becomes infected, the indication of surgery for debridement and/orremovingthedevicemustbeconsidered(A-II).

•Itis necessarytoperformanechocardiographytoallpatients withcomplicatedSAB.Inpatientswithanintracardiacdeviceor inthosewithpersistentbacteremiaperformingaTEE(A-II)is preferable.

Whatisthetreatmentforcomplicatedbacteremiacaused

byMSSA?

Recommendations

•Thetreatmentofchoiceforcomplicatedbacteremiacausedby MSSAiscloxacillin,either2gevery4h,oradministeredin con-tinuousinfusion(A-I).

•Combined therapy is recommended in the following scenar-ios:(1)persistenceoffever;lackofimprovementofsignsand symptoms(B-III);(2)microbiologicalfailuredetectedby posi-tivesubsequentbloodcultures,especiallyinepisodescausedby anisolatewithvancomycinMIC≥1.5mg/L(measuredbyE-test). Thepossibleoptionsforcombinedtherapyare(A-III):

oCloxacillin2g/4hiv+Daptomycin10mg/kg/div oCloxacillin2g/4hiv+Fosfomycin2g/6hiv

•Thelengthoftherapyincomplicatedbacteremiaisvariable, ran-gingbetween4and6weekssincethefirststerilebloodculture, accordingtotheclinicalevolutionandthesourceofinfection. Thelengthofcombinedtherapyisnotestablished,butitseems reasonabletomaintainit atleastuntilblood culturesbecame negative.

Whatisthetreatmentforcomplicatedbacteremiacaused

byMRSA?

Recommendations

•ThebesttreatmentforcomplicatedMRSAbacteremia hasnot beenelucidated

•Treatmentwithvancomycin is associated witha highrateof treatmentfailure(A-II),especially,inthefollowingsituations: oifvancomycinMIC≥1.5mg/L(measuredbyE-test)(A-II) oifthepatienthasrenalimpairmentorisatriskofrenaltoxicity

(A-II).

•Dosesof6mg/kg/24hofdaptomycinhavebeenassociatedwith treatmentfailureandemergenceofresistance.Daptomycinat dosesof10mg/kg/disthetreatmentofchoiceforMRSA compli-catedbacteremia(A-III).

•Patientswithpersistentbacteremiaorseveresepsisorshockin thesettingoftreatmentwithhighdosesofdaptomycinmay ben-efitfromcombinedtherapy.Theoptionsare

oDaptomycin(10mg/kg/d)+fosfomycin(2g/6h)(A-III) oDaptomycin(10mg/kg/d)+cloxacillin2g/4h(A-III) oImipenem(1g/6h)plusfosfomycin(2g/6h)(A-III).

•The administration of high doses of fosfomycin may lead to sodiumoverloadandhypokalemia(1goffosfomycin-disodium carries13.5mEq[330mg]ofNa).

•Thedurationoftreatmentforcomplicatedbacteremiaisvariable, rangingfrom4to6weeks,dependingontheclinicalevolution andthesourceoftheinfection.

HowistreatmentfailureincomplicatedSABdefinedclinically

andmicrobiologically?

Recommendations

•InpatientswithcomplicatedSAB,adailyclinicalmonitoringis necessaryforevaluatingtheresponsetotheantimicrobial ther-apy(A-III).

•ConsecutivedeterminationsofC-reactive protein(CRP)(every 24–48h) during thefirst weekof treatmentmay bea useful markerforanearlyevaluationofthetreatmentefficacy(B-III). •Itisalsorecommendedtotakenewbloodculturesevery72h

untiltheyarenegative(C-III).

•In casesofpersistent bacteremia,theantimicrobialtreatment shouldbere-evaluated(A-III).

630 F.Gudioletal./EnfermInfeccMicrobiolClin.2015;33(9):626–632

Isitnecessarytoadministerthewholetreatmentbythe

intravenousroute?

Recommendations

•IncomplicatedSAB,antimicrobialtreatmentshouldbe adminis-teredentirelybytheintravenousroute.

•Anoral sequential treatmentmay be consideredfor patients accomplishingthefollowingrequirements(C-III):

othepatienthaspresentednofeverforatleast24h obloodculturesarenegative

otheoriginofinfectionhasbeendrained

otheparametersofsystemicinflammation(i.e.CRP)have signif-icantlydecreased.

•In exceptional situations where an intravenous access is not possible,thereis someexperience supportingtheuseof oral fluoroquinolonesplusrifampin(BII).

ManagementofinfectiveendocarditiscausedbyS.aureus

1EmpiricalantimicrobialtreatmentinIEcausedbyS.aureus

HowfrequentisS.aureusinIEandhowimportantisittoinclude

thisetiologyintheempiricaltreatmentofIE?

Recommendations

•Theempiricalantimicrobialtreatmentofcomplicatedbacteremia orIEshould includeS. aureuswhenever thereare reasonable doubtsonitspotentialroleasetiology,givenitshighand increas-ingincidenceandseverity.

•Therefore,activeantibioticsagainstS.aureusshouldbeincluded intheempiricaltreatmentinthefollowingcases:

osuspicion of community-acquired IE [either in intravenous drugusers(IVDUs)ornot];

osuspicionofacuteIEorpresentingwithseveresepis(B-II); oandearlyPVE,associatedtopacemakersordefibrillators(B-II),

orinnosocomialcasesorinhealthcareassociatedcases(B-II).

InwhichpatientswithSABthepossibilityofIEshouldbetaken

intoaccountwhenchoosingempiricaltreatment?

Recommendation

•InthesettingofSAB,itisrecommendedconsideringthediagnosis ofIEuntilithasbeenruledoutbycomplementarytests(namely TEE)inthefollowingscenarios:

ocommunity-acquiredepisodes(B-II); oIVDUs(B-II);

opresence of skin lesions suggesting hematogenous seeding (B-II);

oandnosocomialbacteremiainthepresenceofprostheticvalves orintracardiacdevices(B-II).

Whatclinicalandepidemiologicalcharacteristicsmaylead

toincludeMRSAintheempiricaltreatment?

Recommendation

•TheempiricalantimicrobialtreatmentforIEshouldinclude activ-ityagainstMRSAinanyofthefollowinginstances:

onosocomialcases(B-II),

opreviousnasalorskincolonizationbyMRSA(B-II),

opatientsfromnursing-homes(B-II)orinhemodialysis(B-II), osurgicalprocedurewithinthe6 monthsprecedingthe

bac-teremia(B-II),

oorthepresenceofcertainbaselineconditions(diabetes,cancer, immunosuppressanttherapy)(B-II).

Whatisthemostappropriateempiricalantimicrobialtreatment

forcommunity-acquiredIEcausedbyS.aureus?

Recommendations

•Whencommunity-acquiredIEcausedbyS.aureusissuspected, thetreatmentofchoiceiscloxacillin(B-II).

•Inacriticallyillpatient,orinpatientswithseveresepsisor sep-ticshock,manyexpertsrecommendaddingdaptomycintothe treatmentwithcloxacillin(C-III).

•Patientsallergicto␤-lactamsmaybetreatedwithcefazolin(ifno previousanafilaxiahasbeenreported)(B-II),orwiththe combi-nationofdaptomycinplusfosfomycin(C-III).

Inthesettingofcommunity-acquiredIEcausedbyS.aureus,

shouldgentamicinbeaddedtotheempiricaltreatment?

Recommendation

•The inclusion of gentamicin in the empiricial treatment of community-acquirednativevalveIEcausedbyS.aureusduring thefirst3–5daysisnotrecommended(D-I).

Whatistheempiricaltreatmentofhospital-acquiredorhealth

carerelatedIEcausedbyS.aureus?

Recommendations

•In the setting of health care related IE caused by S. aureus, monotherapywithvancomycinisnotrecommended(D-II). •Inthiscontext,daptomycinincombinationwithcloxacillinis

rec-ommended(B-II).Forpatientsallergicto␤-lactams,cloxacillin maybesubstitutedbyfosfomycin(C-III).

•FacedwithasuspectedIEbutnoavailablebloodcultures,the useofdaptomycinincombinationwitha␤-lactamwithactivity against nosocomial Gram-negative microorganismsis recom-mended(C-III).

2DefinitiveantimicrobialtreatmentforIEcausedbyS.aureus

WhatisthetreatmentfornativevalveIEcausedbyMSSA?

Recommendations

•For native valve left side IE caused by MSSA, cloxacillin for 4to6weeksisrecommended(B-II),andtwo weeksfor non-complicatedrightvalveIEamongIVDUs(A-I).

•Daptomycinmaybeaddedtocloxacillininthecaseof persis-tentbacteremiadetectedbythepositivityofsubsequentblood cultures,especiallyinepisodescausedbyanisolatewith van-comycinMIC≥1.5mg/L(measuredbyE-test)(C-III).

•Systematiccombinationwithgentamicinisnotrecommended (D-II).Inpatientsallergicto␤-lactams,thecombinationof dap-tomycinplusfosfomycinisrecommended(C-III).

WhatisthetreatmentforprostheticvalveIEcaused

byMSSA?

Recommendations

•Cloxacillin is recommended in prosthetic IE caused by MSSA (C-II),inassociationwithrifampinafterthefirst5daysof treat-ment(C-III),andgentamycininaonce-dailydoseduringthefirst twoweeksoftherapy(C-II).

•In thecase of allergy to␤-lactams, thesame combination of antibioticsmaybeused,withthesubstitutionofcloxacillinby daptomycin(C-III).

WhatisthetreatmentfornativevalveIEcausedbyMRSA?

Recommendations

•DaptomycinpluscloxacillinisrecommendedinnativevalveIE causedbyMRSAwhenvancomycinMICis≥1.5mg/L(measured byE-test)(B-II).

•ThesametreatmentmaybeadministeredwhenvancomycinMIC is<1.5mg/L(measuredbyE-test),orvancomycinisatdoses pro-vidingtroughlevelsof15–20mg/L(B-II).

•Inpatientsallergicto␤-lactams,thecombinationofdaptomycin plusfosfomycinisrecommended(B-II),ortheuseofvancomycin atdosesprovidingtroughlevelsof15–20mg/L(B-II).

•Neithertheadditionofrifampin(D-III)orgentamicin(D-III)to thetreatmentisrecommended.

WhatisthetreatmentforprostheticvalveIEcausedbyMRSA?

Recommendations

•In prosthetic valve IE caused by MRSA with vancomycin MIC≥1.5mg/L(usingE-test),theuseofdaptomycin,in combi-nationwithrifampinafter5daysoftreatment,andgentamicin inonesingledailydoseduringthefirsttwoweeksoftherapyis recommended(C-III).Daptomycinplusfosfomycincouldbeused alternatively(C-III)

•InthecaseofMIC<1.5mg/L(usingE-test),thesamecombination maybeused(C-III),orvancomycincombinedwithrifampinafter 5daysoftreatment,plusgentamicininaonesingledailydose duringthefirsttwoweeksoftreatment(B-II).

ArethereanyalternativetreatmentsforIEcausedbyMRSA?

Recommendation

In patientswithIE caused by MRSA presenting clinical fail-urewithpreviousrecommendedschedules,theadministrationof daptomycinplusfosfomycinmaybeused(B-II).Fosfomycinplus imipenemcouldalsobeused(C-II)

•Ifthiscannotbedone,eitherbecauseofallergyora highrisk of sodiumoverload, ceftaroline, either alone (B-II) or combi-nedwithdaptomycin(C-II),orlinezolid,alone(C-II)orassociated withdaptomycin(C-III),maybevalidalternatives.

3RoleforsurgeryinIEcausedbyS.aureus.

IsthereanyspecificindicationforsurgeryinthesettingofIE

causedbyS.aureus?

Recommendations

•PatientssufferingfromIEcausedbyS.aureussharethesame indi-cationsforsurgeryasothercasesduetoothermicroorganisms, withtheexceptionofprolongedMRSAbacteremia(A-II). •Therefore,internationalguidelinesmaybefollowed(A-II);butif

bloodculturesafter72hfromtheonsetofappropriatetreatment stillyieldMRSA,complementarytestsshouldbeperformedin ordertoruleoutmetastaticfoci,andthecardiacsurgeonsshould becontacted(B-II).

Howlongshouldbethetreatmentinpatientssubmitted

tocardiacsurgeryforIE?

Recommendations

•InpatientswithnativeorprostheticvalveIEcausedbyS.aureus

undergoingvalvereplacementandculturesbeingnegative,itis recommendedtoadministertwomoreweeksoftherapyor sim-plyfinishtheinitiallyscheduledtreatment(B-II).

•Inpatientswithpositivevalveculturesaftersurgery,itis recom-mendedtorestartthetreatmentofIE(i.e.,≥4weeksfornative valveIE,and≥6weeksforprostheticIE)(C-III).

MeasuresforimprovingthemanagementofSAB

Whicharethequality-of-careindicatorstoevaluatethe

managementofSAB?

Recommendation

•Atleast quality-of-careindicatorsshouldbe consideredin all patientswithSAB(BII).

Whatinterventionsshouldbeimplementedtoimprovethe

managementofSAB?

Recommendations

•Active, unsolicited infectious diseases specialist (IDS) consul-tation for management and follow-up should beprovided to physiciansinchargeofallpatientswithSAB(BII).

•The specialized recommendations to physicians in charge of patientswithSABshouldbeprovidedinastructuredmannerso allquality-of-careindicatorsofthemanagementareconsidered (BII).

Conflictsofinterest

FrancescGudiolhasreceivedacademicgrantsfromNovartis, Astellas and AstraZeneca. José María Aguado has been a con-sultant to and is onthe speakers’ bureau for Astellas Pharma, AstraZeneca,Pfizer,GileadSciences,Novartis,MerckSharpand Dohme,andRoche.BenitoAlmirantehascarriedoutconsultancy workorreceivedmonetarypaymentsforgivingtalksfrom Astel-las,AstraZeneca,GileadSciences,Janssen-Cilag,MerckSharpand Dhome, Novartis and Pfizer. Jesús Rodríguez-Ba ˜no has been a consultantand speakerfor Pfizer,Novartis, Merck,AstraZeneca andAstellas,andhasreceivedresearchgrantsfromNovartisand Gilead.JoseM.MirohasreceivedconsultinghonorariafromAbbvie, Bristol-MyersSquibb,GileadSciences,Merck,NovartisandSanofi, researchandacademicgrantsfromCubist,Gilead,ViiV,Novartis, Merck,FondodeInvestigacionesSanitarias(FIS)delInstitutode SaludCarlos III(Madrid),FundaciónparalaInvestigacióny Pre-vencióndelSidaenEspa ˜na(FIPSE,Madrid),MinisteriodeSanidad, ServiciosSocialeseIgualdad(MSSSI,Madrid),NationalInstitutesof Health(NIH,Bethesda,MA,USA)andNEATandhonorariafor lec-turesfromAbbvie,Bristol-MyersSquibb,GileadSciences,Merck, NovartisandViiVHealthcare.AlexSorianohasbeenaspeakerfor PfizerandNovartis.

Acknowledgments

WeareindebtedtoDr.RafaelSanJuanforhisinvaluablehelpin thereferencemanagementofthisarticle.REIPIissupportedbythe PlanNacionaldeI+D+i2008–2011andtheInstitutodeSaludCarlos III,SubdirecciónGeneraldeRedesyCentrosdeInvestigación Coop-erativa,Ministerio deEconomía y Competitividad, and Spanish

632 F.Gudioletal./EnfermInfeccMicrobiolClin.2015;33(9):626–632

NetworkforResearchinInfectiousDiseases(REIPIRD12/0015)– co-financedbyEuropeanDevelopmentRegionalFund“Awayto achieveEurope”ERDF.

AnnexeI.

Levelofscientificevidence

I Evidenceobtainedfrom≥1randomized

clinicaltrial

II Evidenceobtainedfrom≥1well-designed

non-randomizedclinicaltrial,orcohort studies,orcase–controlstudies,especiallyif theyhavebeenperformedinmorethanone center.

III Evidenceobtainedfromdocumentsor

opinionsofexperts,basedonclinical experienceorcaseseries

Gradesofrecommendation

A Goodevidencetorecommendtheuseofa

measureorpractice

B Moderateevidencetorecommendtheuseofa

measureorpractice

C Poorevidencetorecommendtheuseofa

measureorpractice

D Moderateevidencetodiscouragetheuseofa measureorpractice

E Goodevidencetodiscouragetheuseofa

measureorpractice

References

1.GudiolF,AguadoJM,PascualA,PujolM,AlmiranteB,MiróJM,etal.Consensus documentforthetreatmentofbacteremiaandendocarditiscausedby methicillin-resistentStaphylococcusaureusSociedadEspa ˜noladeEnfermedadesInfecciosasy MicrobiologíaClínica.EnfermInfeccMicrobiolClin.2009;27:105–15.

2.GudiolF,AguadoJM,AlmiranteB,BouzaE,CercenadoE,DomínguezMA,etal. DiagnosisandtreatmentofbacteremiaandendocarditisduetoStaphylococcus

aureus.AClinicalguidelinefromtheSpanishSocietyofClinicalMicrobiologyand