Infective Endocarditis in Adults: Diagnosis, Antimicrobial ...

Infective endocarditis (IE) is an uncommon infectious disease with an annual incidence ranging from 3 to 7 per 100 000 person-years in the most ... HomeCirculationVol.132,No.15InfectiveEndocarditisinAdults:Diagnosis,AntimicrobialTherapy,andManagementofComplications FreeAccessResearchArticlePDF/EPUBAboutViewPDFViewEPUBSections ToolsAddtofavoritesDownloadcitationsTrackcitationsPermissions ShareShareonFacebookTwitterLinkedInMendeleyRedditDiggEmail JumptoFreeAccessResearchArticlePDF/EPUBInfectiveEndocarditisinAdults:Diagnosis,AntimicrobialTherapy,andManagementofComplicationsAScientificStatementforHealthcareProfessionalsFromtheAmericanHeartAssociationLarryM.Baddour,MD,FAHAWalterR.Wilson,MDArnoldS.Bayer,MDVanceG.FowlerJr,MD,MHSImadM.Tleyjeh,MD,MScMichaelJ.Rybak,PharmD,MPHBrunoBarsic,MD,PhDPeterB.Lockhart,DDSMichaelH.Gewitz,MD,FAHAMatthewE.Levison,MDAnnF.Bolger,MD,FAHAJamesM.Steckelberg,MDRobertS.Baltimore,MDAnneM.Fink,PhD,RNPatrickO’GaraandMD,FAHAKathrynA.TaubertPhD,FAHAandonbehalfoftheAmericanHeartAssociationCommitteeonRheumaticFever,Endocarditis,andKawasakiDiseaseoftheCouncilonCardiovascularDiseaseintheYoung,CouncilonClinicalCardiology,CouncilonCardiovascularSurgeryandAnesthesia,andStrokeCouncilLarryM.BaddourLarryM.BaddourSearchformorepapersbythisauthor,WalterR.WilsonWalterR.WilsonSearchformorepapersbythisauthor,ArnoldS.BayerArnoldS.BayerSearchformorepapersbythisauthor,VanceG.FowlerJrVanceG.FowlerJrSearchformorepapersbythisauthor,ImadM.TleyjehImadM.TleyjehSearchformorepapersbythisauthor,MichaelJ.RybakMichaelJ.RybakSearchformorepapersbythisauthor,BrunoBarsicBrunoBarsicSearchformorepapersbythisauthor,PeterB.LockhartPeterB.LockhartSearchformorepapersbythisauthor,MichaelH.GewitzMichaelH.GewitzSearchformorepapersbythisauthor,MatthewE.LevisonMatthewE.LevisonSearchformorepapersbythisauthor,AnnF.BolgerAnnF.BolgerSearchformorepapersbythisauthor,JamesM.SteckelbergJamesM.SteckelbergSearchformorepapersbythisauthor,RobertS.BaltimoreRobertS.BaltimoreSearchformorepapersbythisauthor,AnneM.FinkAnneM.FinkSearchformorepapersbythisauthor,PatrickO’GaraPatrickO’GaraSearchformorepapersbythisauthorandKathrynA.TaubertKathrynA.TaubertSearchformorepapersbythisauthorandonbehalfoftheAmericanHeartAssociationCommitteeonRheumaticFever,Endocarditis,andKawasakiDiseaseoftheCouncilonCardiovascularDiseaseintheYoung,CouncilonClinicalCardiology,CouncilonCardiovascularSurgeryandAnesthesia,andStrokeCouncilSearchformorepapersbythisauthorOriginallypublished15Sep2015https://doi.org/10.1161/CIR.0000000000000296Circulation.2015;132:1435–1486iscorrectedbyCorrectionCorrectionto:InfectiveEndocarditisinAdults:Diagnosis,AntimicrobialTherapy,andManagementofComplications:AScientificStatementforHealthcareProfessionalsFromtheAmericanHeartAssociationCorrectionto:InfectiveEndocarditisinAdults:Diagnosis,AntimicrobialTherapy,andManagementofComplications:AScientificStatementforHealthcareProfessionalsFromtheAmericanHeartAssociationOtherversion(s)ofthisarticleYouareviewingthemostrecentversionofthisarticle.Previousversions:AbstractBackground—Infectiveendocarditisisapotentiallylethaldiseasethathasundergonemajorchangesinbothhostandpathogen.Theepidemiologyofinfectiveendocarditishasbecomemorecomplexwithtoday’smyriadhealthcare-associatedfactorsthatpredisposetoinfection.Moreover,changesinpathogenprevalence,inparticularamorecommonstaphylococcalorigin,haveaffectedoutcomes,whichhavenotimproveddespitemedicalandsurgicaladvances.MethodsandResults—Thisstatementupdatesthe2005iteration,bothofwhichweredevelopedbytheAmericanHeartAssociationundertheauspicesoftheCommitteeonRheumaticFever,Endocarditis,andKawasakiDisease,CouncilonCardiovascularDiseaseoftheYoung.Itincludesanevidence-basedsystemfordiagnosticandtreatmentrecommendationsusedbytheAmericanCollegeofCardiologyandtheAmericanHeartAssociationfortreatmentrecommendations.Conclusions—Infectiveendocarditisisacomplexdisease,andpatientswiththisdiseasegenerallyrequiremanagementbyateamofphysiciansandalliedhealthproviderswithavarietyofareasofexpertise.Therecommendationsprovidedinthisdocumentareintendedtoassistinthemanagementofthisuncommonbutpotentiallydeadlyinfection.Theclinicalvariabilityandcomplexityininfectiveendocarditis,however,dictatethattheserecommendationsbeusedtosupportandnotsupplantdecisionsinindividualpatientmanagement.IntroductionInfectiveendocarditis(IE)isanuncommoninfectiousdiseasewithanannualincidencerangingfrom3to7per100 000person-yearsinthemostcontemporarypopulationsurveys.1–3Althoughrelativelyrare,IEcontinuestobecharacterizedbyincreasedmorbidityandmortalityandisnowthethirdorfourthmostcommonlife-threateninginfectionsyndrome,aftersepsis,pneumonia,andintra-abdominalabscess.Globally,in2010,IEwasassociatedwith1.58milliondisability-adjustedlife-yearsoryearsofhealthylifelostasaresultofdeathandnonfatalillnessorimpairment.4EpidemiologicalsurveysfromFranceandtheInternationalCollaborationonEndocarditishaveconfirmedthattheepidemiologicalprofileofIEhaschangedsubstantially.AlthoughtheoverallIEincidencehasremainedstable,1,2,5–9theincidenceofIEcausedbyStaphylococcusaureushasincreased,andSaureusisnowthemostcommoncausativeorganisminmostoftheindustrializedworld.TheemergenceofSaureusIEisdueinparttotheincreasingimportanceofhealthcarecontactasaleadingriskassociatedwithinfection.CharacteristicsofIEpatientshavealsoshiftedtowardanincreasedmeanpatientage,ahigherproportionofprostheticvalvesandothercardiacdevices,andadecreasingproportionofrheumaticheartdisease.Moreover,theproportionofIEpatientsundergoingsurgeryhasincreasedovertimetoreach≈50%.1,10,11Inadditiontothesetemporalepidemiologicalchanges,majornewfindingsfrommultiplediagnostic,prognostic,andtherapeuticstudieshavebeenpublishedsincethelastiterationoftheAmericanHeartAssociation(AHA)statementondiagnosisandmanagementofIEcomplicationswaspublishedin2005.12Forexample,therapiddetectionofpathogensfromvalvetissuefrompatientsundergoingsurgeryforIEbypolymerasechainreaction(PCR)hasbeenvalidated.Moreover,diagnosticinnovationshaveemergedthroughnewimagingtechniquessuchas3-dimensional(3D)echocardiography,“head-to-toe”multislicecomputedtomography(CT),andcardiacmagneticresonanceimaging(MRI).Furthermore,theroleofcerebralMRIandmagneticresonanceangiographyinthediagnosisandmanagementofIEhasbeenbetterdefinedinseveralstudies.Inaddition,severalriskstratificationmodelsforquantifyingmorbidityandmortalityinIEpatientsoverallandparticularlyinthoseundergoingvalvesurgerieshavebeendevelopedandvalidated.Finally,daptomycinhasbeenevaluatedinthetreatmentofSaureusbacteremiaandIEinarandomized,controlledtrial.13Severalrigorouslyconductedobservationalstudies11,14–16andarandomized,controlledtrial17haveexaminedtheimpactandtimingofvalvesurgeryinIEmanagement.Inaddition,updatedinternationalmanagementguidelineshavebeenpublished.18,19ThepresentAHAIEWritingCommitteeconductedcomprehensiveandfocusedreviewsoftheliteraturepublishedbetweenJanuary2005andOctober2013toupdatethepreviousversionoftheguidelines.LiteraturesearchesofthePubMed/MEDLINEdatabaseswereundertakentoidentifypertinentarticles.SearcheswerelimitedtotheEnglishlanguage.Themajorsearchtermsincludedendocarditis,infectiveendocarditis,infectiousendocarditis,intracardiac,valvular,mural,infection,diagnosis,bacteremia,casedefinition,epidemiology,risks,demographics,injectiondruguse,echocardiography,microbiology,culture-negative,therapy,antibiotic,antifungal,antimicrobial,antimicrobialresistance,adversedrugeffects,drugmonitoring,outcome,meta-analysis,complications,abscess,heartfailure,embolicevents,stroke,conductionabnormalities,survival,pathogens,organisms,treatment,surgery,indications,valvereplacement,valverepair,ambulatorycaretrials,andprevention.Inaddition,thepresentstatementincludesanewsection,SurgicalTherapy.ThisworkaddressesprimarilyIEinadults;amoredetailedreviewoftheuniquefeaturesofIEinchildrenisavailableinanotherstatementfromtheAHACommitteeonRheumaticFever,Endocarditis,andKawasakiDisease.20Thecommitteealsopublishedstatementsonendocarditisthatcomplicateselectrophysiological(pacemakers,intracardiacdefibrillators),21ventricularassist,andothernonvalvularcardiacdevices.22Evidence-BasedSystemforDiagnosticandTreatmentRecommendationsThewritinggroupwaschargedwiththetaskofperforminganevidence-basedassessmentofthedataandprovidingaclassofrecommendationandalevelofevidenceforeachrecommendationaccordingtotheAmericanCollegeofCardiology/AHAclassificationsystem(http://circ.ahajournals.org/manual/manual_IIstep6.shtml).Theclassofrecommendationisanestimateofthesizeofthetreatmenteffect,consideringrisksversusbenefits,inadditiontoevidenceoragreementthatagiventreatmentorprocedureisorisnotusefuloreffectiveorinsomesituationsmaycauseharm.Thelevelofevidenceisanestimateofthecertaintyorprecisionofthetreatmenteffect.TheWritingGroupreviewedandassessedthestrengthofevidencesupportingeachrecommendationwiththelevelofevidencerankedasA,B,orCaccordingtothespecificdefinitionsincludedinTable1.Forcertainconditionsforwhichdatawereeitherunavailableorinadequate,recommendationswerebasedonexpertconsensusandclinicalexperience,andthesewererankedasLevelofEvidenceC.TheschemefortheclassofrecommendationsandlevelsofevidenceissummarizedinTable1,whichalsoprovidessuggestedphrasesforwritingrecommendationswithineachclassofrecommendation.Table1.ApplyingClassificationofRecommendationsandLevelofEvidenceTable1.ApplyingClassificationofRecommendationsandLevelofEvidenceDiagnosisThediagnosisofIEisstraightforwardintheminorityofpatientswhopresentwithaconsistenthistoryandclassicoslerianmanifestations:sustainedbacteremiaorfungemia,evidenceofactivevalvulitis,peripheralemboli,andimmunologicalvascularphenomena.Inmostpatients,however,the“textbook”historyandphysicalexaminationfindingsmaybefeworabsent.CaseswithlimitedmanifestationsofIEmayoccurearlyduringIE,particularlyamongpatientswhoareinjectiondrugusers(IDUs),inwhomIEisoftentheresultofacuteSaureusinfectionofright-sidedheartvalves.AcuteIEmayevolvetooquicklyforthedevelopmentofimmunologicalvascularphenomena,whicharemorecharacteristicofthelaterstagesofthemoreinsidioussubacuteformofuntreatedIE.Inaddition,valvelesionsinright-sidedIEusuallydonotcreatetheperipheralemboliandimmunologicalvascularphenomenathatcanresultfromleft-sidedvalvularinvolvement.Right-sidedIE,however,cancausesepticpulmonaryemboli.ThevariabilityinclinicalpresentationofIEandtheimportanceofearlyaccuratediagnosisrequireadiagnosticstrategythatisbothsensitivefordiseasedetectionandspecificforitsexclusionacrossallformsofthedisease.In1994,Durackandcolleagues23fromtheDukeUniversityMedicalCenterproposedadiagnosticschemathatstratifiedpatientswithsuspectedIEinto3categories:definite,possible,andrejectedcases(Tables2and3).Table2.DefinitionofIEAccordingtotheModifiedDukeCriteria*DefiniteIE Pathologicalcriteria  Microorganismsdemonstratedbycultureorhistologicalexaminationofavegetation,avegetationthathasembolized,oranintracardiacabscessspecimen;orpathologicallesions;vegetationorintracardiacabscessconfirmedbyhistologicalexaminationshowingactiveendocarditis Clinicalcriteria  2Majorcriteria,1majorcriterionand3minorcriteria,or5minorcriteriaPossibleIE 1Majorcriterionand1minorcriterion,or3minorcriteriaRejected FirmalternativediagnosisexplainingevidenceofIE;orresolutionofIEsyndromewithantibiotictherapyfor≤4d;ornopathologicalevidenceofIEatsurgeryorautopsywithantibiotictherapyfor≤4d;ordoesnotmeetcriteriaforpossibleIEasaboveIEindicatesinfectiveendocarditis.Modificationsappearinboldface.*Thesecriteriahavebeenuniversallyacceptedandareincurrentuse.ReprintedfromLietal24bypermissionoftheInfectiousDiseasesSocietyofAmerica.Copyright©2000,theInfectiousDiseasesSocietyofAmerica.Table3.DefinitionofTermsUsedintheModifiedDukeCriteriafortheDiagnosisofIE*Majorcriteria BloodculturepositiveforIE TypicalmicroorganismsconsistentwithIEfrom2separatebloodcultures:Viridansstreptococci,Streptococcusbovis,HACEKgroup,Staphylococcusaureus;orcommunity-acquiredenterococciintheabsenceofaprimaryfocus,ormicroorganismsconsistentwithIEfrompersistentlypositivebloodculturesdefinedasfollows:atleast2positiveculturesofbloodsamplesdrawn>12hapartorall3oramajorityof≥4separateculturesofblood(withfirstandlastsampledrawnatleast1hapart) SinglepositivebloodcultureforCoxiellaburnetiioranti–phase1IgGantibodytiter≥1:800 Evidenceofendocardialinvolvement EchocardiogrampositiveforIE(TEErecommendedforpatientswithprostheticvalves,ratedatleastpossibleIEbyclinicalcriteria,orcomplicatedIE[paravalvularabscess];TTEasfirsttestinotherpatients)definedasfollows:oscillatingintracardiacmassonvalveorsupportingstructures,inthepathofregurgitantjets,oronimplantedmaterialintheabsenceofanalternativeanatomicexplanation;abscess;ornewpartialdehiscenceofprostheticvalveornewvalvularregurgitation(worseningorchangingorpre-existingmurmurnotsufficient)Minorcriteria Predisposition,predisposingheartcondition,orIDU Fever,temperature>38°C Vascularphenomena,majorarterialemboli,septicpulmonaryinfarcts,mycoticaneurysm,intracranialhemorrhage,conjunctivalhemorrhages,andJanewaylesions Immunologicalphenomena:glomerulonephritis,Oslernodes,Rothspots,andrheumatoidfactor Microbiologicalevidence:positivebloodculturebutdoesnotmeetamajorcriterionasnotedabove(excludessinglepositiveculturesforcoagulase-negativestaphylococciandorganismsthatdonotcauseendocarditis)orserologicalevidenceofactiveinfectionwithorganismconsistentwithIE EchocardiographicminorcriteriaeliminatedHACEKindicatesHaemophilusspecies,Aggregatibacterspecies,Cardiobacteriumhominis,Eikenellacorrodens,andKingellaspecies;IDU,injectiondruguse;IE,infectiveendocarditis;IgG,immunoglobulinG;TEEtransesophagealechocardiography;andTTE,transthoracicechocardiography.Modificationsappearinboldface.*Thesecriteriahavebeenuniversallyacceptedandareincurrentuse.ReprintedfromLietal24bypermissionoftheInfectiousDiseasesSocietyofAmerica.Copyright©2000,theInfectiousDiseasesSocietyofAmerica.AdiagnosisofIEwiththeoriginalDukecriteriawasbasedonthepresenceofeithermajororminorclinicalcriteria(Tables2and3).TheDukecriteriagavediagnosticweighttobacteremiawithstaphylococciorenterococcionly,onthebasisofthelocationofacquisitionandwithoutanapparentprimaryfocus;thesetypesofbacteremiahavethehighestriskofbeingassociatedwithIE.23,25,26TheDukecriteriaincorporatedechocardiographicfindingsintothediagnosticstrategy(Tables2and3;seetheEchocardiographysection).SixcommonbutlessspecificfindingsofIEwereincludedasminorcriteriaintheoriginalDukeschema(Tables2and3).Inthemidtolate1990s,directanalysesoftheDukecriteriaweremadein12majorstudies27–38includingnearly1700patientscomposedofgeographicallyandclinicallydiversegroups(adult,pediatric,andolderadult[≥60yearsofage]patients;patientsfromthecommunity;IDUandnon-IDUpatients;andthosewithbothnativeandprostheticvalves).Thestudies27–38confirmedthehighsensitivityandspecificityoftheDukecriteriaandthediagnosticutilityofechocardiographyinidentifyingclinicallydefinitecases.Moreover,aretrospectivestudyof410patientsshowedgoodagreement(72%–90%)betweentheDukecriteriaandclinicalassessmentbyinfectiousdiseaseexpertsblindedtounderlyingIEriskfactors.39SeveralrefinementshavebeenmadetoboththemajorandminorDukecriteria.IntheoriginalDukecriteria,bacteremiaresultingfromSaureusorenterococciwasconsideredtofulfillamajorcriteriononlyifitwascommunityacquiredbecauseampleliteraturesuggestedthatthisparameterwasanimportantsurrogatemarkerforunderlyingIE.27However,anincreasingnumberofmorecontemporarystudiesdocumentedIEinpatientsexperiencingnosocomialstaphylococcalbacteremia.Forexample,of59consecutivepatientswithSaureusIE,45.8%hadnosocomialinfections,and50.8%hadaremovablefocusofinfection.39Inananalysisof262patientsattheDukeUniversityMedicalCenterwhohadhospital-acquiredSaureusbacteremia,34(13%)weresubsequentlydiagnosedwithdefiniteIE.Therefore,themodifiedDukecriteria(Tables2and3)recommendtheinclusionofSaureusbacteremiaasamajorcriterion,regardlessofwhethertheinfectionishospitalacquired(withorwithoutaremovablesourceofinfection)orcommunityacquired.24SpecificserologicaldatahavebeenincludedintheDukeIEdiagnosticschematoestablishthepathogenicagentsofculture-negativeIEmoreprecisely(ie,asasurrogateforpositivebloodcultures).Theseserologicalcriteriawouldbeappliedincircumstancesinwhichthepathogenicorganismisslowgrowinginroutinebloodcultures(eg,Brucellaspecies)orrequiresspecialbloodculturemedia(eg,Bartonellaspecies,Legionellaspecies,Tropherymawhipplei,fungi,andMycobacteriumspecies)orinwhichtheorganismisnotculturable(eg,Coxiellaburnetii,theagentofQfever).Forexample,intheoriginalDukecriteria,apositiveserologyforQfeverwasconsideredaminormicrobiologicalcriterion.Subsequently,Fournieretal40studied20pathologicallyconfirmedcasesofQfeverIE.WhentheoriginalDukecriteriawereused,4ofthe20patientswereclassifiedashavingpossibleIE.WhenQfeverserologicalresultsandasinglebloodculturepositiveforCburnetiiwereconsideredtobeamajorcriterion,however,eachofthese4caseswasreclassifiedfrompossibleIEtodefiniteIE.Onthebasisofthesedata,specificserologicaldataasasurrogatemarkerforpositivebloodcultureshavenowbeenincludedintheDukecriteria.Thus,ananti–phaseIimmunoglobulinGantibodytiter≥1:800orasinglebloodculturepositiveforCburnetiishouldbeamajorcriterioninthemodifiedDukeschema.24SerologicaltestsandPCR-basedtestingforotherdifficult-to-cultivateorganismssuchasBartonellaquintanaorTropherymawhippeliialsohavebeendiscussedasfuturemajorcriteria.Atpresent,therearesignificantmethodologicalproblemsassociatedwithproposingantibodytitersthatarepositiveforBartonellaandChlamydiaspeciesorPCR-basedtestingforTwhippeliiasamajorcriterionintheDukeschema.Forexample,IEcausedbyBartonellaandChlamydiaspeciesoftenareindistinguishableinserologicaltestresultsbecauseofcross-reactions.41LowsensitivityisamajorlimitationofPCRunlesscardiacvalvulartissueisavailablefortesting.42–45FewcentersprovidetimelyPCR-basedtestingfortheserarecausesofIE.Therefore,theinclusionoftheseassaysasmajorcriteriashouldbedeferreduntiltheserodiagnosticandPCRapproachescanbestandardizedandvalidatedinasufficientnumberofcasesoftheseraretypesofIE,theaforementionedtechnicalproblemsareresolved,andtheavailabilityofsuchassaysbecomesmorewidespread.TheexpansionofminorcriteriatoincludeelevatederythrocytesedimentationrateorC-reactiveprotein,thepresenceofnewlydiagnosedclubbing,splenomegaly,andmicroscopichematuriaalsohasbeenproposed.Inastudyof100consecutivecasesofpathologicallyprovennativevalveIE(NVE),inclusionoftheseadditionalparameterswiththeexistingDukeminorcriteriaresultedina10%increaseinthefrequencyofcasesbeingdeemedclinicallydefinite,withnolossofspecificity.ThemajorlimitationsoftheerythrocytesedimentationrateandC-reactiveproteinarethattheyarenonspecificandparticularlychallengingtointerpretinpatientswithcomorbidconditions.TheseadditionalparametershavenotbeenformallyintegratedintothemodifiedDukecriteria,24however,whichareuniversallyaccepted.OneminorcriterionfromtheoriginalDukeschema,“echocardiogramconsistentwithIEbutnotmeetingmajorcriterion,”wasre-evaluated.Thiscriterionoriginallywasusedincasesinwhichnonspecificvalvularthickeningwasdetectedbytransthoracicechocardiography(TTE).InareanalysisofpatientsintheDukeUniversitydatabase(containingrecordscollectedprospectivelyon>800casesofdefiniteandpossibleIEsince1984),thisechocardiographiccriterionwasusedinonly5%ofcasesandwasneverusedinthefinalanalysisofanypatientwhounderwenttransesophagealechocardiography(TEE).Therefore,thisminorcriterionwaseliminatedinthemodifiedDukecriteria.24Finally,adjustmentoftheDukecriteriatorequireaminimumof1majorplus1minorcriterionor3minorcriteriaasa“floor”todesignateacaseaspossibleIE(asopposedto“findingsconsistentwithIEthatfallshortof‘definite’butnot‘rejected’ ”)hasbeenincorporatedintothemodifiedcriteriatoreducetheproportionofpatientsassignedtotheIEpossiblecategory.ThisapproachwasusedinaseriesofpatientsinitiallycategorizedaspossibleIEbytheoriginalDukecriteria.Withtheguidanceofthe“diagnosticfloor,”anumberofthesecaseswerereclassifiedasrejectedforIE.24Follow-upinthesereclassifiedpatientsdocumentedthespecificityofthisdiagnosticschemabecausenopatientsdevelopedIEduringthesubsequent12weeksofobservation.Thus,onthebasisoftheweightofclinicalevidenceinvolvingnearly2000patientsinthecurrentliterature,itappearsthatpatientssuspectedofhavingIEshouldbeclinicallyevaluated,withthemodifiedDukecriteriaastheprimarydiagnosticschema.ItshouldbepointedoutthattheDukecriteriawereoriginallydevelopedtofacilitateepidemiologicalandclinicalresearcheffortssothatinvestigatorscouldcompareandcontrasttheclinicalfeaturesandoutcomesofvariouscaseseriesofpatients.Extendingthesecriteriatotheclinicalpracticesettinghasbeensomewhatmoredifficult.ItshouldalsobeemphasizedthatfullapplicationoftheDukecriteriarequiresdetailedclinical,microbiological,radiological,andechocardiographicqueries.BecauseIEisaheterogeneousdiseasewithhighlyvariableclinicalpresentations,theuseofthesecriteriaalonewillneversuffice.Criteriachangesthataddsensitivityoftendosoattheexpenseofspecificityandviceversa.TheDukecriteriaaremeanttobeaguidefordiagnosingIEandmustnotreplaceclinicaljudgment.Cliniciansmayappropriatelyandwiselydecidewhetherornottotreatanindividualpatient,regardlessofwhetherthepatientmeetsorfailstomeetthecriteriafordefiniteorpossibleIEbytheDukecriteria.Webelieve,however,thatthemodificationsoftheDukecriteria(Tables2and3)willhelpinvestigatorswhowishtoexaminetheclinicalandepidemiologicalfeaturesofIEandwillserveasaguideforcliniciansstrugglingwithdifficultdiagnosticproblems.Thesemodificationsrequirefurthervalidationamongpatientswhoarehospitalizedinbothcommunity-basedandtertiarycarehospitals,withparticularattentiontolonger-termfollow-upofpatientsrejectedashavingIEbecausetheydidnotmeettheminimalfloorcriteriaforpossibleIE.ThediagnosisofIEmustbemadeassoonaspossibletoinitiateappropriateempiricalantibiotictherapyandtoidentifypatientsathighriskforcomplicationswhomaybebestmanagedbyearlysurgery.IncaseswithahighsuspicionofIEbasedoneithertheclinicalpictureorthepatient’sriskfactorprofilesuchasinjectiondruguse,anotherfocusofcardiovascularinfection,includingcatheter-relatedbloodstreaminfectionscausedbySaureus,orahistoryofpreviousIE,thepresumptionofIEoftenismadebeforebloodcultureresultsareavailable.IdentificationofvegetationsandincrementalvalvularinsufficiencywithechocardiographyoftencompletesthediagnosticcriteriaforIEandaffectsthedurationoftherapy.AlthoughtheuseofcasedefinitionstoestablishadiagnosisofIEshouldnotreplaceclinicaljudgment,46therecentlymodifiedDukecriteria24havebeenusefulinbothepidemiologicalandclinicaltrialsandinindividualpatientmanagement.Clinical,echocardiographic,andmicrobiologicalcriteria(Tables2and3)areusedroutinelytosupportadiagnosisofIE,andtheydonotrelyonhistopathologicalconfirmationofresectedvalvularmaterialorarterialembolus.Ifsuggestivefeaturesareabsent,thenanegativeechocardiogramshouldpromptamorethoroughsearchforalternativesourcesoffeverandsepsis.Inlightoftheseimportantfunctions,atleast3setsofbloodculturesobtainedfromseparatevenipuncturesitesshouldbeobtained,withthefirstandlastsamplesdrawnatleast1hourapart.Inaddition,echocardiographyshouldbeperformedexpeditiouslyinpatientssuspectedofhavingIE.RecommendationsAtleast3setsofbloodculturesobtainedfromdifferentvenipuncturesitesshouldbeobtained,withthefirstandlastsamplesdrawnatleast1hourapart(ClassI;LevelofEvidenceA).EchocardiographyshouldbeperformedexpeditiouslyinpatientssuspectedofhavingIE(ClassI;LevelofEvidenceA).EchocardiographyEchocardiographyiscentraltothediagnosisandmanagementofpatientswithIE.Aspreviouslystated(Table3),echocardiographicevidenceofanoscillatingintracardiacmassorvegetation,anannularabscess,prostheticvalvepartialdehiscence,andnewvalvularregurgitationaremajorcriteriainthediagnosisofIE.BothTTEandTEEaredoneinmanypatientswithIEduringinitialevaluationandsubsequentfollow-upandprovidecomplementaryinformation.Therefore,TTEshouldbedoneinitiallyinallcasesofsuspectedIE(Figure).Ifanycircumstancesprecludethesecuringofoptimalechocardiographicwindows,includingchronicobstructivelungdisease,previousthoracicorcardiovascularsurgery,morbidobesity,orotherconditions,thenTEEshouldbeperformedassoonaspossibleafterTTE.WhenTTEisnegativeandclinicalsuspicionremainslow,thenotherclinicalentitiesshouldbeconsidered.IfTTEshowsvegetationsbutthelikelihoodofcomplicationsislow,thensubsequentTEEisunlikelytoalterinitialmedicalmanagement.Ontheotherhand,ifclinicalsuspicionofIEoritscomplicationsishigh(eg,prostheticvalveornewatrioventricularblock),thenanegativeTTEwillnotdefinitelyruleoutIEoritspotentialcomplications,andTEEshouldbeperformedfirst.InvestigationinadultshasshownTEEtobesignificantlymoresensitivethanTTEforthedetectionofvegetationsandabscesses.47Inthesettingofaprostheticvalve,transthoracicimagesaregreatlyhamperedbythestructuralcomponentsoftheprosthesisandareinadequateforassessmentoftheperivalvularareawherethoseinfectionsoftenstart.48Althoughcost-effectivenesscalculationssuggestthatTEEshouldbethefirstexaminationinadultswithsuspectedIE(Table4),particularlyinthesettingofstaphylococcalbacteremia,49,50manypatientsarenotcandidatesforimmediateTEEbecauseofhavingeatenwithinthepreceding6hoursorbecausethepatientsareininstitutionsthatcannotprovide24-hourTEEservices.WhenTEEisnotclinicallypossibleormustbedelayed,earlyTTEshouldbeperformedwithoutdelay.AlthoughTTEwillnotdefinitivelyexcludevegetationsorabscesses,itwillallowidentificationofvery-high-riskpatients,establishthediagnosisinmany,andguideearlytreatmentdecisions.AlthoughinterestingresultssuggestthattheremaybeahighnegativepredictivevalueofTTEinsomepatients,51furtherworkisneededtobetterdefinethesubgroupofpatientswithbloodstreaminfectioncausedbySaureuswhoneedonlyTTEtoevaluateforIE.Table4.UseofEchocardiographyDuringDiagnosisandTreatmentofEndocarditisEarly Echocardiographyassoonaspossible(<12hafterinitialevaluation) TEEpreferred;obtainTTEviewsofanyabnormalfindingsforlatercomparison TTEifTEEisnotimmediatelyavailable TTEmaybesufficientinsmallchildrenRepeatechocardiography TEEafterpositiveTTEassoonaspossibleinpatientsathighriskforcomplications TEE3–5dafterinitialTEEifsuspicionexistswithoutdiagnosisofIEorwithworrisomeclinicalcourseduringearlytreatmentofIEIntraoperative Prepump Identificationofvegetations,mechanismofregurgitation,abscesses,fistulas,andpseudoaneurysmsPostpumpConfirmationofsuccessfulrepairofabnormalfindings Assessmentofresidualvalvedysfunction Elevatedafterloadifnecessarytoavoidunderestimatingvalveinsufficiencyorpresenceofresidualabnormalflow Completionoftherapy Establishnewbaselineforvalvefunctionandmorphologyandventricularsizeandfunction TTEusuallyadequate;TEEorreviewofintraoperativeTEEmaybeneededforcomplexanatomytoestablishnewbaselineTEEindicatestransesophagealechocardiography;andTTE,transthoracicechocardiography.DownloadfigureDownloadPowerPointFigure.Anapproachtothediagnosticuseofechocardiography(echo).Rxindicatesprescription;TEE,transesophagealechocardiography;andTTE,transthoracicechocardiography.*Forexample,apatientwithfeverandapreviouslyknownheartmurmurandnootherstigmataofinfectiveendocarditis(IE).†Highinitialpatientrisksincludeprostheticheartvalves,manycongenitalheartdiseases,previousendocarditis,newmurmur,heartfailure,orotherstigmataofendocarditis.‡High-riskechocardiographicfeaturesincludelargeormobilevegetations,valvularinsufficiency,suggestionofperivalvularextension,orsecondaryventriculardysfunction(seetext).ModifiedfromBaddouretal.12Copyright©2005,AmericanHeartAssociation,Inc.ManyfindingsidentifiedbyTEEalsocanbedetectedonTTE.ConcurrentTTEimagescanserveasabaselineforrapidandnoninvasivecomparisonofvegetationsize,valvularinsufficiency,orchangeinabscesscavitiesduringthecourseofthepatient’streatmentshouldclinicaldeteriorationoccur.Fortricuspidvegetationsorabnormalitiesoftherightventricularoutflowtract,visualizationmaybeenhancedbychoosingTTEratherthanTEE.52Finally,manycardiologistsbelieveTTEissuperiortoTEEforquantifyinghemodynamicdysfunctionmanifestedbyvalvularregurgitation,ventriculardysfunction,andelevatedleftandrightventricularfillingpressuresandpulmonaryarterypressure.Theseechocardiographicfindingscanoccurinpatientswhohavenoheartfailuresymptoms.BothTEEandTTEmayproducefalse-negativeresultsifvegetationsaresmallorhaveembolized.53EvenTEEmaymissinitialperivalvularabscesses,particularlywhenthestudyisperformedearlyinthepatient’sillness.54Insuchcases,theincipientabscessmaybeseenonlyasnonspecificperivalvularthickening,whichonrepeatimagingacrossseveraldaysmaybecomemorerecognizableasitexpandsanddevelopsacavity.Similarly,perivalvularfistulasandpseudoaneurysmsdevelopovertime,andnegativeearlyTEEimagesdonotexcludethepotentialfortheirdevelopment.False-positiveresultsfromTEEorTTEstudiesmayoccurwhenvalvularabnormalitiesareseenthatmaynotberelatedtoacurrentinfection.Previousscarring,severemyxomatouschange,andevennormalstructuressuchasLamblexcrescencesmaybeindistinguishablefromactivechangesinthevalves.Asechocardiographictechnologyimproveswithhigherfrequenciesandrefinedbeam-formingtechnology,subtlefindingscontinuetoberecognizedandmayaddtothecategoryofindeterminatefindings.Oneapproachtominimizingconfusionfromtheselatterstructuresistoexploitthehighframeratesthatareoftenavailablewithcurrentequipmenttoimprovetemporalresolutionandtoclearlyvisualizerapidlymovingstructuressuchasmicrocavitiesfromprostheticvalvesorfibrillarcomponents.Severalechocardiographicfeaturesidentifypatientsathighriskforacomplicatedcourseorwithaneedforsurgery(Table5).Thesefeaturesincludelarge(>10mmindiameter)vegetations,severevalvularinsufficiency,abscesscavitiesorpseudoaneurysms,valvularperforationordehiscence,andevidenceofdecompensatedheartfailure.21Theabilityofechocardiographicfeaturestopredictemboliceventsislimited.55–57Thegreatestriskofemboliccomplicationsappearstooccurwithlarge(≥10mm)vegetationsontheanteriormitralleaflet.58Vegetationsizeandmobilitymaybetakenintoaccount,alongwithbacteriologicalfactorsandotherindicationsforsurgery,whenconsideringearlysurgerytoavoidembolization,althoughmobilitycharacteristicsaloneshouldnotbetheprincipaldriverasasurgicalindication.59Table5.ClinicalandEchocardiographicFeaturesThatSuggestPotentialNeedforSurgicalInterventionVegetation Persistentvegetationaftersystemicembolization Anteriormitralleafletvegetation,particularlywithsize>10mm* ≥1Emboliceventsduringfirst2wkofantimicrobialtherapy* Increaseinvegetationsizedespiteappropriateantimicrobialtherapy*†Valvulardysfunction Acuteaorticormitralinsufficiencywithsignsofventricularfailure† Heartfailureunresponsivetomedicaltherapy†Valveperforationorrupture† Perivalvularextension Valvulardehiscence,rupture,orfistula† Newheartblock†‡ Largeabscessorextensionofabscessdespiteappropriateantimicrobialtherapy†Seetextforamorecompletediscussionofindicationsforsurgerybasedonvegetationcharacterizations.*Surgerymayberequiredbecauseofriskofembolization.†Surgerymayberequiredbecauseofheartfailureorfailureofmedicaltherapy.‡Echocardiographyshouldnotbetheprimarymodalityusedtodetectormonitorheartblock.RecommendationTTEshouldbeperformedinallcasesofsuspectedIE(ClassI;LevelofEvidenceB).RepeatEchocardiographyIftheinitialTTEimagesarenegativeandthediagnosisofIEisstillbeingconsidered,thenTEEshouldbeperformedassoonaspossible(Table4).AmongpatientswithaninitiallypositiveTTEandahighriskforintracardiaccomplications,includingperivalvularextensionofinfection,TEEshouldbeobtainedassoonaspossible.RepeatingtheTEEin3to5days(orsoonerifclinicalfindingschange)afteraninitialnegativeresultisrecommendedwhenclinicalsuspicionofIEpersists.60Insomecases,vegetationsmayreachadetectablesizeintheinterval,orabscesscavitiesorfistuloustractsmaybecomeevident.Anintervalincreaseinvegetationsizeonserialechocardiographydespitetheadministrationofappropriateantibiotictherapyhasseriousimplicationsandhasbeenassociatedwithanincreasedriskofcomplicationsandtheneedforsurgery.60RepeatTEEshouldbedonewhenapatientwithaninitiallypositiveTEEdevelopsworrisomeclinicalfeaturesduringantibiotictherapy.Thesefeatures,includingunexplainedprogressionofheartfailuresymptoms,changeincardiacmurmurs,andnewatrioventricularblockorarrhythmia,shouldpromptemergentevaluationbyTEEifpossible.RecommendationsTEEshouldbedoneifinitialTTEimagesarenegativeorinadequateinpatientsforwhomthereisanongoingsuspicionforIEorwhenthereisconcernforintracardiaccomplicationsinpatientswithaninitialpositiveTTE(ClassI;LevelofEvidenceB).IfthereisahighsuspicionofIEdespiteaninitialnegativeTEE,thenarepeatTEEisrecommendedin3to5daysorsoonerifclinicalfindingschange(ClassI;LevelofEvidenceB).RepeatTEEshouldbedoneafteraninitiallypositiveTEEifclinicalfeaturessuggestanewdevelopmentofintracardiaccomplications(ClassI;LevelofEvidenceB).IntraoperativeEchocardiographyPreoperativesurgicalplanningforpatientswithIEwillbenefitfromechocardiographicdelineationofthemechanismsofvalvulardysfunctionorregionsofmyocardialabscessformation(Table5).Theuseofaortichomograftsisfacilitatedbypreoperativeestimatesofannularsize,whichallowtheselectionofappropriatelysizeddonortissues.61,62Intraoperatively,echocardiographicgoalsincludeassessmentofnotonlytheobviouslydysfunctionalvalvebutalsotheothervalvesandcontiguousstructures.Post–cardiopulmonarybypassimagesshouldconfirmtheadequacyoftherepairorreplacementanddocumentthesuccessfulclosureoffistuloustracts.Perivalvularleaksrelatedtotechnicalfactorsshouldbedocumentedtoavoidlaterconfusionaboutwhethersuchleaksaretheresultofrecurrentinfection.Duringpostpumpimaging,itisoftennecessarytoaugmentafterloadtoreachrepresentativeambulatorylevelstoavoidunderestimationofregurgitantjetsizeandsignificanceandtoensurethatabnormalcommunicationswereclosed.63Afterloadaugmentation,however,maynotmimicactual“awakephysiology”andmaystillleadoccasionallytoaninaccurateevaluationoftheawakepostoperativehemodynamicstate.EchocardiographyattheCompletionofTherapyAllpatientswhohaveexperiencedanepisodeofIEremainatincreasedriskforrecurrentinfectionindefinitely.Manybelievethatitisextremelyimportantforthefuturecareofthesepatientstoestablishanewbaselineforvalvularmorphology,includingthepresenceofvegetationsandvalvularinsufficiency,oncetreatmenthasbeencompleted.Documentationofheartrate,heartrhythm,andbloodpressureatthetimeofechocardiographicstudyisimportantbecausechangesintheseconditionsmayexplainfuturedifferencesinvalvularinsufficiencyindependentofpathology(Table4).TTEisreasonableforthisevaluationbecausespectralDopplerinterrogationforfunctionalitymetricsismorethoroughthanTEE.TEE,however,maybemeritedtodefinethenewbaselineinsomepatientswithpooracousticwindowsorcomplicatedanatomysuchasafterextensivedebridementandreconstruction.AlthoughintraoperativepostpumpTEEviewsmaybeadequateforthisnewbaseline,theyshouldbereviewedforadequacyandrepeatedifnecessary.Somepatientswillhavesignificantvalvulardysfunctionattheendofotherwisesuccessfulantimicrobialtreatmentthatwillrequireeventualvalvularsurgery.Posttreatmentechocardiographycanguidebothmedicalmanagementandthediscussionoftheappropriatetimingofsuchinterventions.RecommendationTTEatthetimeofantimicrobialtherapycompletiontoestablishbaselinefeaturesisreasonable(ClassIIa;LevelofEvidenceC).3DEchocardiographyandOtherImagingModalitiesAlthoughnewerimagingmodalitiesareundergoingpreliminaryevaluation,echocardiographywillcontinuetobepivotalinpatientswithIEfortheforeseeablefuture.Inthisregard,earlyinvestigations64,65of3DTEEhavedemonstratedadvantagesover2-dimensionalTEE(whichisroutinelyused)tobetterdetectanddelineatevegetationsandtoidentifyIEcomplicationsandtheirrelationshipswithsurroundingstructures.Unfortunately,thelowertemporalandlateralresolutionwith3Dechocardiographycomparedwith2-dimensionalechocardiographyleadstoanoverestimationofvegetationsizeandtechnicallychallengingvisualizationoffast-movingstructures.AlthoughcardiacCTisusedprincipallytoevaluategreatvesselsandcoronaryarterydisease,theremaybearoleforthistool66–68incasesofIEinwhichdefinitiveevidenceofIEanditscomplicationsisnotsecuredwithTEE.Moreover,coronaryCTangiographycanprovidecoronaryarteryevaluationinpatientswhoaretoundergocardiacsurgeryforIEcomplications.Inaddition,thismethodologymaybeusefulinhead-to-toepreoperativescreening,includingevaluationforcentralnervoussystem(CNS)lesions,andinintra-abdominallesions(eg,silentsplenicabscesses).Limitationsincludetheassociatedexposuretoradiation,nephrotoxicityassociatedwithcontrastdye,andrelativelackofsensitivityin1studytodemonstratevalveperforations.67MRIhashadamajorimpactonIEdiagnosisandmanagement,especiallyasatooltodetectcerebralembolicevents,manyofwhichareclinicallysilent.69IndicationsfortheroutineuseofMRIandmagneticresonanceangiographyinIEmanagement,however,arenotwellestablished.Commentsrelatedtomycoticorinfectiousaneurysmsareprovidedinalatersectionofthisdocument.Morestudyisneededtodefinetheutilityof18F-fluorodeoxyglucosepositronemissiontomography/CTinthediagnosisandmanagementofIE.Inaprospectivestudyof25IEcases,18F-fluorodeoxyglucosepositronemissiontomography/CTwasusefulinidentifyingperipheralembolizationin11patientsandindetectingIEextracardiacmanifestationsin7patientswhodidnotdemonstrateanyclinicalmanifestationsofIE.70TheuseofmultimodalityimaginginIEmayincreaseinthefutureastherisksandbenefitsofeachdiagnostictoolaredefined.71AntimicrobialTherapyTherapeuticPrinciplesTheprimarygoalofantibiotictreatmentistoeradicateinfection,includingsterilizingvegetations,althoughtheuniquecharacteristicsofinfectedvegetationscanposeavarietyofchallenges.Thesecharacteristicsincludefocalinfectionwithhighbacterialdensity,slowrateofbacterialgrowthwithinbiofilms,andlowmicroorganismmetabolicactivity.72Hostcharacteristicssuchasimpairedimmunityalsocontributetochallengesintherapeutics.Inaddition,antibioticsmayfailtoeradicateinfectionasaresultofincreasedbindingofthedrugtoserumproteins,perturbationsofantibioticpenetrationintothevegetation,anduniqueantibioticpharmacokinetic/pharmacodynamic(PK/PD)features.Therefore,prolonged,parenteral,bactericidaltherapyisrequiredforattemptedinfectioncure.InoculumEffectTheeffectofhighbacterialdensitiesonantimicrobialactivityiscalledtheinoculumeffectinwhichcertaingroupsofantimicrobialscommonlyusedtotreatIEsuchasβ-lactamsandglycopeptides(and,toalesserextent,lipopeptidessuchasdaptomycin)arelessactiveagainsthighlydensebacterialpopulations.73–75Therefore,theeffectiveminimuminhibitoryconcentration(MIC)atthesiteofinfectionwithbacterialdensitiesof108to1011colony-formingunitsper1gtissuecanbemuchhigherthananticipatedbyinvitrosusceptibilityteststhatuseastandardinoculum(105.5colony-formingunitspermilliliter).Inaddition,bacteriathatareotherwisekilledatlowdensitiesbybactericidalantibioticssuchaspenicillinscanberelativelyresistanttoortolerantoftheirbactericidaleffectindensepopulations.Aninoculumeffecthasbeendemonstratedwithpenicillinversusstreptococciinbothinvitroandanimalmodels.Forexample,thecurativedoseofpenicillinforstreptococcalinfectionsinanimalmodelshasbeenshowntoincreasemarkedlywiththenumberoforganismsinoculatedandthedurationoftheinfection,presumablybecauseoftheinterimincreaseinthenumberoforganismsintheinfectedhost.76Inaddition,thestationarygrowth-phaseconditionsmakeitlesslikelythatbacterialcellwall–activeantibiotics(β-lactamsandglycopeptides)areoptimallyeffective.77–79Stationary-phaseorganismshavebeenassociatedwithalossofpenicillin-bindingproteinsthataretheactivetargetsitesrequiredforβ-lactamantibacterialactivity.Thislossofpenicillin-bindingproteinsduringstationary-phasegrowthmayberesponsibleinpartfortheinoculumeffectobservedinvivoandmayaccountforthefailureofpenicillininbothexperimentalandhumancasesofseverestreptococcalinfections.80Importantly,fluoroquinolonesandaminoglycosideantibioticsarelessaffectedbythesizeoftheinoculumbecauseoftheirdifferentmechanismsofbactericidalactivity.81,82Aninoculumeffectalsooccurswithβ-lactamase–susceptibleβ-lactamantibioticsversusβ-lactamase–producingbacteria,presumablybecausemoreβ-lactamaseispresentindenserβ-lactamase–producingbacterialpopulations,asobservedinvitrowithsomeenterococci,83Saureus,84andGram-negativebacilli85;inanimalmodelsofexperimentalIE86,87;andclinically.88Highinoculaarealsomorelikelytohaveantibiotic-resistantsubpopulationsthatcanemergeinthesettingofantibiotictherapy.Forexample,inaninvitroPDmodel,theactivityofvancomycinagainstheterogeneousvancomycin-intermediateSaureus(hVISA)andnon-hVISAisolateswasreducedinthepresenceofahighinoculumamount(108colony-formingunitspermilliliter).75BactericidalDrugsDatafromanimalmodelsofIEandclinicalinvestigationssupporttheneedforbactericidalantibioticstosterilizevegetationsinIEwithhighbacterialdensities.89Forenterococci,bactericidalactivitycanbeachievedbythecombinationofcertainβ-lactamantibiotics(eg,penicillin,ampicillin,andpiperacillin)withanaminoglycoside.Thebactericidaleffectachievedbyacombinationofantibacterialdrugsthataloneonlyinhibitbacterialgrowthiscalledsynergy.Therateofbactericidalactivityagainstsomeotherorganismscanalsobeenhancedbyacombinationofaβ-lactamantibioticplusanaminoglycoside.DurationofAntimicrobialTherapyThedurationoftherapyinIEmustbesufficienttoensurecompleteeradicationofmicroorganismswithinvegetations.Prolongedtherapyisnecessarybecauseofthehighbacterialdensitieswithinvegetationsandtherelativelyslowbactericidalactivityofsomeantibioticssuchasβ-lactamsandvancomycin.Whenthebactericidalactivityisknowntobemorerapidorthelikelyvegetationbacterialburdenislower,thentheclinicianmayprescribeashorterdurationofantimicrobialtherapyinuniqueinstances.Combinationtherapywithpenicillinorceftriaxoneandanaminoglycosidefor2weeksishighlyeffectiveinviridansgroupstreptococci(VGS)IE90inveryselectpatientswithuncomplicatedinfection.Bothβ-lactamtherapyaloneandcombinationtherapywithnafcillinandanaminoglycosideforonly2weekshavebeeneffectiveinpatientswithuncomplicatedright-sidedIEcausedbySaureus91;monotherapywithaβ-lactamwouldbeselectedforuseincasesofuncomplicatedIE.92Ofinterest,right-sidedvegetationstendtohavelowerbacterialdensities,whichmayresultfromhostdefensemechanisms,includingpolymorphonuclearactivityorplatelet-derivedantibacterialcationicpeptides.90,91,93DrugPenetrationThepenetrationofantibioticsisasignificantissueinthetreatmentofIEbecausecardiacvegetations,whicharecomposedoflayersoffibrinandplatelets,poseaconsiderablemechanicalbarrierbetweentheantibioticandtheembeddedtargetedmicroorganisms.94,95Theefficacyofantimicrobialdrugsvaries,dependingonthedegreeofpenetrationintothevegetation,patternofdistributionwithinthevegetation,andvegetationsize.96,97Patternsofdiffusiondifferbyclassofantibiotic,whichmayhaveimplicationsfortherapeuticoutcomesinpatientsbeingtreatedforIE.98–100PK/PDandDosingImplicationsinIEInthedesignofdoseregimensforthetreatmentofIE,itisimportanttofullyoptimizethePK/PDparameterfortheselectedantibiotictoincreasethelikelihoodofsuccessandtodecreasethepotentialfordevelopingresistance.101AntibioticPK/PDisrelatedtobothPKandmicroorganismsusceptibilitytothedrug.102Withtheuseofinvitroandinvivoevaluations,antibioticsarecategorizedonthebasisofwhethertheypossessconcentration-dependentortime-dependenteffectsonmicroorganismsandonthebasisof4commonPK/PDparametersthatpredictantibioticefficacy:theratioofthemaximumserumconcentrationtotheMIC,theratiooftheareaunderthe24-hourplasmaconcentration-timecurvetotheMIC(AUC24/MIC),thedurationoftimethattheserumconcentrationexceedstheMIC,andthedurationofthepostantibioticeffect.101,103Moredetaileddiscussionofthecalculationoftheseparametershasbeengivenpreviously.100WhereasboththeratioofmaximumserumconcentrationtoMICandtheAUC24/MICratiohavebeenshowntopredictefficacyastheoptimizedPDparametersforaminoglycoside,fluoroquinolone,anddaptomycintherapy,theAUC24/MICistheoptimizedPDactivityforglycopeptidessuchasvancomycin,teicoplanin,telavancin,oritavancin,andlipopeptidessuchasdaptomycin.β-Lactamefficacy,incontrast,isbestpredictedbythepercentdurationoftimethattheserumconcentrationexceedstheMIC.102Forpenicillinsandcephalosporinstoachieveabacteriostaticeffectinamurinemodel,thetimethefreedrugmustexceedtheMICis35%to40%ofthedosinginterval,whereasabactericidalresponserequires60%to70%ofthedosinginterval.104Tworetrospectivestudiesexaminedthecontinuousinfusionof2β-lactams(cefazolinandoxacillin)formethicillin-sensitiveSaureus(MSSA)infections,includingIE,withresultssupportingcontinuousinfusionofthesedrugs.Morestudyisneeded,however,beforeastrongrecommendationcanbemade.105,106Forconcentration-dependentantibioticssuchasaminoglycosidesandfluoroquinolones,aratioofmaximumserumconcentrationtoMICof>10wasassociatedwithimprovedefficacyinpatientswithGram-negativepneumonia,whereasanAUC24/MIC>125wasassociatedwithanimprovedclinicalefficacyforciprofloxacinagainstinfectionscausedbyPseudomonasaeruginosa.107,108Liuetal109demonstratedthattheminimalAUC24/MICrequirementfordaptomycinwithan80%killefficacyinaSaureusinfectionmousemodelwas≈250,whichwouldbeeasilyachievedbytherecommendeddoseof6mg·kg−1·d−1forcomplicatedbacteremia,includingright-sidedIE.Someexpertshaverecommendeddaptomycindosesof8to10mg·kg−1·d−1forthetreatmentofcomplicatedmethicillin-resistantSaureus(MRSA)bacteremia,particularlyIE.Thisrecommendationisbasedontheconcentration-dependentpropertiesofdaptomycin,improvedefficacyforinfectionscausedbyorganismswithreducedsusceptibilitytodaptomycin,andanattempttoreducetheemergenceofresistancetodaptomycinaftervancomycintherapy.110TheevidencefortheserecommendationshascomelargelyfrominvitroPK/PDmodelsusinghigh-inoculum–simulatedendocardialvegetationswithSaureus111andenterococciandfromanimalmodelsofIE.112Withregardtovancomycin,anAUC24/MIC≥400isrecommendedasthetargetedPK/PDparameterforpatientswithseriousSaureusinfections.112Inanevaluationof320MRSApatientswithcomplicatedbacteremia,includingIE,Kullaretal113demonstratedthatanAUC24/MIC>421wassignificantlyassociatedwithimprovedpatientoutcomes.ThisAUC24/MICratiowasassociatedwithtroughserumconcentrations>15mg/L,attainableifthevancomycinMICwas<1mg/L.AntimicrobialTreatmentPerspectivesInmanycases,theinitialtherapyofIEisempirical;typically,resultsofbloodculturesaremonitoredforhourstodaysuntilapathogenisidentified.Duringthistime,empiricalantimicrobialtherapyisadministeredwiththeexpectationthattheregimenwillberevisedonceapathogenisdefinedandsusceptibilityresultsareobtained.Theselectionofanoptimalempiricregimenisusuallybroadandisbasedonfactorsthatrelatetopatientcharacteristics,priorantimicrobialexposuresandmicrobiologicalfindings,andepidemiologicalfeatures.Therefore,infectiousdiseasesconsultationshouldoccuratthetimeofempiricaltherapyinitiationtohelpdefinearegimen114,115becausetheselectionofaregimenishighlyvariable.Inthisregard,pleaserefertheCulture-NegativeEndocarditissectionofthisstatementandtherelatedTable6foradditionaldetails.Table6.EpidemiologicalCluesThatMaybeHelpfulinDefiningtheEtiologicalDiagnosisofCulture-NegativeEndocarditisEpidemiologicalFeatureCommonMicroorganismIDUSaureus,includingcommunity-acquiredoxacillin-resistantstrainsCoagulase-negativestaphylococciβ-HemolyticstreptococciFungiAerobicGram-negativebacilli,includingPseudomonasaeruginosaPolymicrobialIndwellingcardiovascularmedicaldevicesSaureusCoagulase-negativestaphylococciFungiAerobicGram-negativebacilliCorynebacteriumspGenitourinarydisorders,infection,andmanipulation,includingpregnancy,delivery,andabortionEnterococcusspGroupBstreptococci(Sagalactiae)ListeriamonocytogenesAerobicGram-negativebacilliNeisseriagonorrhoeaeChronicskindisorders,includingrecurrentinfectionsSaureusβ-HemolyticstreptococciPoordentalhealth,dentalproceduresVGSNutritionallyvariantstreptococciAbiotrophiadefectivaGranulicatellaspGemellaspHACEKorganismsAlcoholism,cirrhosisBartonellaspAeromonasspListeriaspSpneumoniaeβ-HemolyticstreptococciBurnSaureusAerobicGram-negativebacilli,includingPaeruginosaFungiDiabetesmellitusSaureusβ-HemolyticstreptococciSpneumoniaeEarly(≤1y)prostheticvalveplacementCoagulase-negativestaphylococciSaureusAerobicGram-negativebacilliFungiCorynebacteriumspLegionellaspLate(>1y)prostheticvalveplacementCoagulase-negativestaphylococciSaureusViridansgroupstreptococciEnterococcusspeciesFungiCorynebacteriumspDogorcatexposureBartonellaspPasteurellaspCapnocytophagaspContactwithcontaminatedmilkorinfectedfarmanimalsBrucellaspCoxiellaburnetiiErysipelothrixspHomeless,bodyliceBartonellaspAIDSSalmonellaspSpneumoniaeSaureusPneumonia,meningitisSpneumoniaeSolidorgantransplantationSaureusAspergillusfumigatusEnterococcusspCandidaspGastrointestinallesionsSgallolyticus(bovis)EnterococcusspClostridiumsepticumHACEKindicatesHaemophilusspecies,Aggregatibacterspecies,Cardiobacteriumhominis,Eikenellacorrodens,andKingellaspecies;IDU,injectiondruguse;andVGS,viridansgroupstreptococci.Resultsofclinicalefficacystudiessupporttheuseofmosttreatmentregimensdescribedintheseguidelines.Otherrecommendationslistedinthissectionarebasedlargelyoninvitrodataandconsensusopinionandincludethefollowingmanagementconsiderations.Itisreasonableforthecountingofdaysforthedurationoftherapytobeginonthefirstdayonwhichbloodculturesarenegativeincasesinwhichbloodcultureswereinitiallypositive.Itisreasonabletoobtain2setsofbloodculturesevery24to48hoursuntilbloodstreaminfectioniscleared.However,ifapatientundergoesvalvesurgeryandtheresectedvalvetissueisculturepositiveoraperivalvularabscessisfound,thenanentirecourseofantimicrobialtherapyisreasonableaftervalvesurgery.Iftheresectedtissueisculturenegative,thenitmaybereasonableforthedurationofpostoperativetreatmentgivenlessthenumberofdaysoftreatmentadministeredfornativevalveinfectionbeforevalvereplacement.This,however,hasbeenchallengedbyretrospectivelycollecteddatafrom2differentmedicalcenters116,117thatsuggestthat2weeksofantibiotictherapymaybesufficientinpatientswhoundergovalvesurgeryandhavenegativevalvetissuecultures,particularlyinIEcasescausedbyVGSorStreptococcusgallolyticus(bovis).Whethera2-weektreatmentcoursewouldbesufficientaftervalvesurgeryinpatientswithpositivevalvecultureseitherwasnotaddressedin1survey116orincludedonly5patientsintheother.117HistopathologicalevidenceofbacteriawithvalvetissueGramstaininginpatientswithnegativetissueculturescanrepresentkilledorganismsandisnotafactorindefiningthelengthoftherapyaftervalvesurgery.110ForpatientswithNVEwhoundergovalveresectionwithprostheticvalvereplacementorrepairwithanannuloplastyring,thereisalackofconsensusastowhetherthepostoperativetreatmentregimenshouldbeonethatisrecommendedforprostheticvalvetreatmentratherthanonethatisrecommendedfornativevalvetreatment.Inregimensthatcontaincombinationantimicrobialtherapy,itisreasonabletoadministeragentsatthesametimeortemporallyclosetogethertomaximizethesynergistickillingeffectonaninfectingpathogen.RecommendationsInfectiousdiseasesconsultationshouldbeobtainedtodefineanoptimalempiricaltreatmentregimenatthetimeofinitiationofantimicrobialtherapy(ClassI;LevelofEvidenceB).Itisreasonablethatthecountingofdaysforthedurationofantimicrobialtherapybeginonthefirstdayonwhichbloodculturesarenegativeincasesinwhichbloodcultureswereinitiallypositive(ClassIIa;LevelofEvidenceC).Itisreasonabletoobtainatleast2setsofbloodculturesevery24to48hoursuntilbloodstreaminfectionhascleared(ClassIIa;LevelofEvidenceC).Ifoperativetissueculturesarepositive,thenanentireantimicrobialcourseisreasonableaftervalvesurgery(ClassIIa;LevelofEvidenceB).Ifoperativetissueculturesarenegative,itmaybereasonabletocountthenumberofdaysofantimicrobialtherapyadministeredbeforesurgeryintheoveralldurationoftherapy(ClassIIb;LevelofEvidenceC).Itisreasonabletotimetheadministrationofantimicrobialtherapyatthesametimeortemporallyclosetogetherforregimensthatinclude>1antimicrobialagent(ClassIIa;LevelofEvidenceC).OverviewofVGS,Streptococcusgallolyticus(FormerlyKnownasStreptococcusbovis),Abiotrophiadefectiva,andGranulicatellaSpeciesVGSarecommonpathogenicagentsincommunity-acquiredNVEinpatientswhoarenotIDUs.ThetaxonomyofVGSisevolving.ThespeciesthatmostcommonlycauseIEareSsanguis,Soralis(mitis),Ssalivarius,Smutans,andGemellamorbillorum(formerlycalledSmorbillorum).MembersoftheSanginosusgroup(Sintermedius,anginosus,andconstellatus)alsohavebeenreferredtoastheSmillerigroup,andthishascausedsomeconfusion.Incontrasttootherα-hemolyticstreptococcalspecies,theSanginosusgrouptendstoformabscessesandtocausehematogenouslydisseminatedinfection(eg,myocardialandvisceralabscesses,septicarthritis,andvertebralosteomyelitis).Inaddition,althoughtheSanginosusgroupusuallyissensitivetopenicillin,somestrainsmayexhibitvariablepenicillinresistance.TherecommendationsthatfollowareintendedtoassistcliniciansinselectingappropriateantimicrobialtherapyforpatientswithIEcausedbyVGSandSgallolyticus(bovis,anonenterococcalpenicillin-susceptiblegroupDStreptococcus).Sgallolyticus(bovis)expressesthegroupDantigen,butitcanbedistinguishedfromgroupDEnterococcusbyappropriatebiochemicaltests.PatientswitheitherSgallolyticus(bovis)bacteremiaorIEshouldundergoacolonoscopytodeterminewhethermalignancyorothermucosallesionsarepresent.CertainVGShavebiologicalcharacteristicsthatmaycomplicatediagnosisandtherapy.AdefectivaandGranulicatellaspecies(Gelegans,Gadiacens,Gparaadiacens,andGbalaenopterae),formerlyknownasnutritionallyvariantstreptococci,aredetectedbyautomatedbloodculturesystemsbutmayyieldpleomorphicformsbyGramstainandwillnotgrowonsubcultureunlesschocolateagarorothermediasupplementedwithpyridoxalorcysteineisused.TreatmentregimensoutlinedforVGS,A.defectiva,andGranulicatellaspeciesaresubdividedintocategoriesbasedonpenicillinMICdata.NativeValveHighlyPenicillin-SusceptibleVGSandSgallolyticus(bovis)(MIC≤0.12µg/mL)Bacteriologicalcurerates≥98%maybeanticipatedinpatientswhocomplete4weeksoftherapywithparenteralpenicillinorceftriaxoneforIEcausedbyhighlypenicillin-susceptibleVGSorSgallolyticus(bovis)118,119(Table7).Ampicillinisareasonablealternativetopenicillinandhasbeenusedwhenpenicillinisnotavailablebecauseofsupplydeficiencies.Table7.TherapyofNVECausedbyHighlyPenicillin-SusceptibleVGSandStreptococcusgallolyticus(bovis)RegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsAqueouscrystallinepenicillinGsodium12–18millionU/24hIVeithercontinuouslyorin4or6equallydivideddoses4ClassIIa;LevelofEvidenceBPreferredinmostpatients>65yorpatientswithimpairmentofeighthcranialnervefunctionorrenalfunction.OrAmpicillin2gIVevery4hisareasonablealternativetopenicillinifapenicillinshortageexists.Ceftriaxonesodium2g/24hIV/IMin1dose4ClassIIa;LevelofEvidenceBAqueouscrystallinepenicillinGsodium12–18millionU/24hIVeithercontinuouslyorin6equallydivideddoses2ClassIIa;LevelofEvidenceB2-wkregimennotintendedforpatientswithknowncardiacorextracardiacabscessorforthosewithcreatinineclearanceof<20mL/min,impairedeighthcranialnervefunction,orAbiotrophia,Granulicatella,orGemellasppinfection;gentamicindoseshouldbeadjustedtoachievepeakserumconcentrationof3–4μg/mLandtroughserumconcentrationof<1μg/mLwhen3divideddosesareused;therearenooptimaldrugconcentrationsforsingledailydosing.†OrCeftriaxonesodium2g/24hIVorIMin1dose2ClassIIa;LevelofEvidenceBPlusGentamicinsulfate‡3mg/kgper24hIVorIMin1dose2Vancomycinhydrochloride§30mg/kgper24hIVin2equallydivideddoses4ClassIIa;LevelofEvidenceBVancomycintherapyisreasonableonlyforpatientsunabletotoleratepenicillinorceftriaxone;vancomycindoseshouldbeadjustedtoatroughconcentrationrangeof10–15μg/mL.IMindicatesintramuscular;IV,intravenous;NVE,nativevalveinfectiveendocarditis;andVGS,viridansgroupstreptococci.Minimuminhibitoryconcentrationis≤0.12μg/mL.ThesubdivisionsdifferfromClinicalandLaboratoryStandardsInstitute–recommendedbreakpointsthatareusedtodefinepenicillinsusceptibility.*Dosesrecommendedareforpatientswithnormalrenalfunction.†Dataforonce-dailydosingofaminoglycosidesforchildrenexist,butnodatafortreatmentofIEexist.‡Otherpotentiallynephrotoxicdrugs(eg,nonsteroidalanti-inflammatorydrugs)shouldbeusedwithcautioninpatientsreceivinggentamicintherapy.Althoughitispreferredthatgentamicin(3mg/kg)begivenasasingledailydosetoadultpatientswithendocarditiscausedbyviridansgroupstreptococci,asasecondoption,gentamicincanbeadministereddailyin3equallydivideddoses.§Vancomycindosagesshouldbeinfusedduringthecourseofatleast1hourtoreducetheriskofhistamine-release“redman”syndrome.TheadditionofgentamicinsulfatetopenicillinexertsasynergistickillingeffectinvitroonVGSandSgallolyticus(bovis).ThecombinationofpenicillinorceftriaxonewithgentamicinresultsinsynergistickillinginanimalmodelsofVGSorSgallolyticus(bovis)experimentalIE.Inselectedpatients,treatmentwitha2-weekregimenwitheitherpenicillinorceftriaxonecombinedwithanaminoglycosideresultedincureratesthataresimilartothoseaftermonotherapywithpenicillinorceftriaxoneadministeredfor4weeks.83,120StudiesperformedinEurope,SouthAmerica,andtheUnitedStatesdemonstratedthatthecombinationofonce-dailyceftriaxonewitheithernetilmicinorgentamicinadministeredoncedailywasequivalentinefficacyto2weeksoftherapywithpenicillinwithanaminoglycosideadministeredindailydivideddoses.83,120The2-weekregimenofpenicillinorceftriaxonecombinedwithsingledaily-dosegentamicinisreasonableforuncomplicatedcasesofIEcausedbyhighlypenicillin-susceptibleVGSorSgallolyticus(bovis)inpatientsatlowriskforadverseeventscausedbygentamicintherapy(Table7).This2-weekregimenisnotrecommendedforpatientswithknownextracardiacinfectionorthosewithacreatinineclearanceof<20mL/min.Althoughthetwo,4-weekß-lactam–containingregimensshowninTable7producesimilaroutcomes,eachregimenhasadvantagesanddisadvantages.Monotherapywitheitherpenicillinorceftriaxonefor4weeksavoidstheuseofgentamicin,whichispotentiallyototoxicandnephrotoxic.Comparedwithpenicillin,theadvantageofonce-dailyceftriaxoneisitssimplicityforuseintherapyadministeredtooutpatients.118,121Bothpenicillinandceftriaxoneareoverallwelltoleratedbut,likeallantimicrobials,havethepotentialforcausingadversedrugevents;someofthemorecommononesincluderash,fever,diarrhea,andneutropenia.Liverfunctionabnormalitiescanbeseenwithceftriaxoneuseandaresometimesassociatedwith“sludging”ofdruginthegallbladder.122Forpatientswhoareunabletotoleratepenicillinorceftriaxone,vancomycinisareasonablyeffectivealternative.Prolongedintravenoususeofvancomycinmaybecomplicatedbythrombophlebitis,rash,fever,neutropenia,andrarelyototoxicreactions.Thelikelihoodof“redman”syndromeisreducedwithaninfusionofvancomycinover≥1hour.Desiredtroughvancomycinlevelsshouldrangebetween10and15µg/mL.RecommendationsBothaqueouscrystallinepenicillinGandceftriaxonearereasonableoptionsfora4-weektreatmentduration(ClassIIa;LevelofEvidenceB).A2-weektreatmentregimenthatincludesgentamicinisreasonableinpatientswithuncomplicatedIE,rapidresponsetotherapy,andnounderlyingrenaldisease(ClassIIa;LevelofEvidenceB).Vancomycinfora4-weektreatmentdurationisareasonablealternativeinpatientswhocannottoleratepenicillinorceftriaxonetherapy(ClassIIa;LevelofEvidenceB).Thedesiredtroughvancomycinlevelshouldrangebetween10and15µg/mL(ClassI;LevelofEvidenceC).RelativelyPenicillin-ResistantVGSandSgallolyticus(bovis)(MIC>0.12–<0.5µg/mL)PenicillinresistanceinvitrooccursamongsomestrainsofVGSandSgallolyticus(bovis).Todate,however,thenumberofIEcasesthathavebeenreportedasaresultofVGSorSgallolyticus(bovis)strainsthatharboranydegreeofpenicillinresistanceissmall.123–126Therefore,itisdifficulttodefinetheoptimaltreatmentstrategiesforthisgroupofpatients.Table8showsregimensfortreatmentofNVEcausedbyrelativelypenicillin-resistantstrains(MIC>0.12–<0.5µg/mL).ForpatientswithVGSorSgallolyticus(bovis)IEcausedbytheserelativelyresistantstrains,itisreasonabletoadministerpenicillinfor4weeks,togetherwithsingledaily-dosegentamicinforthefirst2weeksoftreatment.Ampicillinisareasonablealternativetopenicillinifshortagesofpenicillinexist.Table8.TherapyofNVECausedbyStrainsofVGSandStreptococcusgallolyticus(bovis)RelativelyResistanttoPenicillinRegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsAqueouscrystallinepenicillinGsodium24millionU/24hIVeithercontinuouslyorin4–6equallydivideddoses4ClassIIa;LevelofEvidenceBItisreasonabletotreatpatientswithIEcausedpenicillin-resistant(MIC≥0.5μg/mL)VGSstrainswithacombinationofampicillinorpenicillinplusgentamicinasdoneforenterococcalIEwithinfectiousdiseasesconsultation(ClassIIa;LevelofEvidenceC).Ampicillin2gIVevery4hisareasonablealternativetopenicillinifapenicillinshortageexists. PlusGentamicinsulfate†3mg/kgper24hIVorIMin1dose2CeftriaxonemaybeareasonablealternativetreatmentoptionforVGSisolatesthataresusceptibletoceftriaxone(ClassIIb;LevelofEvidenceC).Vancomycinhydrochloride‡30mg/kgper24hIVin2equallydivideddoses4ClassIIa;LevelofEvidenceCVancomycintherapyisreasonableonlyforpatientsunabletotoleratepenicillinorceftriaxonetherapy.IEindicatesinfectiveendocarditis;IM,intramuscular;IV,intravenous;MIC,minimuminhibitoryconcentration;NVE,nativevalveinfectiveendocarditis;andVGS,viridansgroupstreptococci.MICis>0.12to<0.5μg/mLforpenicillin.ThesubdivisionsdifferfromClinicalandLaboratoryStandardsInstitute–recommendedbreakpointsthatareusedtodefinepenicillinsusceptibility.)*Dosesrecommendedareforpatientswithnormalrenalfunction.†SeeTable7forappropriatedoseofgentamicin.Althoughitispreferredthatgentamicin(3mg/kg)begivenasasingledailydosetoadultpatientswithendocarditiscausedbyviridansgroupstreptococci,asasecondoption,gentamicincanbeadministereddailyin3equallydivideddoses.‡SeeTable7forappropriatedosageofvancomycin.Iftheisolateisceftriaxonesusceptible,thenceftriaxonealonemaybeconsidered(ClassIIb;LevelofEvidenceC).Vancomycinalonemaybeareasonablealternativeifthepatientisintolerantofβ-lactamtherapy(ClassIIb;LevelofEvidenceC).Consultationwithaninfectiousdiseasesspecialistisencouragedinbothofthesescenarios.RecommendationsItisreasonabletoadministerpenicillinfor4weekswithsingledaily-dosegentamicinforthefirst2weeksoftherapy(ClassIIa;LevelofEvidenceB).Iftheisolateisceftriaxonesusceptible,thenceftriaxonealonemaybeconsidered(ClassIIb;LevelofEvidenceC).Vancomycinalonemaybeareasonablealternativeinpatientswhoareintolerantofβ-lactamtherapy(ClassIIa;LevelofEvidenceC).AdefectivaandGranulicatellaSpeciesandVGSWithaPenicillinMIC≥0.5µg/mLThedeterminationofantimicrobialsusceptibilitiesofAdefectivaandGranulicatellaspecies(bothformerlyknownasnutritionallyvariantstreptococci)isoftentechnicallydifficult,andtheresultsmaynotbeaccurate.Moreover,IEcausedbythesemicroorganismsisuncommonandhasbeenmoredifficulttocuremicrobiologicallycomparedwithIEcausedbyastrainofnon–nutritionallyvariantVGS.127Forthesereasons,inpatientswithIEcausedbyAdefectivaandGranulicatellaspecies,itisreasonabletoadministeracombinationregimenthatincludesampicillin(12g/dindivideddoses)orpenicillin(18–30millionU/Dindivideddosesorbycontinuousinfusion)plusgentamicin(3mg·kg−1·d−1in2–3divideddoses)withinfectiousdiseasesconsultationtodeterminelengthoftherapy.Findingsfromananimalmodelofexperimentalendocarditissuggestthatifvancomycinischosenforuseinpatientsintolerantofpenicillinorampicillin,thentheadditionofgentamicinisnotneeded.128Ceftriaxonecombinedwithgentamicinmaybeareasonablealternativetreatmentoption125,126forVGSisolatesthataresusceptibletoceftriaxoneonthebasisoftheClinicalandLaboratoryStandardsInstitutedefinitionandareresistanttopenicillin(MIC≥0.5µg/mL,asdefinedinthisstatement).Currently,thereisnoreportedclinicalexperiencewiththecombinationofampicillinplusceftriaxoneforIEcausedbytheseorganisms.RecommendationsItisreasonabletotreatpatientswithIEcausedbyAdefectiva,Granulicatellaspecies,andVGSwithapenicillinMIC≥0.5µg/mLwithacombinationofampicillinorpenicillinplusgentamicinasdoneforenterococcalIEwithinfectiousdiseasesconsultation(ClassIIa;LevelofEvidenceC).Ifvancomycinisusedinpatientsintolerantofampicillinorpenicillin,thentheadditionofgentamicinisnotneeded(ClassIII;LevelofEvidenceC).CeftriaxonecombinedwithgentamicinmaybeareasonablealternativetreatmentoptionforVGSisolateswithapenicillinMIC≥0.5µg/mLthataresusceptibletoceftriaxone(ClassIIb;LevelofEvidenceC).ProstheticValveorValvularProstheticMaterialEndocarditisofProstheticValvesorOtherProstheticMaterialCausedbyVGSandSgallolyticus(bovis)ForpatientswithIEcomplicatingprostheticvalvesorotherprostheticmaterialcausedbyahighlypenicillin-susceptiblestrain(MIC≤0.12µg/mL),itisreasonabletoadminister6weeksoftherapywithpenicillinorceftriaxonewithorwithoutgentamicinforthefirst2weeks(Table9).Itisreasonabletoadminister6weeksoftherapywithacombinationofpenicillinorceftriaxoneandgentamicininpatientswithIEcausedbyastrainthatisrelativelyorhighlyresistanttopenicillinMIC>0.12µg/mL.Vancomycinisusefulonlyforpatientswhoareunabletotoleratepenicillin,ceftriaxone,orgentamicin.Ampicillinisanacceptablealternativetopenicillinifshortagesofpenicillinexist.Table9.TherapyforEndocarditisInvolvingaProstheticValveorOtherProstheticMaterialCausedbyVGSandStreptococcusgallolyticus(bovis)RegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsPenicillin-susceptiblestrain(≤0.12μg/mL) AqueouscrystallinepenicillinGsodium24millionU/24hIVeithercontinuouslyorin4–6equallydivideddoses6ClassIIa;LevelofEvidenceBPenicillinorceftriaxonetogetherwithgentamicinhasnotdemonstratedsuperiorcureratescomparedwithmonotherapywithpenicillinorceftriaxoneforpatientswithhighlysusceptiblestrain;gentamicintherapyshouldnotbeadministeredtopatientswithcreatinineclearance<30mL/min.Or Ceftriaxone2g/24hIVorIMin1dose6ClassIIa;LevelofEvidenceB  Withorwithout Gentamicinsulfate†3mg/kgper24hIVorIMin1dose2Ampicillin2gIVevery4hisareasonablealternativetopenicillinifapenicillinshortageexists. Vancomycinhydrochloride‡30mg/kgper24hIVin2equallydivideddoses6ClassIIa;LevelofEvidenceBVancomycinisreasonableonlyforpatientsunabletotoleratepenicillinorceftriaxone.Penicillinrelativelyorfullyresistantstrain(MIC>0.12μg/mL) Aqueouscrystallinepenicillinsodium24millionU/24hIVeithercontinuouslyorin4–6equallydivideddoses6ClassIIa;LevelofEvidenceBAmpicillin2gIVevery4hisareasonablealternativetopenicillinifapenicillinshortageexists.Or Ceftriaxone2g/24hIV/IMin1dose6ClassIIa;LevelofEvidenceBPlus Gentamicinsulfate3mg/kgper24hIV/IMin1dose6 Vancomycinhydrochloride30mg/kgper24hIVin2equallydivideddoses6ClassIIa;LevelofEvidenceBVancomycinisreasonableonlyforpatientsunabletotoleratepenicillinorceftriaxone.IMindicatesintramuscular;IV,intravenous;MICindicatesminimuminhibitoryconcentration;andVGS,viridansgroupstreptococci.*Dosesrecommendedareforpatientswithnormalrenalfunction.†SeeTable7forappropriatedoseofgentamicin.Althoughitispreferredthatgentamicin(3mg/kg)begivenasasingledailydosetoadultpatientswithendocarditisresultingfromVGS,asasecondoption,gentamicincanbeadministereddailyin3equallydivideddoses.‡SeetextandTable7forappropriatedoseofvancomycin.RecommendationsAqueouscrystallinepenicillinGorceftriaxonefor6weekswithorwithoutgentamicinforthefirst2weeksisreasonable(ClassIIa;LevelofEvidenceB).Itisreasonabletoextendgentamicinto6weeksiftheMICis>0.12µg/mLfortheinfectingstrain(ClassIIa;LevelofEvidenceC).Vancomycincanbeusefulinpatientsintolerantofpenicillin,ceftriaxone,orgentamicin(ClassIIa;LevelofEvidenceB).Streptococcuspneumoniae,Streptococcuspyogenes,andGroupsB,C,F,andGβ-HemolyticStreptococciIEcausedbythesestreptococciisuncommon.TherearefewpublishedreportsoflargecaseseriesevaluatingmanagementstrategiesforIEcausedbythesemicroorganisms.ResultsoflogisticregressionanalysisofclinicalvariablesfromcasesofpneumococcalIEdemonstratedthepotentialvalueofvalvereplacementinpreventingearlydeathin1investigation.129ForpatientswithNVEcausedbyhighlypenicillin-susceptibleSpneumoniae,itisreasonabletoadminister4weeksofantimicrobialtherapywithpenicillin,cefazolin,orceftriaxone.Vancomycinisreasonableonlyforpatientswhoareunabletotolerateβ-lactamtherapy.Sixweeksoftherapyisreasonableforpatientswithprostheticvalveendocarditis(PVE).Pneumococciwithintermediatepenicillinresistance(MIC>0.1–1.0µg/mL)orhighpenicillinresistance(MIC≥2.0µg/mL)arerecovereduncommonlyfrompatientswithbacteremia.130Moreover,cross-resistanceofpneumococcitootherantimicrobialagentssuchascephalosporins,macrolides,fluoroquinolones,carbapenems,andevenvancomycinisincreasinginfrequency.In1multicenterstudy131witharelativelylargenumberofpatientswithIEcausedbySpneumoniaeresistanttopenicillin(MIC,0.1–4µg/mL),patientswereevaluatedandcomparedwith39patientswhowereinfectedwithpenicillin-susceptiblestrains.Severalkeyobservationsweremade.Infectionbypenicillin-resistantstrainsdidnotworsenprognosis.High-dosepenicillinorathird-generationcephalosporinisreasonableinpatientswithpenicillin-resistantIEwithoutmeningitis.InpatientswithIEandmeningitis,highdosesofcefotaximearereasonable.Iftheisolateisresistant(MIC≥2µg/mL)tocefotaxime,thentheadditionofvancomycinandrifampinmaybeconsidered.Ceftriaxonemaybeconsideredinsteadofcefotaximeinthepreviousrecommendations.Thesefindingsarebasedoncurrentlevelsofresistance,andincreasingMICscoulddictaterevisionsinfuturetreatmentselections.Accordingly,thetreatmentofpatientswithpneumococcalIEshouldbecoordinatedinconsultationwithaninfectiousdiseasesspecialist.ForSpyogenesIE,penicillinGadministeredintravenouslyfor4to6weeksisreasonabletreatmentonthebasisoflimitedpublisheddata.Ceftriaxoneisareasonablealternativetopenicillin.Vancomycinisreasonableonlyforpatientswhoareunabletotolerateaβ-lactamantibiotic.Ingeneral,strainsofgroupB,C,F,andGstreptococciareslightlymoreresistanttopenicillinthanarestrainsofgroupAstreptococci.Inthesepatients,theadditionofgentamicintopenicillinortoceftriaxoneforatleastthefirst2weeksofa4-to6-weekcourseofantimicrobialtherapyforgroupB,C,andGstreptococcalIEmaybeconsidered.132,133Thereisaclinicalimpression134,135thatearlycardiacsurgicalinterventionhasimprovedoverallsurvivalratesamongtreatedpatientswithβ-hemolyticstreptococcalIEcomparedwithpatientstreateddecadesago.BecauseoftherelativeinfrequencyofIEcausedbythesemicroorganisms,consultationwithaninfectiousdiseasesspecialistduringtreatmentisrecommended.RecommendationsFourweeksofantimicrobialtherapywithpenicillin,cefazolin,orceftriaxoneisreasonableforIEcausedbySpneumoniae;vancomycincanbeusefulforpatientsintolerantofβ-lactamtherapy(ClassIIa;LevelofEvidenceC).SixweeksoftherapyisreasonableforPVEcausedbySpneumoniae(ClassIIa;LevelofEvidenceC).High-dosepenicillinorathird-generationcephalosporinisreasonableinpatientswithIEcausedbypenicillin-resistantSpneumoniaewithoutmeningitis;ifmeningitisispresent,thenhighdosesofcefotaxime(orceftriaxone)arereasonable(ClassIIa;LevelofEvidenceC).Theadditionofvancomycinandrifampintocefotaxime(orceftriaxone)maybeconsideredinpatientswithIEcausedbySpneumoniaethatareresistanttocefotaxime(MIC>2µg/mL)(ClassIIb;LevelofEvidenceC).BecauseofthecomplexitiesofIEcausedbySpneumoniae,consultationwithaninfectiousdiseasesspecialistisrecommended(ClassI;LevelofEvidenceC).ForIEcausedbySpyogenes,4to6weeksoftherapywithaqueouscrystallinepenicillinGorceftriaxoneisreasonable;vancomycinisreasonableonlyinpatientsintolerantofβ-lactamtherapy(ClassIIa;LevelofEvidenceC).ForIEcausedbygroupB,C,orGstreptococci,theadditionofgentamicintoaqueouscrystallinepenicillinGorceftriaxoneforatleastthefirst2weeksofa4-to6-weektreatmentcoursemaybeconsidered(ClassIIb;LevelofEvidenceC).ConsultationwithaninfectiousdiseasesspecialisttoguidetreatmentisrecommendedinpatientswithIEcausedbyβ-hemolyticstreptococci(ClassI;LevelofEvidenceC).StaphylococciIEmaybecausedbystaphylococcithatarecoagulasepositive(Saureus)orcoagulasenegative(Sepidermidis,Slugdunensis,andvariousotherspecies).Althoughcoagulase-positivestaphylococciweretraditionallybelievedtocauseprimarilyNVEandcoagulase-negativestaphylococci(CoNS)wereassociatedwithPVE,considerableoverlapnowexists.Forexample,inamulticenter,prospective,observationalinvestigationinvolving>1000consecutivepatientswithdefiniteIEfrom>20countries,SaureuswasthemostcommoncauseofPVE(25.8%of214cases),whereas64casesofNVE(8%)resultedfromCoNS.136Inaddition,theprevalenceofCoNSNVEappearstobeincreasing.137Thus,itisimportanttoconsiderbothpathogengroupswhenapatientwithsuspectedIEhasapreliminarybloodculturethatsuggestsstaphylococcibyGramstaininterpretation.SaureusSaureusisthemostcommoncauseofIEinmuchofthedevelopedworld.6–8Datafrom>70millionhospitalizationsintheUnitedStatessuggestthatratesofSaureusIEhaveincreasedsignificantlyrelativetoothercausesofIE.3Thisincreaseisprimarilyaconsequenceofhealthcarecontact(eg,intravascularcatheters,surgicalwounds,indwellingprostheticdevices,hemodialysis)6,8,9andisespeciallyprevalentinNorthAmerica.6,138,139Increasingratesofoxacillin-resistantSaureusorMRSAisolatesinbothhospitalandcommunitysettingsandtherecoveryofclinicalSaureusisolatesbothpartiallyandfully138,139resistanttovancomycinhavecomplicatedthetreatmentofSaureusIE.Anincreasingbodyofevidencesuggestsanassociationbetweenhigh(butstillsusceptibleonthebasisoftheClinicalandLaboratoryStandardsInstitutedefinition)vancomycinMICsinSaureusandworseclinicaloutcomeinbothMRSAinfectionstreatedwithvancomycin140andMRSAbacteremiatreatedwithantistaphylococcalpenicillins.141Importantly,thisassociationbetweenhighervancomycinMICininfectingMSSAandworseclinicaloutcomesamongpatientstreatedwithantistaphylococcalpenicillins(notvancomycin)wasexternallyvalidatedinalargecohortofpatientswithMSSAIE.142Thesedatasuggestthathost-orpathogen-specificfactors,ratherthanhigherMICsoftheinfectingpathogentovancomycin,contributetothepooroutcomesinthesepatients(becausethelatterpatientswerenottreatedwithaglycopeptide).Innon-IDUs,SaureusIEinvolvesprimarilytheleftsideoftheheartandisassociatedwithmortalityratesrangingfrom25%to40%.SaureusIEinIDUsofteninvolvesthetricuspidvalve.Cureratesforright-sidedSaureusIEinIDUsarehigh(>85%)andmaybeachievedwithrelativelyshortcoursesofeitherparenteralororaltreatment(2–4weeks;seebelow).ComplicatedIEmanifested,forexample,bydeeptissueabscessesorosteoarticularinfectionmayrequiremoreprolongedtherapy.Coagulase-NegativeStaphylococciAsnotedabove,inadditiontotheirimportanceinPVE,CoNSnowcauseasignificantbutrelativelysmallproportionofNVEcases.2RiskfactorsforCoNSIEaresimilartothoseforSaureusandincludetypicalriskfactorsassociatedwithextensivehealthcarecontact.Ofinterest,datasuggestthattheoveralloutcomesforpatientswithCoNSIEandSaureusIEaresimilar.137MostCoNSareresistanttomethicillin.Theseresistantorganismsareparticularlyprominentamongpatientswithhealthcare-associatedstaphylococcalIE.Methicillin-resistantstrainsalsoareclinicallyresistanttocephalosporinsandcarbapenems,althoughthisfactisnotalwaysreflectedaccuratelyintheresultsofstandardinvitrotests.AnimportantsubsetofpatientswithCoNSIEhasbeenidentified:thosewithinfectioncausedbySlugdunensis.ThisspeciesofCoNStendstocauseasubstantiallymorevirulentformofIE,withahighrateofperivalvularextensionofinfectionandmetastaticinfection.Thisorganismisuniformlysusceptibleinvitrotomostantibiotics.143–145MostexpertsbelievethatIEcausedbythisorganismcanbetreatedwithstandardregimensbasedontheinvitrosusceptibilityprofilesofthestrain.Thepatientalsoshouldbemonitoredcarefullyforthedevelopmentofperiannularextensionorextracardiacspreadofinfection.AlthoughmicrobiologicaldifferentiationofSlugdunensisrequiresspecificbiochemicalassays,thepooroutcomesassociatedwithSlugdunensisunderscoretheimportanceofperformingthesespecializedassays.Initialscreeningcanbedonewithpyrrolidonylaminopeptidasehydrolysistesting,andisolatesthattestpositiveshouldbefurtheridentifiedbyamultisubstrateidentificationsystem,matrix-assistedlaserdesorptionionization–timeofflight,orothermethods,includingPCR.146,147RecommendationOngoingvigilanceforIEcomplications,includingperivalvularextensionofinfectionandextracardiacfociofinfection,isreasonable(ClassIIa;LevelofEvidenceC).IECausedbyStaphylococciintheAbsenceofProstheticValvesorOtherProstheticMaterialRight-SidedIEinIDUsTheadditionofgentamicintonafcillinoroxacillinhastraditionallybeenastandardapproachforthetreatmentofright-sidedIE.Forexample,inIDUswithuncomplicatedright-sidedSaureusIE(noevidenceofrenalfailure,extrapulmonarymetastaticinfections,aorticormitralvalveinvolvement,meningitis,orinfectionbyMRSA),combinedshort-course(2weeks)β-lactamplusaminoglycosidetherapywashighlyeffectiveinseveralstudies.91,92148In1study,92patientsprovidedsuchcombinationtherapyhadexcellentoutcomes,evenHIV-infectedpatientsandthosewhohadlargetricuspidvalvevegetations(>10mmindiameter).Incontrast,short-courseregimenswithglycopeptides(teicoplaninorvancomycin)plusgentamicinappearedtobelesseffectiveforright-sidedSaureusIEcausedbyeitherMSSAorMRSAstrains.148Theseglycopeptidesmaybelesseffectivebecauseoflimitedbactericidalactivity,poorpenetrationintovegetations,orincreaseddrugclearanceamongIDUs.Agrowingbodyofevidencesuggeststhattheadditionofadjunctiveaminoglycosidetherapynotonlyisunnecessaryforpatientswithuncomplicatedright-sidednativevalveSaureusIEbutmaycauseharm.Forexample,1studyshowedthata2-weekmonotherapyregimenofintravenouscloxacillinwasequivalenttocloxacillinplusgentamicinadministeredfor2weeks.92In2006,theUSFoodandDrugAdministration(FDA)approvedtheuseofdaptomycin(6mg·kg−1·d−1)forthetreatmentofSaureusbacteremiaandright-sidedSaureusIE.13Inaregistrationalopen-label,multinational,clinicaltrialforthetreatmentofSaureusbacteremiaorright-sidedIEcomparingtheefficacyofdaptomycinmonotherapywiththerapythatincludedlow-dose(1mg/kgIVevery8hoursoradjustedonthebasisofrenalfunction)gentamicinforthefirst4days,patientsdidequallywellineithertreatmentarm.InthepredefinedsubgroupofthosewithMRSAbacteremia,daptomycindemonstrateda44.4%successratecomparedwith31.8%forstandardtherapy;thisdifferencewasnotstatisticallysignificant(absolutedifference,12.6%,95%confidenceinterval,−7.4to32.6;P=0.28).Ofnote,inaposthocanalysisofthislandmarkclinicaltrial,149theadditionofevensuchlow-dose,short-coursegentamicinin1armofthestudywassignificantlyassociatedwithrenaltoxicity,whichoccurredearlyandoften,andtheclinicalassociationbetweengentamicindoseanddurationwasminimal.Thus,currentevidencesuggeststhateitherparenteralβ-lactamordaptomycinshort-coursetherapyisadequateforthetreatmentofuncomplicatedMSSAright-sidedIE.Incontrast,glycopeptidetherapyforMRSAright-sidedIEmayrequiremoreprolongedtreatmentregimens.ForbothMSSAandMRSAinfections,useofadjunctivegentamicinforthetreatmentofSaureusbacteremiaorright-sidedNVEisdiscouragedRecommendationGentamicinisnotrecommendedfortreatmentofright-sidedstaphylococcalNVE(ClassIII;LevelofEvidenceB).Inpatientsforwhomparenteralantibiotictherapyisproblematic,oraltreatmentmaybeareasonableoption.Twostudieshaveevaluatedtheuseofpredominantlyoral4-weekantibioticregimens(featuringciprofloxacinplusrifampin)forthetherapyofuncomplicatedright-sidedMSSAIEinIDUs.150,151Ineachstudy,includingoneinwhich>70%ofpatientswereHIVseropositive,150curerateswere>90%.However,therelativelyhighrateofquinoloneresistanceamongcontemporarySaureusstrainshasmadethisalternativetreatmentstrategyproblematic.IEinNon-IDUsOlderanecdotalcasereportsinnon-IDUswithSaureusIEsuggestedthattheuseofcombinedgentamicin-methicillintherapymaybeofbenefitinpatientswhofailtorespondtomonotherapywithmethicillin.152Thisissuewasaddressedinamulticenter,prospectivetrialcomparingnafcillinalonefor6weekswithnafcillinplusgentamicin(fortheinitial2weeks)inthetreatmentofpredominantlyleft-sidedIEcausedbySaureus.153Nafcillin-gentamicintherapyreducedthedurationofbacteremiaby≈1daycomparedwithnafcillinmonotherapy.However,combinationtherapydidnotreducemortalityorthefrequencyofcardiaccomplications.Furthermore,combinationtherapyincreasedthefrequencyofgentamicin-associatednephrotoxicity.Asnotedabove,149theriskofclinicallysignificantnephrotoxicitywithevenshortcoursesofadjunctivelow-dosegentamicinforSaureusbacteremiaandright-sidedIEcanbesubstantial.Inaddition,gentamicinshouldnotbeusedwithvancomycininpatientswithMRSANVEbecauseofthenephrotoxicityrisk.13,149IncasesofbrainabscesscomplicatingMSSAIE,nafcillinisthepreferredagentratherthancefazolin,whichhasinadequateblood-brainbarrierpenetrability.Ifthepatientcannottoleratenafcillintherapy,thenvancomycinshouldbeused.VancomycinisoftenincludedwithcefazolinasempiricalcoverageforpatientswithIEcausedbySaureuswhileawaitingsusceptibilityresults.Ananalysisoftheliterature,however,comparedtheuseofempiricalcombinationofvancomycinandantistaphylococcalβ-lactamtherapywithvancomycinaloneanddemonstratedthesuperiorityofβ-lactam–containingregimensovervancomycinmonotherapyforbacteremicMSSAinfections,includingIE.154Thisdifferentialoutcomeincludedstudiesinwhichtherewasanearlyshiftfromempiricalvancomycintoβ-lactamtherapyassoonasbloodculturesyieldedMSSA(notMRSA).Themeta-analysisincludedsmall,retrospectivestudies,however,whichlimitssupportforinitialcombinationtherapybysomeexperts.Therefore,theusefulnessofempiriccombinationtherapyinpatientswithSaureusbacteremiauntiloxacillinsusceptibilityisknownisuncertain.Althoughthelargemajorityofstaphylococciareresistanttopenicillin,occasionalstrainsremainsusceptible.Unfortunately,thecurrentlaboratoryscreeningproceduresfordetectingpenicillinsusceptibilitymaynotbereliable.Therefore,IEcausedbytheseorganismsshouldbetreatedwithregimensoutlinedforMSSAthatincludesnafcillin(orequivalentantistaphylococcalpenicillin)asanoptionratherthanpenicillin(Table10).Table10.TherapyforNVECausedbyStaphylococciRegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsOxacillin-susceptiblestrains Nafcillinoroxacillin12g/24hIVin4–6equallydivideddoses6ClassI;LevelofEvidenceCForcomplicatedright-sidedIEandforleft-sidedIE;foruncomplicatedright-sidedIE,2wk(seetext). Forpenicillin-allergic(nonanaphylactoidtype)patientsConsiderskintestingforoxacillin-susceptiblestaphylococciandquestionablehistoryofimmediate-typehypersensitivitytopenicillin.  Cefazolin*6g/24hIVin3equallydivideddoses6ClassI;LevelofEvidenceBCephalosporinsshouldbeavoidedinpatientswithanaphylactoid-typehypersensitivitytoβ-lactams;vancomycinshouldbeusedinthesecases.Oxacillin-resistantstrains Vancomycin§30mg/kgper24hIVin2equallydivideddoses6ClassI;LevelofEvidenceCAdjustvancomycindosetoachievetroughconcentrationof10–20μg/mL(seetextforvancomycinalternatives). Daptomycin≥8mg/kg/dose6ClassIIb;LevelofEvidenceBAwaitadditionalstudydatatodefineoptimaldosing.IEindicatesinfectiveendocarditis;IV,intravenous;andNVE,nativevalveinfectiveendocarditis.*Dosesrecommendedareforpatientswithnormalrenalfunction.‡Forspecificdosingadjustmentandissuesconcerningvancomycin,seeTable7footnotes.Therearenoevidence-baseddatathatdemonstratethemostappropriatedurationofnafcillintherapyfortreatmentofleft-sidedNVEcausedbyMSSA.Forpatientswithuncomplicatedinfection,6weeksoftherapyisrecommended.ForpatientswithcomplicationsofIEsuchasperivalvularabscessormationandsepticmetastaticcomplications,atleast6weeksofnafcillinisrecommended.Currently,definingtheoptimaltherapyforNVEattributabletoMRSAischallenging.Historically,vancomycinhasbeenusedandisrecommended.AsoutlinedintheTherapyofMSSAIEinPatientsAllergictoorIntolerantofβ-Lactamssectionbelow,daptomycinmaybeareasonablealternativetodaptomycinforleft-sidedNVEcausedbyMRSAonthebasisoflimiteddatainaprospective,randomizedtrial;amultinational,prospectivecohortinvestigationoftheuseofhigh-dose(≈9mg/kgperdose)daptomycin;andamulticenter,retrospective,observationalstudythatincludeddaptomycinat≥8mg/kgperdose.13,155Selectionofdaptomycindosingshouldbeassistedbyinfectiousdiseasesconsultation.Atthistime,additionalstudyofceftarolineisneededtodefineitsrole,ifany,inthetreatmentofleft-sidedNVEcausedbyMRSA.RecommendationsGentamicinshouldnotbeusedfortreatmentofNVEcausedbyMSSAorMRSA(ClassIII;LevelofEvidenceB).IncasesofbrainabscessresultingfromMSSAIE,nafcillinshouldbeusedinsteadofcefazolin;vancomycinshouldbegivenincasesofnafcillinintolerance(ClassI;LevelofEvidenceC).Theusefulnessofempiricalcombinationtherapywithvancomycinplusanantistaphylococcalβ-lactamantibioticinpatientswithSaureusbacteremiauntiloxacillinsusceptibilityisknownisuncertain(ClassIIb;LevelofEvidenceB).IEcausedbystaphylococcithatarepenicillinsusceptibleshouldbetreatedwithantistaphylococcalβ-lactamantibioticsratherthanaqueouscrystallinepenicillinGbecauseclinicallaboratoriesarenotabletodetectpenicillinsusceptibility(ClassI;LevelofEvidenceB).Sixweeksofnafcillin(orequivalentantistaphylococcalpenicillin)isrecommendedforuncomplicatedleft-sidedNVEcausedbyMSSA;atleast6weeksofnafcillin(orequivalentantistaphylococcalpenicillin)isrecommendedforcomplicatedleft-sidedNVEcausedbythisorganism(ClassI;LevelofEvidenceC).Daptomycinmaybeareasonablealternativetovancomycinfortreatmentofleft-sidedIEresultingfromMRSA(ClassIIb;LevelofEvidenceB).Selectionofdaptomycindosingshouldbeassistedbyinfectiousdiseasesconsultation(ClassI;LevelofEvidenceC).TherapyofMSSAIEinPatientsAllergictoorIntolerantofβ-LactamsTherapyforMSSAIEinpatientstrulyunabletotolerateβ-lactamsisproblematic.Onedecisionanalysisstudyconcludedthatpatientswithaquestionablehistoryofimmediate-typehypersensitivitytopenicillinsinthecontextofIEcausedbyMSSAshouldbeskintestedbeforestartingantibiotictherapy.156However,thelimitedavailabilityofstandardizedskintestreagentsmakestestingimpractical.Instead,mostexpertsendorseoneofthepublishedstandarddesensitizationprotocols.Forpatientswithawell-definedhistoryofnonanaphylactoidreactionstopenicillins(eg,simpleskinrash),afirst-generationcephalosporinsuchascefazolinisreasonable.Althoughcefazolinmaybemoresusceptibletoβ-lactamase–mediatedhydrolysisthannafcillin157andlesseffectiveinthetreatmentofMSSAexperimentalIE,theclinicalsignificanceoftheseobservationsisunknown.ManyexpertsregularlyusecefazolinforSaureusIEinsteadofnafcillinbecauseofdrugtolerabilityandcost,forMSSAIEinpenicillin-intolerantpatients,ortofacilitateoutpatientantibioticadministration.Vancomycinisoftenrecommendedasanalternativetoβ-lactamtherapyforMSSAIE.Asoutlinedabove,β-lactamallergyevaluationshouldbeconductedineverycaseinwhichvancomycinisconsideredforusebecausepooreroutcomesrelatedtovancomycintherapyforavarietyofMSSAinfectionsarewellrecognized.140ClindamycinhasbeenassociatedwithIErelapseandisnotrecommended.158ForMSSAIEinpatientswithanaphylactoid-typeβ-lactamallergywhoexhibiteitherasuboptimalresponsetovancomycinorvancomycinallergy,β-lactamdesensitizationshouldbeconsideredasnotedabove.159DaptomycinisareasonablealternativetovancomycinforadultsinthetreatmentofSaureusNVE.Intheabove-notedmultinationaltrial13ofSaureusbacteremiaandright-sidedIE,thisagent(at6mg·kg−1·d−1)wasnoninferiortostandardtherapywithvancomycinoranantistaphylococcalpenicillinpluslow-dose,short-coursegentamicin.Importantly,thesmallnumber(n=18;9ineacharm)ofpatientswithleft-sidedIEenrolledinthetrialpreventedmeaningfulconclusionsonthecomparativeefficacyofdaptomycininthisinfection.Forthisreason,theFDAindicationfordaptomycinexplicitlyomittedleft-sidedIE.However,inanobservationalstudy,high-dosedaptomycin(≈9mg/kgperdose)fortreatmentofleft-sidedIEwasaseffectiveasstandard-of-caretherapyandclearedMRSAbacteremiasignificantlyfasterthandidstandard-of-caretreatment.155Theemergenceoforganismswithdecreasedsusceptibilitytodaptomycinwasobservedin≈5%ofdaptomycin-treatedpatients.Allofthesepatientsneededbutforavarietyofreasonsdidnotreceivesurgicalinterventionfordebridementofdeep-seatedinfectionsorleft-sidedIE.Asindicated,theFDA-approveddoseofdaptomycinforSaureusbacteremiaandright-sidedIEiscurrently6mg/kgIVoncedaily.Someexpertsrecommendhigherdosesofdaptomycinat8to10mg/kgforcomplicatedinfections,includingleft-sidedIE(thesedosesarenotapprovedbytheFDA).109Thisrecommendationisbasedinpartonevidencesuggestingthathigher-dosedaptomycinmayreducethelikelihoodoftreatment-emergentresistance,isgenerallywelltolerated,andisnotassociatedwithexcesstoxicities.Whetherthishigherdosingstrategypreventstreatment-emergentresistanceofdaptomycinisstillnotanswered.Daptomycinisinhibitedbypulmonarysurfactant160andthusiscontraindicatedinthetreatmentofSaureuspneumoniaacquiredviatheaspirationroute.Intheregistrationaltrial,13however,thisagentperformedaswellasvancomycinorβ-lactamsintreatingsepticpulmonaryembolicausedbySaureus,reflectingthedistinctpathogenesisofthissyndromeasopposedtotraditionalpneumonia.RecommendationsCefazolinisreasonableinpatientswithawell-definedhistoryofnonanaphylactoidreactionstopenicillins(ClassIIa;LevelofEvidenceB).Allergyevaluationfortolerancetoβ-lactamtherapyshouldbedoneineverycaseinwhichvancomycinisconsideredfortreatmentofMSSAIE(ClassI;LevelofEvidenceB).ClindamycinisnotrecommendedasaresultofanincreasedIErelapserate(ClassIII;LevelofEvidenceB).DaptomycinisareasonablealternativetovancomycinforNVEcausedbyMSSA(ClassIIa;LevelofEvidenceB).AdditionalorAdjunctiveTherapiesAsdiscussedabove,combinationtherapywithgentamicintherapyinSaureusNVEisdiscouragedbecauseoftherelativelyhighratesofintrinsicgentamicinresistance,alackofclear-cutefficacy,anddocumentedtoxicityissues.149,153,161Althoughmoststaphylococciarehighlysusceptibletorifampin,resistancedevelopsrapidlywhenthisagentisusedalone.Theinvivoefficacyofrifampinincombinationwithnafcillin,oxacillin,vancomycin,trimethoprim/sulfamethoxazole,oraminoglycosidesishighlyvariable.Moreover,useofrifampinasadjuncttherapyforSaureusNVEhasbeenassociatedwithhigherratesofadverseevents(primarilyhepatotoxicity)andasignificantlylowersurvivalrate.162Thus,routineuseofrifampinisnotrecommendedfortreatmentofstaphylococcalNVE.Ofnote,aprospectivetrialinpatientswithIEcausedbyMRSAfailedtodemonstratethattheadditionofrifampintovancomycineitherenhancedsurvivalorreducedthedurationofbacteremiacomparedwithtreatmentwithvancomycinalone.163RifampinisoftenusedinnativevalveSaureusIEwhenthisinfectioniscomplicatedbyinvolvementofselectedanatomicsiteswhererifampinpenetrateseffectively(eg,bone,joint,cerebrospinalfluid).164NostandardtherapiesexistforthetreatmentofSaureusIEcausedbyisolatesthatarenotsusceptibletovancomycin.Classificationoftheseisolateshasbecomecomplexandincludesdesignationsofreducedsusceptibility(hVISA),intermediateresistance(VISA),andhigh-levelresistance(VRSA).Todate,thelimitednumberofpatientsreportedtohaveIEcausedbytheseisolatesprecludesspecifictreatmentrecommendations.Thus,theseinfectionsshouldbemanagedinconjunctionwithaninfectiousdiseasesconsultant.AlthoughMarkowitzetal165showedthattrimethoprim-sulfamethoxazolewasinferiortovancomycininthetreatmentofinvasiveSaureusinfections,itissometimesusedinsalvagesituations.Interestingly,alltreatmentfailureswithtrimethoprim-sulfamethoxazoleoccurredinpatientsinfectedwithMSSAinthatreport,165whereaspatientswithMRSAinfectionwereuniformlycured.Theefficacyoftrimethoprim-sulfamethoxazoleandotherfolateantagonistsmaybeattenuatedbythymidinereleasefromdamagedhostcells(eg,atsitesoftissuedamagesuchasabscesses).166Inaninvitrostudy,167theadditionoftrimethoprim-sulfamethoxazoletodaptomycinwasrapidlybactericidalforadaptomycin-nonsusceptiblestraincomparedwithdaptomycinmonotherapy.Thecombinationofdaptomycinandaβ-lactamantibiotichasbeenreportedtobeeffectiveintreatingalimitednumberofpatientswithpersistentMRSAbacteremia.168Thepotentialeffectivenessofthiscombinationmaybedueinparttothecapacityoftheβ-lactamagenttoalterthesurfacechargeoftheorganisminanonbactericidalmechanism,allowingenhancedsurfacebindingofdaptomycin.169–171LinezolidwasreportedtobeeffectiveinthetreatmentofpersistentMRSAbacteremia,172butthisstudyhadimportantstudydesignweaknesses.173PatientoutcomeswithlinezolidtherapyforSaureusleft-sidedIEhavegenerallybeenpoor.174–176Quinupristin-dalfopristin177andtelavancin178havebeenusedsuccessfullyassalvagetherapyinselectedpatientswithMRSAIEwhoclinicallyfailedvancomycintherapy.CeftarolinereceivedFDAregistrationalindicationsforacutebacterialskinandsofttissueinfectionscausedbybothMRSAandMSSA,aswellascommunity-acquiredpneumoniacausedbyMSSA.SeveralcaseseriessuggestthatitmayhaveutilityincomplicatedSaureusinfections,includingIE.179–181Thesepromisingobservationsshouldbeverifiedwithappropriatelydesignedclinicalstudiesbeforeceftarolinecanberecommendedforwidespreaduseinsuchoff-labelsettings.RecommendationsRoutineuseofrifampinisnotrecommendedfortreatmentofstaphylococcalNVE(ClassIII;LevelofEvidenceB).IEcausedbyvancomycin-resistantstaphylococci(hVISA,VISA,orVRSA)shouldbemanagedinconjunctionwithaninfectiousdiseasesconsultant(ClassI;LevelofEvidenceC).IECausedbyStaphylococciinthePresenceofProstheticValvesorOtherProstheticMaterialCoagulase-NegativeStaphylococciCoNSthatcausePVEusuallyaremethicillinresistant,particularlywhenIEdevelopswithin1yearaftersurgery.182Unlesssusceptibilitytomethicillincanbedemonstratedconclusively,itshouldbeassumedthattheorganismismethicillinresistant,andtreatmentshouldbeplannedaccordingly.ExperimentalIEmodelscausedbymethicillin-resistantstaphylococcidemonstratedthatvancomycincombinedwithrifampinandgentamicinistheoptimalregimen,andlimitedclinicalreportssupportthisapproach.183ThedosingofrifampinisdonebyconventionandisnotbasedonPKdata.Vancomycinandrifampinarerecommendedforaminimumof6weeks,withtheuseofgentamicinlimitedtothefirst2weeksoftherapy(Table11).Iftheorganismisresistanttogentamicin,thenanaminoglycosidetowhichitissusceptibleshouldbesubstitutedforgentamicin.Someauthoritiesrecommenddelayingtheinitiationofrifampintherapyforseveraldaystoallowadequatepenetrationofvancomycinintothecardiacvegetationsinanattempttopreventtreatment-emergentresistancetorifampin.Iftheorganismisresistanttoallavailableaminoglycosides,suchadjunctivetreatmentshouldbeomitted.Inthissituation,iftheorganismissusceptibletoafluoroquinolone,animalstudiesoftherapyforforeign-bodyinfectionsuggestthatafluoroquinolonecanbeusedinsteadofgentamicin.184Thus,althoughclinicaldataarenotavailabletosupportthepractice,selectionforfluoroquinoloneresistanceduringtreatmentcanoccur,andprevalentfluoroquinoloneresistanceamongCoNSwilllimititsuse,itmayreasonabletouseafluoroquinoloneinthissetting.Table11.TherapyforEndocarditisInvolvingaProstheticValveorOtherProstheticMaterialCausedbyStaphylococciRegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsOxacillin-susceptiblestrains Nafcillinoroxacillin12g/24hIVin6equallydivideddoses≥6ClassI;LevelofEvidenceBVancomycinshouldbeusedinpatientswithimmediate-typehypersensitivityreactionstoβ-lactamantibiotics(seeTable5fordosingguidelines);cefazolinmaybesubstitutedfornafcillinoroxacillininpatientswithnon–immediate-typehypersensitivityreactionstopenicillins.Plus Rifampin900mgper24hIVororallyin3equallydivideddoses≥6Plus Gentamicin†3mg/kgper24hIVorIMin2or3equallydivideddoses2Oxacillin-resistantstrains Vancomycin30mg/kg24hin2equallydivideddoses≥6ClassI;LevelofEvidenceBAdjustvancomycintoatroughconcentrationof10–20μg/mL.(seetextforgentamicinalternatives)Plus Rifampin900mg/24hIV/POin3equallydivideddoses≥6Plus Gentamicin3mg/kgper24hIV/IMin2or3equallydivideddoses2IMindicatesintramuscular;andIV,intravenous.*Dosesrecommendedareforpatientswithnormalrenalfunction.†Gentamicinshouldbeadministeredincloseproximitytovancomycin,nafcillin,oroxacillindosing.SeeTable7forappropriatedoseofgentamicin.PVE,particularlywhenonsetiswithin12monthsofcardiacvalveimplantationandanaorticvalveprosthesisisinvolved,isfrequentlycomplicatedbyperivalvularormyocardialabscessesorvalvulardysfunction.136Surgeryisoftenrequiredinthesepatientsandmaybelifesaving.Asnotedabove,CoNSmaybecomeresistanttorifampinduringtherapyforPVE.Becauseofthepotentialforchangesinthepatternsofantibioticsusceptibilityduringtherapy,organismsrecoveredfromsurgicalspecimensorbloodfrompatientswhohavehadabacteriologicalrelapseshouldbecarefullyretestedforcompleteantibioticsusceptibilityprofiles.Althoughpublisheddataoncombinationsofantimicrobialtherapyarelimited,wesuggestthatPVEcausedbyoxacillin-susceptibleCoNSshouldbetreatedwithnafcillinoroxacillinplusrifampinincombinationwithgentamicinforthefirst2weeksoftherapy.Afirst-generationcephalosporinorvancomycinmaybesubstitutedfornafcillin/oxacillinforpatientswhoaretrulyallergictopenicillin.RecommendationsVancomycinandrifampinarerecommendedforaminimumof6weeks,withtheuseofgentamicinlimitedtothefirst2weeksoftherapy(ClassI;LevelofEvidenceB).IfCoNSareresistanttogentamicin,thenanaminoglycosidetowhichtheyaresusceptiblemaybeconsidered(ClassIIb;LevelofEvidenceC).IfCoNSareresistanttoallaminoglycosides,thensubstitutionwithafluoroquinolonemaybeconsiderediftheisolateissusceptibletoafluoroquinolone(ClassIIb;LevelofEvidenceC).Organismsrecoveredfromsurgicalspecimensorbloodfrompatientswhohavehadabacteriologicalrelapseshouldbecarefullyretestedforcompleteantibioticsusceptibilityprofiles(ClassI;LevelofEvidenceC).SaureusBecauseofthehighmortalityrateassociatedwithSaureusPVE,136combinationantimicrobialtherapyisrecommended(Table11).TheuseofcombinationtherapyisbasednotonstudiesofinvitrosynergybutratherontheefficacyofthistherapyfortreatmentofCoNSPVE,aswellastheresultsoftreatmentofexperimentalIEandinfecteddevices.Inanimalstudies,rifampinappearstobekeyinthecompletesterilizationofforeignbodiesinfectedbyMRSA.184,185ForinfectioncausedbyMSSA,nafcillinoroxacillintogetherwithrifampinissuggested;withMRSA,vancomycinandrifampinshouldbeused.Gentamicinshouldbeadministeredfortheinitial2weeksoftherapywitheitherβ-lactamorvancomycin-containingregimens.Ifastrainisresistanttogentamicin,thenafluoroquinolonemaybeusedifthestrainissusceptible.EarlycardiacsurgicalinterventionsplayanimportantroleinmaximizingoutcomesinSaureusPVE,186especiallyinthepresenceofheartfailure.11RecommendationsCombinationantimicrobialtherapyisrecommended(ClassI;LevelofEvidenceC).Gentamicinshouldbeadministeredfortheinitial2weeksoftherapywitheitherβ-lactamorvancomycin-containingregimens(ClassI;LevelofEvidenceC).EnterococciAlthoughthereare>15specieswithintheEnterococcusgenus,EfaecalisandEfaeciumarethemajorspeciesisolatedfromclinicalsourcesinIEpatients.EnterococciarethethirdleadingcauseofIEandaccountfor≈10%ofcasesinnon-IDUs.Efaecaliscauses≈97%ofcasesofIE;Efaecium,≈1%to2%;andotherspecies,≈1%.RegimensrecommendedforenterococcalIEareshowninTables12through15.Enterococcishouldberoutinelytestedinvitroforsusceptibilitytopenicillinorampicillinandvancomycin(MICdetermination)andforhigh-levelresistancetogentamicintopredictsynergisticinteractions(seebelow).Becauseofthestrikingincreaseinresistanceofenterococcitovancomycin,aminoglycosides,andpenicillin,additionalsusceptibilitytestsmaybenecessarytoidentifyalternativeantimicrobialregimens.Forstrainsofenterococciresistanttoβ-lactams,vancomycin,oraminoglycosides,itisreasonabletotestforsusceptibilityinvitrotodaptomycinandlinezolid.Linezolidisbacteriostaticinvitroagainstenterococci,whereasdaptomycinisbactericidalinvitroinsusceptiblestrains.Althoughrarelyidentified,β-lactamase–producingenterococcimayaccountforrelapseofinfection.Routinescreeningforβ-lactamaseproductionisnotsensitiveenough,andspecializedtestingwillbeneededfordetection.ComparedwithVGSandβ-hemolyticstreptococci,enterococciarerelativelyresistanttopenicillin,ampicillin,andvancomycin.Thesestreptococciusuallyarekilledbymonotherapywiththeseantimicrobials,whereasenterococciareinhibitedbutnotkilled.Killingofsusceptiblestrainsofenterococcirequiresthesynergisticactionofpenicillin,ampicillin,orvancomycinincombinationwitheithergentamicinorstreptomycin.Enterococciarerelativelyimpermeabletoaminoglycosides.Highconcentrationsofaminoglycosidesintheextracellularenvironmentarerequiredtoachievesufficientconcentrationsofthedrugatthesiteoftheribosomaltargetwithinthebacterialcellforbactericidalactivity.Theseconcentrationsarehigherthancanbeachievedsafelyinpatients;however,cellwall–activeagentssuchaspenicillin,ampicillin,andvancomycinraisethepermeabilityoftheenterococcalcellsothatabactericidaleffectcanbeachievedbyrelativelylowconcentrationsofanaminoglycoside.Ifanenterococcalstrainisresistanttothecellwall–activeagentorhighconcentrationsofanaminoglycoside(500µg/mLgentamicinor1000µg/mLstreptomycin),thenthecombinationofanaminoglycosideandthecellwall–activeagentwillnotresultinbactericidalactivityinvitroorinvivo(ie,inexperimentalIEmodels),norwillitpredictablyproduceamicrobiologicalcureinhumanenterococcalIE.RecommendationsEnterococcishouldbetestedroutinelyinvitroforsusceptibilitytopenicillinandvancomycin(MICdetermination)andforhigh-levelresistancetogentamicintopredictsynergisticinteractions(ClassI;LevelofEvidenceA).Invitrosusceptibilitytodaptomycinandlinezolidshouldbeobtainedforstrainsthatareresistanttoβ-lactams,vancomycin,oraminoglycosides(ClassI;LevelofEvidenceC).RoleofAminoglycosidesintheTreatmentofPatientsWithEnterococcalIE:SpecialConsiderationsAminoglycoside-containingregimenshavebeenacornerstoneofantimicrobialtherapyforenterococcalIE187andhavebeenrecommendedasstandardtherapyinprevious(1995)AHAguidelines.188Sincethepublicationofthelatest(2005)AHAstatementonantimicrobialtherapyofpatientswithIE,12thefrequencyofaminoglycoside-resistantstrainsofenterococcihasincreasedsignificantly.Inaddition,anumberofstudieshavebeenpublishedonthedosingofaminoglycosides,thedurationofaminoglycosidetherapy,andthepossibleroleofnon–aminoglycoside-containingregimensforthetreatmentofEfaecalisIE.189–191Approximately97%ofcasesofenterococcalIEarecausedbyEfaecalis,andthemajorityoftheseremainsusceptibletoβ-lactamsandvancomycin,butaminoglycosideresistanceisincreasinginfrequency.InthestudybyGavaldàetal,190approximatelyhalfofthepatientshadIEcausedbyhigh-levelaminoglycoside-resistantstrainsofEfaecalis.InthestudybyFernández-Hidalgoetal,19126%ofthe272patientshadhigh-levelaminoglycoside-resistantstrainsofEfaecalis.Therefore,aminoglycoside-containingregimenswouldnotbeeffectivetherapyforthesepatients.Anumberoffactorsshouldbeconsideredintheselectionofaminoglycoside-containingregimens.ComparedwithotherpatientswithIE,ingeneral,patientswithenterococcalIEareolder;areoftendebilitated;mayhavecomplicated,underlyingurologicalconditions,includingpre-existingrenalfailure;mayhavehealthcare-associatedinfections;andhavesignificantotherunderlyingcomorbiditiescommoninolderagegroups.192Inthesepatients,gentamicin-associatednephrotoxicitymaysignificantlycomplicatea“standard”4-to6-weekcourseoftherapyandcouldresultinserious,possiblylife-threatening,complicationssuchasrenalfailurerequiringhemodialysis.Inthesesituations,thepotentialriskofattemptingtocompletea4-to6-weekcourseofgentamicintherapymayexceedthebenefit.193InpatientswithVGSIEtreatedwithmultipledivideddosesofgentamicin,singledaily-dosetherapywithgentamicinresultedinsimilarresponseratesandwaswelltolerated(seetreatmentofVGSIEabove).StudiesofsingledailydosingofgentamicincomparedwithdivideddosesinenterococcalexperimentalIEandinhumanshaveyieldedconflictingresults.TheseresultsmayreflectdifferentPKofaminoglycosidesinanimalscomparedwithhumans.Studiesinhumansofthedosingintervalofgentamicinwerenotcontrolledorstandardized.Dosingofgentamicinrangedfromoncedailyto3timesdaily;therefore,thedatawereinsufficienttocomparetheefficacyofonce-dailydoseswithdivideddoses.Untilmoreconvincingdatademonstratethatonce-dailydosingofgentamicinisaseffectiveasmultipledosing,inpatientswithnormalrenalfunction,gentamicinshouldbeadministeredindailymultipledivideddoses(total,≈3mg·kg−1·d−1)ratherthanadailysingledosetopatientswithenterococcalIE.Inpatientswithnormalrenalfunction,itisreasonabletoadministergentamicinevery8hourswiththedoseadjustedtoachievea1-hourserumconcentrationof≈3µg/mLandatroughconcentrationof<1µg/mL.Increasingthedoseofgentamicininthesepatientsdidnotresultinenhancedefficacybutdidincreasetheriskofnephrotoxicity.194ManypatientswithenterococcalIEaremanagedinanontertiarycarefacility,andthelaboratorymaynothavethecapabilityforrapiddeterminationofserumgentamicinconcentrationsormaynothaveaclinicalpharmacistavailabletoassistinoptimaldosingadjustments.Theseandotherfactorshavepromptedstudiestoevaluatetheefficacyofnon–gentamicin-containingregimensforthetreatmentofenterococcalIE.195Thedecisionofwhethertouseanaminoglycoside-containingregimenmustbeindividualizedforeachpatient.Therationaleandrecommendationsforspecificaminoglycoside-containingregimensforthetreatmentofenterococcalIEbasedoninvitrosusceptibilitiesarediscussedinthefollowinggroupsofpatientsandinTables12through15.RecommendationsGentamicinshouldbeadministeredindailymultipledivideddoses(total,≈3mg·kg−1·d−1)ratherthanasingledailydosetopatientswithenterococcalIEandnormalrenalfunction(ClassI;LevelofEvidenceB).Itisreasonabletoadministergentamicinevery8hourswiththedoseadjustedtoachievea1-hourserumconcentrationof≈3µg/mLandatroughconcentrationof<1µg/mL(ClassIIa;LevelofEvidenceB).EnterococcalEndocarditisSusceptibletoPenicillin,Vancomycin,andAminoglycosidesAntimicrobialregimensoutlinedinTable12arereasonablefortreatmentofpatientswithIEcausedbytheseorganisms.Inaprospectivestudy,thedurationofantimicrobialtherapyinnativevalveEfaecalisIEwasbasedonthedurationofinfectionbeforediagnosisandonsetofeffectivetherapy.196Patientswith<3months’durationofsymptomsweretreatedsuccessfullywith4weeksofantimicrobialtherapy.Patientswith≥3months’durationofsymptomsweresuccessfullytreatedwith6weeksoftherapy.ThedurationoftherapyforNVEisbasedonthiswork,andtheregimensthatmaybeconsideredarelistedinTable12.InpatientswithPVE,6weeksofantimicrobialtherapyisreasonable.Table12.TherapyforEndocarditisInvolvingaNativeorProstheticValveorOtherProstheticMaterialResultingFromEnterococcusSpeciesCausedbyStrainsSusceptibletoPenicillinandGentamicininPatientsWhoCanTolerateβ-LactamTherapy*RegimenDose†andRouteDuration,wkStrengthofRecommendationCommentsEitherClassIIa;LevelofEvidenceBNativevalve:4-wktherapyrecommendedforpatientswithsymptomsofillness<3mo;6-wktherapyrecommendedfornativevalvesymptoms>3moandforpatientswithprostheticvalveorprostheticmaterial.Recommendedforpatientswithcreatinineclearance>50mL/min. Ampicillinsodium2gIVevery4h4–6Or4–6ClassIIa;LevelofEvidenceB AqueouspenicillinGsodium18–30millionU/24hIVeithercontinuouslyorin6equallydivideddoses4–6Plus Gentamicinsulfate‡3mg/kgidealbodyweightin2–3equallydivideddosesOr Doubleβ-lactamAmpicillin2gIVevery4h6ClassIIa;LevelofEvidenceBRecommendedforpatientswithinitialcreatinineclearance<50mL/minorwhodevelopcreatinineclearance<50mL/minduringtherapywithgentamicin-containingregimen.Plus Ceftriaxone2gIVevery12h6IVindicatesintravenous.*Forpatientsunabletotolerateaβ-lactam,seeTable14.†Dosesrecommendedareforpatientswithnormalrenalandhepaticfunction.‡Doseofgentamicinshouldbeadjustedtoachieveapeakserumconcentrationof3to4µg/mLandatroughconcentrationof<1µg/mL.Patientswithpreexistingmild(creatinineclearance,30–50mL/min)orsevere(creatinineclearance,<30mL/min)renalfailuremaynotbeabletosafelycompletea4-to6-weekcourseofgentamicintherapybecauseofgentamicin-associatednephrotoxicity.Alternativeregimensthatshouldbeconsideredincludetheuseofstreptomycininsteadofgentamicin,short-coursegentamicintherapy(2–3weeks),anduseofanon–aminoglycoside-containingdouble–β-lactamregimen.Therisksandbenefitsofthealternativeregimensareasfollows.StreptomycinTherapyAlthoughtherearenopublishedstudiescomparingtheefficacyofregimenscontainingstreptomycinorgentamicin,asimilarcureratewasreportedinasinglenoncomparativestudy.197Themainadvantageisthatstreptomycinislessnephrotoxicthangentamicin.Thereareseveraldisadvantagesofusingstreptomycin-containingregimens,includingalackoffamiliarityamongclinicianswithstreptomycin,ahigherriskofototoxicity,whichmaynotbereversible,anddrugavailabilitylimitations.Inaddition,mostlaboratoriesdonotroutinelyperformserumstreptomycinassaysandmaynothaveaccesstoaclinicalpharmacisttoassistindosingadjustments.Streptomycinuseshouldbeavoidedinpatientswithcreatinineclearance<50mL/min.Ifthestrainofenterococcusissusceptibletobothgentamicinandstreptomycin,itisreasonabletousegentamicinratherthanstreptomycinfortherapy.Whengentamicintherapyisnotanoption,thenadouble–β-lactamregimen(seelatersection)isreasonable.Short-Course(≈2-Week)GentamicinTherapyOlaisonandSchadewitz189inSwedenreporteda5-yearprospectivestudyof78casesofenterococcalIEtreatedwithaβ-lactamandanaminoglycoside.Theolderageofthesepatientswasafactorintheirinabilitytotolerateprolongedaminoglycosidetherapy.Themediandurationofaminoglycosidetherapywas15days,andthemicrobiologicalcureandsurvivalratesweresimilartothoseforpatientswhoreceivedlongercoursesofgentamicintherapy.Themajoradvantageofshort-courseaminoglycosidetherapyisreducedriskofaminoglycoside-associatednephrotoxicity.Thedisadvantageisthatthisisasinglenonrandomized,noncomparativestudy.TheresultsofaDanishpilotstudy185thatrepresenteda“beforeandafter”study,whichwasbasedon2007guidelinesthatrecommendeda2-weektreatmentcourseofgentamicinforenterococcalIEincombinationwithβ-lactamtherapyfor4to6weeks,confirmedtheresultsseenintheSwedishinvestigation.181Double–β-LactamRegimensforEfaecalisIEMoststrainsofEfaecalisareinhibitedbutnotkilledinvitrobypenicillinorampicillin,withMICsusually2to4µg/mLpenicillin;ampicillinMICsareusually1dilutionlower.Cephalosporinsandantistaphylococcalpenicillins(oxacillin,nafcillin)haveminimalornoinvitroactivityagainstenterococci.Theinvitroactivityofcarbapenemsisvariable,withimipenembeingmostactive.Becausetherearefewtherapeuticalternativestoaminoglycoside-containingregimens,combinationsofβ-lactamsweretestedinvitroandinanimalmodelsofenterococcalexperimentalIE.Thecombinationofampicillinandimipenemactedsynergisticallyinvitroandwaseffectivetherapyofmultidrug-resistantenterococcalexperimentalIE.198ThisstudyledtoadditionalstudiesofexperimentalIEthatdemonstratedthatthecombinationofampicillin-ceftriaxonewaseffectivetherapyforgentamicin-susceptibleorhigh-levelgentamicin-resistantEfaecalisexperimentalIE.199Thelikelymechanismofdouble–β-lactamcombinationsagainstenterococciissaturationofdifferentpenicillin-bindingproteins.Theseinvitroandinvivostudiesprovidedtherationalefordouble–β-lactamtherapeutictrialsinhumanswithEfaecalisIEcausedbygentamicin-susceptibleorhigh-levelgentamicin-resistantstrains.Alarge,multicenterstudybySpanishandItalianinvestigatorscomparedampicillin-ceftriaxonewithampicillin-gentamicintherapyofEfaecalisIE.191Patientswithhigh-levelaminoglycoside-resistantstrainswerenottreatedwithampicillin-gentamicin.Asmallerstudybythisgroupcomparedceftriaxone-ampicillintherapyofaminoglycoside-susceptiblewithhigh-levelaminoglycoside-resistantEfaecalisIE.190Bothofthesestudieshadsignificantlimitations:Theywereobservational,largelyretrospective,andnonrandomized;theregimenswerenotstandardizedamongthedifferentcenters;discontinuationofgentamicintherapywasatthediscretionoftheinvestigatorsandnotalwaystheresultofgentamicin-associatednephrotoxicity;andtheserumconcentrationsofgentamicinwerenotassessedorreportedinallstudysites.Despitetheselimitations,these2studiesprovideimportantdata.First,thesearethelargestseriesofEfaecalisIEreportedtodate,43patientsin1study190and272intheotherstudy.191Second,high-levelaminoglycoside-resistantEfaecalisIEtreatedwithampicillin-ceftriaxonetherapywaspresentin50%ofthepatientsinthesmallerstudyand33%ofpatientsinthelargerstudy.Third,noneofthepatientsineitherstudydevelopednephrotoxicitywithampicillin-ceftriaxonetherapy,whereas20of87(23%)ampicillin-gentamicin–treatedpatientsdevelopednephrotoxicity(P<0.001).Fourth,inthelargerstudy,themedianagewas70yearsinbothtreatmentgroups;however,patientsintheampicillin-ceftriaxonegroupweregenerallysickerandhadmorecomorbidconditions(eg,chronicrenalfailure[P=0.004],neoplasm[P=0.015],andnosocomialacquisitionofinfection[P=0.006]).Fifth,in1study,PVEwaspresentin59(37%)and30(34%)ofpatientstreatedwithampicillin-ceftriaxoneandampicillin-gentamicin,respectively,withsimilarsuccessrates.Sixth,inthelargerstudy,therewerenosignificantdifferencesbetweenampicillin-ceftriaxoneandampicillin-gentamicinintheneedforsurgery,complications(exceptforfewercasesofrenalfailureintheampicillin-ceftriaxonegroup),relapse,ormortality.Finally,theoverallmicrobiologicalcureandsuccessratesforampicillin-ceftriaxonetherapyinbothstudiesweresimilartoratesinpreviouslyreportedstudiesinpatientstreatedwithaminoglycoside-containingregimens.190,191Themajoradvantagesoftheampicillin-ceftriaxoneregimenarethelowerriskofnephrotoxicityandthelackofneedformeasuringaminoglycosideserumconcentrations.Thepotentialdisadvantageisthepossibilityofhypersensitivityreactionsto2separateβ-lactams.Becauseitwouldlikelynotbepossibletodiscriminatebetweenhypersensitivitiesrelatedtoampicillinortoceftriaxone,bothdrugsmighthavetobediscontinuedwithsubstitutionofvancomycin-gentamicintherapy.Atthistime,thewritinggroupdoesnothaveapreferenceforoneregimenovertheotherbutratheradvocatesanindividualizedapproachtoregimenselectionforeachpatient.RecommendationsTherapythatincludeseitherampicillinoraqueouscrystallinepenicillinGplusgentamicinorampicillinplusceftriaxoneisreasonable(ClassIIa;LevelofEvidenceB).Either4or6weeksoftherapyisreasonableforNVE,dependingonthedurationofIEsymptomsbeforetheinitiationoftherapyifampicillinorpenicillinplusgentamicinisused(ClassIIa;LevelofEvidenceB).Sixweeksoftherapyisreasonableifampicillinplusceftriaxoneisselectedasthetreatmentregimen,regardlessofsymptomduration(ClassIIa;LevelofEvidenceB).SixweeksofantimicrobialtherapyisreasonableforPVE(ClassIIa;LevelofEvidenceB).Streptomycinshouldbeavoidedinpatientswithcreatinineclearance<50mL/min(ClassIII;LevelofEvidenceB).IfthestrainofEnterococcusissusceptibletobothgentamicinandstreptomycin,itisreasonabletousegentamicinratherthanstreptomycinfortherapy(ClassIIa;LevelofEvidenceC).Whengentamicintherapyisnotanoption,thenadouble–β-lactamregimen(seelatersection)isreasonable(ClassIIa;LevelofEvidenceB).EfaecalisIESusceptibletoPenicillin,ResistanttoAminoglycosides,orGentamicinResistantandStreptomycinSusceptibleAminoglycosideresistanceinenterococciismostcommonlytheresultoftheacquisitionofplasmid-mediatedaminoglycoside-modifyingenzymes.Efaecalisstrainsresistanttohighlevelsofgentamicinareresistanttomostotheraminoglycosides,althoughsomeofthemaresusceptibletostreptomycin.TheregimensforEfaecalisIEwithstrainsthatarepenicillin-susceptibleandaminoglycoside-resistantareshowninTable13.Ceftriaxone-ampicillintherapyisreasonableandisgivenfor6weeks.Therationalefordouble–β-lactamtherapyisoutlinedabove.Table13.TherapyforEndocarditisInvolvingaNativeorProstheticValveorOtherProstheticMaterialResultingFromEnterococcusspeciesCausedbyaStrainSusceptibletoPenicillinandResistanttoAminoglycosidesorStreptomycin-SusceptibleGentamicin-ResistantinPatientsAbletoTolerateβ-LactamTherapy*RegimenDose†andRouteDuration,wkStrengthofRecommendationCommentsDoubleβ-lactamAmpicillin2gIVevery4h6ClassIIa;LevelofEvidenceBDoubleβ-lactamisreasonableforpatientswithnormalorimpairedrenalfunctionabnormalcranialnerveVIIIfunctionorifthelaboratoryisunabletoproviderapidresultsofstreptomycinserumconcentration;nativevalveinfectionwithsymptomsofinfection<3-modurationmaybetreatedfor4wkwiththestreptomycin-containingregimen.PVE,NVEwithsymptoms>3mo,ortreatmentwithadoubleβ-lactamregimenrequireaminimumof6wkoftherapy. PlusCeftriaxone2gIVevery12hAlternativeforstreptomycinsusceptible/gentamicinresistant Either4–6ClassIIa;LevelofEvidenceBUseisreasonableonlyforpatientswithavailabilityofrapidstreptomycinserumconcentrations.Patientswithcreatinineclearance<50mL/minorwhodevelopcreatinineclearance<50mL/minduringtreatmentshouldbetreatedwithdouble–β-lactamregimen.PatientswithabnormalcranialnerveVIIIfunctionshouldbetreatedwithdouble–β-lactamregimen.  Ampicillinsodium2gIVevery4h Or  AqueouspenicillinGsodium18–30millionU/24hIVeithercontinuouslyorin6equallydivideddoses Plus  Streptomycinsulfate‡15mg/kgidealbodyweightper24hIVorIMin2equallydivideddosesIMindicatesintramuscular;IV,intravenous;NVE,nativevalveinfectiveendocarditis;andPVE,prostheticvalveinfectiveendocarditis.*Forpatientsunabletotolerateaβ-lactam,seeTable14.†Dosesrecommendedforpatientswithnormalrenalandhepaticfunction.‡Streptomycindoseshouldbeadjustedtoobtainaserumpeakconcentrationof20to35µg/mLandatroughconcentrationof<10µg/mL.Forgentamicin-resistantandstreptomycin-susceptibleEfaecalis,ampicillin-ceftriaxoneisreasonable.The2005AHAdocument12recommendedstreptomycinforpatientswithgentamicin-resistantstrainsofenterococci.Thelimitationsofstreptomycinusearesummarizedabove.ThetotalnumberofcasespublishedintheEuropeanstudiesfarexceedstherelativelysmallnumberofreportedstreptomycin-treatedpatientswithenterococcalIE.Althoughtherearenopublisheddatacomparingampicillin-ceftriaxonewithstreptomycin-containingregimens,webelievethatampicillin-ceftriaxoneisreasonableforthesepatients.Disadvantagesofstreptomycin-containingregimensareoutlinedabove.RecommendationsCeftriaxone-ampicillincombinationtherapyisreasonableforIEcausedbyaminoglycoside-resistantenterococcalstrains(ClassIIa;LevelofEvidenceB).Forgentamicin-resistantandstreptomycin-susceptibleEnterococcusspecies,ampicillin-ceftriaxonecombinationtherapyisreasonable(ClassIIa;LevelofEvidenceB).VancomycinTherapyforEnterococcalIEinPatientsUnabletoTolerateβ-LactamsorPatientsWithEfaecalisResistanttoPenicillinTheregimensthatarereasonableforthesepatientsareshowninTable14.Vancomycinshouldbeadministeredonlyifapatientisunabletotoleratepenicillinorampicillin.Combinationsofpenicillinorampicillinwithgentamicinarepreferabletocombinedvancomycin-gentamicinbecauseofthepotentialincreasedriskofototoxicityandnephrotoxicitywiththevancomycin-gentamicincombination.Moreover,combinationsofpenicillinorampicillinandgentamicinaremoreactivethancombinationsofvancomycinandgentamicininvitroandinanimalmodelsofexperimentalIE.ItisreasonablethatpatientswithNVEreceive6weeksofvancomycin-gentamicintherapyandthatpatientswithPVEreceiveatleast6weeksoftherapy.Table14.Vancomycin-ContainingRegimensforVancomycin-andAminoglycoside-SusceptiblePenicillin-ResistantEnterococcusSpeciesforNativeorProstheticValve(orOtherProstheticMaterial)IEinPatientsUnabletoTolerateβ-LactamRegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsUnabletotolerateβ-lactams Vancomycin†30mg/kgper24hIVin2equallydivideddoses6ClassIIa;LevelofEvidenceBPlus Gentamicin‡3mg/kgper24hIVorIMin3equallydivideddoses6Penicillinresistance;intrinsicorβ-lactamaseproducer Vancomycin30mg/kgper24hIVin2equallydivideddoses6ClassIIb;LevelofEvidenceCForβ-lactamase–producingstrain,ifabletotolerateaβ-lactamantibiotic,ampicillin-sulbactam§plusaminoglycosidetherapymaybeused.PlusGentamicin‡3mg/kgper24hIVorIMin3equallydivideddoses6IEindicatesinfectiveendocarditis;IM,intramuscular;andIV,intravenous.*Dosesrecommendedareforadultswithnormalrenalfunction.†Doseofvancomycinshouldbeadjustedtoobtainaserumtroughconcentrationof10to20µg/mL.‡Doseofgentamicinshouldbeadjustedtoobtainserumpeakandtroughconcentrationsof3to4and<1µg/mL,respectively.§Ampicillin-sulbactamdosingis3g/6hourIV.Rarely,strainsofEfaecalisproduceaninducibleβ-lactamase.Theseβ-lactamase–producingstrainsaresusceptibletoampicillin-sulbactamandtovancomycin.IntrinsicpenicillinresistanceisuncommoninEfaecalisbutiscommoninEfaecium.ItisreasonabletotreatpatientswithEfaecalisIEcausedbystrainsthatareintrinsicallyresistanttopenicillinwithacombinationofvancomycinplusgentamicin.RecommendationsfortreatmentofIEcausedbythesestrainsareshowninTable14.RecommendationsVancomycinshouldbeadministeredonlyifapatientisunabletotoleratepenicillinorampicillin(ClassI;LevelofEvidenceB).ItisreasonablethatpatientswithNVEreceive6weeksofvancomycin-gentamicintherapyandthatpatientswithPVEreceiveatleast6weeksoftherapy(ClassIIa;LevelofEvidenceB).PatientswithEfaecalisIEcausedbystrainsthatareintrinsicallyresistanttopenicillinshouldbetreatedwithacombinationofvancomycinplusgentamicin(ClassI;LevelofEvidenceB).EnterococcalEndocarditisResistanttoPenicillin,Aminoglycosides,andVancomycinTherapidemergenceofvancomycin-resistantenterococcihasbecomeaglobalissueofmajorclinicalimportance.MostofthesestrainsareEfaecium,andasmanyas95%ofstrainsexpressmultidrugresistancetovancomycin,aminoglycosides,andpenicillins.Onlyabout3%ofEfaecalisstrainsaremultidrugresistant,andmanyvancomycin-resistantEfaecalisarepenicillinsusceptible.Fortunately,EfaeciumIEisuncommon.Mostofthereportsofmultidrug-resistantEfaeciumIEaresinglecasereports,reportsofasmallnumberofcollectedcases,orcasesreportedinnewdrugtrials.200EnterococciareconsideredtoberesistanttovancomycinifMICsare>4µg/mL.Linezolidanddaptomycinaretheonly2antimicrobialagentscurrentlyavailableintheUnitedStatesthatmaybeusefulforthetreatmentofmultidrug-resistantEfaeciumIE.Quinupristin-dalfopristinmaybeactiveinvitrobutonlyagainststrainsofEfaeciumandisinactiveagainstEfaecalis.Quinupristin-dalfopristinisrarelyusedbecauseofseveresideeffects,includingintractablemusclepain.Tigecyclineisactiveinvitroagainstsomestrainsofmultidrug-resistantenterococci,butthereareminimalpublisheddataonitsuseclinically.Thesamecanbesaidfortedizolid,whichhasbeenreleased.Table15listspossibletherapeuticoptionsforthetreatmentofmultidrug-resistantenterococcalIE.Thesepatientsshouldbemanagedbyspecialistsininfectiousdiseases,cardiology,cardiovascularsurgery,clinicalpharmacy,and,ifnecessary,pediatrics.Antimicrobialregimensarediscussedasfollows.Table15.TherapyforEndocarditisInvolvingaNativeorProstheticValveorOtherProstheticMaterialResultingFromEnterococcusSpeciesCausedbyStrainsResistanttoPenicillin,Aminoglycosides,andVancomycinRegimenDose*andRouteDuration,wkStrengthofRecommendationCommentsLinezolid600mgIVororallyevery12h>6ClassIIb;LevelofEvidenceCLinezolidusemaybeassociatedwithpotentiallyseverebonemarrowsuppression,neuropathy,andnumerousdruginteractions.PatientswithIEcausedbythesestrainsshouldbetreatedbyacareteamincludingspecialistsininfectiousdiseases,cardiology,cardiacsurgery,clinicalpharmacy,and,inchildren,pediatrics.Cardiacvalvereplacementmaybenecessaryforcure.OrDaptomycin10–12mg/kgperdose>6ClassIIb;LevelofEvidenceCIEindicatesinfectiveendocarditis,andIV,intravenous.*Dosesrecommendedareforpatientswithnormalrenalandhepaticfunction.LinezolidLinezolidisasyntheticdrugthatisthefirstmemberoftheoxazolidinoneclass.ItactsbyinhibitingribosomalproteinsynthesisandisapprovedforusebytheFDAinadultsandchildren.ItisnotapprovedbytheFDAfortreatmentofIE.Linezolidisbacteriostaticinvitroagainstenterococci,andsusceptibilityofenterococcitolinezolidrangesfrom97%to99%,includingstrainsthataremultidrugresistant.EnterococciwithMIC>2µg/mLareconsideredtoberesistanttolinezolid.However,linezolid-resistantstrainshavedevelopedduringtreatment.201Inasmallnumberofpatients,linezolidwaseffectivetherapyofvancomycin-resistantEfaeciumIE.174Birminghametal202reportedcurein17of22coursesoftherapy(77%)forEfaeciumIE.Maveetal203reportedcurein2of3patientswithEfaeciumIEwithlinezolid.OthercasereportsofcureofEfaeciumIEofnativevalve204orprostheticvalve205werereported.However,linezolidtreatmentfailuresofEfaeciumIEalsowerereported.206Theadvantagesoflinezolidtherapyincludehighbioavailabilityoftheoralformulation,approvalforpediatricpatients,andalackofmanytherapeuticalternatives.Thedisadvantagesaretoxicity(mildtosevereneutropeniaandthrombocytopeniathatisreversible);peripheralandopticneuritis,whichismoreoftenseenwithlongerdurationsoftherapyandmaynotbereversible;multidruginteractions,especiallyserotoninuptakeinhibitors;andemergenceofresistanceduringtreatment.Theprevioushighcostshoulddecreasewithgenericavailabilitysoon.Cardiacvalvereplacementsurgerymaybenecessaryinpatientswhodonotrespondtolinezolidtherapy.DaptomycinDaptomycinisacycliclipopeptideantibioticthathasbactericidalactivityinvitroagainstsusceptiblestrainsofenterococci.EnterococciareconsidereddaptomycinsusceptiblewithMIC<4µg/mL.Although>90%ofenterococciarereportedlysusceptibleinvitrotodaptomycin,theemergenceofdaptomycinresistanceisanincreasingproblem.207DaptomycinisFDAapprovedfortreatmentofSaureusinfectionsbutnotforenterococcalinfections.Daptomycinisnotapprovedforuseinpediatricpatients.Thenumberofpublishedcasesofvancomycin-resistantEfaeciumIEtreatedwithdaptomycinisextremelysmall,somanagementconclusionsaredifficulttodefine,andthesuccessratehasvariedamongreportedcases.LevineandLamp208reporteddaptomycincurein6of9patientswithEfaeciumIE;bothdaptomycin-treatedpatientswithEfaeciumIEreportedbySegretietal209died.Multipleothercasereportsdescribedaptomycinfailures,someasaresultofemergenceofdaptomycin-resistanceduringtreatment.210,211Otherinvestigatorshavesuggestedthathigherdosesofdaptomycin(8–10mg·kg−1·d−1);daptomycincombinedwithgentamicin,ampicillin,ceftaroline,rifampin,ortigecycline;orvariouscombinationsoftheseshouldbeusedinsteadofdaptomycinmonotherapy.211–217Anumberofinvitroevaluations214–216suggestedthatampicillinandceftarolineincombinationwithdaptomycindemonstratethegreatestsynergisticactivitycomparedwithotherβ-lactam–daptomycincombinations.Maveetal203compareddaptomycinwithlinezolidforvancomycin-resistantEnterococcusbacteremia.FivepatientshadEfaeciumIE;1of2daptomycin-treatedpatientsand2of3linezolid-treatedpatientssurvived.Thenumberofcasesofvancomycin-resistantEnterococcusbacteremiawastoosmalltodrawsignificantconclusionsabouttreatmentresponserates.Insummary,thereareinsufficientdatatorecommendmonotherapywithdaptomycinforthetreatmentofmultidrug-resistantenterococcalIE.Ifdaptomycintherapyisselected,thendosesof10to12mg·kg−1·24h−1maybeconsidered.Considerationmaybegiventocombinationsoftherapywithdaptomycin,includingampicillinorceftaroline,particularlyinpatientsinfectedwithstrainswithrelativelyhighMICstodaptomycinwithinthesusceptiblerange(<4µg/mL).Otherlessactive(invitro)combinationswithdaptomycinincludegentamicin,rifampin,ortigecycline.RecommendationsPatientswithIEattributabletoEnterococcusspeciesresistanttopenicillin,aminoglycosides,andvancomycinshouldbemanagedbyspecialistsininfectiousdiseases,cardiology,cardiovascularsurgery,clinicalpharmacy,and,ifnecessary,pediatrics(ClassI;LevelofEvidenceC).Ifdaptomycintherapyisselected,thendosesof10to12mg·kg−1·24h−1maybeconsidered(ClassIIb;LevelofEvidenceC).Combinationtherapywithdaptomycinandampicillinorceftarolinemaybeconsidered,especiallyinpatientswithpersistentbacteremiaorenterococcalstrainswithhighMICs(ie,3µg/mL)todaptomycinwithinthesusceptiblerange(ClassIIb;LevelofEvidenceC).HACEKMicroorganismsIEcausedbyfastidiousGram-negativebacillioftheHACEKgroup(HACEKindicatesHaemophilusspecies,Aggregatibacterspecies,Cardiobacteriumhominis,Eikenellacorrodens,andKingellaspecies)accountsfor≈5%to10%ofcommunity-acquiredNVEinpatientswhoarenotIDUs.218Thesemicroorganismsgrowslowlyinstandardbloodculturemedia,andrecoverymayrequireprolongedincubation.Typically,onlyasmallfractionofbloodculturebottlesinpatientswithHACEKIEdemonstrategrowth.BacteremiacausedbyHACEKmicroorganismsintheabsenceofanobviousfocusofinfectionishighlysuggestiveofIEevenwithouttypicalphysicalfindingsofIE.Previously,theHACEKgroupofmicroorganismswasuniformlysusceptibletoampicillin.However,β-lactamase–producingstrainsofHACEKareappearingwithincreasedfrequency;rarely,resistancetoampicillincanoccurinβ-lactamase–negativestrains.219Moreover,difficultyinperformingantimicrobialsusceptibilitytestingasaresultoffailureofgrowthininvitrosusceptibilitytestingiscommonplace.In1survey,60%ofisolatesdidnotgrowadequatelyincontrolwells,andnovalidinvitrosusceptibilityresultswereavailable.219Therefore,unlessgrowthisadequateforinvitroscreening,thenHACEKmicroorganismsshouldbeconsideredampicillinresistant,andpenicillinandampicillinshouldnotbeusedtotreatpatientswithIEinthesecases.AlmostallstrainsoftheHACEKgrouparesusceptibletoceftriaxone(orotherthird-orfourth-generationcephalosporins).CeftriaxonehascommonlybeenusedtotreatHACEKIE220andisreasonablefortreatment(Table16).ThedurationoftherapyforNVEof4weeksisreasonable;forPVE,thedurationoftherapyof6weeksisreasonable.Gentamicinisnolongerrecommendedbecauseofitsnephrotoxicityrisks.Table16.TherapyforEndocarditisInvolvingaNativeorProstheticValveorOtherProstheticMaterialCausedbyHACEKMicroorganismsRegimenDoseandRouteDuration,wkStrengthofRecommendationCommentsCeftriaxonesodium*2g/24hIVorIMin1dose4,NVE;6,PVEClassIIa;LevelofEvidenceBPreferredtherapy:cefotaximeoranotherthird-orfourth-generationcephalosporinmaybesubstituted.OrAmpicillinsodium2gIVevery4hClassIIa;LevelofEvidenceBAmpicillinsodiummaybeanoptionifthegrowthoftheisolateissufficienttopermitinvitrosusceptibilityresults.OrCiprofloxacin†1000mg/24horallyor800mg/24hIVin2equallydivideddosesClassIIb;LevelofEvidenceCFluoroquinolonetherapy‡maybeconsideredforpatientsunabletotoleratecephalosporinandampicillintherapy;levofloxacinormoxifloxacinmaybesubstituted;fluoroquinolonesgenerallyisnotrecommendedforpatients<18yold.Treatmentfor6wkisreasonableinpatientswithPVE(ClassIIa;LevelofEvidenceC).HACEKindicatesHaemophilusspecies,Aggregatibacterspecies,Cardiobacteriumhominis,Eikenellacorrodens,andKingellaspecies;IM,intramuscular;IV,intravenous;NVE,nativevalveinfectiveendocarditis;andPVE,prostheticvalveinfectiveendocarditis.*Patientsshouldbeinformedthatintramuscularinjectionofceftriaxoneispainful.†Doserecommendedforpatientswithnormalrenalfunction.‡FluoroquinolonesarehighlyactiveinvitroagainstHACEKmicroorganisms.PublisheddataontheuseoffluoroquinolonesforendocarditiscausedbyHACEKareminimal.TheHACEKgroupisusuallysusceptibleinvitrotofluoroquinolones.206Onthebasisofthesesusceptibilitydata,afluoroquinolone(ciprofloxacin,levofloxacin,ormoxifloxacin)maybeconsideredasanalternativeagentinpatientsunabletotolerateceftriaxone(orotherthird-orfourth-generationcephalosporins)therapy.ThereareonlyafewcasereportsofHACEKIEtreatedwithafluoroquinolone,however.Inaddition,ampicillin-sulbactammaybeconsideredatreatmentoption,althoughHACEKresistancetothisagentinvitrohasbeendescribed.219Accordingly,patientswithHACEKIEwhocannottolerateceftriaxonetherapyshouldbetreatedinconsultationwithaninfectiousdiseasesspecialist.RecommendationsUnlessgrowthisadequateinvitrotoobtainsusceptibilitytestingresults,HACEKmicroorganismsareconsideredampicillinresistant,andpenicillinandampicillinshouldnotbeusedforthetreatmentofpatientswithIE(ClassIII;LevelofEvidenceC).CeftriaxoneisreasonablefortreatmentofHACEKIE(ClassIIa;LevelofEvidenceB).ThedurationoftherapyforHACEKNVEof4weeksisreasonable(ClassIIa;LevelofEvidenceB);forHACEKPVE,thedurationoftherapyof6weeksisreasonable(ClassIIa;LevelofEvidenceC).Gentamicinisnotrecommendedbecauseofitsnephrotoxicityrisks(ClassIII;LevelofEvidenceC).Afluoroquinolone(ciprofloxacin,levofloxacin,ormoxifloxacin)maybeconsideredanalternativeagentforpatientsunabletotolerateceftriaxone(orotherthird-orfourth-generationcephalosporins)(ClassIIb;LevelofEvidenceC).Ampicillin-sulbactammaybeconsideredatreatmentoptionforHACEKIE(ClassIIb;LevelofEvidenceC).PatientswithHACEKIEwhodonottolerateceftriaxonetherapyshouldbetreatedinconsultationwithaninfectiousdiseasesspecialist(ClassI;LevelofEvidenceC).Non-HACEKGram-NegativeBacilliIEcausedbynon-HACEKGram-negativeaerobicbacilli(EnterobacteriaceaeandPseudomonasspecies)israre.In1largemultinationaldatabase221thatincluded2761patientsseenin61hospitalsin28countries,only49cases(1.8%)wereattributabletonon-HACEKGram-negativeaerobicbacilli.ItisnoteworthythathealthcareexposurewasassociatedwiththedevelopmentofIEcausedbythisgroupoforganismsin57%ofpatients.Incontrast,IDU,aprominentriskfactorforthedevelopmentofthisIEsyndromeinearlieryears,wasrecognizedinonly4%ofcasesinthemultinationalsurveythatincludedcasesseenbetween2000and2005.EscherichiacoliandPseudomonasaeruginosaaccountedfor51%ofcases,and59%hadPVE.Althoughmanagementincludedcardiacsurgeryin51%ofcases,thein-hospitalmortalityratewas24%.DespitetheveryrareoccurrenceofIEcausedbySalmonellaspeciesinNorthAmerica,thissyndromedeservesspecificmentionbecauseitoccurswithsomefrequencyinothergeographicareas.222Salmonellaspecieshaveaproclivitytoinfectcardiovascularstructuresinadults.Therefore,allpatientswithbloodstreaminfectionresultingfromSalmonellaspeciesshouldbeevaluatedforcomplicatingcardiovascularinfections,includingIE,myocarditis,pericarditis,andendarteritis.Althoughmanyserotypeshavebeenimplicated,mostcasesarecausedbyScholeraesuis,Styphimurium,andSenteritidis.222CardiacsurgeryincombinationwithprolongedcoursesofcombinedantibiotictherapyisreasonableformostpatientswithIEcausedbynon-HACEKGram-negativeaerobicbacilli,particularlyinthesettingofleft-sidedvalvularinvolvement.ProspectivetrialdataarelackingtodefinetheoptimalantimicrobialregimenforthetreatmentofIEcausedbynon-HACEKGram-negativeaerobicbacilli.InputfromspecialistsininfectiousdiseaseswhoareexperiencedinthemedicalmanagementofIEshouldbeobtainedtodefineanantibioticregimenineachcase.ThisisparticularlyimportantinIEcausedbynon-HACEKGram-negativeaerobicbacilliforseveralreasons.First,asstatedpreviously,healthcareexposureiscommonlyseeninthesecases;thus,multidrugresistanceoftencharacterizesthesepathogens.Second,therapymayincludeagentswithincreasedtoxicityriskssuchasaminoglycosides(giveninhighdosages)andcolistin.Third,becauseregimensthatinclude>1agentareoftenselectedforuse,therisksofdrug-druginteractionsandincreaseddrug-relatedadverseeventsareproblematic.Fourth,mortalityishighintheseinfections,andmedical-surgicalapproachesareoftenrequiredforoptimalmanagementandfavorableoutcomes.Combinationantibiotictherapywithaβ-lactam(penicillins,cephalosporins,orcarbapenems)andeitheranaminoglycosideorfluoroquinolonefor6weeksisreasonable.221ConsultationwithaninfectiousdiseasesexpertinIEshouldbesoughtbecauseofthevariousmechanismsofantibioticresistancethatcanbefoundinthenon-HACEKGram-negativeaerobicbacilli.Forexample,severalofthesebacteriamayharbor“inducibleβ-lactamases”thatcouldrequiresupplementallaboratoryscreening,inadditiontoroutineinvitrosusceptibilitytesting.Medicaltherapymaybesuccessfulinright-sidedPaeruginosaIEin50%to75%ofcases.Ifthediseaseisrefractorytoantibiotics,thenpartialtricuspidvalvulectomyor“vegetectomy”223withoutvalvereplacementisindicated.224Typically,thesepatientshavebeenIDUs,andbecauseoftheirhighrecidivismrisk,avoidanceofplacementofprostheticvalvesisdesirable.RecommendationsCardiacsurgeryisreasonableincombinationwithprolongedcoursesofcombinedantibiotictherapyformostpatientswithIEcausedbynon-HACEKGram-negativeaerobicbacilli,particularlyPaeruginosa(ClassIIb;LevelofEvidenceB).Combinationantibiotictherapywithaβ-lactam(penicillins,cephalosporins,orcarbapenems)andeitheranaminoglycosideorfluoroquinolonefor6weeksisreasonable(ClassIIa;LevelofEvidenceC).ConsultationwithaninfectiousdiseasesexpertinIEshouldbesoughtbecauseofthevariousmechanismsofantibioticresistancethatcanbefoundinthenon-HACEKGram-negativeaerobicbacilli(ClassI;LevelofEvidenceC).Culture-NegativeEndocarditisPositivebloodculturesareamajordiagnosticcriterioninIEandkeytoidentifyinganpathogenicagentandanoptimalantimicrobialregimen.225,226Continuousbacteremiaandahighfrequencyofpositivebloodculturesaretypicalhallmarksofthisinfection.Theintensityofbacteremiamaynotbegreat,however,with<50colony-formingunitsper1mLblooddetectedinthemajorityofpatientsinaninvestigation.227FailuretoculturemicroorganismsthatcauseIEcanbeamajorproblemthatcomplicatesdiagnosisandtimely,effectivetreatment.Althoughmostpreviousstudieshaveputthefrequencyofbloodculture–negativeIEat5%to10%,aEuropeanstudyofIEthatincluded820casesindicatedthat≈20%ofpatientswithconfirmedIEhadallnegativebloodcultures.228Thismaybeattributabletoinadequatemicrobiologicaltechniques,infectionwithhighlyfastidiousbacteriaorfungi,noncultivatableagents,orthepreviousadministrationofantimicrobialagentsbeforebloodcultureswereobtained.AdministrationofantimicrobialagentstoIEpatientsbeforebloodculturesareobtainedreducestherecoveryrateofbacteriaby35%to40%.228–232Theantimicrobialsusceptibilityoftheorganism,thedose,andthedurationandnatureofpreviousantimicrobialtherapytogetherdeterminethelengthoftimethatbloodcultureswillremainnegative.232IEpatientswithbloodculturesthatareinitiallynegativeafteronlyafewdaysofantibiotictherapymayhavepositivebloodculturesafterseveraldayswithoutantibiotics.Thebloodculturesofpatientswhoreceivelongercoursesofhigh-dosebactericidalantimicrobialsmayremainnegativeforweeks.Selectionofmedicaltherapyforpatientswithculture-negativeIEisdifficult.Ontheonehand,thereisaneedtoprovideempiricalantimicrobialsforalllikelypathogens.Ontheotherhand,certaintherapeuticagents,includingaminoglycosides,havepotentiallytoxiceffectsthatdictatelimitationoravoidanceofuseifatallpossible.Moreover,someofthelaboratory-baseddiagnostictechniquestodefinefastidiousorunusualpathogensarenotavailableinmostclinicallaboratoriesandrequireconsiderabletimeforcompletionoftestingifspecimensaresenttoareferrallaboratory.233Duringthisperiod,patientsareoftentreatedempiricallyforthemorecommonbacterialcausesofIE,whichcanresultinexposuretopotentiallytoxictherapythatcouldbeavoidedwithearlierpathogenidentification.Anevaluationofepidemiologicalfactors(Table6),historyofpriorinfectionsincludingcardiovascularinfections,exposuretoantimicrobials,clinicalcourse,severity,andextracardiacsitesofinfectionofthecurrentinfectionshouldbedoneinallIEcases.Duringtheperiodbetweenthecollectionofbloodculturesandthedeterminationofapathogenorifbloodculturesareultimatelydeemedculturenegative,empiricaltherapyisgenerallyrequired.Consultationwithaninfectiousdiseasesspecialisttodefinethemostappropriatechoiceoftherapyisrecommended.Collectionofadditionalclinicalandlaboratorydataoftendictatessubsequentrevisionsininitialempiricaltherapythatwillbeadministeredoverthetreatmentcourse.Forpatientswithacute(days)clinicalpresentationsofnativevalveinfection,coverageforSaureus,β-hemolyticstreptococci,andaerobicGram-negativebacilliisreasonable.Empiricalcoveragecouldincludevancomycinandcefepimeasaninitialregimen.Forpatientswithasubacute(weeks)presentationofNVE,empiricalcoverageofSaureus,VGS,HACEK,andenterococciisreasonable.Onetreatmentoptioncouldincludevancomycinandampicillin-sulbactamtoprovidesomecoveragefortheseorganisms.Subsequentregimenrevisioncanbedonewhenapathogenisrecoveredfrombloodcultures.Forpatientswithculture-negativePVE,coverageforstaphylococci,enterococci,andaerobicGram-negativebacilliisreasonableiftheonsetofsymptomsiswithin1yearofprostheticvalveplacement.Aregimencouldincludevancomycin,rifampin,gentamicin,andcefepime.Ifsymptomonsetis>1yearaftervalveplacement,thenIEismorelikelytobecausedbystaphylococci,VGS,andenterococci,andantibiotictherapyforthesepotentialpathogensisreasonable.Oneinitialtreatmentoptioncouldincludevancomycinandceftriaxone.Ifsubsequentbloodcultureresultsorotherlaboratorymethodologiesdefineapathogen,thenempiricaltherapyshouldberevisedtofocusedtherapythatisrecommendedforthespecificpathogenidentified.Trueculture-negativeIEcanbecausedbyuncommonorrarepathogensthatdonotgrowinroutinelyusedbloodculturesystems.234–237TheorganismsthathavegarneredthemostattentionareBartonellaspecies,Chlamydiaspecies,Cburnetii,Brucellaspecies,Legionellaspecies,Tropherymawhipplei,Candida,andnon-Candidafungi(particularlyAspergillusspecies).Thelast2groupsoforganismsareespeciallyrelevanttoPVrecipients.Withtheuseofspecialdiagnostictechniques,Bartonellaspecies,Cburnetii,andBrucellaspecieshavebeenidentifiedinthemajorityofcasesofculture-negativeIEcausedbyfastidiousorganisms.Additionallaboratoryscreeningisrequiredtoidentifythecausesofculture-negativeIE.233Insomecases,serologicalandspecialbloodculturetechniquescanbehelpful.Inothercases,tissue(usuallyvalve)screeningisrequired.Diagnosticmethodsforresectedvalvetissueincludemicrobiological,histopathological,andmoleculartechniques,thelastofwhichincludesgeneamplificationwithPCRmethods.Unfortunately,mostclinicallaboratoriesdonotperformmolecularscreening,andspecimensmustbesenttoreferencelaboratories.Themostprevalentpathogenamongtheseuncommoncausesofculture-negativeIEinthisgrouphasvariedgloballyaccordingtopublisheddata.236Incidencedatafrompopulation-basedsurveysforIEcausedbytheseorganismsarelackingintheUnitedStates.InPVEcases,thetimingofinfectiononsetcanalsobeimportantindefiningpathogens.235Limitationssuchasreferralbiasandsamplingbiasmayhaveaffectedthefindings.235–237Resultsofalargeprospectiveanalysisofreferredsamplesfromculture-negativeIEperformedbyawell-recognizedreferencelaboratorydeserveadditionalcomment.236First,therewasidentificationofapathogenin62.7%of759cases;in2.5%,anoninfectiousorigin(seebelow)wasconfirmed.Second,serologicalresultswerepositivein47.7%ofcases,primarilyforCoxiellaandBartonellaspeciesinfection.Third,PCRidentifiedapathogenintwothirdsofthevalvesstudied.Fourth,nocausewasdefinedin35%ofcases.Treatmentofthewidevarietyofmicroorganismsthatcauseculture-negativeIEwithoutpriorantibioticexposurehasbeendescribedanecdotally,andregimensofchoicearebasedonlimiteddataandcanbefoundinotherpublications.Noninfectiouscausesofvalvularvegetationscanproduceasyndromesimilartoculture-negativeIE.Perhapstheonethathasreceivedthemostattentionisanti-phospholipidantibody(APA)syndrome,238whichhasbeendescribedasbothaprimaryandasecondarysyndromeandisassociatedwiththepresenceofAPA.Initssecondaryform,theAPAsyndromehasbeenlinkedtoautoimmunedisorders,particularlysystemiclupuserythematosus,andmalignancies.Sterilevalvularvegetationsformandembolize,clinicallymimickinginmanyrespectsculture-negativeIE.Themitralvalveismostoftenaffected,andvalvularregurgitationisthepredominantfunctionalabnormalityseeninAPAsyndromewithcomplicatingvalvularinvolvement.Tocomplicatematters,theAPAsyndromemaydevelopsecondarytoIE.239NumerousothercausesofnoninfectivevegetativeendocarditiscanmimicIE.Thesecanbecategorizedinto4groups230:neoplasiaassociated(atrialmyxoma,maranticendocarditis,neoplasticdisease,andcarcinoid),autoimmuneassociated(rheumaticcarditis,systemiclupuserythematosus,polyarteritisnodosa,andBehçetdisease),postvalvularsurgery(thrombus,stitch,orotherpostsurgerychanges),andmiscellaneous(eosinophilicheartdisease,rupturedmitralchordae,andmyxomatousdegeneration).RecommendationsAnevaluationofepidemiologicalfactors,historyofpriorinfectionsincludingcardiovascularinfections,exposuretoantimicrobials,clinicalcourse,severity,andextracardiacsitesofinfectionofthecurrentinfectionshouldbeperformedinallculture-negativeendocarditiscases(ClassI;LevelofEvidenceC).Consultationwithaninfectiousdiseasesspecialisttodefinethemostappropriatechoiceoftherapyinpatientswithculture-negativeendocarditisisrecommended(ClassI;LevelofEvidenceC).Forpatientswithacute(days)clinicalpresentationsofnativevalveinfection,coverageforSaureus,β-hemolyticstreptococci,andaerobicGram-negativebacilliisreasonable(ClassIIa;LevelofEvidenceC).Forpatientswithasubacute(weeks)presentationofNVE,coverageofSaureus,VGS,HACEK,andenterococciisreasonable(ClassIIa;LevelofEvidenceC).Forpatientswithculture-negativePVE,coverageforstaphylococci,enterococci,andaerobicGram-negativebacilliisreasonableifonsetofsymptomsiswithin1yearofprostheticvalveplacement(ClassIIa;LevelofEvidenceC).Ifsymptomonsetis>1yearaftervalveplacement,thenIEismorelikelytobecausedbystaphylococci,VGS,andenterococci,andantibiotictherapyforthesepotentialpathogensisreasonable(ClassIIa;LevelofEvidenceC).Ifsubsequentbloodcultureresultsorotherlaboratorymethodologiesdefineapathogen,thenempiricaltherapyshouldberevisedtofocusedtherapythatisrecommendedforthespecificpathogenidentified(ClassI;LevelofEvidenceC).FungiFungalIEisrarebutcandevelopinawiderangeofpatients.240,241Thewell-recognizedriskfactorsassociatedwithfungalIE(eg,IDUandimmunocompromisedstate)havebecomelessprevalentcomparedwiththepresenceofacardiovasculardevice,includingcentralvenouscatheters,permanentpacemakersanddefibrillators,andprostheticvalves.240–246FungalIEhasbeenrecognizedasacauseofearlyPVE,butacaseseriesfromasinglemedicalcenterdemonstratedthat43%ofthesecaseshadsymptomonset>1yearsafterprostheticvalveplacement.242IncontrasttotheexpectedolderagepredilectionforthedevelopmentofIE,patientswithfungalIEhavebeenyounger,whichwassomewhatunanticipated,consideringthelowprevalenceofIDUamongthecohort.CandidaandAspergillusspeciesaccountforthelargemajorityoffungalIE,andCandida-relatedIEismuchmorecommonthanAspergillus-relateddisease.240,241Bloodculturesareultimatelypositiveinmostcasescausedbytheformerpathogen,whereastheyarerarelypositiveincasescausedbythelatterfungus.Thus,Aspergillusisacauseofculture-negativeIE,andwhenthisoccurs,itisusuallyinapatientwithaprostheticcardiacvalve.240Avarietyofotherfungi,includingendemicmycoses,canrarelycauseIEandcaninvolvebothnativeandprostheticvalves.NoncardiacsitesofmetastaticinfectionoftencomplicatefungalIE;thiscaninclude,forexample,endophthalmitisinpatientswithcandidalIE,whichmayrequirebothsystemicandintraocularantifungaltherapy.FurtherguidelinesareavailablefromtheInfectiousDiseasesSocietyofAmericaforadditionalmanagementaspectsofseveralofthefungalpathogens(http://www.idsociety.org/IDSA_Practice_Guidelines/).Despiteaggressivecombinedmedicalandsurgicalinterventionsandayoungercohort,mortalityratesforfungalIEareunacceptablyhigh.Thesurvivalrateforpatientswithmold-relatedIEis<20%.Historically,2treatmentdoctrineshaveprevailedinfungalIEdespitethelackofprospectivetrialsconductedtodefinethemostappropriatetherapy:FungalIEisa“stand-aloneindication”forsurgicalreplacementofaninfectedvalve;andamphotericinB,afungicidalagent,istheinitialdrugofchoiceforfungalIE.BecauseofthealarmingmortalityrateassociatedwithfungalIEandtheavailabilityofnewerantifungaldrugs,inparticularfungicidaldrugsliketheechinocandins,are-evaluationoftheseprinciplesseemsinorder.Ifdone,however,thiswillprobablybebasedonanecdotalexperienceandexpertopinionratherthanonclinicaltrialdatabecauseoftherarityofthesyndrome.A2-phasetreatmentoffungalIEhasevolved.Theinitialorinductionphaseconsistsofcontrolofinfection.Treatmentincludesacombinationofaparenteralantifungalagent,usuallyanamphotericinB–containingproduct,andvalvesurgery.ValvesurgeryshouldbedoneinmostcasesoffungalIE.Resultsofameta-analysisthatincluded879casesofCandidaIEdemonstratedamarkedreductionindeath(prevalenceoddsratio,0.56;95%confidenceinterval,0.16–1.99)amongthosewhounderwentadjunctivevalvesurgery.244Inaddition,patientswhoweretreatedwithcombinationtherapyincludingamphotericinBandflucytosinehadreducedmortalitycomparedwiththosewhoreceivedantifungalmonotherapy.Antifungaltherapyusuallyisgivenfor>6weeks.Aftercompletionofthisinitialtherapy,long-term(lifelong)suppressivetherapywithanoralazoleisreasonable.243,244,246Suppressivetherapyhasbeenusedin2populations.First,becauseofthehighrelapserateoffungalIEandtheprolongeddelay(yearsinsomecases)inrelapse,oralazoleshavebeenadministeredaftercombinedmedicalandsurgicalinductiontherapy.InasecondpopulationwithfungalIE,lifelongoralantifungalsuppressivetherapyhasbeengiventopatientswhorespondclinicallytoinductionmedicaltherapybutarenotdeemedappropriatesurgicalcandidatesforvalvereplacementforattemptedinfectioncure.Anecdotalcaseseries243,245indicatethatIEhasbeensuccessfullysuppressedformonthstoyears.Ameta-analysisthatincluded64reportedpatientswithCandidaIEwhodidnotundergovalvesurgerybecausetheyweredeemedtobeunacceptablesurgicalcandidatessupportsthenotionthatfluconazolesuppressivetherapyisuseful;20of21patients(95%)whowereultimatelytreatedwithlong-termsuppressivetherapysurvivedduringfollow-up,whichwas≥6months.244RecommendationsValvesurgeryshouldbedoneinmostcasesoffungalIE(ClassI;LevelofEvidenceB).Aftercompletionofinitialparenteraltherapy,lifelongsuppressivetherapywithanoralazoleisreasonable(ClassIIa;LevelofEvidenceB).SurgicalManagementThereisaprevailingopinionthatvalvesurgeryiscrucialforoptimaltherapyinselectedpatientswithcomplicatedIE.247–249Inasystematicreview5of15population-basedIEinvestigationsfrom7countries,afteradjustmentforcountry,theproportionofIEcasesundergoingvalvesurgeryincreased7%perdecade(95%confidenceinterval,−0.4%to14%;P=0.06)between1969and2000.Insurveysinvolvingpopulation-based1andinternationalmulticentercohorts,10,11≈50%ofbothNVEandPVEpatientsundergovalvesurgeryduringtheactivephaseofIE(duringinitialhospitalizationbeforecompletionofafulltherapeuticcourseofantibiotics).AlthoughvalvereplacementsurgeryhasservedasanimportantoptioninthemanagementofindividualIEcases,only1small,randomizedtrial17hasbeenperformedtodatetoexaminetheroleofvalvesurgeryinthemanagementofIE.Inthistrial,76patientswithleft-sidedNVE,severevalveregurgitationwithoutheartfailure,andvegetations>10mmwereassignedtoearlysurgerywithin48hoursortoconventionaltreatment.Althoughtheauthors17reportareductioninthecompositeoutcomeofin-hospitaldeathsandemboliceventswithearlysurgery(3%versus23%),thedifferencesbetweenthe2groupsweredrivenbyasignificantdecreaseinemboliceventswithearlysurgery.Thus,firmconclusionscannotbedrawnfromthistrialontheeffectofearlysurgeryonmortality,giventhesmallsamplesizeofthestudy.Inaddition,patientsinthistrialwereyoungandhadlimitedcomorbiditybasedonaEuroSCORE,acalculatedriskofsurgicalmortality(http://www.euroscore.org),alowprevalenceofSaureusIE,andlowermortalitycomparedwithmostcontemporarypatientcohorts.Moreover,manypatientshadsignsofembolization(aClassIIaindicationforsurgery)beforerandomization.Datafromnonrandomizedtrialsfromasingle-centerexperience250andaninternationalcollaboration251supportthenotion252thatearlyvalvesurgerymaynotbebeneficialinallpatientswithnativeorPVEcausedbySaureus.Overseveraldecades,expertpanelshavereliedondatafromobservationalstudiestomakerecommendationsontheindicationsforearlysurgery.Despitetheavailabilityofnewstudies,theindicationsforsurgeryhavenotchangedappreciablyovertime.18Consideringthatobservationalstudiesarepronetobiasandconfounding,researchershaveusedregressionanalysisandcalculatedpropensityscorestoadjustforprognosticallyimportantbaselinedifferencesbetweensurgicalandmedicalpatients.14,253Studies14,15,136,249,253–256examiningtheassociationbetweenvalvesurgeryandoutcomeinleft-sidedIEusingpropensityscoreanalysis,however,havedemonstratedconflictingresults,likelybecauseoftheuseofdifferentanalyticalapproaches.Until2007,noneofthepublishedstudiesadjustedforsurvivorbias,whichoccursbecausepatientswholivelongeraremorelikelytoundergosurgerythanthosewhodieearly.Acorrelationbetweenlongersurvivalandsurgerymaybewronglyinterpretedasevidencethatsurgicaltreatmentimprovessurvival.257Since2007,atleast3studies15,16,258havedocumentedtheeffectofsurvivorbiasontheassociationbetweensurgeryandmortalityinIEpatients.Whenadjustedforsurvivorbias,analyseshaveshowneitherastatisticallossofbenefitofearlysurgeryorfindingsindicatingthatthesurgicalinterventionmayactuallyresultinharm.Between2007and2013,atleast6observationalstudies10,11,14–16,259thatadjustedforselectionbias,confounding,andsurvivorbiaswereconducted.Threestudiesthatincluded2cohortsofpatientswithNVEandPVEand1cohortwithNVEshowedanassociationbetweenearlysurgeryandlowermortalityinIEpatientsingeneralorinspecificsubgroupsofpatientssuchasthosewithheartfailureorparavalvularcomplications.Only1studyexaminedtheroleofvalvesurgeryinPVE.259Afteradjustmentfordifferencesinclinicalcharacteristicsandsurvivalbias,earlyvalvereplacementwasnotassociatedwithlowermortalitycomparedwithmedicaltherapyintheoverallcohort.Subgroupanalysisindicatedalowerin-hospitaland1-yearmortalitywithearlysurgeryonlyinthegroupofpatientswiththehighestsurgicalpropensity.Table17summarizesthecharacteristicsofrigorouslyconductedobservationalstudiesthatsupporttheroleofsurgeryinIEmanagement.Table17.DirectEvidenceSupportinganAssociationBetweenValveSurgeryandLowerMortalityFromObservationalStudies:LevelofEvidenceBStudyMortalityIEGroupPEvsSALalanietal10In-hospitalmortalityNVEPEBannayetal155-ymortalityNVE+PVEPEKieferetal11In-hospitaland1-ymortalityCHF(NVE+PVE)PELalanietal10In-hospitalmortalityParavalvularcomplications(NVE)SABannayetal155-ymortalityIntracardiacabscess(NVE+PVE)SALalanietal10In-hospitalmortalitySystemicembolization(NVE)SABannayetal155-ymortalitySystemicembolization(NVE+PVE)SALalanietal10In-hospitalmortalitySaureus(NVE)SABannayetal155-ymortalityCHF(NVE+PVE)SALalanietal259In-hospitaland1-ymortalityPVEwiththehighestpropensitytoundergosurgerySACHFindicatescongestiveheartfailure;NVE,nativevalveinfectiveendocarditis;PE,primaryendpoint;PVE,prostheticvalveinfectiveendocarditis;andSA,subgroupanalysis.Allstudieshaveadjustedforselectionandsurvivorbiasandconfounding.Valvesurgerywasperformedduringtheactivephaseofthedisease(duringinitialhospitalizationbeforecompletionofafulltherapeuticcourseofantibiotics).IndicationsforSurgeryDecisionsonsurgicalinterventionarecomplexanddependonmanyclinicalandprognosticfactors257–262thatvaryamongpatients,includinginfectingorganism,vegetationsize,presenceofperivalvularinfection,presenceofembolismorheartfailure,age,noncardiaccomorbidities,andavailablesurgicalexpertise.Thereisapaucityofevidenceavailabletodefinetheoptimaltimingofvalvesurgery.Decisionsontheindicationandtimingofsurgicalinterventionshouldbedeterminedbyamultispecialtyteamwithexpertiseincardiology,imaging,cardiothoracicsurgery,andinfectiousdiseases.261Recommendationsforearlysurgeryinpatientswithrecurrentemboliandpersistentvegetationshavegenerallybeenenactedafterclinicalevents.Whetherrecurrent,asymptomaticembolidetectedonadvancedimagingstudiesshouldinfluencedecisionmakingshouldbeconsideredonanindividualbasis.RiskstratificationmodelssuchastheSocietyofThoracicSurgeonsEndocarditisScoreareavailabletopredictmorbidityandmortalityrisksinIEpatientsaftervalvesurgeryandtoassistindecisionmakingandpatientcounseling.260EarlyValveSurgeryinLeft-SidedNVE:RecommendationsEarlysurgery(duringinitialhospitalizationandbeforecompletionofafullcourseofantibiotics)isindicatedinpatientswithIEwhopresentwithvalvedysfunctionresultinginsymptomsorsignsofheartfailure(ClassI;LevelofEvidenceB).EarlysurgeryshouldbeconsideredparticularlyinpatientswithIEcausedbyfungiorhighlyresistantorganisms(eg,vancomycin-resistantEnterococcus,multidrug-resistantGram-negativebacilli)(ClassI;LevelofEvidenceB).EarlysurgeryisindicatedinpatientswithIEcomplicatedbyheartblock,annularoraorticabscess,ordestructivepenetratinglesions(ClassI;LevelofEvidenceB).Earlysurgeryisindicatedforevidenceofpersistentinfection(manifestedbypersistentbacteremiaorfeverlasting>5–7daysandprovidedthatothersitesofinfectionandfeverhavebeenexcluded)afterthestartofappropriateantimicrobialtherapy(ClassI;LevelofEvidenceB).Earlysurgeryisreasonableinpatientswhopresentwithrecurrentemboliandpersistentorenlargingvegetationsdespiteappropriateantibiotictherapy(ClassIIa;LevelofEvidenceB).Earlysurgeryisreasonableinpatientswithseverevalveregurgitationandmobilevegetations>10mm(ClassIIa,LevelofEvidenceB).Earlysurgerymaybeconsideredinpatientswithmobilevegetations>10mm,particularlywheninvolvingtheanteriorleafletofthemitralvalveandassociatedwithotherrelativeindicationsforsurgery(ClassIIb;LevelofEvidenceC).EarlyValveSurgeryinPVE:RecommendationsEarlysurgeryisindicatedinpatientswithsymptomsorsignsofheartfailureresultingfromvalvedehiscence,intracardiacfistula,orsevereprostheticvalvedysfunction(ClassI;LevelofEvidenceB).Earlysurgeryshouldbedoneinpatientswhohavepersistentbacteremiadespiteappropriateantibiotictherapyfor5to7daysinwhomothersitesofinfectionhavebeenexcluded(ClassI;LevelofEvidenceB).EarlysurgeryisindicatedwhenIEiscomplicatedbyheartblock,annularoraorticabscess,ordestructivepenetratinglesions(ClassI;LevelofEvidenceB).EarlysurgeryisindicatedinpatientswithPVEcausedbyfungiorhighlyresistantorganisms(ClassI;LevelofEvidenceB).EarlysurgeryisreasonableforpatientswithPVEwhohaverecurrentembolidespiteappropriateantibiotictreatment(ClassIIa;LevelofEvidenceB).EarlysurgeryisreasonableforpatientswithrelapsingPVE(ClassIIa;LevelofEvidenceC).Earlysurgerymaybeconsideredinpatientswithmobilevegetations>10mm(ClassIIb;LevelofEvidenceC).ValveSurgeryinPatientsWithRight-SidedIEAlthoughoutcomesarebetterforpatientswithright-sidedIEcomparedwithpatientswithleft-sidedinfection,surgicalinterventionisoccasionallyconsideredintheformergroup.Becausemanyofthepatientswithright-sidedIEdevelopinfectionasaresultofIDU(seetheRight-SidedIEinIDUssection),thegeneralapproachistotreatthesepatientsmedicallyandtoavoidplacementofvalveprosthesesbecauseofthesubsequentriskofdeviceinfectionwithcontinuedIDU.Surgicalinterventionisreasonableforpatientswiththefollowingcomplications:rightheartfailuresecondarytoseveretricuspidregurgitationwithpoorresponsetomedicaltherapy,sustainedinfectioncausedbydifficult-to-treatorganisms(ie,fungi,multidrugresistantbacteria)orlackofresponsetoappropriateantimicrobialtherapy,andtricuspidvalvevegetationsthatare≥20mmindiameterandrecurrentpulmonaryembolismdespiteantimicrobialtherapy.Valverepairratherthanreplacementshouldbeperformedwhenfeasible.Ifvalvereplacementisperformed,thenanindividualizedchoiceofprosthesisbythesurgeonisreasonable.263,264RecommendationsSurgicalinterventionisreasonableforpatientswithcertaincomplications(ClassIIa;LevelofEvidenceC).Valverepairratherthanreplacementshouldbeperformedwhenfeasible(ClassI;LevelofEvidenceC).Ifvalvereplacementisperformed,thenanindividualizedchoiceofprosthesisbythesurgeonisreasonable(ClassIIa;LevelofEvidenceC).ItisreasonabletoavoidsurgerywhenpossibleinpatientswhoareIDUs(ClassIIa;LevelofEvidenceC).ValveSurgeryinPatientsWithPriorEmboli/Hemorrhage/StrokeThetimingofvalvesurgeryinIEpatientswithstrokeremainscontroversial.StrokeisanindependentriskfactorforpostoperativemortalityinIEpatients.Afterstroke,neurologicaldeteriorationcanoccurasaresultofhemorrhagictransformationwithanticoagulationduringcardiopulmonarybypassorexacerbationofcerebralischemiaattributabletohypotensionduringcardiacsurgery.Theriskofintracranialhemorrhageisdependentonseveralfactors,includingextentandsizeofinfarction,whetheritisischemicorhemorrhagic,andtheexacttimingofsurgery.Oneclinicalquandaryiswhetherearlyvalvesurgerycanbesafelyperformedwithin7daysafterastrokeorifitisbettertopostponesurgeryforatleast1week.Norandomizedtrialshaveaddressedthisconundrum.Thehighratesofpostoperativemorbidityandmortalityseeninearlierstudies265–267haveresultedinareluctancetoreferpatientswithIEandacutestrokeforimmediatevalvesurgery.However,theseinitialstudiesincludedalimitednumberofpatients,andriskadjustmentswerenotperformed.Thelargestearlyseriesofoperatedpatientswithcerebralcomplicationsincluded181patients.267Hospitalmortalityratesasafunctionoftheintervalbetweenevidenceofcerebralinfarctiontocardiacsurgerywere66.3%whensurgerywasperformedwithin24hoursofstrokeandgraduallydecreasedeveryweekto7.0%withsurgery>4weeksafterstroke.InvestigationshavesuggestedbetteroutcomesforIEpatientswithischemicstrokewhoundergoearlycardiacsurgery.268–272Ruttmannetal270analyzed65patientswhounderwentcardiacsurgeryaftercardioembolic(embolic)stroke(mediantime,4days;range,0–38days).Surgeryinthistimeframewasnotassociatedwithworsepatientoutcomes.Fiftyofthe61patients(81.9%)withCT-verifiedpreoperativestrokesurvivedcardiacsurgery.Latencybetweentheneurologicaleventandcardiacsurgerywasnotasignificantfactorwithrespecttotheperioperativeneurologicalcomplicationrateorthepostoperativeneurologicalrecoveryrate.Fullneurologicalrecoverywasachievedin70%of50strokepatients.Otherstudies6–8suggestthattheriskofneurologicaldeteriorationduringcardiacsurgeryafterastrokeislowerthanpreviouslyassumed,particularlyinpatientswithsilentcerebrovascularemboli.ThefirststudytoevaluatethetimingofsurgeryafterstrokeinIEthatincludedariskadjustmentfordifferencesinpatientcharacteristicscomprised198patients.273Fifty-eightpatientswhounderwentsurgerywithin1weekofstrokewerecomparedwith140patientswhounderwentsurgery≥8daysafterstroke.Hospitalmortalitywasnumericallybutnotsignificantlyhigherintheearlysurgerygroup(22.4%versus12%).Afteradjustmentforotherriskfactorssuchasage,paravalvularabscess,andheartfailure,theriskofhospitalmortalityremainednonsignificantlyhigherintheearlysurgerygroup(oddsratio,2.308;95%confidenceinterval,0.942–5.652).Differencesin1-yearmortalitywerelesspronounced,withanadjustedhazardratioof1.138(95%confidenceinterval,0.802–1.650).In-hospitalmortalityintheearlysurgerygroupwascomparabletothatofthemedicallytreatedpatients.Afterhemorrhagicstroke,theriskofexacerbationbysurgeryisprohibitivelyhighinthefirstmonthbutcanextendbeyond1monthinsomepatients,possiblybecauseofthepresenceofundetectedmycoticaneurysms(MAs).Inamulticenterstudyofpatientswithhemorrhagicstroke,mortalitywashigherwhensurgerywasperformedwithin4weeksofthehemorrhagiceventcomparedwithlatersurgery(75%versus40%,respectively).274Thesedatasupportthefollowingrecommendations:ValvesurgerymaybeperformedinIEpatientswithstrokeorsubclinicalcerebralemboliwithoutdelayifintracranialhemorrhagehasbeenexcludedbyimagingstudiesandneurologicaldamageisnotsevere(ie,coma).Inpatientswithmajorischemicstrokeorintracranialhemorrhage,itisreasonabletodelayvalvesurgeryforatleast4weeks.RecommendationsValvesurgerymaybeconsideredinIEpatientswithstrokeorsubclinicalcerebralemboliandresidualvegetationwithoutdelayifintracranialhemorrhagehasbeenexcludedbyimagingstudiesandneurologicaldamageisnotsevere(ie,coma)(ClassIIb;LevelofEvidenceB).Inpatientswithmajorischemicstrokeorintracranialhemorrhage,itisreasonabletodelayvalvesurgeryforatleast4weeks(ClassIIa;LevelofEvidenceB).RiskofEmbolizationSystemicembolizationoccursin22%to50%ofcasesofIE.55,57,274–277Ratescanbehigherifnoninvasiveimaging,includingMRIandCTscanning,isroutinelydonetodetectasymptomatic(silent)emboli.Emboliofteninvolvemajorarterialbeds,includingthebrain,lungs,coronaryarteries,spleen,bowel,andextremities.Upto65%ofemboliceventsinvolvetheCNS,and>90%ofCNSembolilodgeinthedistributionofthemiddlecerebralartery.277ThehighestincidenceofemboliccomplicationsisseenwithmitralvalveIE(andmorewithanteriorratherthanposteriormitralleafletinvolvement)andwithIEcausedbySaureus,Candida,andHACEKorganisms.Embolicanoccurbeforediagnosis,duringtherapy,oraftertherapyiscompleted,althoughmostembolioccurwithinthefirst2to4weeksofantimicrobialtherapy.58,278Ofnote,2independentstudieshaveconfirmedthattherateofemboliceventsdecreasesdramaticallyduringandafterthefirst2to3weeksofsuccessfulantibiotictherapy.Inastudyfrom1991,theembolicratedroppedfrom13to<1.2emboliceventsper1000patient-daysduringthattime.58Vilacostaetal278confirmedthereducedfrequencyofembolizationafter2weeksoftherapy.Moreover,thelatterstudyreemphasizedtheincreasedriskofembolizationwithincreasingvegetationsizeduringtherapy,mitralvalveinvolvement,andstaphylococcalpathogenesis.InasurveythatincludedtheInternationalCollaborationonEndocarditiscohort,Dickermanandcolleagues280focusedontheincidenceofstrokeinamulticenterIEpopulationanddemonstratedthatacutestrokeratesfellsignificantlyafterinitiationofantibiotictherapyregardlessofvalveinvolvedorpathogenidentified.Moreover,only3.1%ofthecohortsufferedstrokeafterthefirstweekofantimicrobialtherapy;thisfindinghasledtotheopinionthatstrokepreventionasasoleindicationforvalvesurgeryafter1weekofappropriateantibiotictherapyisnotwarranted.Predictionofindividualpatientriskforembolizationisextremelydifficult.Manystudieshaveattemptedtouseechocardiographytoidentifyahigh-risksubsetofIEpatientswhomightbenefitfromearlysurgerytoavoidembolization.SeveralstudieswithTTEhavedemonstratedatrendtowardhigherembolicrateswithleft-sidedvegetations>1cmindiameter.55DeCastroandcolleagues276comparedTTEwithmultiplaneTEEandfoundthatneithertechniquewashelpfulindefiningembolicriskinpatientswithvegetations.Inastudy57basedonTEE,mitralvegetations>1cmindiameterwereassociatedwiththegreatestfrequencyofembolism.Theassociationwasstrengthenedwhentheanalysiswaslimitedtothosepatientswhohadnotyetexperiencedaclinicalembolicevent.AnotherprospectiveTEEstudy,however,foundnoclearcorrelationofvegetationsizewithembolization.59Nevertheless,thesameinvestigatorslaterreportedtheresultsofanewprospectivestudyof118patientswhounderwentTEEandfoundthat,onmultivariableanalysis,riskfactorsassociatedwithembolicriskincludedvegetationsize>10mmandmitralvalveinvolvement.56Overall,thesedataarecompatiblewithpreviousobservationsthatindicatethat,ingeneral,mitralvegetationsofanysizeareassociatedwithahigherriskofembolization(25%)thanaorticvegetations(10%).Asnotedabove,thehighestembolicrisk(37%)hasbeenseeninthesubsetofpatientswithmitralvegetationsattachedtotheanteriorratherthantheposteriormitralleaflet.59,63Thissuggeststhatthemechanicaleffectsofbroadandabruptleafletexcursion,occurringtwiceperheartbeat,maycontributetothepropensityofavegetationinthislocationtofragmentandembolize.Inanotherstudy,theeffectofvegetationsizeonembolicpotentialwasdependentontheinfectingorganism,withlargevegetationsindependentlypredictingemboliceventsonlyinthesettingofstreptococcalIE.60Incontrast,asconfirmedabovebyVilacostaetal,278staphylococcalorfungalIEappearstocarryahighincidencerateofembolizationindependentlyofvegetationsize.Prognosisbasedonechocardiographicfindingswasexaminedinalarge,multicenter,prospectiveinvestigation.OnthebasisofTEEfindingsin384consecutiveadultpatientswithdefiniteIE,vegetationlength>15mmwasapredictorof1-yearmortality(adjustedrelativerisk,1.8;95%confidenceinterval,1.10–2.82;P=0.02)inmultivariableanalysis.281Theroleofechocardiographyinpredictingemboliceventshasbeencontroversial.In1survey282thatincluded4echocardiographerswhowereblindedtoclinicaldata,interobserveragreementwasmixedonthecharacterizationofvegetations.Agreementwashighforthepresenceofvegetation(98%)andinvolvedsite(97%);interobserveragreementwasconsiderablylessforvegetationsize(73%),mobility(57%),shape(37%),andattachment(40%).However,alloftheseriesthatincluded>100patientswhounderwentTEEshowedapositiverelationshipbetweenemboliceventsandvegetationsize.Moreover,thestudywiththelargestnumberofpatients(n=176)thatassessedthevalueofTEEandincludedsilentembolismdetectedbyCTscanningdemonstratedthattheriskofemboliceventswashighlyrelatedtovegetationsizeandmobilitybutnottootherknownriskfactorsassociatedwithembolisminIE.283TheconflictingresultsontherelationshipbetweenechocardiographyandembolicriskcanbeexplainedatleastpartiallybythepoorstandardizationofdiagnosticcriteriaforIEinolderseries,inclusionornotofsilentembolism,inclusionornotofpreviousembolism,echocardiographicmethodused,lackoffocusonfutureemboliceventsafterTEE,andsamplesize.Anincreaseinvegetationsizeover4to8weeksoftherapyasdocumentedbyTEEappearstopredictembolicevents.282Inaddition,asecond,albeitinfrequent,peakoflateemboliceventshasbeenobservedtooccur15to30weeksafterthediagnosisofIEandhasbeenassociatedwithnonhealingvegetations(failureofavegetationtostabilizeordiminishinsize)asdefinedbyechocardiography.63ThetraditionalindicationforvalvularsurgeryforIEtoavoidembolizationhasbeen≥2majorembolicevents.284Thiscriterionisarbitraryandexcludescutaneousembolization,whichiscommon,orembolismoccurringbeforetheinstitutionoftherapy,whichiscommonamongIEpatientswhodevelopembolicevents.Becauseoftheobserveddecreasesinembolicriskduringthefirst2weeksofantibiotictherapy,thebenefitofsurgeryinavoidingcatastrophicemboliceventsisgreatestearlyinthetreatmentcourseofIE.Earlysurgicalinterventionmayprecludeaprimaryorrecurrentmajoremboliceventbutexposesthepatienttobothimmediateandlifelongrisksofvalvereplacementifthevalvecannotbeprimarilyrepaired.Atthistime,thestrategyforsurgicalinterventiontoavoidsystemicembolizationinIEremainsspecifictotheindividualpatient,withbenefitbeinggreatestintheearlyphaseofIEwhenembolicratesarehighestandotherpredictorsofacomplicatedcourse(ie,recurrentembolization;heartfailure;aggressive,antibiotic-resistantorganisms;orPVE)arepresent(Table5).Thebenefitsofearlysurgeryweredemonstratedintheprospective,randomizedtrial17thatwasdiscussedearlierinthisdocument.Becauseofseverallimitationsofthattrial,additionalstudyisneededbeforeroutineapplicationofearlysurgerysolelytoreduceembolicriskcanbestronglyadvocated.EmboliceventsareimportantprognosticindicatorsofIEoutcomes.In1analysis,anemboliceventwas1of4earlypredictorsofin-hospitaldeathcausedbyIE.285Otherindependentpredictorsofdeathbylogisticregressionmodelingamong267consecutivepatientswithdefiniteorpossibleIEbymodifiedDukecriteriawerediabetesmellitus,Saureusinfection,andAcutePhysiologyAndChronicHealthEvaluation(APACHE)IIscore.AnothercontroversialtopiciswhetherimagingtodetectembolishouldbeperformedinallIEpatients.Thecurrentparadigmincludesdedicated,anatomicimagingiftherearesignsorsymptomssuggestiveofanembolicevent.Thereislessagreementonimaging,whichcanposerisksbecausecontrastmaterialisusuallyrequired,inpatientswithoutsymptomsorsignsofemboli,someofwhommayhavesilentorsubclinicalevents.Inparticular,shouldMRIofthebrainbeobtainedinallIEpatientsbecausecerebralemboliaresocommonplace?Aspreviouslymentionedinanearliersection(3DEchocardiographyandOtherImagingModalities),somehaveadvocatedthisstrategyinallpatientswhoaretoundergovalvesurgerytoidentifythosewhomayharboremboliclesionsthatcouldposeahigherriskofintracranialbleedingwithcardiopulmonarybypassandheparinadministrationusedforcardiacsurgery.AnticoagulationAnticoagulationinIEpatientsiscontroversial,particularlyinmechanicalvalveIE.286SomeauthoritiesrecommendcontinuationofanticoagulanttherapyinpatientswithmechanicalvalveIE.However,thegeneraladviceistodiscontinueallformsofanticoagulationinpatientswithmechanicalvalveIEwhohaveexperiencedaCNSemboliceventforatleast2weeks.286Thistimeshouldallowforthrombusorganizationandpreventtheacutehemorrhagictransformationofemboliclesions.Reintroductionofanticoagulationinthesepatientsshouldbedonewithgreatcaution,beginningwithintravenousunfractionatedheparintitratedtoanactivatedpartialthromboplastintimerangeof50to70secondsandtransitioningcarefullytoadjusteddosewarfarin.Thenoveloralanticoagulantsarenotapprovedforusewitheithermechanicalvalvesorbioprostheticvalveswhenriskfactorsforthromboembolismexist(eg,atrialfibrillation).ThebenefitoftherapeuticanticoagulationhasneverbeendemonstratedconvincinglyinpatientswithNVE.InpartrelatedtofindingsthatdemonstratedasalutaryeffectofintravenousaspirintherapyinestablishedexperimentalSaureusIE,287arandomizedtrialcomparedoralaspirin325mg/dwithplaceboin115IEpatients.288Nosignificantbenefitwasobservedinaspirin-treatedpatientsintermsofvegetationresolutionandembolicevents.Moreover,therewasatrendtowardmorebleedingepisodesintheaspirin-treatedpatients.Aspirinlevels,acriticalcorrelateofantimicrobialefficacyinananimalmodel,werenotmonitoredinthisstudy.289Retrospective,observationalstudies290–296haveexaminedtheimpact,ifany,oflong-termantiplatelettherapybeforetheonsetofIEoninfection-relatedoutcomes.FindingsfromtheseinvestigationshavebeenmixedintermsofIE-relatedoutcomes.Untildefinitivedataareavailable,theinitiationofaspirinorotherantiplateletagentsasadjunctivetherapyinIEisnotrecommended.Incontrast,thecontinuationoflong-termantiplatelettherapyatthetimeofdevelopmentofIEwithnobleedingcomplicationsmaybeconsidered.RecommendationsDiscontinuationofallformsofanticoagulationinpatientswithmechanicalvalveIEwhohaveexperiencedaCNSemboliceventforatleast2weeksisreasonable(ClassIIa;LevelofEvidenceC).InitiationofaspirinorotherantiplateletagentsasadjunctivetherapyinIEisnotrecommended(ClassIII;LevelofEvidenceB).Thecontinuationoflong-termantiplatelettherapyatthetimeofdevelopmentofIEwithnobleedingcomplicationsmaybeconsidered(ClassIIb;LevelofEvidenceB).PeriannularExtensionofInfectionExtensionofIEbeyondthevalveannuluspredictsahighermortalityrate,morefrequentdevelopmentofheartfailure,andmorefrequentneedforcardiacsurgery.284,297,298Perivalvularcavitiesformwhenannularinfectionsbreakthroughandspreadintocontiguoustissue.InaorticNVE,thisgenerallyoccursthroughtheweakestportionoftheannulus,whichisnearthemembranousseptumandatrioventricularnode.299Theanatomicvulnerabilityofthisareaexplainsbothwhyabscessesoccurinthislocationandwhyheartblockisafrequentsequela.300Periannularextensioniscommon,occurringin10%to40%ofallNVEandcomplicatingaorticIEmorecommonlythanmitralortricuspidIE.301–304PeriannularinfectionisofevengreaterconcernwithPVE,occurringin56%to100%ofpatients.298,302Perivalvularabscessesareparticularlycommonwithprostheticvalvesbecausetheannulus,ratherthantheleaflet,istheusualprimarysiteofinfection,especiallyinearlyPVEandonbioprostheticvalves.302Undertheinfluenceofsystemicintravascularpressures,abscessesmayprogresstofistuloustractsthatcreateintracardiacorpericardialshunts.Themortalityratewas41%inaseries304ofpatientswithaorto-cavitaryfistulizationdespitesurgicalinterventionin87%.Multivariateanalysisdemonstratedthatfactorsassociatedwithanincreasedriskofdeathincludedmoderatetosevereheartfailure,PVE,andurgentoremergencysurgicalintervention.Insomecases,progressiveperiannularinfectiontotallydisruptstheventricular-aorticcontinuityorthemitral-aortictrigone.Suchstructurallesionsandintracardiacfistulasmaybecatastrophic;eveniftheirhemodynamicimpactistolerated,theselesionswillnothealwithmedicaltreatmentaloneandrequireurgentoperativeintervention.ClinicalparametersforthediagnosisofperivalvularextensionofIEareinadequate.Persistentbacteremiaorfever,recurrentemboli,heartblock,heartfailure,oranewpathologicalmurmurinapatientwithIEonappropriateantibioticsmaysuggestextension.303OnlyaorticvalveinvolvementandcurrentIDUhavebeenprospectivelyidentifiedasindependentriskfactorsforperivalvularabscess.297OnECG,newatrioventricularblockhasapositivepredictivevalueof88%forabscessformationbutlow(45%)sensitivity.298PatientsatriskforperivalvularextensionofIErequirepromptevaluation.Thesizeofvegetationsisnothelpfulforpredictingperivalvularextension.297ThesensitivityofTTEfordetectingperivalvularabscessislow(18%to63%inprospectiveandretrospectivestudies,respectively).305,306TEEdramaticallyimprovesthesensitivityfordefiningperiannularextensionofIE(76%to100%)whileretainingexcellentspecificity(95%)andpositiveandnegativepredictivevalues(87%and89%,respectively).54,307WhencombinedwithspectralandcolorDopplertechniques,TEEcandemonstratethedistinctiveflowpatternsoffistulasandpseudoaneurysmsandcanruleoutcommunicationsfromunrupturedabscesscavities.Becauseofthesecombinedcapabilities,TEEisrecommendedfortheinitialassessmentofanypatientsuspectedofhavingperivalvularextensionofIE.Asmallnumberofpatientswithperiannularextensionofinfectionormyocardialabscessmaybetreatedsuccessfullywithoutsurgicalintervention.307,308Thesepatientspotentiallyincludethosewhohavesmaller(<1cm)abscessesandwhodonothavecomplicationssuchasheartblock,echocardiographicevidenceofprogressionofabscessduringtherapy,valvulardehiscence,orinsufficiency.SuchpatientsshouldbemonitoredcloselywithserialTEE;TEEshouldberepeatedatintervalsof2,4,and8weeksaftercompletionofantimicrobialtherapy.SurgeryforpatientswithperivalvularextensionofIEisdirectedtowarderadicationoftheinfectionandcorrectionofhemodynamicabnormalities.Drainageofabscesscavities,excisionofnecrotictissue,andclosureoffistuloustractsoftenaccompanyvalvereplacementorrepairsurgery.309Althoughvalvereplacementisusuallyrequired,itssuccessfulperformancemaybecompromisedbyextensivedestructionoftheperiannularsupportingtissues.Undertheseconditions,humanaortichomografts,whenavailable,canbeusedtoreplacethedamagedaorticvalveandtoreconstructthedamagedaorta.310,311HomograftshaveaconstantbutlowincidencerateofIE.312Somegroupshaveadvocatedtheuseofstentlessormini-stentedaorticvalveprostheseswithdebridementinthesameclinicalscenario,particularlyifhomograftsarenotreadilyavailable.313RecommendationTEEisrecommendedfortheinitialassessmentofanypatientsuspectedofhavingperivalvularextensionofIE(ClassI;LevelofEvidenceB).MetastaticFociofInfectionSimilartoemboliccomplications,metastaticfociofinfectionfrequentlyoccurinIEandcangreatlyaffectmanagementstrategies,inparticulartimingofvalvesurgery,durationofantimicrobialtherapy,andneedforinvasiveinterventions(usuallysurgicalorinterventionalradiologicaldrainage).Muchlikeembolicevents,metastaticfociofinfectioneithercanremainasymptomaticormaycausemajorclinicalsignsorsymptoms.Inthelattercase,sustainedfevercanbeavaluableclue,particularlywhenbloodstreaminfectionhasbeenclearedorincaseswhenbloodstreaminfectionpersistsdespiteadequateantimicrobialcoverage.Inaddition,distinguishingblandinfarctioncausedbyanembolusfromametastaticfocus(abscess)sometimescanbedifficult.Inpatientswhoaresymptomatic,adiagnosticevaluationincludingradiological,ultrasonographic,andinvasiveproceduressuchasjointaspirationforbothdiagnosticandtherapeuticreasonsisrecommended.Invasiveproceduressuchaspercutaneousdrainageofsofttissueororganabscessmaybeneeded.Surgicalintervention,asmentionedabove,mayberequiredforradicalinfectioncure.Forexample,splenicabscessesgenerallyrequiresplenectomyoradrainageprocedurebecausetheusefulnessofantimicrobialtherapyisinpreventingdiseaseextensioninthespleenandtreatingsystemicinfectionratherthaneliminatingabscesses.314Whetherpercutaneousaspirationordrainageofsplenicabscessescanbeperformedsafelyandeffectivelyshouldbedecidedbyanexperiencedteamofclinicians.Identificationandmanagementofmetastaticfociofinfectionarecriticallyimportantinpatientswhorequirevalvesurgery.Whenfeasible,allinvasiveproceduresfortheinitialmanagementofmetastaticfociofinfectionshouldbedonebeforevalvesurgerytoreducethelikelihoodofinfectingaplacedprostheticvalveorannuloplastyring.Cerebrovascularimagingmaybeconsideredinallpatientswithleft-sidedIEwhohavenoCNSsignsorsymptoms(seetheIntracranialMAssectionbelow).TherearecurrentlynootherrecommendationsforroutinelyevaluatingallpatientswithIEformetastaticfociofinfection,althoughmanycliniciansrecommendsuchroutinescreeningforallcasesofSaureusIE.Rather,adirectedworkupisadvocatedonthebasisoflocalizingsignsorsymptoms.Dependingonthesiteofinterest,thechoiceofdiagnosticprocedure(eg,CT,MRI,ultrasonography)varies,andtheselectionshouldbeindividualizedforeachpatient.Thechoiceofproceduremayrequireconsultationwithexperts.Itisstronglyrecommendedthatadiscussionofwhichlaboratory(microbiology,pathologyincludingcytology)studieswillbeneededoncetissueorfluidaspiratespecimensareavailabletakesplacebeforeaninvasiveprocedureisperformed.RecommendationThechoiceofdiagnosticprocedure(eg,CT,MRI,ultrasonography)variesandtheselectionshouldbeindividualizedforeachpatient(ClassI;LevelofEvidenceC).MycoticAneurysmsMAsareuncommoncomplicationsofIEthatresultfromsepticembolizationofvegetationstothearterialvasavasorumortheintraluminalspace,withsubsequentspreadofinfectionthroughtheintimaandoutwardthroughthevesselwall.ArterialbranchingpointsfavortheimpactionofemboliandarethemostcommonsitesofdevelopmentofMAs.MAscausedbyIEoccurmostfrequentlyintheintracranialarteries,followedbythevisceralarteriesandthearteriesoftheupperandlowerextremities.AdetailedanalysisofthecomplexmanagementofMAshasbeenincludedinaseparateAHAScientificStatementthataddressesvascularinfectionsandispendingpublication;pleaserefertothisdocumentforadditionalinformation.IntracranialMAsIntracranialMAs(ICMAs)representarelativelysmallbutextremelydangeroussubsetofneurologicalcomplications.TheoverallmortalityrateamongIEpatientswithICMAsis60%.AmongpatientswithunrupturedICMAs,themortalityrateis30%;inpatientswithrupturedICMAs,themortalityrateapproaches80%.315,316ThereportedoccurrenceofICMAsin1.2%to5%ofcases316–320isprobablyunderestimatedbecausesomeICMAsremainasymptomaticandresolvewithantimicrobialtherapy.StreptococciandSaureusaccountfor50%and10%ofcases,respectively,317,318andICMAsareseenwithincreasedfrequencyamongIDUswithIE.318Thedistalmiddlecerebralarterybranchesaremostofteninvolved,especiallythebifurcations.MultipleICMAsoccurin20%ofcases319;mortalityratesaresimilarformultipleandsingledistalICMAs.ThemortalityrateforpatientswithproximalICMAsis>50%.321TheclinicalpresentationofpatientswithICMAsishighlyvariable.Patientsmaydevelopsevereheadache,alteredsensorium,orfocalneurologicaldeficitssuchashemianopsiaorcranialneuropathies.Neurologicalsignsandsymptomsarenonspecificandmaysuggestamasslesionoranembolicevent.315,317SomeICMAsleakslowlybeforeruptureandproducemildmeningealirritation.Frequently,thespinalfluidinthesepatientsissterile,anditusuallycontainserythrocytes,leukocytes,andelevatedprotein.Inotherpatients,therearenoclinicallyrecognizedpremonitoryfindingsbeforesuddensubarachnoidorintraventricularhemorrhage.315SymptomaticcerebralembolifrequentlybutnotinvariablyprecedethefindingofanICMA.315Therefore,imagingprocedurestodetectICMAsareindicatedinIEpatientswithlocalizedorsevereheadaches;“sterile”meningitis,especiallyiferythrocytesorxanthochromiaispresent;orfocalneurologicalsigns.SeveralimagingmodalitiescanbeusedtoidentifyICMAs;currently,thereisnopreferredinitialimagingstudythatcanberecommended.322Techniquesincludecardiac(multislice)CTangiographywith3Dreconstruction,digitalsubtractionangiography,andmagneticresonanceangiographywith3Dreconstruction.IncaseswhenthereisahighclinicalsuspicionofICMAsandanegativeinitialscreeningwith1ofthesemodalities,thenconventionalangiographyisreasonabletoperform.CerebralMRImaybeconsideredinallpatientswithleft-sidedIEwhohavenoCNSsignsorsymptoms.MRIfindingsmayassistinsubsequentmedicalandsurgicalmanagement.322RecommendationsCerebrospinalimagingshouldbeperformedtodetectICMAorCNSbleedinginallpatientswithIEorcontiguousspreadofinfectionwhodevelopsevere,localizedheadache,neurologicaldeficits,ormeningealsigns(ClassI;LevelofEvidenceB).Cerebrovascularimagingmaybeconsideredinallpatientswithleft-sidedIEwhohavenoCNSsignsorsymptoms(ClassIIb;LevelofEvidenceC).CTangiography,magneticresonanceangiography,ordigitalsubtractionangiographyisreasonableasaninitialimagingtestfordetectionofICMA(ClassIIa,LevelofEvidenceB).ConventionalangiographyfordetectionofsuspectedICMAisreasonableinpatientswithnegativeCTangiography,magneticresonanceangiography,ordigitalsubtractionangiography(ClassIIa;LevelofEvidenceB).ExtracranialMAsIntrathoracicorintra-abdominalMAsoftenareasymptomaticuntilleakageorruptureoccurs.Presumably,mostextracranialMAswillruptureifnotexcised.Theappearanceofatender,pulsatilemassinapatientwithIEsuggestsanextracranialMA.Hematemesis,hematobilia,andjaundicesuggestruptureofahepaticarteryMA;arterialhypertensionandhematuriasuggestruptureofarenalMA;andmassivebloodydiarrheasuggeststheruptureofanextracranialMAintothesmallorlargebowel.EitherCTscanningormultisliceCTangiographywith3Dreconstructionisindicatedforinitialimaging.TEEisusefulinidentifyingMAsofthesinusofValsalvaandthoracicaorta.RecommendationsEitherCTscanningormultisliceCTangiographywith3Dreconstructionisindicatedforinitialimaging(ClassI;LevelofEvidenceB).TEEisusefulinidentifyingMAsofthesinusofValsalvaandthoracicaorta(ClassI;LevelofEvidenceB).OutpatientTherapyOutpatientparenteralantibiotictherapy(OPAT)isefficacious,safe,andcost-effectiveforavarietyofinfections,323–325includingIEthatrequiresprolongedparenteraltherapyinhospitalizedpatientswhootherwisenolongerrequireinpatientcarebutdorequirecontinuedparenteralantimicrobialtherapy.AntibioticregimensrecommendedforIEvarywidelyandoftenrequire≥4weeksoftherapy,generallygivenbytheintravenousroute.Absorptionoforallyadministeredantimicrobialagentsmaybeunreliable,andsuchastrategyisgenerallynotrecommendedassoletherapyforIE.SeveralotheraspectsofOPATsuchasdrugstabilityatroomtemperature;frequencyofdrugdosing;accesstoancillaryequipment,includingambulatorypumps;insurancecoverage;andwhetherthepatienthasahistoryofIDUcanallaffecttheultimateuseofOPAT.ThetimingfortransitionfrominpatientantibiotictherapytoOPATandpatientexclusioncriteriahavebeencriticallyevaluatedbyAndrewsandvonReyn.326Theseguidelinesarebasedonthelocalavailabilityofmedicalcareintheoutpatientsettingandriskfactorsandtimingofpotentialadverseoutcomesthatwouldbebestmanagedintheinpatientsetting.BeforeOPATisconsidered,mostpatientswithIEshouldfirstbeevaluatedandstabilizedinthehospital;onlyrarelycansomepatientsbetreatedentirelyasoutpatients.PatientsselectedforOPATshouldbeatlowriskforthecomplicationsofIE,themostfrequentofwhichareheartfailureandsystemicemboli.Theperiodofgreatestriskforsystemicemboliisbeforeorwithinthefirst1to2weeksofantimicrobialtherapy,althoughseriouscomplicationssuchasheartfailureandruptureofMAsmaydevelopweekstomonthsaftertheinitiationofantimicrobialtherapy.Thepresenceofpoorlycontrolledheartfailure,neurologicalfindingsthatmayresultfromsystemicemboliorbleedingMAs,cardiacconductionabnormalities,valveringabscesses(usuallydetectedbyTEE),persistentfever,orpersistentlypositivebloodculturesshouldprecludeOPAT.Theriskfordrug-relatedsideeffectsusuallyincreaseswithaprolongeddrugexposure(eg,vestibular,auditory,andnephrotoxicityresultingfromaminoglycosides;leukopeniacausedbyβ-lactamsandvancomycin;andnephrotoxicityresultingfromthecombinationofvancomycinandgentamicin)andrequiresclosemonitoringbythehomeinfusionteamconsistingofrepresentativesfromnursingandpharmacyandclinicianswithexpertiseinIEmanagement.ThefollowingcriteriaareessentialforaneffectiveOPATprogram:Areliablesupportsystemathomeandeasyaccesstoahospitalforpromptre-evaluationbyanexperiencedclinicianifacomplicationsuchasrecurrenceoffever,symptomsofacardiacarrhythmia,heartfailure,oraneurologicaleventdevelopsRegularvisitsbyahomeinfusionnursewhocarefullymonitorsthepatientforearlydetectionofcomplications,failuretorespondtotherapy,problemswithadherencetotherapy,orcomplications(eg,catheter-relatedinfection,catheterleakageordisplacement,venousthrombosis)directlyrelatedtotheantibioticsorintravenousaccessRegularvisitswithanexperiencedcliniciantoassessclinicalstatusduringtheOPATRecommendationsPatientswithIEshouldfirstbeevaluatedandstabilizedinthehospitalbeforebeingconsideredforoutpatienttherapy(ClassI;LevelofEvidenceC).PatientsselectedforOPATshouldbeatlowriskforthecomplicationsofIE,themostfrequentofwhichareheartfailureandsystemicemboli(ClassI;LevelofEvidenceC).CareatCompletionofAntimicrobialTherapyShort-TermFollow-UpThemajorityofpatientswithIEarecuredwithappropriatemedicaland,ifnecessary,surgicaltreatment.Echocardiographyisreasonablebeforeorsynchronouswithcompletionofantimicrobialtherapytoestablishanewbaselineforsubsequentcomparison(Table18).AreferraltoaprogramtoassistinthecessationofdruguseshouldbemadeforIDUs.Patientsshouldbeeducatedaboutthesignsofendocarditisandurgedtoseekimmediatemedicalattentionshouldtheyoccur.Iffeasible,athoroughdentalevaluationisreasonable,especiallyinpatientsdeemedlikelytorequirevalvereplacement,withallactivesourcesoforalinfectioneradicated.Allindwellingintravenouscathetersusedtoinfuseantimicrobialtreatmentshouldberemovedpromptlyattheendoftherapy.Routinebloodculturesarenolongerrecommendedafterthecompletionofantimicrobialtherapybecausethelikelihoodofapositivecultureresultinapatientwhoisotherwisewithoutevidenceofactiveinfectionislow.Table18.CareDuringandAfterCompletionofAntimicrobialTreatmentInitiationbeforeoratcompletionoftherapy Echocardiographytoestablishnewbaseline Drugrehabilitationreferralforpatientswhouseillicitinjectiondrugs Educationonthesignsofendocarditisandneedforantibioticprophylaxisforcertaindental/surgical/invasiveprocedures Thoroughdentalevaluationandtreatmentifnotperformedearlierinevaluation PromptremovalofintravenouscatheteratcompletionofantimicrobialtherapyShort-termfollow-up Atleast3setsofbloodculturesfromseparatesitesforanyfebrileillnessandbeforeinitiationofantibiotictherapy Physicalexaminationforevidenceofheartfailure Evaluationfortoxicityresultingfromcurrent/previousantimicrobialtherapyLong-termfollow-up Atleast3setsofbloodculturesfromseparatesitesforanyfebrileillnessandbeforeinitiationofantibiotictherapy Evaluationofvalvularandventricularfunction(echocardiography) ScrupulousoralhygieneandfrequentdentalprofessionalofficevisitsIntheshort-termfollow-up,patientsshouldbemonitoredfordevelopmentofseveralcomplications(Table18).ArelapseofIEisaprimaryconcern.Patientsshouldbeawarethatrelapsescanoccurandthatnewonsetoffever,chills,orotherevidenceofsystemictoxicitymandatesimmediateevaluation,includingathoroughhistoryandphysicalexaminationand≥3setsofbloodcultures.Everyeffortshouldbemadetodeterminethecauseofsignsorsymptomsofinfection.Inaddition,prescribingempiricalantimicrobialtherapyshouldbeavoidedforanundefinedfebrileillnessunlessthepatient’sclinicalcondition(eg,sepsis)warrantsempiricaltherapy.Itisreasonableforpatientswhohavecompletedtherapytoundergoanexaminationaftercompletingantibiotictherapy.Developingorworseningheartfailureisasecondcomplicationthatshouldbeconsideredduringshort-termfollow-up.Althoughnewonsetofheartfailurecausedbyvalvulardysfunctionisunlikelyduringthisperiod,valvefunctioncandeteriorateasaresultofongoinginfectionormechanicalstressunrelatedtoinfection.Inadditiontophysicalexamination,echocardiographicfindingscansupportthisdiagnosis.Ifheartfailuredevelopsorworsens,thepatientshouldbeevaluatedimmediatelyforcardiacsurgery.Antibiotictoxicitystillcanoccurafterthecompletionoftreatmentandisthethirdcomplicationthatshouldbeconsideredduringshort-termfollow-up.Twodrug-relatedadverseeventsareconcerns.Thefirstisdelayedototoxicitybecauseoftheprevioususeofaminoglycosides.Audiologicalandvestibulartoxicitycandevelopdespitethemaintenanceofappropriateserumdrugconcentrationsduringtreatment.Forpatientsreceivinglong-termaminoglycosides,particularlythosewithunderlyingrenaloroticdisorders,serialaudiogramsmaybeconsideredduringtherapyiffeasibleandavailable.Notoolsareroutinelyavailableformonitoringvestibularfunction,andpatientsshouldbetoldtoreporttheonsetofanysymptomsofvestibulartoxicityduringoraftertreatment.Thesecondantibiotic-relatedadverseeventisClostridiumdifficileinfection.Onsetofdiarrheacanbedelayedaslongas4weeksafterthelastdoseofantibiotic.Thehopeisthatpromptrecognitionandtreatmentofthisinfectiouscomplicationwilldiminishthelikelihoodofseverecomplications.Recommendations1.Echocardiographyisreasonablebeforeorsynchronouswithcompletionofantimicrobialtherapytoestablishanewbaselineforsubsequentcomparison(ClassIIa;LevelofEvidenceC).2.AreferraltoaprogramtoassistinthecessationofdruguseshouldbemadeforIDUs(ClassI;LevelofEvidenceC).3.Patientsshouldbeeducatedaboutthesignsofendocarditisandurgedtoseekimmediatemedicalattentionshouldtheydevelop(ClassI;LevelofEvidenceC).4.Athoroughdentalevaluationisreasonable,especiallyinpatientsdeemedlikelytorequirevalvereplacement,withallactivesourcesoforalinfectioneradicated(ClassIIa;LevelofEvidenceC).5.Routinebloodculturesarenotrecommendedafterthecompletionofantimicrobialtherapybecausethelikelihoodofapositivecultureresultinapatientwhoisotherwisewithoutevidenceofactiveinfectionislow(ClassIII;LevelofEvidenceC).6.Allindwellingintravenouscathetersusedtoinfuseantimicrobialtreatmentshouldberemovedpromptlyattheendoftherapy(ClassI;LevelofEvidenceC).7.Forpatientsreceivinglong-termaminoglycosides,particularlythosewithunderlyingrenaloroticdisorders,serialaudiogramsmaybeconsideredduringtherapyifavailable(ClassIIb;LevelofEvidenceC).8.Intheshort-termfollow-up,patientsshouldbemonitoredforthedevelopmentofseveralcomplications,includingIErelapseandheartfailure(ClassI;LevelofEvidenceC).9.Patientsshouldbeawarethatrelapsescanoccurandthatnewonsetoffever,chills,orotherevidenceofsystemictoxicitymandatesimmediateevaluation,includingathoroughhistoryandphysicalexaminationand≥3setsofbloodcultures(ClassI;LevelofEvidenceC).10.BecauseofconcernsforIErelapse,athoroughevaluationshouldbedonetodeterminethecauseofinfectionsignsandsymptoms(ClassI;LevelofEvidenceC).11.Empiricalantimicrobialtherapyforsuspectedinfectionshouldbeavoidedunlessthepatient’sclinicalcondition(eg,sepsis)warrantsit(ClassIII;LevelofEvidenceC).12.Itisreasonabletohavepatientswhohavecompletedtherapyanddonothavesymptomsofsystemictoxicityundergoanexaminationaftercompletingantibiotictherapy(ClassIIa;LevelofEvidenceC).13.Developingorworseningheartfailureisacommoncomplicationthatshouldbemonitoredforduringshort-termfollow-up(ClassI;LevelofEvidenceC).14.Ifheartfailuredevelopsorworsens,thepatientshouldbeevaluatedimmediatelyforcardiacsurgery(ClassI;LevelofEvidenceB).15.Antibiotictoxicitystillcanoccurafterthecompletionoftreatmentandisacomplicationthatshouldbeconsideredduringshort-termfollow-up(ClassI;LevelofEvidenceC).16.Notoolsareroutinelyavailableformonitoringvestibularfunction,andpatientsshouldbetoldtoreporttheonsetofanysymptomsofvestibulartoxicityduringoraftertreatment(ClassI;LevelofEvidenceC).Long-TermFollow-UpMonthstoyearsaftercompletionofmedicaltherapyforIE,patientsshouldhaveongoingobservationforandeducationaboutrecurrentinfectionanddelayedonsetofworseningvalvedysfunction(Table18).Dailydentalhygieneshouldbestressed,withserialevaluationsbyadentistwhoisfamiliarwiththispatientpopulation.Patientsshouldbequestionedaboutsymptomsofheartfailure,andathoroughphysicalexaminationshouldbedone.Additionalevaluationwithechocardiographyisindicatedinselectedpatientswithpositivefindingsfromhistoryandphysicalexamination.Patientsshouldbeinstructedtoseekimmediatemedicalevaluationforpersistentfever(Table18).ThisisnecessarybecauseIEcanmimicavarietyoffebrileillnesses.Bloodculturesshouldbeobtained.Antibiotictherapyshouldnotbeinitiatedfortreatmentofundefinedfebrileillnesseswithoutbloodculturesbeingobtainedfirst.Antibioticsprescribedfornonspecificorunprovedfebrilesyndromesareamajorcauseof(blood)culture-negativeIE,andthispracticeshouldbestronglydiscouraged.RecommendationsMonthstoyearsaftercompletionofmedicaltherapyforIE,patientsshouldhaveongoingobservationforandeducationaboutrecurrentinfectionanddelayedonsetofworseningvalvedysfunction(ClassI;LevelofEvidenceC).Dailydentalhygieneshouldbestressed,withserialevaluationsbyadentistwhoisfamiliarwiththispatientpopulation(ClassI;LevelofEvidenceC).Patientsshouldbequestionedaboutsymptomsofheartfailure,andathoroughphysicalexaminationshouldbedone(ClassI;LevelofEvidenceC).Additionalevaluationswithechocardiographyshouldbeobtainedinselectedpatientswithpositivefindingsfromhistoryandphysicalexamination(ClassI;LevelofEvidenceC).Patientsshouldbeinstructedtoseekimmediatemedicalevaluationforfever,andbloodculturesshouldbeobtained(ClassI;LevelofEvidenceC).Antimicrobialtherapyshouldnotbeinitiatedforthetreatmentofundefinedfebrileillnessesunlessthepatient’scondition(eg,sepsis)warrantsit(ClassIII;LevelofEvidenceC).DentalManagementAlarge,prospectivestudydemonstratedastrongassociationbetween3indexesoforalhygieneandgingivaldiseaseandtheincidenceofbacteremiafromIE-relatedspecies.327Poororalhygieneresultsingingivitis,whichoftenleadstoperiodontitis,anditislikelythatthese2periodontaldiseasesareassociatedwithcommunity-acquiredIE.Currentevidencesuggeststhatpoororalhygieneandperiodontaldiseases,notdentalofficeprocedures,arelikelytoberesponsibleforthevastmajorityofcasesofIEthatoriginateinthemouth.328Regardlessofthesourceofinfection,inpatientswithIEshouldbethoroughlyevaluatedbyadentistfamiliarwiththepotentialroleofthemouthinthesecases.Theoptimaltimingforthisevaluationmaybeafterthepatient’scardiacstatushasstabilizedandearlyenoughthatallinvasivedentalprocedurescanbeaccomplishedduringintravenousantibiotictherapy.Theclinicalexaminationshouldruleoutperiodontalinflammationandpocketingaroundtheteethandcariesthatwilleventuallyresultinpulpalinfection.Afullseriesofintraoralradiographsisrequiredfortheidentificationofcariesandperiodontaldisease(eg,boneloss,toothfractures).Allofthisisaimedatreducingtheincidenceandmagnitudeofbacteremiafromanymanipulationofthegingivaltissues,includingnormaldailyeventssuchasbrushingteethandchewingfood.Treatmentinvariablyinvolvesathoroughdentalcleaningbyahygienistwhowillreviewwithpatientstheimportanceofmaintainingscrupulousoralhygiene.Dentaldiseaseisalmostentirelypreventableifpatientsarecompliantwith4measures.First,thecauseofbothperiodontaldiseaseandcariesisbacterialplaqueaccumulationonteeth,andpreventionisdependentonkeepingteethfreeofplaque.Second,patientsmustunderstandthatdietarymeasuresarecriticallyimportantinpreventingtheformationofplaque,especiallyinareasontheteeththataredifficulttokeepclean.Thedegreetowhichsugarandotherrefinedcarbohydratesareeliminatedfromthedietwillhaveamajorimpactonthegrowthofpathogenicbacterialspecies,someofwhichareresponsibleforIE.Third,routinefollow-upwiththeirfamilydentistisnecessaryforclosemonitoringoforalhygieneandtheearlyidentificationanderadicationoforaldisease.Finally,thedailyuseofahigh-concentrationfluoridatedtoothpastewillhelptoensurethattheacidfromplaquedoesnotdecalcifytoothstructuresandresultincaries.Afocusonall4measuresshouldhelptoreducetheincidenceofbacteremiaandtheriskforrecurrentIE.RecommendationsInpatientswithIEshouldbethoroughlyevaluatedbyadentisttoidentifyandeliminateoraldiseasesthatpredisposetobacteremiaandmaythereforecontributetotheriskforrecurrentIE(ClassI;LevelofEvidenceC).Theclinicalexaminationshouldfocusonperiodontalinflammationandpocketingaroundteethandcariesthatmayresultinpulpalinfectionandsubsequentabscess(ClassI;LevelofEvidenceC).Afullseriesofintraoralradiographswillallowtheidentificationofcariesandperiodontaldiseaseandotherdisease(eg,toothfractures)notevidentfromthephysicalexamination.Thisshouldoccurwhenthepatientisabletotraveltoadentalfacility(ClassI;LevelofEvidenceC).WritingGroupDisclosuresWritingGroupMemberEmploymentResearchGrantOtherResearchSupportSpeakers’Bureau/HonorariaExpertWitnessOwnershipInterestConsultant/AdvisoryBoardOtherLarryM.BaddourMayoClinicNoneNoneNoneNoneNoneNoneNoneRobertS.BaltimoreYaleUniversitySchoolofMedicineNoneNoneNoneNoneNoneNoneNoneBrunoBarsicHospitalforInfectiousDiseases,SchoolofMedicineZagrebNoneNoneAstellas*;Pfizer*;MSD*NoneNoneNoneNoneArnoldS.BayerLABiomedicalResearchInstituteInfectiousDiseasesAstellas†;Cubist†;NIH/NIAID*;Theravance*NoneNoneJohnsonGraffeetal*;Morrow,Kidman,Tinkeretal*;Galloway,Luccheseetal*;MESSolutions*;Hoffman,Sheffieldetal*;CliffordLaw*NoneNoneNoneAnnF.BolgerUCSFNoneNoneNoneNoneNoneNoneNoneAnneM.FinkUniversityofIllinoisatChicagoNoneNoneNoneNoneNoneNoneNoneVanceG.Fowler,Jr.DukeUniversityCDC†;Cerexa/Forest†;MedImmune†;NIH†;FDA†;Cubist*NoneNoneWitnessincaseinvolvinggroupBStreptococcalVertebralosteomyelitis†NoneMedImmune*;Novartis†;TheMedicinesComapy*;Novadigm*;Debiopharm*;Cerexa*;Affinium*;Tetraphase*;Bayer*;Theravance*;Cubist*;Genetech*;Basilea*NoneMichaelH.GewitzNewYorkMedicalCollegeNoneNoneNoneNoneNoneNoneNoneMatthewE.LevisonDrexelUniversityCollegeofMedicineNoneNoneNoneNoneNoneMerckManual†NonePeterB.LockhartCarolinasMedicalCenterNoneNoneNoneNoneNoneNoneNonePatrickO’GaraBrighamandWomen’sHospitalNoneNoneNoneNoneNoneNoneNoneMichaelJ.RybakWayneStateUniversityCubist*;Forest*;MDCH*;NIH*;Actavis*;Theravance*NoneCubist*;Forest*;Novartis*;Actavis*;TheMedicinesCompany*NoneNoneCubist*;Forest*;Theravance*;Actavis†;TheMedicinesCompany*NoneJamesM.SteckelbergMayoClinicNoneNoneNoneNoneNoneNoneNoneKathrynA.TaubertAmericanHeartAssociationNoneNoneNoneNoneNoneNoneNoneImadM.TleyjehKingFahdMedicalCityNoneNoneNoneNoneNoneNoneNoneWalterR.WilsonMayoClinicNoneNoneNoneNoneNoneNoneNoneThistablerepresentstherelationshipsofwritinggroupmembersthatmaybeperceivedasactualorreasonablyperceivedconflictsofinterestasreportedontheDisclosureQuestionnaire,whichallmembersofthewritinggrouparerequiredtocompleteandsubmit.Arelationshipisconsideredtobe“significant”if(a)thepersonreceives$10 000ormoreduringany12-monthperiod,or5%ormoreoftheperson’sgrossincome;or(b)thepersonowns5%ormoreofthevotingstockorshareoftheentity,orowns$10 000ormoreofthefairmarketvalueoftheentity.Arelationshipisconsideredtobe“modest”ifitislessthan“significant”undertheprecedingdefinition.*Modest.†Significant.ReviewerDisclosuresReviewerEmploymentResearchGrantOtherResearchSupportSpeakers’Bureau/HonorariaExpertWitnessOwnershipInterestConsultant/AdvisoryBoardOtherGiovanniDiSalvoKingFaisalHospitalandResearchCenter(SaudiArabia)NoneNoneNoneNoneNoneNoneNoneFranklinD.LowyColumbiaUniversityNoneNoneNoneNoneNoneNoneUptoDate*StanfordT.ShulmanLurieChildren’sHospital,Children’sMemorialHospital,NorthwesternUniversityMedicalSchoolNoneNoneNoneNoneNoneNoneNoneThistablerepresentstherelationshipsofreviewersthatmaybeperceivedasactualorreasonablyperceivedconflictsofinterestasreportedontheDisclosureQuestionnaire,whichallreviewersarerequiredtocompleteandsubmit.Arelationshipisconsideredtobe“significant”if(a)thepersonreceives$10 000ormoreduringany12-monthperiod,or5%ormoreoftheperson’sgrossincome;or(b)thepersonowns5%ormoreofthevotingstockorshareoftheentity,orowns$10 000ormoreofthefairmarketvalueoftheentity.Arelationshipisconsideredtobe“modest”ifitislessthan“significant”undertheprecedingdefinition.*Modest.DisclosuresFootnotesEndorsedbytheInfectiousDiseasesSocietyofAmericaTheAmericanHeartAssociationmakeseveryefforttoavoidanyactualorpotentialconflictsofinterestthatmayariseasaresultofanoutsiderelationshiporapersonal,professional,orbusinessinterestofamemberofthewritingpanel.Specifically,allmembersofthewritinggrouparerequiredtocompleteandsubmitaDisclosureQuestionnaireshowingallsuchrelationshipsthatmightbeperceivedasrealorpotentialconflictsofinterest.ThisstatementwasapprovedbytheAmericanHeartAssociationScienceAdvisoryandCoordinatingCommitteeonMay12,2015,andtheAmericanHeartAssociationExecutiveCommitteeonJune12,2015.Acopyofthedocumentisavailableathttp://my.americanheart.org/statementsbyselectingeitherthe“ByTopic”linkorthe“ByPublicationDate”link.Topurchaseadditionalreprints,call843-216-2533ore-mailkelle.[email protected]com.TheAmericanHeartAssociationrequeststhatthisdocumentbecitedasfollows:BaddourLM,WilsonWR,BayerAS,FowlerVGJr,TleyjehIM,RybakMJ,BarsicB,LockhartPB,GewitzMH,LevisonME,BolgerAF,SteckelbergJM,BaltimoreRS,FinkAM,O’GaraP,TaubertKA;onbehalfoftheAmericanHeartAssociationCommitteeonRheumaticFever,Endocarditis,andKawasakiDiseaseoftheCouncilonCardiovascularDiseaseintheYoung,CouncilonClinicalCardiology,CouncilonCardiovascularSurgeryandAnesthesia,andStrokeCouncil.Infectiveendocarditisinadults:diagnosis,antimicrobialtherapy,andmanagementofcomplications:ascientificstatementforhealthcareprofessionalsfromtheAmericanHeartAssociation.Circulation.2015;132:1435–1486.ExpertpeerreviewofAHAScientificStatementsisconductedbytheAHAOfficeofScienceOperations.FormoreonAHAstatementsandguidelinesdevelopment,visithttp://my.americanheart.org/statementsandselectthe“PoliciesandDevelopment”link.Permissions:Multiplecopies,modification,alteration,enhancement,and/ordistributionofthisdocumentarenotpermittedwithouttheexpresspermissionoftheAmericanHeartAssociation.Instructionsforobtainingpermissionarelocatedathttp://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp.Alinktothe“CopyrightPermissionsRequestForm”appearsontherightsideofthepage.References1.DuvalX,DelahayeF,AllaF,TattevinP,ObadiaJF,LeMoingV,Doco-LecompteT,CelardM,PoyartC,StradyC,ChirouzeC,BesM,CambauE,IungB,Selton-SutyC,HoenB;AEPEIStudyGroup.Temporaltrendsininfectiveendocarditisinthecontextofprophylaxisguidelinemodifications:threesuccessivepopulation-basedsurveys.JAmCollCardiol.2012;59:1968–1976.doi:10.1016/j.jacc.2012.02.029.CrossrefMedlineGoogleScholar2.CorreadeSaDD,TleyjehIM,AnavekarNS,SchultzJC,ThomasJM,LahrBD,BachuwarA,PazdernikM,SteckelbergJM,WilsonWR,BaddourLM.Epidemiologicaltrendsofinfectiveendocarditis:apopulation-basedstudyinOlmstedCounty,Minnesota[publishedcorrectionappearsinMayoClinProc.2010;85:772].MayoClinProc.2010;85:422–426.CrossrefMedlineGoogleScholar3.FederspielJJ,StearnsSC,PeppercornAF,ChuVH,FowlerVG.IncreasingUSratesofendocarditiswithStaphylococcusaureus:1999-2008.ArchInternMed.2012;172:363–365.doi:10.1001/archinternmed.2011.1027.CrossrefMedlineGoogleScholar4.MurrayCJ,VosT,LozanoR,NaghaviM,FlaxmanAD,MichaudC,EzzatiM,ShibuyaK,SalomonJA,AbdallaS,AboyansV,AbrahamJ,AckermanI,AggarwalR,AhnSY,AliMK,AlvaradoM,AndersonHR,AndersonLM,AndrewsKG,AtkinsonC,BaddourLM,BahalimAN,Barker-ColloS,BarreroLH,BartelsDH,BasáñezMG,BaxterA,BellML,BenjaminEJ,BennettD,BernabéE,BhallaK,BhandariB,BikbovB,BinAbdulhakA,BirbeckG,BlackJA,BlencoweH,BloreJD,BlythF,BolligerI,BonaventureA,BoufousS,BourneR,BoussinesqM,BraithwaiteT,BrayneC,BridgettL,BrookerS,BrooksP,BrughaTS,Bryan-HancockC,BucelloC,BuchbinderR,BuckleG,BudkeCM,BurchM,BurneyP,BursteinR,CalabriaB,CampbellB,CanterCE,CarabinH,CarapetisJ,CarmonaL,CellaC,CharlsonF,ChenH,ChengAT,ChouD,ChughSS,CoffengLE,ColanSD,ColquhounS,ColsonKE,CondonJ,ConnorMD,CooperLT,CorriereM,CortinovisM,deVaccaroKC,CouserW,CowieBC,CriquiMH,CrossM,DabhadkarKC,DahiyaM,DahodwalaN,Damsere-DerryJ,DanaeiG,DavisA,DeLeoD,DegenhardtL,DellavalleR,DelossantosA,DenenbergJ,DerrettS,DesJarlaisDC,DharmaratneSD,DheraniM,Diaz-TorneC,DolkH,DorseyER,DriscollT,DuberH,EbelB,EdmondK,ElbazA,AliSE,ErskineH,ErwinPJ,EspindolaP,EwoigbokhanSE,FarzadfarF,FeiginV,FelsonDT,FerrariA,FerriCP,FèvreEM,FinucaneMM,FlaxmanS,FloodL,ForemanK,ForouzanfarMH,FowkesFG,FransenM,FreemanMK,GabbeBJ,GabrielSE,GakidouE,GanatraHA,GarciaB,GaspariF,GillumRF,GmelG,Gonzalez-MedinaD,GosselinR,GraingerR,GrantB,GroegerJ,GuilleminF,GunnellD,GuptaR,HaagsmaJ,HaganH,HalasaYA,HallW,HaringD,HaroJM,HarrisonJE,HavmoellerR,HayRJ,HigashiH,HillC,HoenB,HoffmanH,HotezPJ,HoyD,HuangJJ,IbeanusiSE,JacobsenKH,JamesSL,JarvisD,JasrasariaR,JayaramanS,JohnsN,JonasJB,KarthikeyanG,KassebaumN,KawakamiN,KerenA,KhooJP,KingCH,KnowltonLM,KobusingyeO,KorantengA,KrishnamurthiR,LadenF,LallooR,LaslettLL,LathleanT,LeasherJL,LeeYY,LeighJ,LevinsonD,LimSS,LimbE,LinJK,LipnickM,LipshultzSE,LiuW,LoaneM,OhnoSL,LyonsR,MabweijanoJ,MacIntyreMF,MalekzadehR,MallingerL,ManivannanS,MarcenesW,MarchL,MargolisDJ,MarksGB,MarksR,MatsumoriA,MatzopoulosR,MayosiBM,McAnultyJH,McDermottMM,McGillN,McGrathJ,Medina-MoraME,MeltzerM,MensahGA,MerrimanTR,MeyerAC,MiglioliV,MillerM,MillerTR,MitchellPB,MockC,MocumbiAO,MoffittTE,MokdadAA,MonastaL,MonticoM,Moradi-LakehM,MoranA,MorawskaL,MoriR,MurdochME,MwanikiMK,NaidooK,NairMN,NaldiL,NarayanKM,NelsonPK,NelsonRG,NevittMC,NewtonCR,NolteS,NormanP,NormanR,O’DonnellM,O’HanlonS,OlivesC,OmerSB,OrtbladK,OsborneR,OzgedizD,PageA,PahariB,PandianJD,RiveroAP,PattenSB,PearceN,PadillaRP,Perez-RuizF,PericoN,PesudovsK,PhillipsD,PhillipsMR,PierceK,PionS,PolanczykGV,PolinderS,PopeCA,PopovaS,PorriniE,PourmalekF,PrinceM,PullanRL,RamaiahKD,RanganathanD,RazaviH,ReganM,RehmJT,ReinDB,RemuzziG,RichardsonK,RivaraFP,RobertsT,RobinsonC,DeLeònFR,RonfaniL,RoomR,RosenfeldLC,RushtonL,SaccoRL,SahaS,SampsonU,Sanchez-RieraL,SanmanE,SchwebelDC,ScottJG,Segui-GomezM,ShahrazS,ShepardDS,ShinH,ShivakotiR,SinghD,SinghGM,SinghJA,SingletonJ,SleetDA,SliwaK,SmithE,SmithJL,StapelbergNJ,SteerA,SteinerT,StolkWA,StovnerLJ,SudfeldC,SyedS,TamburliniG,TavakkoliM,TaylorHR,TaylorJA,TaylorWJ,ThomasB,ThomsonWM,ThurstonGD,TleyjehIM,TonelliM,TowbinJA,TruelsenT,TsilimbarisMK,UbedaC,UndurragaEA,vanderWerfMJ,vanOsJ,VavilalaMS,VenketasubramanianN,WangM,WangW,WattK,WeatherallDJ,WeinstockMA,WeintraubR,WeisskopfMG,WeissmanMM,WhiteRA,WhitefordH,WiebeN,WiersmaST,WilkinsonJD,WilliamsHC,WilliamsSR,WittE,WolfeF,WoolfAD,WulfS,YehPH,ZaidiAK,ZhengZJ,ZoniesD,LopezAD,AlMazroaMA,MemishZA.Disability-adjustedlifeyears(DALYs)for291diseasesandinjuriesin21regions,1990-2010:asystematicanalysisfortheGlobalBurdenofDiseaseStudy2010[publishedcorrectionappearsinLancet.2013;381:628].Lancet.2012;380:2197–2223.doi:10.1016/S0140-6736(12)61689-4.CrossrefMedlineGoogleScholar5.TleyjehIM,Abdel-LatifA,RahbiH,ScottCG,BaileyKR,SteckelbergJM,WilsonWR,BaddourLM.Asystematicreviewofpopulation-basedstudiesofinfectiveendocarditis.Chest.2007;132:1025–1035.doi:10.1378/chest.06-2048.CrossrefMedlineGoogleScholar6.FowlerVG,MiroJM,HoenB,CabellCH,AbrutynE,RubinsteinE,CoreyGR,SpelmanD,BradleySF,BarsicB,PappasPA,AnstromKJ,WrayD,FortesCQ,AngueraI,AthanE,JonesP,vanderMeerJT,ElliottTS,LevineDP,BayerAS;ICEInvestigators.Staphylococcusaureusendocarditis:aconsequenceofmedicalprogress[publishedcorrectionappearsinJAMA.2005;294:900].JAMA.2005;293:3012–3021.doi:10.1001/jama.293.24.3012.CrossrefMedlineGoogleScholar7.Selton-SutyC,CélardM,LeMoingV,Doco-LecompteT,ChirouzeC,IungB,StradyC,RevestM,VandeneschF,BouvetA,DelahayeF,AllaF,DuvalX,HoenB;AEPEIStudyGroup.PreeminenceofStaphylococcusaureusininfectiveendocarditis:a1-yearpopulation-basedsurvey.ClinInfectDis.2012;54:1230–1239.doi:10.1093/cid/cis199.CrossrefMedlineGoogleScholar8.MurdochDR,CoreyGR,HoenB,MiróJM,FowlerVG,BayerAS,KarchmerAW,OlaisonL,PappasPA,MoreillonP,ChambersST,ChuVH,FalcóV,HollandDJ,JonesP,KleinJL,RaymondNJ,ReadKM,TripodiMF,UtiliR,WangA,WoodsCW,CabellCH;InternationalCollaborationonEndocarditis-ProspectiveCohortStudy(ICE-PCS)Investigators.Clinicalpresentation,etiology,andoutcomeofinfectiveendocarditisinthe21stcentury:theInternationalCollaborationonEndocarditis-ProspectiveCohortStudy.ArchInternMed.2009;169:463–473.doi:10.1001/archinternmed.2008.603.CrossrefMedlineGoogleScholar9.BenitoN,MiróJM,deLazzariE,CabellCH,delRíoA,AltclasJ,CommerfordP,DelahayeF,DragulescuS,GiamarellouH,HabibG,KamarulzamanA,KumarAS,NacinovichFM,SuterF,TribouilloyC,VenugopalK,MorenoA,FowlerVG;ICE-PCS(InternationalCollaborationonEndocarditisProspectiveCohortStudy)Investigators.Healthcare-associatednativevalveendocarditis:importanceofnon-nosocomialacquisition[publishedcorrectio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October13,2015Vol132,Issue15ArticleInformationMetrics Download:153,896 ©2015AmericanHeartAssociation,Inc.https://doi.org/10.1161/CIR.0000000000000296PMID: 26373316 OriginallypublishedSeptember15,2015 KeywordsechocardiographyendocarditisAHAScientificStatementsanti-infectiveagentsinfectionPDFdownload SubjectsStatementsandGuidelines TitleCaptionTitleCaptionTitleCaptionTitleCaption