2015 ESC Guidelines for the management of infective ...

Criteria that determine suitability of outpatient parenteral antibiotic therapy for infective endocarditis (adapted from Andrews et al.205). graphic. HF = heart ... SkiptoMainContent Advertisement SearchMenu AccountMenu Menu SignIn Register NavbarSearchFilter ThisissueAllEuropeanHeartJournal AllESCFamilyAllJournals MobileMicrositeSearchTerm Search SignIn Register Issues MoreContent AdvanceArticles Editor'sChoice Guidelines CardioPulse WeeklyJournalScan IntheNews Podcasts Webinars CardioImageBank ESCJournalsApp Submit AuthorGuidelines SubmissionSite OpenAccessOptions AuthorResources Self-ArchivingPolicy Read&Publish Purchase Advertise AdvertisingandCorporateServices Advertising ReprintsandePrints SponsoredSupplements JournalsCareerNetwork About AboutEuropeanHeartJournal EditorialBoard AbouttheEuropeanSocietyofCardiology ESCMembership Alerts DevelopingCountriesInitiative DispatchDates TermsandConditions Issues MoreContent AdvanceArticles Editor'sChoice Guidelines CardioPulse WeeklyJournalScan IntheNews Podcasts Webinars CardioImageBank ESCJournalsApp Submit AuthorGuidelines SubmissionSite OpenAccessOptions AuthorResources Self-ArchivingPolicy Read&Publish Purchase Advertise AdvertisingandCorporateServices Advertising ReprintsandePrints SponsoredSupplements JournalsCareerNetwork About AboutEuropeanHeartJournal EditorialBoard AbouttheEuropeanSocietyofCardiology ESCMembership Alerts DevelopingCountriesInitiative DispatchDates TermsandConditions Close searchfilter Thisissue AllEuropeanHeartJournal AllESCFamily AllJournals searchinput Search AdvancedSearch SearchMenu ArticleNavigation Closemobilesearchnavigation ArticleNavigation Volume36 Issue44 21November2015 ArticleContents Abbreviationsandacronyms 1.Preamble 2.Justification/scopeoftheproblem 3.Prevention 4.The‘EndocarditisTeam’ 5.Diagnosis 6.Prognosticassessmentatadmission 7.Antimicrobialtherapy:principlesandmethods 8.Maincomplicationsofleft-sidedvalveinfectiveendocarditisandtheirmanagement 9.Othercomplicationsofinfectiveendocarditis 10.Surgicaltherapy:principlesandmethods 11.Outcomeafterdischarge:follow-upandlong-termprognosis 12.Managementofspecificsituations 13.Todoandnottodomessagesfromtheguidelines 14.Appendix 15.References ArticleNavigation ArticleNavigation Editor'sChoiceGuidelines 2015ESCGuidelinesforthemanagementofinfectiveendocarditis:TheTaskForcefortheManagementofInfectiveEndocarditisoftheEuropeanSocietyofCardiology(ESC)Endorsedby:EuropeanAssociationforCardio-ThoracicSurgery(EACTS),theEuropeanAssociationofNuclearMedicine(EANM) GilbertHabib, GilbertHabib (Chairperson)(France) Correspondingauthors:GilbertHabib,ServicedeCardiologie,C.H.U.DeLaTimone,BdJeanMoulin,13005Marseille,France,Tel:+33491387588,Fax:+33491384764,Email:[email protected] Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar PatrizioLancellotti, PatrizioLancellotti (co-Chairperson)(Belgium) Correspondingauthors:GilbertHabib,ServicedeCardiologie,C.H.U.DeLaTimone,BdJeanMoulin,13005Marseille,France,Tel:+33491387588,Fax:+33491384764,Email:[email protected] Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar ManuelJAntunes, ManuelJAntunes (Portugal) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar MariaGraziaBongiorni, MariaGraziaBongiorni (Italy) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar Jean-PaulCasalta, Jean-PaulCasalta (France) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar FrancescoDelZotti, FrancescoDelZotti (Italy) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar RalucaDulgheru, RalucaDulgheru (Belgium) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar GebrineElKhoury, GebrineElKhoury (Belgium) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar PaolaAnnaErba, PaolaAnnaErba (Italy) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar BernardIung, BernardIung (France) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar ...Showmore JoseMMiro, JoseMMiro (Spain) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar BarbaraJMulder, BarbaraJMulder (TheNetherlands) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar EdytaPlonska-Gosciniak, EdytaPlonska-Gosciniak (Poland) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar SusannaPrice, SusannaPrice (UK) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar JolienRoos-Hesselink, JolienRoos-Hesselink (TheNetherlands) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar UlrikaSnygg-Martin, UlrikaSnygg-Martin (Sweden) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar FranckThuny, FranckThuny (France) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar PilarTornosMas, PilarTornosMas (Spain) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar IsidreVilacosta, IsidreVilacosta (Spain) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar JoseLuisZamorano, JoseLuisZamorano (Spain) Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar ESCScientificDocumentGroup ESCScientificDocumentGroup Searchforotherworksbythisauthoron: OxfordAcademic PubMed GoogleScholar DocumentReviewers:ÇetinErol(CPGReviewCoordinator)(Turkey),PetrosNihoyannopoulos(CPGReviewCoordinator)(UK),VictorAboyans(France),StefanAgewall(Norway),GeorgeAthanassopoulos(Greece),SaideAytekin(Turkey),WernerBenzer(Austria),HéctorBueno(Spain),LidewijBroekhuizen(TheNetherlands),ScipioneCarerj(Italy),BernardCosyns(Belgium),JulieDeBacker(Belgium),MicheleDeBonis(Italy),KonstantinosDimopoulos(UK),ErwanDonal(France),HeinzDrexel(Austria),FrankArnoldFlachskampf(Sweden),RogerHall(UK),SigrunHalvorsen(Norway),BrunoHoenb(France),PaulusKirchhof(UK/Germany),MitjaLainscak(Slovenia),AdelinoF.Leite-Moreira(Portugal),GregoryY.H.Lip(UK),CarlosA.Mestresc(Spain/UnitedArabEmirates),MassimoF.Piepoli(Italy),PrakashP.Punjabi(UK),ClaudioRapezzi(Italy),RaphaelRosenhek(Austria),KaatSiebens(Belgium),JuanTamargo(Spain),andDavidM.Walker(UK) ESCCommitteeforPracticeGuidelines(CPG)andNationalCardiacSocietiesdocumentreviewers:listedintheAppendix ESCentitieshavingparticipatedinthedevelopmentofthisdocument: ESCAssociations:AcuteCardiovascularCareAssociation(ACCA),EuropeanAssociationforCardiovascularPrevention&Rehabilitation(EACPR),EuropeanAssociationofCardiovascularImaging(EACVI),EuropeanHeartRhythmAssociation(EHRA),HeartFailureAssociation(HFA). ESCCouncils:CouncilforCardiologyPractice(CCP),CouncilonCardiovascularNursingandAlliedProfessions(CCNAP),CouncilonCardiovascularPrimaryCare(CCPC). ESCWorkingGroups:CardiovascularPharmacotherapy,CardiovascularSurgery,Grown-upCongenitalHeartDisease,MyocardialandPericardialDiseases,PulmonaryCirculationandRightVentricularFunction,Thrombosis,ValvularHeartDisease. ThecontentoftheseEuropeanSocietyofCardiology(ESC)Guidelineshasbeenpublishedforpersonalandeducationaluseonly.Nocommercialuseisauthorized.NopartoftheESCGuidelinesmaybetranslatedorreproducedinanyformwithoutwrittenpermissionfromtheESC.PermissioncanbeobtaineduponsubmissionofawrittenrequesttoOxfordUniversityPress,thepublisheroftheEuropeanHeartJournalandthepartyauthorizedtohandlesuchpermissionsonbehalfoftheESC. Disclaimer.TheESCGuidelinesrepresenttheviewsoftheESCandwereproducedaftercarefulconsiderationofthescientificandmedicalknowledgeandtheevidenceavailableatthetimeoftheirpublication.TheESCisnotresponsibleintheeventofanycontradiction,discrepancyand/orambiguitybetweentheESCGuidelinesandanyotherofficialrecommendationsorguidelinesissuedbytherelevantpublichealthauthorities,inparticularinrelationtogooduseofhealthcareortherapeuticstrategies.HealthprofessionalsareencouragedtotaketheESCGuidelinesfullyintoaccountwhenexercisingtheirclinicaljudgment,aswellasinthedeterminationandtheimplementationofpreventive,diagnosticortherapeuticmedicalstrategies;however,theESCGuidelinesdonotoverride,inanywaywhatsoever,theindividualresponsibilityofhealthprofessionalstomakeappropriateandaccuratedecisionsinconsiderationofeachpatient'shealthconditionandinconsultationwiththatpatientand,whereappropriateand/ornecessary,thepatient'scaregiver.NordotheESCGuidelinesexempthealthprofessionalsfromtakingintofullandcarefulconsiderationtherelevantofficialupdatedrecommendationsorguidelinesissuedbythecompetentpublichealthauthorities,inordertomanageeachpatient'scaseinlightofthescientificallyaccepteddatapursuanttotheirrespectiveethicalandprofessionalobligations.Itisalsothehealthprofessional'sresponsibilitytoverifytheapplicablerulesandregulationsrelatingtodrugsandmedicaldevicesatthetimeofprescription. ThedisclosureformsofallexpertsinvolvedinthedevelopmentoftheseguidelinesareavailableontheESCwebsitehttp://www.escardio.org/guidelines. aRepresentingtheEuropeanAssociationofNuclearMedicine(EANM);bRepresentingtheEuropeanSocietyofClinicalMicrobiologyandInfectiousDiseases(ESCMID);andcRepresentingtheEuropeanAssociationforCardio-ThoracicSurgery(EACTS). AuthorNotes EuropeanHeartJournal,Volume36,Issue44,21November2015,Pages3075–3128,https://doi.org/10.1093/eurheartj/ehv319 Published: 21November2015 PDF SplitView Views Articlecontents Figures&tables Video Audio SupplementaryData Cite Cite GilbertHabib,PatrizioLancellotti,ManuelJAntunes,MariaGraziaBongiorni,Jean-PaulCasalta,FrancescoDelZotti,RalucaDulgheru,GebrineElKhoury,PaolaAnnaErba,BernardIung,JoseMMiro,BarbaraJMulder,EdytaPlonska-Gosciniak,SusannaPrice,JolienRoos-Hesselink,UlrikaSnygg-Martin,FranckThuny,PilarTornosMas,IsidreVilacosta,JoseLuisZamorano,ESCScientificDocumentGroup,2015ESCGuidelinesforthemanagementofinfectiveendocarditis:TheTaskForcefortheManagementofInfectiveEndocarditisoftheEuropeanSocietyofCardiology(ESC)Endorsedby:EuropeanAssociationforCardio-ThoracicSurgery(EACTS),theEuropeanAssociationofNuclearMedicine(EANM),EuropeanHeartJournal,Volume36,Issue44,21November2015,Pages3075–3128,https://doi.org/10.1093/eurheartj/ehv319 SelectFormat Selectformat .ris(Mendeley,Papers,Zotero) .enw(EndNote) .bibtex(BibTex) .txt(Medlars,RefWorks) Downloadcitation Close PermissionsIcon Permissions Share Email Twitter Facebook More NavbarSearchFilter ThisissueAllEuropeanHeartJournal AllESCFamilyAllJournals MobileMicrositeSearchTerm Search SignIn Register Close searchfilter Thisissue AllEuropeanHeartJournal AllESCFamily AllJournals searchinput Search AdvancedSearch SearchMenu Endocarditis,Cardiacimaging,Valvedisease,Echocardiography,Prognosis,Guidelines,Infection,Nuclearimaging,Cardiacsurgery,Cardiacdevice,Prostheticheartvalves,Congenitalheartdisease,Pregnancy,Prophylaxis,PreventionAbbreviationsandacronyms  3Dthree-dimensional AIDSacquiredimmunedeficiencysyndrome b.i.d.bisindie(twicedaily) BCNIEbloodculture-negativeinfectiveendocarditis CDRIEcardiacdevice-relatedinfectiveendocarditis CHDcongenitalheartdisease CIEDcardiacimplantableelectronicdevice CoNScoagulase-negativestaphylococci CPGCommitteeforPracticeGuidelines CRPC-reactiveprotein CTcomputedtomography E.Enterococcus ESCEuropeanSocietyofCardiology ESRerythrocytesedimentationrate EuroSCOREEuropeanSystemforCardiacOperativeRiskEvaluation FDGfluorodeoxyglucose HFheartfailure HIVhumanimmunodeficiencyvirus HLARhigh-levelaminoglycosideresistance i.m.intramuscular i.v.intravenous ICEInternationalCollaborationonEndocarditis ICUintensivecareunit IDinfectiousdisease IEinfectiveendocarditis Igimmunoglobulin IVDAintravenousdrugabuser MICminimuminhibitoryconcentration MRmagneticresonance MRImagneticresonanceimaging MRSAmethicillin-resistantStaphylococcusaureus MSCTmultislicecomputedtomography MSSAmethicillin-susceptibleStaphylococcusaureus NBTEnon-bacterialthromboticendocarditis NICENationalInstituteforHealthandCareExcellence NVEnativevalveendocarditis OPAToutpatientparenteralantibiotictherapy PBPpenicillinbindingprotein PCRpolymerasechainreaction PETpositronemissiontomography PVEprostheticvalveendocarditis SOFASequentialOrganFailureAssessment SPECTsingle-photonemissioncomputedtomography TOEtransoesophagealechocardiography TTEtransthoracicechocardiography WBCwhitebloodcell1.Preamble Guidelinessummarizeandevaluateallavailableevidenceonaparticularissueatthetimeofthewritingprocess,withtheaimofassistinghealthprofessionalsinselectingthebestmanagementstrategiesforanindividualpatientwithagivencondition,takingintoaccounttheimpactonoutcome,aswellastherisk–benefitratioofparticulardiagnosticortherapeuticmeans.Guidelinesandrecommendationsshouldhelphealthprofessionalstomakedecisionsintheirdailypractice.However,thefinaldecisionsconcerninganindividualpatientmustbemadebytheresponsiblehealthprofessional(s)inconsultationwiththepatientandcaregiverasappropriate.AgreatnumberofGuidelineshavebeenissuedinrecentyearsbytheEuropeanSocietyofCardiology(ESC)aswellasbyothersocietiesandorganisations.Becauseoftheimpactonclinicalpractice,qualitycriteriaforthedevelopmentofguidelineshavebeenestablishedinordertomakealldecisionstransparenttotheuser.TherecommendationsforformulatingandissuingESCGuidelinescanbefoundontheESCwebsite(http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Guidelines-development/Writing-ESC-Guidelines).ESCGuidelinesrepresenttheofficialpositionoftheESConagiventopicandareregularlyupdated.MembersofthisTaskForcewereselectedbytheESCtorepresentprofessionalsinvolvedwiththemedicalcareofpatientswiththispathology.Selectedexpertsinthefieldundertookacomprehensivereviewofthepublishedevidenceformanagement(includingdiagnosis,treatment,preventionandrehabilitation)ofagivenconditionaccordingtoESCCommitteeforPracticeGuidelines(CPG)policy.Acriticalevaluationofdiagnosticandtherapeuticprocedureswasperformed,includingassessmentoftherisk–benefitratio.Estimatesofexpectedhealthoutcomesforlargerpopulationswereincluded,wheredataexist.Thelevelofevidenceandthestrengthoftherecommendationofparticularmanagementoptionswereweighedandgradedaccordingtopredefinedscales,asoutlinedinTables1and2. Table1Classesofrecommendations   Openinnewtab Table1Classesofrecommendations   Openinnewtab Table2Levelsofevidence   Openinnewtab Table2Levelsofevidence   Openinnewtab Theexpertsofthewritingandreviewingpanelsprovideddeclarationsofinterestformsforallrelationshipsthatmightbeperceivedasrealorpotentialsourcesofconflictsofinterest.TheseformswerecompiledintoonefileandcanbefoundontheESCwebsite(http://www.escardio.org/guidelines).AnychangesindeclarationsofinterestthatariseduringthewritingperiodmustbenotifiedtotheESCandupdated.TheTaskForcereceiveditsentirefinancialsupportfromtheESCwithoutanyinvolvementfromthehealthcareindustry.TheESCCPGsupervisesandcoordinatesthepreparationofnewGuidelinesproducedbytaskforces,expertgroupsorconsensuspanels.TheCommitteeisalsoresponsiblefortheendorsementprocessoftheseGuidelines.TheESCGuidelinesundergoextensivereviewbytheCPGandexternalexperts.AfterappropriaterevisionstheGuidelinesareapprovedbyalltheexpertsinvolvedintheTaskForce.ThefinalizeddocumentisapprovedbytheCPGforpublicationintheEuropeanHeartJournal.TheGuidelinesweredevelopedaftercarefulconsiderationofthescientificandmedicalknowledgeandtheevidenceavailableatthetimeoftheirdating.ThetaskofdevelopingESCGuidelinescoversnotonlyintegrationofthemostrecentresearch,butalsothecreationofeducationaltoolsandimplementationprogrammesfortherecommendations.Toimplementtheguidelines,condensedpocketguidelinesversions,summaryslides,bookletswithessentialmessages,summarycardsfornon-specialists,andanelectronicversionfordigitalapplications(smartphones,etc.)areproduced.Theseversionsareabridgedandthus,ifneeded,oneshouldalwaysrefertothefulltextversion,whichisfreelyavailableontheESCwebsite.TheNationalSocietiesoftheESCareencouragedtoendorse,translateandimplementallESCGuidelines.Implementationprogrammesareneededbecauseithasbeenshownthattheoutcomeofdiseasemaybefavourablyinfluencedbythethoroughapplicationofclinicalrecommendations.Surveysandregistriesareneededtoverifythatreal-lifedailypracticeisinkeepingwithwhatisrecommendedintheguidelines,thuscompletingtheloopbetweenclinicalresearch,writingofguidelines,disseminatingthemandimplementingthemintoclinicalpractice.HealthprofessionalsareencouragedtotaketheESCGuidelinesfullyintoaccountwhenexercisingtheirclinicaljudgment,aswellasinthedeterminationandtheimplementationofpreventive,diagnosticortherapeuticmedicalstrategies.However,theESCGuidelinesdonotoverrideinanywaywhatsoevertheindividualresponsibilityofhealthprofessionalstomakeappropriateandaccuratedecisionsinconsiderationofeachpatient'shealthconditionandinconsultationwiththatpatientandthepatient'scaregiverwhereappropriateand/ornecessary.Itisalsothehealthprofessional'sresponsibilitytoverifytherulesandregulationsapplicabletodrugsanddevicesatthetimeofprescription.2.Justification/scopeoftheproblem Infectiveendocarditis(IE)isadeadlydisease.1,2Despiteimprovementsinitsmanagement,IEremainsassociatedwithhighmortalityandseverecomplications.Untilrecently,guidelinesonIEweremostlybasedonexpertopinionbecauseofthelowincidenceofthedisease,theabsenceofrandomizedtrialsandthelimitednumberofmeta-analyses.3–7The2009ESCGuidelinesontheprevention,diagnosisandtreatmentofIE8introducedseveralinnovativeconcepts,includinglimitationofantibioticprophylaxistothehighest-riskpatients,afocusonhealthcare-associatedIEandidentificationoftheoptimaltimingforsurgery.However,severalreasonsjustifythedecisionoftheESCtoupdatethepreviousguidelines:thepublicationofnewlargeseriesofIE,includingthefirstrandomizedstudyregardingsurgicaltherapy;9importantimprovementsinimagingprocedures,10particularlyinthefieldofnuclearimaging;anddiscrepanciesbetweenpreviousguidelines.5–8Inaddition,theneedforacollaborativeapproachinvolvingprimarycarephysicians,cardiologists,surgeons,microbiologists,infectiousdisease(ID)specialistsandfrequentlyotherspecialists—namelythe‘EndocarditisTeam’—hasbeenunderlinedrecently11,12andwillbedevelopedinthesenewguidelines.ThemainobjectiveofthecurrentTaskForcewastoprovideclearandsimplerecommendations,assistinghealthcareprovidersintheirclinicaldecisionmaking.Theserecommendationswereobtainedbyexpertconsensusafterthoroughreviewoftheavailableliterature.Anevidence-basedscoringsystemwasused,basedonaclassificationofthestrengthofrecommendationsandthelevelsofevidence.3.Prevention 3.1Rationale TheprincipleofantibioticprophylaxisforIEwasdevelopedonthebasisofobservationalstudiesandanimalmodelsandaimedatpreventingtheattachmentofbacteriaontotheendocardiumaftertransientbacteraemiafollowinginvasiveprocedures.Thisconceptledtotherecommendationforantibioticprophylaxisinalargenumberofpatientswithpredisposingcardiacconditionsundergoingawiderangeofprocedures.13Therestrictionofindicationsforantibioticprophylaxiswasinitiatedin2002becauseofchangesinpathophysiologicalconceptionsandrisk–benefitanalysesasfollows:14hesepointshavebeenprogressivelytakenintoaccountinmostguidelines,includingthe2009ESCguidelines,5,8,23–26andledtotherestrictionofantibioticprophylaxistothehighest-riskpatients(patientswiththehighestincidenceofIEand/orhighestriskofadverseoutcomefromIE).Low-gradebutrepeatedbacteraemiaoccursmorefrequentlyduringdailyroutineactivitiessuchastoothbrushing,flossingorchewing,andevenmorefrequentlyinpatientswithpoordentalhealth.15Theaccountabilityoflow-gradebacteraemiawasdemonstratedinananimalmodel.16TheriskofIEmaythereforeberelatedmoretocumulativelow-gradebacteraemiaduringdailyliferatherthansporadichigh-gradebacteraemiaafterdentalprocedures.Mostcase–controlstudiesdidnotreportanassociationbetweeninvasivedentalproceduresandtheoccurrenceofIE.17–19TheestimatedriskofIEfollowingdentalproceduresisverylow.AntibioticprophylaxismaythereforeavoidonlyasmallnumberofIEcases,asshownbyestimationsof1caseofIEper150000dentalprocedureswithantibioticsand1per46000forproceduresunprotectedbyantibiotics.20Antibioticadministrationcarriesasmallriskofanaphylaxis,whichmaybecomesignificantintheeventofwidespreaduse.However,thelethalriskofanaphylaxisseemsverylowwhenusingoralamoxicillin.21Widespreaduseofantibioticsmayresultintheemergenceofresistantmicroorganisms.13TheefficacyofantibioticprophylaxisonbacteraemiaandtheoccurrenceofIEhasonlybeenproveninanimalmodels.Theeffectonbacteraemiainhumansiscontroversial.15NoprospectiverandomizedcontrolledtrialhasinvestigatedtheefficacyofantibioticprophylaxisontheoccurrenceofIEanditisunlikelythatsuchatrialwillbeconductedgiventhenumberofsubjectsneeded.22In2008theNationalInstituteforHealthandCareExcellence(NICE)guidelineswentastepfurtherandadvisedagainstanyantibioticprophylaxisfordentalandnon-dentalprocedureswhateverthepatient'srisk.27Theauthorsconcludedtherewasanabsenceofbenefitofantibioticprophylaxis,whichwasalsohighlycost-ineffective.TheseconclusionshavebeenchallengedsinceestimationsoftherisksofIEarebasedonlowlevelsofevidenceduetomultipleextrapolations.28,29FourepidemiologicalstudieshaveanalysedtheincidenceofIEfollowingrestrictedindicationsforantibioticprophylaxis.Theanalysisof2000–2010nationalhospitaldischargecodesintheUKdidnotshowanincreaseintheincidenceofstreptococcalIEafterthereleaseofNICEguidelinesin2008.30Therestrictionofantibioticprophylaxiswasseenina78%decreaseinantibioticprescriptionsbeforedentalcare.However,residualprescriptionsraisedconcernsregardingapersistinguseofantibioticprophylaxis.Asurveyperformedin2012intheUKshowedthatthemajorityofcardiologistsandcardiacsurgeonsfeltthatantibioticprophylaxiswasnecessaryinpatientswithvalveprosthesisorpriorIE.31RecentlyananalysisofUKdatacollectedfrom2000to2013showedasignificantincreaseintheincidenceofIEinbothhigh-riskandlower-riskpatientsintheUKstartingin2008.32However,thistemporalrelationshipshouldnotbeinterpretedasadirectconsequenceoftheNICEguidelines.Thesefindingsmaybeinfluencedbyconfoundingfactors,inparticularchangesinthenumberofpatientsatriskofhospitalizationsandhealthcare-associatedIE.Moreover,microbiologicaldatawerenotavailable.Thuswecannotknowwhetherthatincreaseisduetothemicrobiologicalspeciescoveredbyantibioticprophylaxis.Arepeatedprospective1-yearpopulation-basedFrenchsurveydidnotshowanincreaseintheincidenceofIE,inparticularstreptococcalIE,between1999and2008,whereasantibioticprophylaxishadbeenrestrictedfornativevalvediseasesince2002.33TwostudiesfromtheUSAdidnotfindanegativeimpactoftheabandonmentofantibioticprophylaxisinnativevalvediseaseinthe2007AmericanHeartAssociationguidelines.34,35AmorerecentanalysisonanadministrativedatabasefoundanincreaseintheincidenceofIEhospitalizationsbetween2000and2011,withnosignificantchangeafterthechangeofAmericanguidelinesin2007.36TheincreaseinIEincidencewasobservedforalltypesofmicroorganisms,butwassignificantforstreptococciafter2007.36Itwasnotstatedwhetherthiswasduetooralstreptococciandifintermediate-orhigh-riskpatientswereinvolved.Thepresentguidelinesmaintaintheprincipleofantibioticprophylaxisinhigh-riskpatientsforthefollowingreasons:TheremaininguncertaintiesregardingestimationsoftheriskofIE,whichplayanimportantroleintherationaleofNICEguidelines.TheworseprognosisofIEinhigh-riskpatients,inparticularthosewithprostheticIE.Thefactthathigh-riskpatientsaccountforamuchsmallernumberthanpatientsatintermediaterisk,therebyreducingpotentialharmduetoadverseeventsofantibioticprophylaxis.3.2Populationatrisk PatientswiththehighestriskofIEcanbeplacedinthreecategories(Table3):Patientswithaprostheticvalveorwithprostheticmaterialusedforcardiacvalverepair:thesepatientshaveahigherriskofIE,ahighermortalityfromIEandmoreoftendevelopcomplicationsofthediseasethanpatientswithnativevalvesandanidenticalpathogen.37Thisalsoappliestotranscatheter-implantedprosthesesandhomografts.PatientswithpreviousIE:theyalsohaveagreaterriskofnewIE,highermortalityandhigherincidenceofcomplicationsthanpatientswithafirstepisodeofIE.38Patientswithuntreatedcyanoticcongenitalheartdisease(CHD)andthosewithCHDwhohavepostoperativepalliativeshunts,conduitsorotherprostheses.39,40Aftersurgicalrepairwithnoresidualdefects,theTaskForcerecommendsprophylaxisforthefirst6monthsaftertheprocedureuntilendothelialisationoftheprostheticmaterialhasoccurred. Table3Cardiacconditionsathighestriskofinfectiveendocarditisforwhichprophylaxisshouldbeconsideredwhenahigh-riskprocedureisperformed  CHD=congenitalheartdisease;IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table3Cardiacconditionsathighestriskofinfectiveendocarditisforwhichprophylaxisshouldbeconsideredwhenahigh-riskprocedureisperformed  CHD=congenitalheartdisease;IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab AlthoughAmericanHeartAssociation/AmericanCollegeofCardiologyguidelinesrecommendprophylaxisincardiactransplantrecipientswhodevelopcardiacvalvulopathy,thisisnotsupportedbystrongevidence5,25,41andisnotrecommendedbytheESCTaskForce.AntibioticprophylaxisisnotrecommendedforpatientsatintermediateriskofIE,i.e.anyotherformofnativevalvedisease(includingthemostcommonlyidentifiedconditions:bicuspidaorticvalve,mitralvalveprolapseandcalcificaorticstenosis).Nevertheless,bothintermediate-andhigh-riskpatientsshouldbeadvisedoftheimportanceofdentalandcutaneoushygiene13(Table4).Thesemeasuresofgeneralhygieneapplytopatientsandhealthcareworkersandshouldideallybeappliedtothegeneralpopulation,asIEfrequentlyoccurswithoutknowncardiacdisease. Table4Non-specificpreventionmeasurestobefollowedinhigh-riskandintermediate-riskpatients   Openinnewtab Table4Non-specificpreventionmeasurestobefollowedinhigh-riskandintermediate-riskpatients   Openinnewtab 3.3Situationsandproceduresatrisk 3.3.1Dentalprocedures At-riskproceduresinvolvemanipulationofthegingivalorperiapicalregionoftheteethorperforationoftheoralmucosa(includingscalingandrootcanalprocedures)(Table5).15,20Theuseofdentalimplantsraisesconcernswithregardtopotentialriskduetoforeignmaterialattheinterfacebetweenthebuccalcavityandblood.Veryfewdataareavailable.42TheopinionoftheTaskForceisthatthereisnoevidencetocontraindicateimplantsinallpatientsatrisk.Theindicationshouldbediscussedonacase-by-casebasis.Thepatientshouldbeinformedoftheuncertaintiesandtheneedforclosefollow-up. Table5Recommendationsforprophylaxisofinfectiveendocarditisinthehighest-riskpatientsaccordingtothetypeofat-riskprocedure  TOE=transoesophagealechocardiography.aClassofrecommendation.bLevelofevidence.cFormanagementwheninfectionsarepresent,pleaserefertoSection3.5.3. Openinnewtab Table5Recommendationsforprophylaxisofinfectiveendocarditisinthehighest-riskpatientsaccordingtothetypeofat-riskprocedure  TOE=transoesophagealechocardiography.aClassofrecommendation.bLevelofevidence.cFormanagementwheninfectionsarepresent,pleaserefertoSection3.5.3. Openinnewtab 3.3.2Otherat-riskprocedures Thereisnocompellingevidencethatbacteraemiaresultingfromrespiratorytractprocedures,gastrointestinalorgenitourinaryprocedures,includingvaginalandcaesareandelivery,ordermatologicalormusculoskeletalprocedurescausesIE(Table5).3.4Prophylaxisfordentalprocedures Antibioticprophylaxisshouldonlybeconsideredforpatientsathighestriskforendocarditis,asdescribedinTable3,undergoingat-riskdentalprocedureslistedinTable5,andisnotrecommendedinothersituations.Themaintargetsforantibioticprophylaxisinthesepatientsareoralstreptococci.Table6summarizesthemainregimensofantibioticprophylaxisrecommendedbeforedentalprocedures.Fluoroquinolonesandglycopeptidesarenotrecommendedduetotheirunclearefficacyandthepotentialinductionofresistance. Table6Recommendedprophylaxisforhigh-riskdentalproceduresinhigh-riskpatients  aAlternatively,cephalexin2gi.v.foradultsor50mg/kgi.v.forchildren,cefazolinorceftriaxone1gi.v.foradultsor50mg/kgi.v.forchildren.Cephalosporinsshouldnotbeusedinpatientswithanaphylaxis,angio-oedema,orurticariaafterintakeofpenicillinorampicillinduetocross-sensitivity. Openinnewtab Table6Recommendedprophylaxisforhigh-riskdentalproceduresinhigh-riskpatients  aAlternatively,cephalexin2gi.v.foradultsor50mg/kgi.v.forchildren,cefazolinorceftriaxone1gi.v.foradultsor50mg/kgi.v.forchildren.Cephalosporinsshouldnotbeusedinpatientswithanaphylaxis,angio-oedema,orurticariaafterintakeofpenicillinorampicillinduetocross-sensitivity. Openinnewtab Cephalosporinsshouldnotbeusedinpatientswithanaphylaxis,angio-oedemaorurticariaafterintakeofpenicillinorampicillinduetocross-sensitivity.3.5Prophylaxisfornon-dentalprocedures Systematicantibioticprophylaxisisnotrecommendedfornon-dentalprocedures.Antibiotictherapyisonlyneededwheninvasiveproceduresareperformedinthecontextofinfection.3.5.1Respiratorytractprocedures PatientslistedinTable3whoundergoaninvasiverespiratorytractproceduretotreatanestablishedinfection(i.e.drainageofanabscess)shouldreceiveanantibioticregimenthatcontainsananti-staphylococcaldrug.3.5.2Gastrointestinalorgenitourinaryprocedures InthecaseofanestablishedinfectionorifantibiotictherapyisindicatedtopreventwoundinfectionorsepsisassociatedwithagastrointestinalorgenitourinarytractprocedureinpatientsdescribedinTable3,itisreasonablethattheantibioticregimenincludesanagentactiveagainstenterococci(i.e.ampicillin,amoxicillinorvancomycin;onlyinpatientsunabletotoleratebeta-lactams).Theuseofintrauterinedeviceswasregardedascontraindicated,butthiswasbasedonlowlevelsofevidence.Useofanintrauterinedeviceisnowconsideredacceptable,inparticularwhenothercontraceptivemethodsarenotpossibleandinwomenatlowriskofgenitalinfections.433.5.3Dermatologicalormusculoskeletalprocedures ForpatientsdescribedinTable3undergoingsurgicalproceduresinvolvinginfectedskin(includingoralabscesses),skinstructureormusculoskeletaltissue,itisreasonablethatthetherapeuticregimencontainsanagentactiveagainststaphylococciandbeta-haemolyticstreptococci.3.5.4Bodypiercingandtattooing Thesegrowingsocietaltrendsareacauseforconcern,particularlyforindividualswithCHDwhoareatincreasedsusceptibilityfortheacquisitionofIE.CasereportsofIEafterpiercingandtattooingareincreasing,particularlywhenpiercinginvolvesthetongue,44althoughpublicationbiasmayover-orunderestimatetheproblem.CurrentlynodataareavailableontheincidenceofIEaftersuchproceduresandtheefficacyofantibioticsforprevention.EducationofpatientsatriskofIEisparamount.Theyshouldbeinformedaboutthehazardsofpiercingandtattooingandtheseproceduresshouldbediscouragednotonlyinhigh-riskpatients,butalsointhosewithnativevalvedisease.Ifundertaken,proceduresshouldbeperformedunderstrictlysterileconditions,thoughantibioticprophylaxisisnotrecommended.3.5.5Cardiacorvascularinterventions Inpatientsundergoingimplantationofaprostheticvalve,anytypeofprostheticgraftorpacemakers,perioperativeantibioticprophylaxisshouldbeconsideredduetotheincreasedriskandadverseoutcomeofaninfection45–49(Table7).Themostfrequentmicroorganismsunderlyingearly(1yearaftersurgery)prostheticvalveinfectionsarecoagulase-negativestaphylococci(CoNS)andStaphylococcusaureus.Prophylaxisshouldbestartedimmediatelybeforetheprocedure,repeatediftheprocedureisprolongedandterminated48hafterwards.Arandomizedtrialhasshowntheefficacyof1gintravenous(i.v.)cefazolinonthepreventionoflocalandsystemicinfectionsbeforepacemakerimplantation.45PreoperativescreeningofnasalcarriageofS.aureusisrecommendedbeforeelectivecardiacsurgeryinordertotreatcarriersusinglocalmupirocinandchlorhexidine.46,47Rapididentificationtechniquesusinggeneamplificationareusefultoavoiddelayingurgentsurgery.Systematiclocaltreatmentwithoutscreeningisnotrecommended.Itisstronglyrecommendedthatpotentialsourcesofdentalsepsisshouldbeeliminatedatleast2weeksbeforeimplantationofaprostheticvalveorotherintracardiacorintravascularforeignmaterial,unlessthelatterprocedureisurgent.48 Table7Recommendationsforantibioticprophylaxisforthepreventionoflocalandsystemicinfectionsbeforecardiacorvascularinterventions  aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table7Recommendationsforantibioticprophylaxisforthepreventionoflocalandsystemicinfectionsbeforecardiacorvascularinterventions  aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab 3.5.6Healthcare-associatedinfectiveendocarditis Healthcare-associatedIErepresentsupto30%ofallcasesofIEandischaracterizedbyanincreasingincidenceandasevereprognosis,thuspresentinganimportanthealthproblem.50,51Althoughroutineantimicrobialprophylaxisadministeredbeforemostinvasiveproceduresisnotrecommended,asepticmeasuresduringtheinsertionandmanipulationofvenouscathetersandduringanyinvasiveprocedures,includinginoutpatients,aremandatorytoreducetherateofthishealthcare-associatedIE.52Insummary,theseguidelinesproposecontinuingtolimitantibioticprophylaxistopatientsathighriskofIEundergoingthehighest-riskdentalprocedures.Theyhighlighttheimportanceofhygienemeasures,inparticularoralandcutaneoushygiene.EpidemiologicalchangesaremarkedbyanincreaseinIEduetostaphylococcusandofhealthcare-associatedIE,therebyhighlightingtheimportanceofnon-specificinfectioncontrolmeasures.51,53Thisshouldconcernnotonlyhigh-riskpatients,butshouldalsobepartofroutinecareinallpatientssinceIEoccurringinpatientswithoutpreviouslyknownheartdiseasenowaccountsforasubstantialandincreasingincidence.Thismeansthatalthoughantibioticprophylaxisshouldberestrictedtothehighest-riskpatients,preventivemeasuresshouldbemaintainedorextendedtoallpatientswithcardiacdisease.AlthoughthissectionoftheguidelinesonIEprophylaxisisbasedonweakevidence,theyhavebeenstrengthenedrecentlybyepidemiologicalsurveys,mostofwhichdidnotshowanincreasedincidenceofIEduetooralstreptococci.33–35Theirapplicationbypatientsshouldfollowashareddecision-makingprocess.Futurechallengesaretogainabetterunderstandingofthemechanismsassociatedwithvalveinfection,theadaptationofprophylaxistotheongoingepidemiologicalchangesandtheperformanceofspecificprospectivesurveysontheincidenceandcharacteristicsofIE.4.The‘EndocarditisTeam’ IEisadiseasethatneedsacollaborativeapproachforthefollowingreasons: hereforethepresenceofanEndocarditisTeamiscrucial.Thismultidisciplinaryapproachhasalreadybeenshowntobeusefulinthemanagementofvalvedisease11(the‘HeartValveClinic’),particularlyintheselectionofpatientsfortranscatheteraorticvalveimplantationprocedures(‘HeartTeam’approach).55InthefieldofIE,theteamapproachadoptedinFrance,includingstandardizedmedicaltherapy,surgicalindicationsfollowingguidelinerecommendationsand1yearofclosefollow-up,hasbeenshowntosignificantlyreducethe1-yearmortality,from18.5%to8.2%.12Otherauthorshaverecentlyreportedsimilarresults.56Takingthesereportstogether,suchateamapproachhasbeenrecommendedrecentlyasclassIBinthe2014AmericanHeartAssociation/AmericanCollegeofCardiologyguidelineforthemanagementofpatientswithvalvularheartdisease.25ThepresentTaskForceonthemanagementofIEoftheESCstronglysupportsthemanagementofpatientswithIEinreferencecentresbyaspecializedteam(the‘EndocarditisTeam’).ThemaincharacteristicsoftheEndocarditisTeamandthereferringindicationsaresummarizedinTables8and9.First,IEisnotasingledisease,butrathermaypresentwithverydifferentaspectsdependingonthefirstorganinvolved,theunderlyingcardiacdisease(ifany),themicroorganisminvolved,thepresenceorabsenceofcomplicationsandthepatient'scharacteristics.8Nosinglepractitionerwillbeabletomanageandtreatapatientinwhomthemainclinicalsymptomsmightbecardiac,rheumatological,infectious,neurologicalorother.Second,averyhighlevelofexpertiseisneededfrompractitionersfromseveralspecialties,includingcardiologists,cardiacsurgeons,IDspecialists,microbiologists,neurologists,neurosurgeons,expertsinCHDandothers.EchocardiographyisknowntohaveamajorimportanceinthediagnosisandmanagementofIE.However,otherimagingtechniques,includingmagneticresonanceimaging(MRI),multislicecomputedtomography(MSCT),andnuclearimaging,havealsobeenshowntobeusefulfordiagnosis,follow-upanddecisionmakinginpatientswithIE.10Includingallofthesespecialistsintheteamisbecomingincreasinglyimportant.Finally,abouthalfofthepatientswithIEundergosurgeryduringthehospitalcourse.54EarlydiscussionwiththesurgicalteamisimportantandisconsideredmandatoryinallcasesofcomplicatedIE[i.e.endocarditiswithheartfailure(HF),abscessorembolicorneurologicalcomplications]. Table8Characteristicsofthe‘EndocarditisTeam’  CHD=Congenitalheartdisease;CT=computedtomography;HF=heartfailure;ID=Infectiousdisease;IE=infectiveendocarditis;MRI=magneticresonanceimaging;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography. Openinnewtab Table8Characteristicsofthe‘EndocarditisTeam’  CHD=Congenitalheartdisease;CT=computedtomography;HF=heartfailure;ID=Infectiousdisease;IE=infectiveendocarditis;MRI=magneticresonanceimaging;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography. Openinnewtab Table9Recommendationsforreferringpatientstothereferencecentre  CHD=congenitalheartdisease;ID=infectiousdisease;IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table9Recommendationsforreferringpatientstothereferencecentre  CHD=congenitalheartdisease;ID=infectiousdisease;IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab 5.Diagnosis 5.1Clinicalfeatures ThediversenatureandevolvingepidemiologicalprofileofIEensurethatitremainsadiagnosticchallenge.TheclinicalhistoryofIEishighlyvariableaccordingtothecausativemicroorganism,thepresenceorabsenceofpre-existingcardiacdisease,thepresenceorabsenceofprostheticvalvesorcardiacdevicesandthemodeofpresentation.ThusIEshouldbesuspectedinavarietyofverydifferentclinicalsituations.Itmaypresentasanacute,rapidlyprogressiveinfection,butalsoasasubacuteorchronicdiseasewithlow-gradefeverandnon-specificsymptomsthatmaymisleadorconfuseinitialassessment.Patientsmaythereforepresenttoavarietyofspecialistswhomayconsiderarangeofalternativediagnoses,includingchronicinfection;rheumatological,neurologicalandautoimmunediseases;ormalignancy.TheearlyinvolvementofacardiologistandanIDspecialisttoguidemanagementishighlyrecommended.Upto90%ofpatientspresentwithfever,oftenassociatedwithsystemicsymptomsofchills,poorappetiteandweightloss.Heartmurmursarefoundinupto85%ofpatients.Upto25%ofpatientshaveemboliccomplicationsatthetimeofdiagnosis.ThereforeIEhastobesuspectedinanypatientpresentingwithfeverandembolicphenomena.ClassicsignsmaystillbeseeninthedevelopingworldinsubacuteformsofIE,althoughperipheralstigmataofIEareincreasinglyuncommonelsewhere,aspatientsgenerallypresentatanearlystageofthedisease.However,vascularandimmunologicalphenomenasuchassplinterhaemorrhages,Rothspotsandglomerulonephritisremaincommon.Embolitothebrain,lungorspleenoccurin30%ofpatientsandareoftenthepresentingfeature.58Inafebrilepatient,diagnosticsuspicionmaybestrengthenedbylaboratorysignsofinfection,suchaselevatedC-reactiveprotein(CRP)orerythrocytesedimentationrate(ESR),leucocytosis,anaemiaandmicroscopichaematuria.However,thesesignslackspecificityandhavenotbeenintegratedintocurrentdiagnosticcriteria.Atypicalpresentationiscommoninelderlyorimmunocompromisedpatients,59inwhomfeverislesscommonthaninyoungerindividuals.Ahighindexofsuspicionandlowthresholdforinvestigationarethereforeessentialintheseandotherhigh-riskgroups,suchasthosewithCHDorprostheticvalves,toexcludeIEoravoiddelaysindiagnosis.5.2Laboratoryfindings Inadditiontospecializedmicrobiologicalandimaginginvestigations,anumberoflaboratoryinvestigationsandbiomarkershavebeenevaluatedinsepsis/sepsissyndromesandendocarditis.Thelargenumberofproposedpotentialbiomarkersreflectsthecomplexpathophysiologyofthediseaseprocess,involvingpro-andanti-inflammatoryprocesses,humoralandcellularreactionsandbothcirculatoryandend-organabnormalities.60However,owingtotheirpoorpositivepredictivevalueforthediagnosisofsepsisandlackofspecificityforendocarditis,thesebiomarkershavebeenexcludedfrombeingmajordiagnosticcriteriaandareonlyusedtofacilitateriskstratification.Sepsisseveritymaybeindicatedbythedemonstrationofanumberoflaboratoryinvestigations,includingthedegreeofleucocytosis/leucopoenia,thenumberofimmaturewhitecellforms,concentrationsofCRPandprocalcitonin,ESRandmarkersofend-organdysfunction(lactataemia,elevatedbilirubin,thrombocytopaeniaandchangesinserumcreatinineconcentration);however,nonearediagnosticforIE.61Further,certainlaboratoryinvestigationsareusedinsurgicalscoringsystemsrelevanttoriskstratificationinpatientswithIE,includingbilirubin,creatinineandplateletcount[SequentialOrganFailureAssessment(SOFA)score]andcreatinineclearance[EuropeanSystemforCardiacOperativeRiskEvaluation(EuroSCORE)II].Finally,thepatternofincreaseininflammatorymediatorsorimmunecomplexesmaysupport,butnotprove,thediagnosisofIE,includingthefindingofhypocomplementaemiainthepresenceofelevatedantineutrophilcytoplasmicantibodyinendocarditis-associatedvasculitisor,whereleadinfectionissuspectedclinically,thelaboratoryfindingofanormalprocalcitoninandwhitecellcountinthepresenceofsignificantlyelevatedCRPand/orESR.625.3Imagingtechniques Imaging,particularlyechocardiography,playsakeyroleinboththediagnosisandmanagementofIE.EchocardiographyisalsousefulfortheprognosticassessmentofpatientswithIE,foritsfollow-upundertherapyandduringandaftersurgery.63EchocardiographyisparticularlyusefulforinitialassessmentoftheembolicriskandindecisionmakinginIE.Transoesophagealechocardiography(TOE)playsamajorrolebothbeforeandduringsurgery(intraoperativeechocardiography).However,theevaluationofpatientswithIEisnolongerlimitedtoconventionalechocardiography,butshouldincludeseveralotherimagingtechniquessuchasMSCT,MRI,18F-fluorodeoxyglucose(FDG)positronemissiontomography(PET)/computedtomography(CT)orotherfunctionalimagingmodalities.105.3.1Echocardiography Echocardiography,eithertransthoracicechocardiography(TTE)orTOE,isthetechniqueofchoiceforthediagnosisofIE,andplaysakeyroleinthemanagementandmonitoringofthesepatients.64,65EchocardiographymustbeperformedassoonasIEissuspected.TOEmustbeperformedincaseofnegativeTTEwhenthereisahighindexofsuspicionforIE,particularlywhenTTEisofsuboptimalquality.TOEshouldalsobeperformedinpatientswithpositiveTTEtoruleoutlocalcomplications.Theindicationsofechocardiographicexaminationfordiagnosisandfollow-upofpatientswithsuspectedIEaresummarizedinTable10andFigure1.InpatientswithS.aureusbacteraemia,echocardiographyisjustifiedinviewofthefrequencyofIEinthissetting,thevirulenceofthisorganismanditsdevastatingeffectsonceintracardiacinfectionisestablished.66,67Inthesepatients,TTEorTOEshouldbeconsideredaccordingtoindividualpatientriskfactorsandthemodeofacquisitionofS.aureusbacteraemia.66,67 Table10Roleofechocardiographyininfectiveendocarditis  HF=heartfailure;IE=infectiveendocarditis;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table10Roleofechocardiographyininfectiveendocarditis  HF=heartfailure;IE=infectiveendocarditis;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Figure1OpeninnewtabDownloadslideIndicationsforechocardiographyinsuspectedinfectiveendocarditis.Figure1OpeninnewtabDownloadslideIndicationsforechocardiographyinsuspectedinfectiveendocarditis.ThreeechocardiographicfindingsaremajorcriteriainthediagnosisofIE:vegetation,abscessorpseudoaneurysmandnewdehiscenceofaprostheticvalve8,64,65(seeTable11foranatomicalandechocardiographicdefinitions).Nowadays,thesensitivityforthediagnosisofvegetationsinnativeandprostheticvalvesis70%and50%,respectively,forTTEand96%and92%,respectively,forTOE.64,65Specificityhasbeenreportedtobearound90%forbothTTEandTOE.Identificationofvegetationsmaybedifficultinthepresenceofpre-existingvalvularlesions(mitralvalveprolapse,degenerativecalcifiedlesions),prostheticvalves,smallvegetations(<2–3mm),recentembolizationandinnon-vegetantIE.DiagnosismaybeparticularlychallenginginIEaffectingintracardiacdevices,evenwiththeuseofTOE. Table11Anatomicalandechocardiographicdefinitions  TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography. Openinnewtab Table11Anatomicalandechocardiographicdefinitions  TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography. Openinnewtab FalsediagnosisofIEmayoccur,andinsomeinstancesitmaybedifficulttodifferentiatevegetationsfromthrombi,Lambl'sexcrescences,cuspprolapse,chordalrupture,valvefibroelastoma,degenerativeormyxomatousvalvedisease,strands,systemiclupus(Libman–Sacks)lesions,primaryantiphospholipidsyndrome,rheumatoidlesionsormaranticvegetations.74Thereforetheresultsoftheechocardiographicstudymustbeinterpretedwithcaution,takingintoaccountthepatient'sclinicalpresentationandthelikelihoodofIE.ThesensitivityofTTEforthediagnosisofabscessesisabout50%,comparedwith90%forTOE.Specificityhigherthan90%hasbeenreportedforbothTTEandTOE.64,65Smallabscessesmaybedifficulttoidentify,particularlyintheearlieststageofthedisease,inthepostoperativeperiodandinthepresenceofaprostheticvalve.IEmustalwaysbesuspectedinpatientswithnewperiprostheticregurgitation,evenintheabsenceofotherechocardiographicfindingsofIE.64Incaseswithaninitiallynegativeexamination,repeatTTE/TOEmustbeperformed5–7dayslateriftheclinicallevelofsuspicionisstillhigh,orevenearlierinthecaseofS.aureusinfection.75Otherimagingtechniquesshouldalsobeusedinthissituation(seesection5.5).Finally,follow-upechocardiographytomonitorcomplicationsandresponsetotreatmentismandatory(Figure1).Real-timethree-dimensional(3D)TOEallowstheanalysisof3Dvolumesofcardiacstructuresinanypossibleplane.ArecentstudyhasshownthatconventionalTOEunderestimatesvegetationsizeandthat3DTOEisafeasibletechniquefortheanalysisofvegetationmorphologyandsizethatmayovercometheshortcomingsofconventionalTOE,leadingtoabetterpredictionoftheembolicriskinIE.763DTOEisparticularlyusefulintheassessmentofperivalvularextensionoftheinfection,prostheticvalvedehiscenceandvalveperforation.77Althoughinclinicalpractice3DTOEisincreasinglyperformedalongwithconventionalTOEinmanycentres,atpresent3DTOEshouldstillberegardedasasupplementtostandardechocardiographyinmostcases.5.3.2Multislicecomputedtomography Thepotentialrisksofvegetationembolizationand/orhaemodynamicdecompensationduringcoronaryangiography(whenindicated)haveledtoproposalstoconsiderMSCTcoronaryangiographyasanalternativetechniqueforsomepatientswithendocarditis.78MSCTcanbeusedtodetectabscesses/pseudoaneurysmswithadiagnosticaccuracysimilartoTOE,andispossiblysuperiorintheprovisionofinformationregardingtheextentandconsequencesofanyperivalvularextension,includingtheanatomyofpseudoaneurysms,abscessesandfistulae.79InaorticIE,CTmayadditionallybeusefultodefinethesize,anatomyandcalcificationoftheaorticvalve,rootandascendingaorta,whichmaybeusedtoinformsurgicalplanning.Inpulmonary/right-sidedendocarditis,CTmayrevealconcomitantpulmonarydisease,includingabscessesandinfarcts.Intheevaluationofprostheticvalvedysfunction,onerecentstudyhassuggestedthatMSCTmaybeequivalentorsuperiortoechocardiographyforthedemonstrationofprostheses-relatedvegetations,abscesses,pseudoaneurysmsanddehiscence.80However,largecomparativestudiesbetweenthetwotechniquesaremissing,andechocardiographyshouldalwaysbeperformedfirst.ThehighersensitivityofMRIcomparedwithCTforthedetectionofcerebrallesionsiswellknownandhasbeenconfirmedinthecontextofendocarditis.However,inthecriticallyillpatient,CTmaybemorefeasibleandpracticalandisanacceptablealternativewhenMRIisnotavailable.MSCTangiographyallowscompletevisualizationoftheintracranialvasculartreeandcarriesalowercontrastburdenandriskofpermanentneurologicaldamagethanconventionaldigitalsubtractionangiography,withasensitivityof90%andspecificityof86%.81Wheresubarachnoidand/orintraparenchymalhaemorrhageisdetected,othervascularimaging(i.e.angiography)isrequiredtodiagnoseorexcludeamycoticaneurysmifnotdetectedonCT.Contrast-enhancedMSCThasahighsensitivityandspecificityforthediagnosisofsplenicandotherabscesses;however,thedifferentiationwithinfarctioncanbechallenging.MSCTangiographyprovidesarapidandcomprehensiveexplorationofthesystemicarterialbed.Detailedmultiplanarand3Dcontrast-enhancedangiographicreconstructionsallowvascularmappingwithidentificationandcharacterizationofperipheralvascularcomplicationsofIEandtheirfollow-up.825.3.3Magneticresonanceimaging GivenitshighersensitivitythanCT,MRIincreasesthelikelihoodofdetectingcerebralconsequencesofIE.DifferentstudiesincludingsystematiccerebralMRIduringacuteIEhaveconsistentlyreportedfrequentlesions,in60–80%ofpatients.83Regardlessofneurologicalsymptoms,mostabnormalitiesareischaemiclesions(in50–80%ofpatients),withmorefrequentsmallischaemiclesionsthanlargerterritorialinfarcts.84Otherlesionsarefoundin<10%ofpatientsandareparenchymalorsubarachnoidalhaemorrhages,abscessesormycoticaneurysms.83–86SystematiccerebralMRIhasanimpactonthediagnosisofIEsinceitaddsoneminorDukecriterion87inpatientswhohavecerebrallesionsandnoneurologicalsymptoms.Inonestudy,findingsofcerebralMRIupgradedthediagnosisofIEin25%ofpatientspresentinginitiallywithnon-definiteIE,therebyleadingtoearlierdiagnosis.85CerebralmicrobleedsaredetectedonlywhenusinggradientechoT2*sequencesandarefoundin50–60%ofpatients.85Microbleedsrepresentsmallareasofhaemosiderindepositsandareconsideredasanindicatorofsmallvesseldisease.Thelackofconcordancebetweenischaemiclesionsandmicrobleedsandthedifferencesintheirpredictivefactorssuggestthatmicrobleedsarenotofembolicorigin.86,88Therefore,althoughIEandthepresenceofmicrobleedsarestronglylinked,microbleedsshouldnotbeconsideredasaminorcriterionintheDukeclassification.87CerebralMRIis,inthemajorityofcases,abnormalinIEpatientswithneurologicalsymptoms.89IthasahighersensitivitythanCTinthediagnosisoftheculpritlesion,inparticularwithregardstostroke,transientischaemicattackandencephalopathy.MRImayalsodetectadditionalcerebrallesionsthatarenotrelatedtoclinicalsymptoms.CerebralMRIhasnoimpactonthediagnosisofIEinpatientswithneurologicalsymptoms,astheyalreadyhaveoneminorDukecriterion,butMRImayimpactthetherapeuticstrategy,particularlythetimingofsurgery.89Inpatientswithoutneurologicalsymptoms,MRIshowscerebrallesionsinatleasthalfofthepatients,mostoftenischaemiclesions.90SystematicabdominalMRIdetectslesionsinoneofthreepatientsevaluated,mostoftenaffectingthespleen.91Ischaemiclesionsaremostcommon,followedbyabscessesandhaemorrhagiclesions.AbdominalMRIfindingshavenoincrementalimpactonthediagnosisofIEwhentakingintoaccountthefindingsofcerebralMRI.Tosummarize,cerebralMRIallowsforabetterlesioncharacterizationinpatientswithIEandneurologicalsymptoms,whereasitsimpactonIEdiagnosisismarkedinpatientswithnon-definiteIEandwithoutneurologicalsymptoms.5.3.4Nuclearimaging Withtheintroductionofhybridequipmentforbothconventionalnuclearmedicine[e.g.single-photonemissionCT(SPECT)/CT]andPET(i.e.PET/CT),nuclearmoleculartechniquesareevolvingasanimportantsupplementarymethodforpatientswithsuspectedIEanddiagnosticdifficulties.SPECT/CTimagingreliesontheuseofautologousradiolabelledleucocytes(111In-oxineor99mTc-hexamethylpropyleneamineoxime)thataccumulateinatime-dependentfashioninlateimagesversusearlierimages,92whereasPET/CTisgenerallyperformedusingasingleacquisitiontimepoint(generallyat1h)afteradministrationof18F-FDG,whichisactivelyincorporatedinvivobyactivatedleucocytes,monocyte-macrophagesandCD4+T-lymphocytesaccumulatingatthesitesofinfection.Severalreportshaveshownpromisingresultsforradiolabelledwhitebloodcell(WBC)SPECT/CTand18F-FDGPET/CTimaginginIE.ThemainaddedvalueofusingthesetechniquesisthereductionintherateofmisdiagnosedIE,classifiedinthe‘PossibleIE’categoryusingtheDukecriteria,andthedetectionofperipheralembolicandmetastaticinfectiousevents.93Limitationstotheuseof18F-FDGPET/CTarerepresentedbylocalizationofsepticemboliinthebrain,duetothehighphysiologicaluptakeofthistracerinthebraincortex,andtothefactthatatthissite,metastaticinfectionsaregenerally<5mm,thespatialresolutionthresholdofcurrentPET/CTscanners.Cautionmustbeexercisedwheninterpreting18F-FDGPET/CTresultsinpatientswhohaverecentlyundergonecardiacsurgery,asapostoperativeinflammatoryresponsemayresultinnon-specific18F-FDGuptakeintheimmediatepostoperativeperiod.Furthermore,anumberofpathologicalconditionscanmimicthepatternoffocallyincreased18F-FDGuptakethatistypicallyobservedinIE,suchasactivethrombi,softatheroscleroticplaques,vasculitis,primarycardiactumours,cardiacmetastasisfromanon-cardiactumour,post-surgicalinflammationandforeignbodyreactions.94RadiolabelledWBCSPECT/CTismorespecificforthedetectionofIEandinfectiousfocithan18F-FDGPET/CTandshouldbepreferredinallsituationsthatrequireenhancedspecificity.95DisadvantagesofscintigraphywithradiolabelledWBCaretherequirementofbloodhandlingforradiopharmaceuticalpreparation,thedurationoftheprocedure,whichismoretimeconsumingthanPET/CT,andaslightlylowerspatialresolutionandphotondetectionefficiencycomparedwithPET/CT.Anadditionalpromisingroleof18F-FDGPET/CTmaybeseeninpatientswithestablishedIE,inwhomitcouldbeemployedtomonitorresponsetoantimicrobialtreatment.However,sufficientdataarenotavailableatthistimetomakeageneralrecommendation.5.4Microbiologicaldiagnosis 5.4.1Bloodculture–positiveinfectiveendocarditis Positivebloodculturesremainthecornerstoneofdiagnosisandprovidelivebacteriaforbothidentificationandsusceptibilitytesting.Atleastthreesetsaretakenat30-minintervals,eachcontaining10mLofblood,andshouldbeincubatedinbothaerobicandanaerobicatmospheres.Samplingshouldbeobtainedfromaperipheralveinratherthanfromacentralvenouscatheter(becauseoftheriskofcontaminationandmisleadinginterpretation),usingameticuloussteriletechnique.Thisisvirtuallyalwayssufficienttoidentifytheusualcausativemicroorganisms.Theneedforculturebeforeantibioticadministrationisself-evident.InIE,bacteraemiaisalmostconstantandhastwoimplications:(i)thereisnorationalefordelayingbloodsamplingwithpeaksoffeverand(ii)virtuallyallbloodculturesarepositive.Asaresult,asinglepositivebloodcultureshouldberegardedcautiouslyforestablishingthediagnosisofIE.ThemicrobiologylaboratoryshouldbeawareoftheclinicalsuspicionofIEatthetimeofbloodculturesampling.Whenamicroorganismhasbeenidentified,bloodculturesshouldberepeatedafter48–72htochecktheeffectivenessoftreatment.Automatedmachinesperformcontinuousmonitoringofbacterialgrowth,whichensuresquickprovisionofreportstophysicians.Whenapositivebloodculturebottleisidentified,presumptiveidentificationisbasedonGramstaining.Thisinformationisimmediatelygiventocliniciansinordertoadaptpresumptiveantibiotictherapy.Completeidentificationisroutinelyachievedwithin2days,butmayrequirelongerforfastidiousoratypicalorganisms.Sincethedelaybetweenbloodculturesamplinganddefinitiveidentificationoftheorganismresponsibleforthebacteraemiaandantibioticsusceptibilitytestingislong,manyimprovementshavebeenproposedtospeeduptheprocessofdetectionandidentification.Oneofthemostrecentproceduresforrapidbacterialidentificationisbasedonpeptidespectraobtainedbymatrix-assistedlaserdesorptionionizationtime-of-flightmassspectrometry.Thistechniquehasrecentlydemonstrateditsusefulnessinclinicalmicrobiology;italsohasthepotentialfordirectidentificationofbacterialcoloniesinthebloodculturebottlesupernatant.965.4.2Bloodculture–negativeinfectiveendocarditis Bloodculture–negativeIE(BCNIE)referstoIEinwhichnocausativemicroorganismcanbegrownusingtheusualbloodculturemethods.BCNIEcanoccurinupto31%ofallcasesofIEandoftenposesconsiderablediagnosticandtherapeuticdilemmas.BCNIEmostcommonlyarisesasaconsequenceofpreviousantibioticadministration,underlyingtheneedforwithdrawingantibioticsandrepeatingbloodculturesinthissituation.BCNIEcanbecausedbyfungiorfastidiousbacteria,notablyobligatoryintracellularbacteria.Isolationofthesemicroorganismsrequiresculturingthemonspecializedmedia,andtheirgrowthisrelativelyslow.Accordingtolocalepidemiology,systematicserologicaltestingforCoxiellaburnetii,Bartonellaspp.,Aspergillusspp.,Mycoplasmapneumonia,Brucellaspp.andLegionellapneumophilashouldbeproposed,followedbyspecificpolymerasechainreaction(PCR)assaysforTropherymawhipplei,Bartonellaspp.andfungi(Candidaspp.,Aspergillusspp.)fromtheblood97(Table12).MoststudiesusingbloodPCRforthediagnosisofBCNIEhavehighlightedtheimportanceofStreptococcusgallolyticusandStreptococcusmitis,enterococci,S.aureus,Escherichiacoliandfastidiousbacteria,therespectiveprevalenceofwhichvariesaccordingtothestatusandconditionofthepatient.98 Table12Investigationofrarecausesofbloodculturenegativeinfectiveendocarditis  Ig=immunoglobulin;PCR=polymerasechainreaction. Openinnewtab Table12Investigationofrarecausesofbloodculturenegativeinfectiveendocarditis  Ig=immunoglobulin;PCR=polymerasechainreaction. Openinnewtab Whenallmicrobiologicalassaysarenegative,thediagnosisofnon-infectiousendocarditisshouldsystematicallybeconsideredandassaysforantinuclearantibodiesaswellasantiphospholipidsyndrome{anticardiolipinantibodies[immunoglobulin(Ig)G]andanti-β2-glycoprotein1antibodies[IgGandIgM]}shouldbeperformed.Whenallothertestsarenegativeandthepatienthasaporcinebioprosthesistogetherwithmarkersofallergicresponse,anti-porkantibodiesshouldbesought.995.4.3Histologicaldiagnosisofinfectiveendocarditis PathologicalexaminationofresectedvalvulartissueorembolicfragmentsremainsthegoldstandardforthediagnosisofIE.Alltissuesamplesthatareexcisedduringthecourseofthesurgicalremovalofcardiacvalvesmustbecollectedinasterilecontainerwithoutfixativeorculturemedium.Theentiresampleshouldbetakentothediagnosticmicrobiologylaboratoryforoptimalrecoveryandidentificationofmicroorganisms.5.4.4ProposedstrategyforamicrobiologicaldiagnosticalgorithminsuspectedIE AproposeddiagnosticschemeisprovidedinFigure2.WhenthereisclinicalsuspicionofIEandbloodculturesremainnegativeat48h,liaisonwiththemicrobiologistisnecessary.AsuggestedstrategyistheuseofadiagnostickitincludingbloodculturesandsystematicserologicaltestingforC.burnetii,Bartonellaspp.,Aspergillusspp.,L.pneumophila,Brucellaspp.,M.pneumonia,aswellasrheumatoidfactor,theserologicaltestsforantiphospholipidsyndrome[anticardiolipin(IgG)andanti-β2-glycoprotein1(IgGandIgM)],antinuclearantibodiesandanti-porkantibodies.Inaddition,cardiacvalvularmaterialsobtainedatsurgeryhavetobesubjectedtosystematicculture,histologicalexaminationandPCRaimedatdocumentingthepresenceoffastidiousorganisms. Figure2OpeninnewtabDownloadslideMicrobiologicaldiagnosticalgorithminculture-positiveandculture-negativeIE.Figure2OpeninnewtabDownloadslideMicrobiologicaldiagnosticalgorithminculture-positiveandculture-negativeIE.5.5Diagnosticcriteria Besidesthepathologicalaspectobtainedaftervalvesurgery,inclinicalpracticethediagnosisofIEusuallyreliesontheassociationbetweenaninfectivesyndromeandrecentendocardialinvolvement.Thisisthecornerstoneofthevariouscriteriaproposedtofacilitatethedifficultdiagnosisofthisdisease.Thus,in2000,themodifiedDukecriteriawererecommendedfordiagnosticclassification(Table13).Thesecriteriaarebasedonclinical,echocardiographicandbiologicalfindings,aswellastheresultsofbloodculturesandserologies.87Thisclassificationhasasensitivityofapproximately80%overallwhenthecriteriaareevaluatedattheendofpatientfollow-upinepidemiologicalstudies.100However,themodifiedDukecriteriashowalowerdiagnosticaccuracyforearlydiagnosisinclinicalpractice,especiallyinthecaseofprostheticvalveendocarditis(PVE)andpacemakerordefibrillatorleadIE,forwhichechocardiographyisnormalorinconclusiveinupto30%ofcases.101,102RecentadvancesinimagingtechniqueshaveresultedinanimprovementinidentificationofendocardialinvolvementsandextracardiaccomplicationsofIE.10,103Thusrecentworkshavedemonstratedthatcardiac/whole-bodyCTscan,cerebralMRI,18F-FDGPET/CTandradiolabelledleucocyteSPECT/CTmightimprovethedetectionofsilentvascularphenomena(emboliceventsorinfectiousaneurysms)aswellasendocardiallesions.79,80,83–85,93,94,104–108TheadditionoftheresultsoftheseimagingmodalitiesmayimprovethesensitivityofthemodifiedDukecriteriaindifficultcases. Table13DefinitionofinfectiveendocarditisaccordingtothemodifiedDukecriteria(adaptedfromLietal.87)   Openinnewtab Table13DefinitionofinfectiveendocarditisaccordingtothemodifiedDukecriteria(adaptedfromLietal.87)   Openinnewtab Giventherecentpublisheddata,theTaskForceproposestheadditionofthreefurtherpointsinthediagnosticcriteria(Table14):Figure3presentstheproposedESCdiagnosticalgorithmincludingtheESC2015modifieddiagnosticcriteria.ThediagnosisofIEisstillbasedontheDukecriteria,withamajorroleofechocardiographyandbloodcultures.Whenthediagnosisremainsonly‘possible’oreven‘rejected’butwithapersistinghighlevelofclinicalsuspicion,echocardiographyandbloodcultureshouldberepeatedandotherimagingtechniquesshouldbeused,eitherfordiagnosisofcardiacinvolvement(cardiacCT,18F-FDGPET/CTorradiolabelledleucocyteSPECT/CT)orforimagingembolicevents(cerebralMRI,whole-bodyCTand/orPET/CT).TheresultsofthesenewinvestigationsshouldthenbeintegratedintheESC2015modifieddiagnosticcriteria.TheidentificationofparavalvularlesionsbycardiacCTshouldbeconsideredamajorcriterion.Inthesettingofthesuspicionofendocarditisonaprostheticvalve,abnormalactivityaroundthesiteofimplantationdetectedby18F-FDGPET/CT(onlyiftheprosthesiswasimplantedfor>3months)orradiolabelledleucocyteSPECT/CTshouldbeconsideredamajorcriterion.Theidentificationofrecentemboliceventsorinfectiousaneurysmsbyimagingonly(silentevents)shouldbeconsideredaminorcriterion. Table14DefinitionsofthetermsusedintheEuropeanSocietyofCardiology2015modifiedcriteriaforthediagnosisofinfectiveendocarditis  CT=computedtomography;FDG=fluorodeoxyglucose;HACEK=Haemophilusparainfluenzae,H.aphrophilus,H.paraphrophilus,H.influenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,Kingellakingae,andK.denitrificans;IE=infectiveendocarditis;Ig=immunoglobulin;PET=positronemissiontomography;SPECT=singlephotonemissioncomputerizedtomography.AdaptedfromLietal.87 Openinnewtab Table14DefinitionsofthetermsusedintheEuropeanSocietyofCardiology2015modifiedcriteriaforthediagnosisofinfectiveendocarditis  CT=computedtomography;FDG=fluorodeoxyglucose;HACEK=Haemophilusparainfluenzae,H.aphrophilus,H.paraphrophilus,H.influenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,Kingellakingae,andK.denitrificans;IE=infectiveendocarditis;Ig=immunoglobulin;PET=positronemissiontomography;SPECT=singlephotonemissioncomputerizedtomography.AdaptedfromLietal.87 Openinnewtab Figure3OpeninnewtabDownloadslideEuropeanSocietyofCardiology2015algorithmfordiagnosisofinfectiveendocarditis.Figure3OpeninnewtabDownloadslideEuropeanSocietyofCardiology2015algorithmfordiagnosisofinfectiveendocarditis.Finally,18F-FDGPET/CTandradiolabelledleucocyteSPECT/CThaveproventheirroleinthediagnosisofcardiovascularelectronicimplanteddevices,108butthedataarenotsufficientforthemtobeincludedinthediagnosticcriteriaofthespecifictopicofIEonpacemakerordefibrillatorleads.Insummary,echocardiography(TTEandTOE),positivebloodculturesandclinicalfeaturesremainthecornerstoneofIEdiagnosis.Whenbloodculturesarenegative,furthermicrobiologicalstudiesareneeded.ThesensitivityoftheDukecriteriacanbeimprovedbynewimagingmodalities(MRI,CT,PET/CT)thatallowthediagnosisofemboliceventsandcardiacinvolvementwhenTTE/TOEfindingsarenegativeordoubtful.Thesecriteriaareuseful,buttheydonotreplacetheclinicaljudgementoftheEndocarditisTeam.6.Prognosticassessmentatadmission Thein-hospitalmortalityrateofpatientswithIEvariesfrom15%to30%.109–114Rapididentificationofpatientsathighestriskofdeathmayoffertheopportunitytochangethecourseofthedisease(i.e.emergencyorurgentsurgery)andimproveprognosis.115PrognosisinIEisinfluencedbyfourmainfactors:patientcharacteristics,thepresenceorabsenceofcardiacandnon-cardiaccomplications,theinfectingorganismandtheechocardiographicfindings(Table15).Theriskofpatientswithleft-sidedIEhasbeenformallyassessedaccordingtothesevariables.116,117PatientswithHF,periannularcomplicationsand/orS.aureusinfectionareathighestriskofdeathandneedforsurgeryintheactivephaseofthedisease.117Whenthreeofthesefactorsarepresent,theriskreaches79%.117ThereforethesepatientswithcomplicatedIEshouldbereferredearlyandmanagedinareferencecentrewithsurgicalfacilitiesandpreferablybyanEndocarditisTeam.118Ahighdegreeofco-morbidity,diabetes,septicshock,moderate-to-severeischaemicstroke,brainhaemorrhageortheneedforhaemodialysisarealsopredictorsofpoorin-hospitaloutcome.111–115,119–122Persistenceofpositivebloodcultures48–72hafterinitiationofantibiotictreatmentindicatesalackofinfectioncontrolandisanindependentriskfactorforin-hospitalmortality.123 Table15Predictorsofpooroutcomeinpatientswithinfectiveendocarditis  HACEK=Haemophilusparainfluenzae,H.aphrophilus,H.paraphrophilus,H.influenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,Kingellakingae,andK.denitrificans;IE=infectiveendocarditis. Openinnewtab Table15Predictorsofpooroutcomeinpatientswithinfectiveendocarditis  HACEK=Haemophilusparainfluenzae,H.aphrophilus,H.paraphrophilus,H.influenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,Kingellakingae,andK.denitrificans;IE=infectiveendocarditis. Openinnewtab Nowadays,40–50%ofpatientsundergocardiacsurgeryduringhospitalization.37,109–114SurgicalmortalityinIEstronglydependsonitsindication.Amongpatientswhoneedemergencyorurgentsurgery,septicshock,persistentsignsofinfectionandrenalfailurearepredictorsofmortality.112,120,124Predictably,patientswithanindicationforsurgerywhocannotproceedduetoprohibitivesurgicalriskhavetheworstprognosis.125Insummary,prognosticassessmentatadmissioncanbeperformedusingsimpleclinical,microbiologicalandechocardiographicparametersandshouldbeusedtoselectthebestinitialapproach.Patientswithpersistentlypositivebloodcultures48–72hafterstartingantibioticshaveaworseprognosis.7.Antimicrobialtherapy:principlesandmethods 7.1Generalprinciples SuccessfultreatmentofIEreliesonmicrobialeradicationbyantimicrobialdrugs.Surgerycontributesbyremovinginfectedmaterialanddrainingabscesses.Hostdefencesareoflittlehelp.Thisexplainswhybactericidalregimensaremoreeffectivethanbacteriostatictherapy,bothinanimalexperimentsandinhumans.126,127Aminoglycosidessynergizewithcell-wallinhibitors(i.e.beta-lactamsandglycopeptides)forbactericidalactivityandareusefulforshorteningthedurationoftherapy(e.g.oralstreptococci)anderadicatingproblematicorganisms(e.g.Enterococcusspp.).Onemajorhindrancetodrug-inducedkillingisbacterialantibiotictolerance.Tolerantmicrobesarenotresistant(i.e.theyarestillsusceptibletogrowthinhibitionbythedrug)butescapedrug-inducedkillingandmayresumegrowthaftertreatmentdiscontinuation.Slow-growinganddormantmicrobesdisplayphenotypictolerancetowardsmostantimicrobials(exceptrifampintosomeextent).Theyarepresentinvegetationsandbiofilms(e.g.inPVE)andjustifytheneedforprolongedtherapy(6weeks)tofullysterilizeinfectedheartvalves.Somebacteriacarrymutationsrenderingthemtolerantduringbothactivegrowthandstationary(dormant)phases.Bactericidaldrugcombinationsarepreferredtomonotherapyagainsttolerantorganisms.DrugtreatmentofPVEshouldlastlonger(atleast6weeks)thanthatofnativevalveendocarditis(NVE)(2–6weeks),butisotherwisesimilar,exceptforstaphylococcalPVE,wheretheregimenshouldincluderifampinwheneverthestrainissusceptible.InNVEneedingvalvereplacementbyaprosthesisduringantibiotictherapy,thepostoperativeantibioticregimenshouldbethatrecommendedforNVE,notforPVE.InbothNVEandPVE,thedurationoftreatmentisbasedonthefirstdayofeffectiveantibiotictherapy(negativebloodcultureinthecaseofinitialpositivebloodculture),notonthedayofsurgery.Anewfullcourseoftreatmentshouldonlystartifvalveculturesarepositive,withthechoiceofantibioticbeingbasedonthesusceptibilityofthelatestrecoveredbacterialisolate.Finally,therearesiximportantconsiderationsinthecurrentrecommendations:Theindicationsandpatternofuseofaminoglycosideshavechanged.TheyarenolongerrecommendedinstaphylococcalNVEbecausetheirclinicalbenefitshavenotbeendemonstrated,buttheycanincreaserenaltoxicity;128whentheyareindicatedinotherconditions,aminoglycosidesshouldbegiveninasingledailydosetoreducenephrotoxicity.129RifampinshouldbeusedonlyinforeignbodyinfectionssuchasPVEafter3–5daysofeffectiveantibiotictherapy,oncethebacteraemiahasbeencleared.Therationalesupportingthisrecommendationisbasedonthelikelyantagonisticeffectoftheantibioticcombinationswithrifampinagainstplanktonic/replicatingbacteria,130thesynergyseenagainstdormantbacteriawithinthebiofilmsandpreventionofrifampin-resistantvariants.131Daptomycinandfosfomycinhavebeenrecommendedfortreatingstaphylococcalendocarditisandnetilmicinfortreatingpenicillin-susceptibleoralanddigestivestreptococci,buttheyareconsideredalternativetherapiesintheseguidelinesbecausetheyarenotavailableinallEuropeancountries.Whendaptomycinisindicated,itmustbegivenathighdoses(≥10mg/kgoncedaily132)andcombinedwithasecondantibiotictoincreaseactivityandavoidthedevelopmentofresistance.133,134Onlypublishedantibioticefficacydatafromclinicaltrialsandcohortstudiesinpatientswithendocarditis(orbacteraemiaiftherearenoendocarditisdata)havebeenconsideredintheseguidelines.Datafromexperimentalendocarditismodelshavenotbeentakenintoaccountinmostcases.WearestillusingtheClinicalandLaboratoryStandardsInstituteminimuminhibitoryconcentration(MIC)breakpointsinsteadoftheEuropeanCommitteeonAntimicrobialSusceptibilityTestingonesbecausemostendocarditisdataarederivedfromstudiesusingtheformerbreakpoints.Althoughaconsensuswasobtainedforthemajorityofantibiotictreatments,theoptimaltreatmentofstaphylococcalIEandtheempiricaltreatmentarestilldebated.7.2Penicillin-susceptibleoralstreptococciandStreptococcusbovisgroup Recommendedregimensagainstsusceptiblestreptococci(penicillinMIC≤0.125mg/L)aresummarizedinTable16.6,8,135,136Thecurerateisexpectedtobe>95%.Inuncomplicatedcases,short-term2-weektherapycanbeadministeredbycombiningpenicillinorceftriaxonewithgentamicinornetilmicin.137,138GentamicinandnetilmicincanbegivenoncedailyinpatientswithIEduetosusceptiblestreptococciandnormalrenalfunction.Ceftriaxonealoneorcombinedwithgentamicinornetilmicingivenonceadayisparticularlyconvenientforoutpatienttherapy.137–139Ifdesensitizationcannotbeperformed,patientsallergictobeta-lactamshouldreceivevancomycin.Teicoplaninhasbeenproposedasanalternative,8butrequiresloadingdoses(6mg/kg/12hfor3days)followedby6–10mg/kg/day.Loadingiscriticalbecausethedrugishighlybound(≥98%)toserumproteinsandpenetratesslowlyintovegetations.140However,onlylimitedretrospectivestudieshaveassesseditsefficacyinstreptococcal141andenterococcal142IE. Table16AntibiotictreatmentofinfectiveendocarditisduetooralstreptococciandStreptococcusbovisgroupa  Cmin=minimumconcentration;IE=infectiveendocarditis;i.m.=intramuscular;i.v.=intravenous;MIC=minimuminhibitoryconcentration;NVE=nativevalveendocarditis;PVE=prostheticvalveendocarditis;U=units.aRefertotextforotherstreptococcalspecies;bClassofrecommendation;cLevelofevidence;dReference(s)supportingrecommendations;eOrampicillin,samedosagesasamoxicillin;fPreferredforoutpatienttherapy;gPaediatricdosesshouldnotexceedadultdoses;hRenalfunctionandserumgentamicinconcentrationsshouldbemonitoredonceaweek.Whengiveninasingledailydose,pre-dose(trough)concentrationsshouldbe<1mg/Landpost-dose(peak;1hoursafterinjection)serumconcentrationsshouldbe∼10–12mg/L.148;iPenicillindesensitizationcanbeattemptedinstablepatients;jSerumvancomycinconcentrationsshouldachieve10–15mg/Latpre-dose(trough)level,althoughsomeexpertsrecommendtoincreasethedoseofvancomycinto45–60mg/kg/dayi.v.in2or3divideddosestoreachserumtroughvancomycinlevels(Cmin)of15–20mg/Lasinstaphylococcalendocarditis.However,vancomycindoseshouldnotexceed2g/dunlessserumlevelsaremonitoredandcanbeadjustedtoobtainapeakplasmaconcentrationof30–45μg/mL1houraftercompletionofthei.v.infusionoftheantibiotic;kPatientswithpenicillin-resistantstrains(MIC>2mg/L)shouldbetreatedasenterococcalendocarditis(seeTable18). Openinnewtab Table16AntibiotictreatmentofinfectiveendocarditisduetooralstreptococciandStreptococcusbovisgroupa  Cmin=minimumconcentration;IE=infectiveendocarditis;i.m.=intramuscular;i.v.=intravenous;MIC=minimuminhibitoryconcentration;NVE=nativevalveendocarditis;PVE=prostheticvalveendocarditis;U=units.aRefertotextforotherstreptococcalspecies;bClassofrecommendation;cLevelofevidence;dReference(s)supportingrecommendations;eOrampicillin,samedosagesasamoxicillin;fPreferredforoutpatienttherapy;gPaediatricdosesshouldnotexceedadultdoses;hRenalfunctionandserumgentamicinconcentrationsshouldbemonitoredonceaweek.Whengiveninasingledailydose,pre-dose(trough)concentrationsshouldbe<1mg/Landpost-dose(peak;1hoursafterinjection)serumconcentrationsshouldbe∼10–12mg/L.148;iPenicillindesensitizationcanbeattemptedinstablepatients;jSerumvancomycinconcentrationsshouldachieve10–15mg/Latpre-dose(trough)level,althoughsomeexpertsrecommendtoincreasethedoseofvancomycinto45–60mg/kg/dayi.v.in2or3divideddosestoreachserumtroughvancomycinlevels(Cmin)of15–20mg/Lasinstaphylococcalendocarditis.However,vancomycindoseshouldnotexceed2g/dunlessserumlevelsaremonitoredandcanbeadjustedtoobtainapeakplasmaconcentrationof30–45μg/mL1houraftercompletionofthei.v.infusionoftheantibiotic;kPatientswithpenicillin-resistantstrains(MIC>2mg/L)shouldbetreatedasenterococcalendocarditis(seeTable18). Openinnewtab 7.3Penicillin-resistantoralstreptococciandStreptococcusbovisgroup Penicillin-resistantoralstreptococciareclassifiedasintermediateresistant(MIC0.25–2mg/L)andfullyresistant(MIC≥4mg/L).However,someguidelinesconsideranMIC>0.5mg/Lasfullyresistant.6,8,135Suchresistantstreptococciareincreasinginnumber.Largestraincollectionshavereported>30%ofintermediate-andfullyresistantStreptococcusmitisandStreptococcusoralis.142,143Conversely,>99%ofdigestivestreptococciremainpenicillinsusceptible.Treatmentguidelinesforpenicillin-resistantstreptococcalIErelyonretrospectivesseries.Compilingfourofthem,47of60patients(78%)weretreatedwithpenicillinorceftriaxone,mostlycombinedwithaminoglycosides,andsomewitheitherclindamycinoraminoglycosidesalone.144–147MostpenicillinMICswere≥1mg/L.Fiftypatients(83%)werecuredand10(17%)died.Deathwasnotrelatedtoresistance,buttothepatients'underlyingconditions.146TreatmentoutcomesweresimilarinPVEandNVE.145Henceantibiotictherapyforpenicillin-resistantandpenicillin-susceptibleoralstreptococciisqualitativelysimilar(Table16).However,inpenicillin-resistantcases,aminoglycosidetreatmentmustbegivenforatleast2weeksandshort-termtherapyregimensarenotrecommended.Littleexperienceexistswithhighlyresistantisolates(MIC≥4mg/L),butvancomycinmightbepreferredinsuchcircumstances(combinedwithaminoglycosides).Thereisverylimitedexperiencewithdaptomycin.7.4Streptococcuspneumoniae,beta-haemolyticstreptococci(groupsA,B,C,andG) IEduetoS.pneumoniaehasbecomeraresincetheintroductionofantibiotics.Itisassociatedwithmeningitisinupto30%ofcases,149whichrequiresspecialconsiderationincaseswithpenicillinresistance.Treatmentofpenicillin-susceptiblestrains(MIC≤0.06mg/L)issimilartothatoforalstreptococci(Table16),exceptfortheuseofshort-term2-weektherapy,whichhasnotbeenformallyinvestigated.Thesameholdstrueforpenicillinintermediate(MIC0.125–2mg/L)orresistantstrains(MIC≥4mg/L)withoutmeningitis,althoughforresistantstrainssomeauthorsrecommendhighdosesofcephalosporins(e.g.cefotaximeorceftriaxone)orvancomycin.Incaseswithmeningitis,penicillinmustbeavoidedbecauseofitspoorpenetrationofthecerebrospinalfluid,andshouldbereplacedwithceftriaxoneorcefotaximealoneorinassociationwithvancomycin150accordingtotheantibioticsusceptibilitypattern.IEduetogroupA,B,C,orGstreptococci—includingStreptococcusanginosusgroup(S.constellatus,S.anginosus,andS.intermedius)—isrelativelyrare.151GroupAstreptococciareuniformlysusceptibletobeta-lactams(MIC≤0.12mg/L),whereasotherserogroupsmaydisplaysomedegreeofresistance.IEduetogroupBstreptococciwasonceassociatedwiththeperipartumperiod,butitnowoccursinotheradults,especiallytheelderly.GroupB,C,andGstreptococciandS.anginosusproduceabscessesandthusmayrequireadjunctivesurgery.151MortalityfromgroupBPVEisveryhighandcardiacsurgeryisrecommended.152Antibiotictreatmentissimilartothatoforalstreptococci(Table16),exceptthatshort-termtherapyisnotrecommended.Gentamicinshouldbegivenfor2weeks.7.5GranulicatellaandAbiotrophia(formerlynutritionallyvariantstreptococci) GranulicatellaandAbiotrophiaproduceIEwithaprotractedcourse,whichisassociatedwithlargevegetations(>10mm),higherratesofcomplicationsandvalvereplacement(around50%),153,154possiblyduetodelayeddiagnosisandtreatment.AntibioticrecommendationsincludepenicillinG,ceftriaxoneorvancomycinfor6weeks,combinedwithanaminoglycosideforatleastthefirst2weeks.153,1547.6Staphylococcusaureusandcoagulase-negativestaphylococci StaphylococcusaureusisusuallyresponsibleforacuteanddestructiveIE,whereasCoNSproducemoreprotractedvalveinfections(exceptS.lugdunensis155andsomecasesofS.capitis).156,157Table17summarizestreatmentrecommendationsformethicillin-susceptibleandmethicillin-resistantS.aureusandCoNSinbothnativeandprostheticvalveIE.Ofnote,theadditionofanaminoglycosideinstaphylococcalnativevalveIEisnolongerrecommendedbecauseitincreasesrenaltoxicity.128,158Short-term(2-week)andoraltreatmentshavebeenproposedforuncomplicatedright-sidednativevalvemethicillin-susceptibleS.aureus(MSSA)IE(seealsosection12.4.2),buttheseregimenscannotbeappliedtoleft-sidedIE.Forpenicillin-allergicpatientswithMSSAIE,penicillindesensitizationcanbeattemptedinstablepatientssincevancomycinisinferiortobeta-lactams159andshouldnotbegiven.Ifbeta-lactamscannotbegiven,whereavailable,daptomycinshouldbechosenandgivenincombinationwithanothereffectiveantistaphylococcaldrugtoincreaseactivityandavoidthedevelopmentofresistance.SomeexpertshaverecommendedacombinationofhighdosesofcotrimoxazoleplusclindamycinasanalternativeforS.aureusIE.160S.lugdunensisisalwaysmethicillinsusceptibleandcanbetreatedwithcloxacillin.155StaphylococcusaureusPVEcarriesaveryhighriskofmortality(>45%)161andoftenrequiresearlyvalvereplacement.OtherdifferencesincomparisonwithNVEincludetheoveralldurationoftherapy,theuseofaminoglycosidesandtheadditionofrifampinafter3–5daysofeffectiveantibiotictherapyoncethebacteraemiahasbeencleared.Therationalesupportingthisrecommendationisbasedontheantagonisticeffectoftheantibioticcombinationswithrifampinagainstplanktonic/replicatingbacteriaandthesynergyseenagainstdormantbacteriawithinthebiofilm,asithasbeendemonstratedinforeignbodyinfectionmodelsandclinicallyinprostheticorthopaedicandvascularinfections.Althoughthelevelofevidenceispoor,addingrifampintothetreatmentofstaphylococcalPVEisstandardpractice,althoughtreatmentmaybeassociatedwithmicrobialresistance,hepatotoxicityanddruginteractions.1647.7Methicillin-resistantandvancomycin-resistantstaphylococci Methicillin-resistantS.aureus(MRSA)produceslow-affinitypenicillinbindingprotein2a(PBP2a),whichconferscross-resistancetomostbeta-lactams.MRSAareusuallyresistanttomultipleantibiotics,leavingonlyvancomycinanddaptomycintotreatsevereinfections.However,vancomycin-intermediateS.aureus(MIC4–8mg/L)andhetero-vancomycin-intermediateS.aureus(MIC≤2mg/L,butwithsubpopulationsgrowingathigherconcentrations)haveemergedworldwideandareassociatedwithIEtreatmentfailures.165,166Moreover,somehighlyvancomycin-resistantS.aureusstrainshavebeenisolatedfrominfectedpatientsinrecentyears,requiringnewapproachestotreatment.Inaddition,asystematicreviewandmeta-analysisofstudiespublishedbetween1996and2011inpatientswithMRSAbacteraemiawithvancomycin-susceptiblestrains(MIC≤2mg/L)167showedthatahighvancomycinMIC(≥1.5mg/L)wasassociatedwithhighermortality.DaptomycinisalipopeptideantibioticapprovedforS.aureusbacteraemiaandright-sidedIE.168CohortstudiesofS.aureusandCoNSIE132,168–170haveshownthatdaptomycinisatleastaseffectiveasvancomycin,andintwocohortstudiesofMRSAbacteraemiawithhighvancomycinMICs(>1mg/L),171,172daptomycinwasassociatedwithbetteroutcomes(includingsurvival)comparedwithvancomycin.Importantly,daptomycinneedstobeadministeredinappropriatedosesandcombinedwithotherantibioticstoavoidfurtherresistanceinpatientswithIE.168,173Forthisreason,daptomycinshouldbegivenathighdoses(≥10mg/kg),andmostexpertsrecommenditbecombinedwithbeta-lactams133orfosfomycin134[beta-lactams(andprobablyfosfomycin)increasemembranedaptomycinbindingbydecreasingthepositivesurfacecharge]forNVEandwithgentamicinandrifampinforPVE.168,173,174Otheralternativesincludefosfomycinplusimipenem,175newerbeta-lactamswithrelativelygoodPBP2aaffinitysuchasceftaroline,176quinupristin–dalfopristinwithorwithoutbeta-lactams,177,178beta-lactamsplusoxazolidinones(linezolid),179beta-lactamsplusvancomycin180andhighdosesoftrimethoprim/sulfamethoxazoleandclindamycin.160SuchcaseswarrantcollaborativemanagementwithanIDspecialist.7.8Enterococcusspp. EnterococcalIEisprimarilycausedbyEnterococcusfaecalis(90%ofcases)and,morerarely,byEnterococcusfaecium(5%ofcases)orotherspecies.181Theyposetwomajorproblems.First,enterococciarehighlyresistanttoantibiotic-inducedkilling,anderadicationrequiresprolongedadministration(upto6weeks)ofsynergisticbactericidalcombinationsoftwocellwallinhibitors(ampicillinplusceftriaxone,whichsynergizebyinhibitingcomplementaryPBPs)oronecellwallinhibitorwithaminoglycosides(Table18).Second,theymayberesistanttomultipledrugs,includingaminoglycosides[high-levelaminoglycosideresistance(HLAR)],beta-lactams(viaPBP5modificationandsometimesbeta-lactamases)andvancomycin.182Fullypenicillin-susceptiblestrains(penicillinMIC≤8mg/L)aretreatedwithpenicillinGorampicillin(oramoxicillin)combinedwithgentamicin.Ampicillin(oramoxicillin)mightbepreferredsinceMICsaretwotofourtimeslower.GentamicinresistanceisfrequentinbothE.faecalisandE.faecium.182AnaminoglycosideMIC>500mg/L(HLAR)isassociatedwiththelossofbactericidalsynergismwithcellwallinhibitors,andaminoglycosidesshouldnotbeusedinsuchconditions.Streptomycinmayremainactiveinsuchcasesandisausefulalternative.Therehavebeentwoimportantadvancesinrecentyears.Firstisthedemonstration,inseveralcohortstudiesofE.faecalisIEincludinghundredsofcases,thatampicillinplusceftriaxoneisaseffectiveasampicillinplusgentamicinfornon-HLARE.faecalisIE.Itisalsosafer,withoutanynephrotoxicity.183–185Inaddition,thisisthecombinationofchoicefortreatingHLARE.faecalisIE.Second,thetotaldailydoseofgentamicincanbegiveninasingledailydoseinsteadofthetwoorthreedivideddosesrecommendeduptonow,andthelengthofthetreatmentfornon-HLARE.faecalisIEmaybesafelyshortenedfrom4–6weeksto2weeks,reducingtheratesofnephrotoxicitytoverylowlevels.129,186,187 Table17AntibiotictreatmentofinfectiveendocarditisduetoStaphylococcusspp.  AUC=areaunderthecurve;Cmin=minimumconcentration;IE=infectiveendocarditis;MIC=minimuminhibitoryconcentration;MRSA=methicillin-resistantStaphylococcusaureus;MSSA=methicillin-susceptibleS.aureus;PVE=prostheticvalveendocarditis.aRenalfunction,serumCotrimoxazoleconcentrationsshouldbemonitoredonce/week(twice/weekinpatientswithrenalfailure);bSerumtroughvancomycinlevels(Cmin)shouldbe≥20mg/L.AvancomycinAUC/MIC>400isrecommendedforMRSAinfections;cMonitorplasmaCPKlevelsatleastonceaweek.Someexpertsrecommendaddingcloxacillin(2g/4hi.v.)orfosfomycin(2g/6hi.v.)todaptomycininordertoincreaseactivityandavoidthedevelopmentofdaptomycinresistance;dDaptomycinandfosfomycinarenotavailableinsomeEuropeancountries;eRifampinisbelievedtoplayaspecialroleinprostheticdeviceinfectionbecauseithelpseradicatebacteriaattachedtoforeignmaterial.157Thesoleuseofrifampinisassociatedwithahighfrequencyofmicrobialresistanceandisnotrecommended.Rifampinincreasesthehepaticmetabolismofwarfarinandotherdrugs;fRenalfunctionandserumgentamicinconcentrationsshouldbemonitoredonce/week(twice/weekinpatientswithrenalfailure);gPaediatricdosesshouldnotexceedadultdoses;hPenicillindesensitizationcanbeattemptedinstablepatients;iClassofrecommendation;jLevelofevidence;kReference(s)supportingrecommendations.**Noclinicalbenefitofaddingrifampicinorgentamicin Openinnewtab Table17AntibiotictreatmentofinfectiveendocarditisduetoStaphylococcusspp.  AUC=areaunderthecurve;Cmin=minimumconcentration;IE=infectiveendocarditis;MIC=minimuminhibitoryconcentration;MRSA=methicillin-resistantStaphylococcusaureus;MSSA=methicillin-susceptibleS.aureus;PVE=prostheticvalveendocarditis.aRenalfunction,serumCotrimoxazoleconcentrationsshouldbemonitoredonce/week(twice/weekinpatientswithrenalfailure);bSerumtroughvancomycinlevels(Cmin)shouldbe≥20mg/L.AvancomycinAUC/MIC>400isrecommendedforMRSAinfections;cMonitorplasmaCPKlevelsatleastonceaweek.Someexpertsrecommendaddingcloxacillin(2g/4hi.v.)orfosfomycin(2g/6hi.v.)todaptomycininordertoincreaseactivityandavoidthedevelopmentofdaptomycinresistance;dDaptomycinandfosfomycinarenotavailableinsomeEuropeancountries;eRifampinisbelievedtoplayaspecialroleinprostheticdeviceinfectionbecauseithelpseradicatebacteriaattachedtoforeignmaterial.157Thesoleuseofrifampinisassociatedwithahighfrequencyofmicrobialresistanceandisnotrecommended.Rifampinincreasesthehepaticmetabolismofwarfarinandotherdrugs;fRenalfunctionandserumgentamicinconcentrationsshouldbemonitoredonce/week(twice/weekinpatientswithrenalfailure);gPaediatricdosesshouldnotexceedadultdoses;hPenicillindesensitizationcanbeattemptedinstablepatients;iClassofrecommendation;jLevelofevidence;kReference(s)supportingrecommendations.**Noclinicalbenefitofaddingrifampicinorgentamicin Openinnewtab Beta-lactamandvancomycinresistancearemainlyobservedinE.faecium.Sincedualresistanceisrare,beta-lactammightbeusedagainstvancomycin-resistantstrainsandviceversa.Varyingresultshavebeenreportedwithquinupristin–dalfopristin(notactiveagainstE.faecalis),linezolid,daptomycin(combinedwithampicillin,ertapenemorceftaroline)andtigecycline.Again,thesesituationsrequiretheexpertiseofanIDspecialist.7.9Gram-negativebacteria 7.9.1HACEK-relatedspecies HACEKGram-negativebacilliarefastidiousorganismsandthelaboratoryshouldbemadeawarethatinfectionwiththeseagentsisunderconsideration,asspecialistinvestigationsmayberequired(seealsosection5).Becausetheygrowslowly,standardMICtestsmaybedifficulttointerpret.SomeHACEK-groupbacilliproducebeta-lactamases,andampicillinisthereforenolongerthefirst-lineoption.Conversely,theyaresusceptibletoceftriaxone,otherthird-generationcephalosporinsandquinolones;thestandardtreatmentisceftriaxone2g/dayfor4weeksinNVEandfor6weeksinPVE.Iftheydonotproducebeta-lactamase,ampicillin(12g/dayi.v.infourorsixdoses)plusgentamicin(3mg/kg/daydividedintotwoorthreedoses)for4–6weeksisanoption.Ciprofloxacin(400mg/8–12hi.v.or750mg/12horally)isalesswell-validatedalternative.188,189 Table18AntibiotictreatmentofinfectiveendocarditisduetoEnterococcusspp.  HLAR:high-levelaminoglycosideresistance;IE:infectiveendocarditis;MIC:minimuminhibitoryconcentration;PBP:penicillinbindingprotein;PVE:prostheticvalveendocarditis.aHigh-levelresistancetogentamicin(MIC>500mg/L):ifsusceptibletostreptomycin,replacegentamicinwithstreptomycin15mg/kg/dayintwoequallydivideddoses.bBeta-lactamresistance:(i)ifduetobeta-lactamaseproduction,replaceampicillinwithampicillin–sulbactamoramoxicillinwithamoxicillin–clavulanate;(ii)ifduetoPBP5alteration,usevancomycin-basedregimens.cMultiresistancetoaminoglycosides,beta-lactamsandvancomycin:suggestedalternativesare(i)daptomycin10mg/kg/dayplusampicillin200mg/kg/dayi.v.infourtosixdoses;(ii)linezolid2×600mg/dayi.v.ororallyfor≥8weeks(IIa,C)(monitorhaematologicaltoxicity);(iii)quinupristin–dalfopristin3×7.5mg/kg/dayfor≥8weeks.Quinupristin–dalfopristinisnotactiveagainstE.faecalis;(iv)forothercombinations(daptomycinplusertapenemorceftaroline),consultinfectiousdiseasesspecialists.dMonitorserumlevelsofaminoglycosidesandrenalfunctionasindicatedinTable16.ePaediatricdosesshouldnotexceedadultdoses.fMonitorserumvancomycinconcentrationsasstatedinTable16.gClassofrecommendation.hLevelofevidence.iReference(s)supportingrecommendations.*Orampicillin,samedosagesasamoxicillin.**Someexpertsrecommendgivinggentamicinforonly2weeks(IIa,B). Openinnewtab Table18AntibiotictreatmentofinfectiveendocarditisduetoEnterococcusspp.  HLAR:high-levelaminoglycosideresistance;IE:infectiveendocarditis;MIC:minimuminhibitoryconcentration;PBP:penicillinbindingprotein;PVE:prostheticvalveendocarditis.aHigh-levelresistancetogentamicin(MIC>500mg/L):ifsusceptibletostreptomycin,replacegentamicinwithstreptomycin15mg/kg/dayintwoequallydivideddoses.bBeta-lactamresistance:(i)ifduetobeta-lactamaseproduction,replaceampicillinwithampicillin–sulbactamoramoxicillinwithamoxicillin–clavulanate;(ii)ifduetoPBP5alteration,usevancomycin-basedregimens.cMultiresistancetoaminoglycosides,beta-lactamsandvancomycin:suggestedalternativesare(i)daptomycin10mg/kg/dayplusampicillin200mg/kg/dayi.v.infourtosixdoses;(ii)linezolid2×600mg/dayi.v.ororallyfor≥8weeks(IIa,C)(monitorhaematologicaltoxicity);(iii)quinupristin–dalfopristin3×7.5mg/kg/dayfor≥8weeks.Quinupristin–dalfopristinisnotactiveagainstE.faecalis;(iv)forothercombinations(daptomycinplusertapenemorceftaroline),consultinfectiousdiseasesspecialists.dMonitorserumlevelsofaminoglycosidesandrenalfunctionasindicatedinTable16.ePaediatricdosesshouldnotexceedadultdoses.fMonitorserumvancomycinconcentrationsasstatedinTable16.gClassofrecommendation.hLevelofevidence.iReference(s)supportingrecommendations.*Orampicillin,samedosagesasamoxicillin.**Someexpertsrecommendgivinggentamicinforonly2weeks(IIa,B). Openinnewtab 7.9.2Non-HACEKspecies TheInternationalCollaborationonEndocarditis(ICE)reportednon-HACEKGram-negativebacteriain49of2761(1.8%)IEcases.190Recommendedtreatmentisearlysurgerypluslong-term(atleast6weeks)therapywithbactericidalcombinationsofbeta-lactamsandaminoglycosides,sometimeswithadditionalquinolonesorcotrimoxazole.Invitrobactericidaltestsandmonitoringofserumantibioticconcentrationsmaybehelpful.Becauseoftheirrarityandseverity,theseconditionsshouldbediscussedbytheEndocarditisTeamorwithanIDspecialist.7.10Bloodculture–negativeinfectiveendocarditis ThemaincausesofBCNIEaresummarizedinsection5.4.2.191,192TreatmentoptionsaresummarizedinTable19.192,193ConsultationwithanIDspecialistfromtheEndocarditisTeamisrecommended. Table19Antibiotictreatmentofbloodculture-negativeinfectiveendocarditis(adaptedfromBrouquietal.193)  ID=infectiousdisease;IE=infectiveendocarditis;Ig=immunoglobulin;i.v.=intravenous;U=units.aOwingtothelackoflargeseries,theoptimaldurationoftreatmentofIEduetothesepathogensisunknown.Thepresenteddurationsarebasedonselectedcasereports.ConsultationwithanIDspecialistisrecommended.bAdditionofstreptomycin(15mg/kg/24hin2doses)forthefirstfewweeksisoptional.cDoxycyclineplushydroxychloroquine(withmonitoringofserumhydroxychloroquinelevels)issignificantlysuperiortodoxycycline.194dSeveraltherapeuticregimenshavebeenreported,includingaminopenicillins(ampicillinoramoxicillin,12g/24hi.v.)orcephalosporins(ceftriaxone,2g/24hi.v.)combinedwithaminoglycosides(gentamicinornetilmicin).195DosagesareasforstreptococcalandenterococcalIE(Tables16and18).196,197eNewerfluoroquinolones(levofloxacin,moxifloxacin)aremorepotentthanciprofloxacinagainstintracellularpathogenssuchasMycoplasmaspp.,Legionellaspp.,andChlamydiaspp.fTreatmentofWhipple'sIEremainshighlyempirical.Inthecaseofcentralnervoussysteminvolvement,sulfadiazine1.5g/6horallymustbeaddedtodoxycycline.Analternativetherapyisceftriaxone(2g/24hi.v.)for2–4weeksorpenicillinG(2millionU/4h)andstreptomycin(1g/24h)i.v.for2–4weeksfollowedbycotrimoxazole(800mg/12h)orally.TrimethoprimisnotactiveagainstT.whipplei.Successeshavebeenreportedwithlong-termtherapy(>1year). Openinnewtab Table19Antibiotictreatmentofbloodculture-negativeinfectiveendocarditis(adaptedfromBrouquietal.193)  ID=infectiousdisease;IE=infectiveendocarditis;Ig=immunoglobulin;i.v.=intravenous;U=units.aOwingtothelackoflargeseries,theoptimaldurationoftreatmentofIEduetothesepathogensisunknown.Thepresenteddurationsarebasedonselectedcasereports.ConsultationwithanIDspecialistisrecommended.bAdditionofstreptomycin(15mg/kg/24hin2doses)forthefirstfewweeksisoptional.cDoxycyclineplushydroxychloroquine(withmonitoringofserumhydroxychloroquinelevels)issignificantlysuperiortodoxycycline.194dSeveraltherapeuticregimenshavebeenreported,includingaminopenicillins(ampicillinoramoxicillin,12g/24hi.v.)orcephalosporins(ceftriaxone,2g/24hi.v.)combinedwithaminoglycosides(gentamicinornetilmicin).195DosagesareasforstreptococcalandenterococcalIE(Tables16and18).196,197eNewerfluoroquinolones(levofloxacin,moxifloxacin)aremorepotentthanciprofloxacinagainstintracellularpathogenssuchasMycoplasmaspp.,Legionellaspp.,andChlamydiaspp.fTreatmentofWhipple'sIEremainshighlyempirical.Inthecaseofcentralnervoussysteminvolvement,sulfadiazine1.5g/6horallymustbeaddedtodoxycycline.Analternativetherapyisceftriaxone(2g/24hi.v.)for2–4weeksorpenicillinG(2millionU/4h)andstreptomycin(1g/24h)i.v.for2–4weeksfollowedbycotrimoxazole(800mg/12h)orally.TrimethoprimisnotactiveagainstT.whipplei.Successeshavebeenreportedwithlong-termtherapy(>1year). Openinnewtab 7.11Fungi FungiaremostfrequentlyobservedinPVEandinIEaffectingi.v.drugabusers(IVDAs)andimmunocompromisedpatients.198CandidaandAspergillusspp.predominate,thelatterresultinginBCNIE.199,200Mortalityisveryhigh(>50%),andtreatmentnecessitatescombinedantifungaladministrationandsurgicalvalvereplacement.135,198–200AntifungaltherapyforCandidaIEincludesliposomalamphotericinB(orotherlipidformulations)withorwithoutflucytosineoranechinocandinathighdoses;andforAspergillusIE,voriconazoleisthedrugofchoiceandsomeexpertsrecommendtheadditionofanechinocandinoramphotericinB.135,198,200,201Suppressivelong-termtreatmentwithoralazoles(fluconazoleforCandidaandvoriconazoleforAspergillus)isrecommended,sometimesforlife.135,198,201ConsultationwithanIDspecialistfromtheEndocarditisTeamisrecommended.7.12Empiricaltherapy TreatmentofIEshouldbestartedpromptly.Threesetsofbloodculturesshouldbedrawnat30-minintervalsbeforeinitiationofantibiotics.202Theinitialchoiceofempiricaltreatmentdependsonseveralconsiderations: uggestedregimensforempiricaltreatmentinacutepatientsaresummarizedinTable20.NVEandlatePVEregimensshouldcoverstaphylococci,streptococciandenterococci.EarlyPVEorhealthcare-associatedIEregimensshouldcovermethicillin-resistantstaphylococci,enterococciand,ideally,non-HACEKGram-negativepathogens.Oncethepathogenisidentified(usuallyin<48h),theantibiotictreatmentmustbeadaptedtoitsantimicrobialsusceptibilitypattern.Whetherthepatienthasreceivedpreviousantibiotictherapy.Whethertheinfectionaffectsanativevalveoraprosthesis[andifso,whensurgerywasperformed(earlyvs.latePVE)].Theplaceoftheinfection(community,nosocomial,ornon-nosocomialhealthcare-associatedIE)andknowledgeofthelocalepidemiology,especiallyforantibioticresistanceandspecificgenuineculture-negativepathogens(Table19).Cloxacillin/cefazolinadministrationisassociatedwithlowermortalityratesthanotherbeta-lactams,includingamoxicillin/clavulanicacidorampicillin/sulbactam,203andvancomycinforempiricallytreatingMSSAbacteraemia/endocarditis.159 Table20Proposedantibioticregimensforinitialempiricaltreatmentofinfectiveendocarditisinacuteseverelyillpatients(beforepathogenidentification)a  BCNIE=bloodculture-negativeinfectiveendocarditis;ID=infectiousdisease;i.m.=intramuscular;i.v.=intravenous;PVE=prostheticvalveendocarditis.aIfinitialbloodculturesarenegativeandthereisnoclinicalresponse,considerBCNIEaetiology(seeSection7.10)andmaybesurgeryformoleculardiagnosisandtreatment,andextensionoftheantibioticspectrumtobloodculture-negativepathogens(doxycycline,quinolones)mustbeconsidered.bClassofrecommendation.cLevelofevidence.dMonitoringofgentamicinorvancomycindosagesisasdescribedinTables16and17. Openinnewtab Table20Proposedantibioticregimensforinitialempiricaltreatmentofinfectiveendocarditisinacuteseverelyillpatients(beforepathogenidentification)a  BCNIE=bloodculture-negativeinfectiveendocarditis;ID=infectiousdisease;i.m.=intramuscular;i.v.=intravenous;PVE=prostheticvalveendocarditis.aIfinitialbloodculturesarenegativeandthereisnoclinicalresponse,considerBCNIEaetiology(seeSection7.10)andmaybesurgeryformoleculardiagnosisandtreatment,andextensionoftheantibioticspectrumtobloodculture-negativepathogens(doxycycline,quinolones)mustbeconsidered.bClassofrecommendation.cLevelofevidence.dMonitoringofgentamicinorvancomycindosagesisasdescribedinTables16and17. Openinnewtab 7.13Outpatientparenteralantibiotictherapyforinfectiveendocarditis Outpatientparenteralantibiotictherapy(OPAT)isusedtoconsolidateantimicrobialtherapyoncecriticalinfection-relatedcomplicationsareundercontrol(e.g.perivalvularabscesses,acuteHF,septicemboliandstroke).204–207Twodifferentphasesmaybeidentifiedduringthecourseofantibiotictherapy:(i)afirstcriticalphase(thefirst2weeksoftherapy),duringwhichOPAThasarestrictedindication;and(ii)asecond,continuationphase(beyond2weeksoftherapy),whereOPATmaybefeasible.Table21summarizesthesalientquestionstoaddresswhenconsideringOPATforIE.205 Table21Criteriathatdeterminesuitabilityofoutpatientparenteralantibiotictherapyforinfectiveendocarditis(adaptedfromAndrewsetal.205)  HF=heartfailure;ID=infectiousdisease;IE=infectiveendocarditis;OPAT=outpatientparenteralantibiotictherapy;PVE=prostheticvalveendocarditis.aForotherpathogens,consultationwithanIDspecialistisrecommended.bForpatientswithlatePVE,consultationwithanIDspecialistisrecommended.cPreferablyfromtheEndocarditisTeam.dGeneralphysiciancanseethepatientonceaweek,ifneeded. Openinnewtab Table21Criteriathatdeterminesuitabilityofoutpatientparenteralantibiotictherapyforinfectiveendocarditis(adaptedfromAndrewsetal.205)  HF=heartfailure;ID=infectiousdisease;IE=infectiveendocarditis;OPAT=outpatientparenteralantibiotictherapy;PVE=prostheticvalveendocarditis.aForotherpathogens,consultationwithanIDspecialistisrecommended.bForpatientswithlatePVE,consultationwithanIDspecialistisrecommended.cPreferablyfromtheEndocarditisTeam.dGeneralphysiciancanseethepatientonceaweek,ifneeded. Openinnewtab 8.Maincomplicationsofleft-sidedvalveinfectiveendocarditisandtheirmanagement SurgicaltreatmentisrequiredinapproximatelyhalfofthepatientswithIEbecauseofseverecomplications.54Reasonstoconsiderearlysurgeryintheactivephase(i.e.whilethepatientisstillreceivingantibiotictreatment)aretoavoidprogressiveHFandirreversiblestructuraldamagecausedbysevereinfectionandtopreventsystemicembolism.6,54,115,208–210Ontheotherhand,surgicaltherapyduringtheactivephaseofthediseaseisassociatedwithsignificantrisk.Surgeryisjustifiedinpatientswithhigh-riskfeaturesthatmakethepossibilityofcurewithantibiotictreatmentunlikelyandwhodonothaveco-morbidconditionsorcomplicationsthatmaketheprospectofrecoveryremote.Ageperseisnotacontraindicationtosurgery.211Earlyconsultationwithacardiacsurgeonisrecommendedinordertodeterminethebesttherapeuticapproach.Identificationofpatientsrequiringearlysurgeryisfrequentlydifficultandisanimportantobjectiveofthe‘HeartTeam’.Eachcasemustbeindividualizedandallfactorsassociatedwithincreasedriskidentifiedatthetimeofdiagnosis.Frequentlytheneedforsurgerywillbedeterminedbyacombinationofseveralhigh-riskfeatures.211Insomecases,surgeryneedstobeperformedonanemergency(within24h)orurgent(withinafewdays,<7days)basis,irrespectiveofthedurationofantibiotictreatment.Inothercases,surgerycanbepostponedtoallow1or2weeksofantibiotictreatmentundercarefulclinicalandechocardiographicobservationbeforeanelectivesurgicalprocedureisperformed.63,115ThethreemainindicationsforearlysurgeryinIEareHF,uncontrolledinfectionandpreventionofembolicevents212–216(Table22). Table22Indicationsandtimingofsurgeryinleft-sidedvalveinfectiveendocarditis(nativevalveendocarditisandprostheticvalveendocarditis)  HACEK=Haemophilusparainfluenzae,Haemophilusaphrophilus,Haemophilusparaphrophilus,Haemophilusinfluenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,KingellakingaeandKingelladenitrificans;HF=heartfailure;IE=infectiveendocarditis;NVE=nativevalveendocarditis;PVE=prostheticvalveendocarditis.aEmergencysurgery:surgeryperformedwithin24h;urgentsurgery:withinafewdays;electivesurgery:afteratleast1–2weeksofantibiotictherapy.bClassofrecommendation.cLevelofevidence.dReference(s)supportingrecommendations.eSurgerymaybepreferredifaprocedurepreservingthenativevalveisfeasible. Openinnewtab Table22Indicationsandtimingofsurgeryinleft-sidedvalveinfectiveendocarditis(nativevalveendocarditisandprostheticvalveendocarditis)  HACEK=Haemophilusparainfluenzae,Haemophilusaphrophilus,Haemophilusparaphrophilus,Haemophilusinfluenzae,Actinobacillusactinomycetemcomitans,Cardiobacteriumhominis,Eikenellacorrodens,KingellakingaeandKingelladenitrificans;HF=heartfailure;IE=infectiveendocarditis;NVE=nativevalveendocarditis;PVE=prostheticvalveendocarditis.aEmergencysurgery:surgeryperformedwithin24h;urgentsurgery:withinafewdays;electivesurgery:afteratleast1–2weeksofantibiotictherapy.bClassofrecommendation.cLevelofevidence.dReference(s)supportingrecommendations.eSurgerymaybepreferredifaprocedurepreservingthenativevalveisfeasible. Openinnewtab 8.1Heartfailure 8.1.1Heartfailureininfectiveendocarditis HFisthemostfrequentcomplicationofIEandrepresentsthemostcommonindicationforsurgeryinIE.54HFisobservedin42–60%ofcasesofNVEandismoreoftenpresentwhenIEaffectstheaorticratherthanthemitralvalve.111,208,212HFismainlycausedbyneworworseningsevereaorticormitralregurgitation,althoughintracardiacfistulae213and,morerarely,valveobstructionmayalsoleadtoHF.ValvularregurgitationinnativeIEmayoccurasaresultofmitralchordalrupture,leafletrupture(flailleaflet),leafletperforationorinterferenceofthevegetationmasswithleafletclosure.AparticularsituationisinfectionoftheanteriormitralleafletsecondarytoaninfectedregurgitantjetofaprimaryaorticIE.214Resultantaneurysmformationontheatrialsideofthemitralleafletmaylaterleadtomitralperforation.215ClinicalpresentationofHFmayincludedyspnoea,pulmonaryoedemaandcardiogenicshock.111,120AmongthelargeICEProspectiveCohortStudypatientswithHFandIE,66%wereinNewYorkHeartAssociationclassIIIorIV.216Inadditiontoclinicalfindings,TTEisofcrucialimportanceforinitialevaluationandfollow-up.64Valveperforation,secondarymitrallesionsandaneurysmsarebestassessedusingTOE.64,65,214Echocardiographyisalsousefultoevaluatethehaemodynamicconsequencesofvalvulardysfunction,measurementofpulmonaryarterypressure,detectionofpericardialeffusionandassessmentandmonitoringofleftventricularsystolicfunctionandleftandrightheartfillingpressures.64B-typenatriureticpeptidehaspotentialuseinthediagnosisandmonitoringofHFinIE.217BothelevatedlevelsofcardiactroponinsandB-typenatriureticpeptideareassociatedwithadverseoutcomesinIE.218,219ModeratetosevereHFisthemostimportantpredictorofin-hospital,6-monthand1-yearmortality.52,109,111,117,2088.1.2Indicationsandtimingofsurgeryinthepresenceofheartfailureininfectiveendocarditis(Table22) IdentificationofsurgicalcandidatesandtimingofsurgerydecisionsshouldpreferablybemadebytheEndocarditisTeam.118ThepresenceofHFindicatessurgeryinthemajorityofpatientswithIEandistheprincipalindicationforurgentsurgery.115,124SurgeryisindicatedinpatientswithHFcausedbysevereaorticormitralregurgitation,intracardiacfistulaeorvalveobstructioncausedbyvegetations.SurgeryisalsoindicatedinpatientswithsevereacuteaorticormitralregurgitationwithoutclinicalHFbutwithechocardiographicsignsofelevatedleftventricularend-diastolicpressure(e.g.prematureclosureofthemitralvalve),highleftatrialpressureormoderatetoseverepulmonaryhypertension.TheserulesapplyinbothNVEandPVE.37,220,221Surgerymustbeperformedonanemergencybasis,irrespectiveofthestatusofinfection,whenpatientsareinpersistentpulmonaryoedemaorcardiogenicshockdespitemedicaltherapy.63SurgerymustbeperformedonanurgentbasiswhenHFislesssevere.Urgentsurgeryshouldalsobeperformedinpatientswithsevereaorticormitralinsufficiencywithlargevegetations,evenwithoutHF.9Inpatientswithwell-tolerated(NewYorkHeartAssociationclassIorII)severevalvularregurgitationandnootherreasonsforsurgery,medicalmanagementwithantibioticsunderstrictclinicalandechocardiographicobservationisagoodoption,althoughearlysurgerymaybeanoptioninselectedpatientsatlowriskforsurgery.ElectivesurgeryshouldbeconsidereddependingonthetoleranceofthevalvelesionandaccordingtotherecommendationsoftheESCGuidelinesonthemanagementofvalvularheartdisease.55Insummary,HFisthemostfrequentandamongthemostseverecomplicationsofIE.Unlesssevereco-morbidityexists,thepresenceofHFisanindicationforearlysurgeryinNVEandPVE,eveninpatientswithcardiogenicshock.8.2Uncontrolledinfection UncontrolledinfectionisoneofthemostfearedcomplicationsofIEandisthesecondmostfrequentcauseforsurgery.54Uncontrolledinfectionisconsideredtobepresentwhenthereispersistinginfectionandwhentherearesignsoflocallyuncontrolledinfection.Infectionduetoresistantorveryvirulentorganismsoftenresultsinuncontrolledinfection.8.2.1Persistinginfection Thedefinitionofpersistinginfectionisarbitraryandconsistsoffeverandpersistingpositiveculturesafter7–10daysofantibiotictreatment.PersistingfeverisafrequentproblemobservedduringtreatmentofIE.Usually,temperaturenormalizeswithin7–10daysunderspecificantibiotictherapy.Persistingfevermayberelatedtoseveralfactors,includinginadequateantibiotictherapy,resistantorganisms,infectedlines,locallyuncontrolledinfection,emboliccomplicationsorextracardiacsiteofinfectionandadversereactiontoantibiotics.3Managementofpersistingfeverincludesreplacementofi.v.lines,repeatlaboratorymeasurements,bloodcultures,echocardiography,andthesearchforanintracardiacorextracardiacfocusofinfection.8.2.2Perivalvularextensionininfectiveendocarditis PerivalvularextensionofIEisthemostfrequentcauseofuncontrolledinfectionandisassociatedwithapoorprognosisandhighlikelihoodoftheneedforsurgery.Perivalvularcomplicationsincludeabscessformation,pseudoaneurysmsandfistulae(definedinTable11).223,224PerivalvularabscessismorecommoninaorticIE(10–40%inNVE)3,225–227andisfrequentinPVE(56–100%).3,6InmitralIE,perivalvularabscessesareusuallylocatedposteriorlyorlaterally.228InaorticIE,perivalvularextensionoccursmostfrequentlyinthemitral-aorticintervalvularfibrosa.229Serialechocardiographicstudieshaveshownthatabscessformationisadynamicprocess,startingwithaorticrootwallthickeningandextendingtothedevelopmentoffistulae.229Inonestudy,themostimportantriskfactorsforperivalvularcomplicationswereprostheticvalve,aorticlocationandinfectionwithCoNS.230PseudoaneurysmsandfistulaeareseverecomplicationsofIEandarefrequentlyassociatedwithveryseverevalvularandperivalvulardamage.213,231–233ThefrequencyoffistulaformationinIEhasbeenreportedtobe1.6%,withS.aureusbeingthemostcommonlyassociatedorganism(46%).233Despitehighratesofsurgeryinthispopulation(87%),hospitalmortalityremainshigh(41%).213,233,234Othercomplicationsduetomajorextensionofinfectionarelessfrequentandmayincludeventricularseptaldefect,third-degreeatrio-ventricularblockandacutecoronarysyndrome.223,224,234Perivalvularextensionshouldbesuspectedincaseswithpersistentunexplainedfeverornewatrio-ventricularblock.Thereforeanelectrocardiogramshouldbeperformedfrequentlyduringcontinuingtreatment,particularlyinaorticIE.TOE,MSCTandPET/CT103areparticularlyusefulforthediagnosisofperivalvularcomplications,whilethesensitivityofTTEis<50%225–228(seesection5).Indeed,perivalvularextensionisfrequentlydiscoveredonasystematicTOE.However,smallabscessescanbemissed,evenusingTOE,particularlythoseinamitrallocationwhenthereisco-existentannularcalcification.1018.2.3Indicationsandtimingofsurgeryinthepresenceofuncontrolledinfectionininfectiveendocarditis(Table22) Theresultsofsurgerywhenthereasonfortheprocedureisuncontrolledinfectionareworsethanwhensurgeryisperformedforotherreasons.124,2358.2.3.1Persistentinfection InsomecasesofIE,antibioticsaloneareinsufficienttoeradicatetheinfection.Surgeryhasbeenindicatedwhenfeverandpositivebloodculturespersistforseveraldays(7–10days)despiteanappropriateantibioticregimenandwhenextracardiacabscesses(splenic,vertebral,cerebralorrenal)andothercausesoffeverhavebeenexcluded.However,thebesttimingforsurgeryinthisdifficultsituationisunclear.Recentlyithasbeendemonstratedthatpersistentbloodcultures48–72hafterinitiationofantibioticsareanindependentriskfactorforhospitalmortality.123Theseresultssuggestthatsurgeryshouldbeconsideredwhenbloodculturesremainpositiveafter3daysofantibiotictherapy,aftertheexclusionofothercausesofpersistentpositivebloodcultures(adaptedantibioticregimen).8.2.3.2Signsoflocallyuncontrolledinfection Signsoflocallyuncontrolledinfectionincludeincreasingvegetationsize,abscessformation,falseaneurysms,andthecreationoffistulae.213,236,237Persistentfeverisalsousuallypresentandsurgeryisrecommendedassoonaspossible.Rarelywhentherearenootherreasonsforsurgeryandfeveriseasilycontrolledwithantibiotics,smallabscessesorfalseaneurysmscanbetreatedconservativelyundercloseclinicalandechocardiographicfollow-up.8.2.3.3Infectionbymicroorganismsatlowlikelihoodofbeingcontrolledbyantimicrobialtherapy SurgeryisindicatedinfungalIE,238,239incasesofmultiresistantorganisms(e.g.MRSAorvancomycin-resistantenterococci)orintherareinfectionscausedbyGram-negativebacteria.SurgeryshouldalsobeconsideredinPVEcausedbystaphylococciornon-HACEKGram-negativebacteria.InNVEcausedbyS.aureus,surgeryisindicatedifafavourableearlyresponsetoantibioticsisnotachieved161,240,241(Table22).Finally,surgeryshouldbeperformedinpatientswithPVEandS.aureusinfection.Insummary,uncontrolledinfectionismostfrequentlyrelatedtoperivalvularextensionor‘difficult-to-treat’organisms.Unlesssevereco-morbidityexists,thepresenceoflocallyuncontrolledinfectionisanindicationforearlysurgeryinpatientswithIE.8.3Preventionofsystemicembolism 8.3.1Emboliceventsininfectiveendocarditis Emboliceventsareafrequentandlife-threateningcomplicationofIErelatedtothemigrationofcardiacvegetations.Thebrainandspleenarethemostfrequentsitesofembolisminleft-sidedIE,whilepulmonaryembolismisfrequentinnativeright-sidedandpacemakerleadIE.Strokeisaseverecomplicationandisassociatedwithincreasedmorbidityandmortality.105Conversely,emboliceventsmaybetotallysilentin20–50%ofpatientswithIE,especiallythoseaffectingthesplenicorcerebralcirculation,andcanbediagnosedbynon-invasiveimaging.83,85,242ThussystematicabdominalandcerebralCTscanningmaybehelpful.However,contrastmediashouldbeusedwithcautioninpatientswithrenalimpairmentorhaemodynamicinstabilitybecauseoftheriskofworseningrenalimpairmentincombinationwithantibioticnephrotoxicity.Overall,embolicriskisveryhighinIE,withemboliceventsoccurringin20–50%ofpatients.72,242–249However,theriskofnewevents(occurringafterinitiationofantibiotictherapy)isonly6–21%.72,115,243AstudyfromtheICEgroup250demonstratedthattheincidenceofstrokeinpatientsreceivingappropriateantimicrobialtherapywas4.8/1000patient-daysinthefirstweekoftherapy,fallingto1.7/1000patient-daysinthesecondweek,andfurtherthereafter.8.3.2Predictingtheriskofembolism Echocardiographyplaysakeyroleinpredictingembolicevents,72,115,246–252althoughpredictionremainsdifficultintheindividualpatient.Severalfactorsareassociatedwithincreasedriskofembolism,includingthesizeandmobilityofvegetations,72,242,246–253thelocationofthevegetationonthemitralvalve,72,246–249theincreasingordecreasingsizeofthevegetationunderantibiotictherapy,72,253particularmicroorganisms(S.aureus,72S.bovis,254Candidaspp.),previousembolism,72multivalvularIE246andbiologicalmarkers.255Amongthese,thesizeandmobilityofthevegetationsarethemostpotentindependentpredictorsofanewembolicevent.253Patientswithvegetations>10mminlengthareathigherriskofembolism,58,253andthisriskisevenhigherinpatientswithlarger(>15mm)andmobilevegetations,especiallyinstaphylococcalIEaffectingthemitralvalve.219Arecentstudy113foundthattheriskofneurologicalcomplicationswasparticularlyhighinpatientswithverylarge(>30mmlength)vegetations.Severalfactorsshouldbetakenintoaccountwhenassessingembolicrisk.Inarecentstudyof847patientswithIE,the6-monthincidenceofnewembolismwas8.5%.222Sixfactors(age,diabetes,atrialfibrillation,previousembolism,vegetationlengthandS.aureusinfection)wereassociatedwithanincreasedembolicriskandwereusedtocreatean‘embolicriskcalculator’.222Whatevertheriskfactorsobservedinanindividualpatient,itmustbere-emphasizedthattheriskofnewembolismishighestduringthefirstdaysfollowinginitiationofantibiotictherapyandrapidlydecreasesthereafter,particularlybeyond2weeks,58,72,243,250althoughsomeriskpersistsindefinitelywhilevegetationsremainpresent,particularlyforverylargevegetations.113Forthisreason,thebenefitsofsurgerytopreventembolismaregreatestduringthefirst2weeksofantibiotictherapy,whenembolicriskpeaks.8.3.3Indicationsandtimingofsurgerytopreventembolismininfectiveendocarditis(Table22) Avoidingemboliceventsisdifficultsincethemajorityoccurbeforeadmission.222Thebestmeanstoreducetheriskofanemboliceventisthepromptinstitutionofappropriateantibiotictherapy.38Whilepromising,256,257theadditionofantiplatelettherapydidnotreducetheriskofembolismintheonlypublishedrandomizedstudy.258Theexactroleofearlysurgeryinpreventingemboliceventsremainscontroversial.IntheEuroHeartSurvey,vegetationsizewasoneofthereasonsforsurgeryin54%ofpatientswithNVEandin25%ofthosewithPVE,54butwasrarelytheonlyreason.Thevalueofearlysurgeryinanisolatedlargevegetationiscontroversial.Arecentrandomizedtrialdemonstratedthatearlysurgeryinpatientswithlargevegetationssignificantlyreducedtheriskofdeathandemboliceventscomparedwithconventionaltherapy.9However,thepatientsstudiedwereatlowriskandtherewasnosignificantdifferenceinall-causemortalityat6monthsintheearlysurgeryandconventional-treatmentgroups.Finally,thedecisiontooperateearlyforpreventionofembolismmusttakeintoaccountthepresenceofpreviousembolicevents,othercomplicationsofIE,thesizeandmobilityofthevegetation,thelikelihoodofconservativesurgeryandthedurationofantibiotictherapy.115Theoverallbenefitsofsurgeryshouldbeweighedagainsttheoperativeriskandmustconsidertheclinicalstatusandco-morbidityofthepatient.ThemainindicationsandtimingofsurgerytopreventembolismaregiveninTable22.Surgeryisindicatedinpatientswithpersistingvegetations>10mmafteroneormoreclinicalorsilentemboliceventsdespiteappropriateantibiotictreatment.58Surgerymaybeconsideredinpatientswithlarge(>15mm)isolatedvegetationsontheaorticormitralvalve,althoughthisdecisionismoredifficultandmustbeverycarefullyindividualizedaccordingtotheprobabilityofconservativesurgery.58Surgeryundertakenforthepreventionofembolismmustbeperformedveryearly,duringthefirstfewdaysfollowinginitiationofantibiotictherapy(urgentsurgery),astheriskofembolismishighestatthistime.58,72Insummary,embolismisveryfrequentinIE,complicating20–50%ofcasesofIE,butfallingto6–21%afterinitiationofantibiotictherapy.Theriskofembolismishighestduringthefirst2weeksofantibiotictherapyandisclearlyrelatedtothesizeandmobilityofthevegetation,althoughotherriskfactorsexist.Thedecisiontooperateearlytopreventembolismisalwaysdifficultandspecificfortheindividualpatient.Governingfactorsincludethesizeandmobilityofthevegetation,previousembolism,typeofmicroorganismanddurationofantibiotictherapy.9.Othercomplicationsofinfectiveendocarditis 9.1Neurologicalcomplications Symptomaticneurologicalcomplicationsoccurin15–30%ofpatientswithIEandaremainlytheconsequenceofembolismfromvegetations.110,113,259NeurologicalmanifestationsoccurbeforeoratIEdiagnosisinamajorityofcases,butneworrecurrenteventscanalsotakeplacelaterinthecourseofIE.Clinicalpresentationisvariableandmayincludemultiplesymptomsorsignsinthesamepatient,butfocalsignspredominateandischaemicstrokesaremostcommonlydiagnosed.Transientischaemicattack,intracerebralorsubarachnoidalhaemorrhage,brainabscess,meningitisandtoxicencephalopathyarealsoseen,andfirmevidencesupportsthatadditionalclinicallysilentcerebralembolismsoccurin35–60%ofIEpatients.83,85,90S.aureusIEismorefrequentlyassociatedwithneurologicalcomplicationscomparedwithIEcausedbyotherbacteria.Vegetationlengthandmobilityalsocorrelatewithembolictendency.88,242Neurologicalcomplicationsareassociatedwithanexcessmortality,aswellassequelae,particularlyinthecaseofstroke.113,259Rapiddiagnosisandinitiationofappropriateantibioticsareofmajorimportancetopreventafirstorrecurrentneurologicalcomplication.250Earlysurgeryinhigh-riskpatientsisthesecondmainstayofembolismprevention,whileantithromboticdrugshavenorole(seesection12.7).SuccessfulmanagementofIErequiresacombinedmedicalandsurgicalapproachinasubstantialproportionofpatients.Followinganeurologicalevent,theindicationforcardiacsurgeryoftenremainsorisstrengthened,butmustbebalancedwithperioperativeriskandpostoperativeprognosis.Randomizedstudiesarenotpossibleandcohortstudiessufferfrombiasthatcanonlybepartlycompensatedforbystatisticalmethods.115,260–262However,theriskofpostoperativeneurologicaldeteriorationislowafterasilentcerebralemboliortransientischaemicattack,andsurgeryisrecommendedwithoutdelayifanindicationremains.105Afteranischaemicstroke,cardiacsurgeryisnotcontraindicatedunlesstheneurologicalprognosisisjudgedtoopoor.263Evidenceregardingtheoptimaltimeintervalbetweenstrokeandcardiacsurgeryisconflicting,butrecentdatafavourearlysurgery.9,115IfcerebralhaemorrhagehasbeenexcludedbycranialCTandneurologicaldamageisnotsevere(i.e.coma),surgeryindicatedforHF,uncontrolledinfection,abscessorpersistenthighembolicriskshouldnotbedelayedandcanbeperformedwithalowneurologicalrisk(3–6%)andgoodprobabilityofcompleteneurologicalrecovery.105,263Conversely,incaseswithintracranialhaemorrhage,neurologicalprognosisisworseandsurgeryshouldgenerallybepostponedforatleast1month,264,265althoughonerecentstudyhasreportedarelativelylowriskofneurologicaldeteriorationinIEpatientsundergoingsurgerywithin2weeksafteranintracranialhaemorrhage.266TheTaskForcehasthusdecidedtoadaptthelevelofevidencetoaclassIIa.Ifurgentcardiacsurgeryisneeded,closecooperationwiththeneurosurgicalteamandtheEndocarditisTeamismandatory.Table23andFigure4summarizetherecommendedmanagementofneurologicalcomplicationsinIE. Table23Managementofneurologicalcomplicationsofinfectiveendocarditis  CT=computedtomography;HF=heartfailure;IE=infectiveendocarditis;MR=magneticresonance;MRI=magneticresonanceimaging.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table23Managementofneurologicalcomplicationsofinfectiveendocarditis  CT=computedtomography;HF=heartfailure;IE=infectiveendocarditis;MR=magneticresonance;MRI=magneticresonanceimaging.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Figure4OpeninnewtabDownloadslideTherapeuticstrategiesforpatientswithinfectiveendocarditisandneurologicalcomplications.Figure4OpeninnewtabDownloadslideTherapeuticstrategiesforpatientswithinfectiveendocarditisandneurologicalcomplications.CerebralimagingismandatoryforanysuspicionofneurologicalcomplicationofIE.CTscanning,withorwithoutcontrastagent,ismostoftenperformed.ThehighersensitivityofMRI,withorwithoutcontrastgadoliniumenhancement,allowsforbetterdetectionandanalysisofcerebrallesionsinpatientswithneurologicalsymptoms,andthismayhaveanimpactonthetimingofsurgery89(seesection5).Inpatientswithoutneurologicalsymptoms,cerebralMRIoftendetectslesionsthatmaychangethetherapeuticstrategy;inparticular,theindicationsandtimingofsurgery.85,90CerebralMRIoftendetectsmicrobleeds(roundT2*hypointensitieswithadiameter≤10mm)inpatientswithIE.Thelackofassociationwithparenchymalhaemorrhageandtheabsenceofpostoperativeneurologicalcomplicationsinpatientswithmicrobleedssuggestthatmicrobleedsshouldnotbeinterpretedasactivebleedingandshouldnotleadtopostponedsurgerywhenthisisindicated.89,90Insummary,symptomaticneurologicaleventsdevelopin15–30%ofallpatientswithIEandadditionalsilenteventsarefrequent.Stroke(ischaemicandhaemorrhagic)isassociatedwithexcessmortality.Rapiddiagnosisandinitiationofappropriateantibioticsareofmajorimportancetopreventafirstorrecurrentneurologicalcomplication.Afterafirstneurologicalevent,cardiacsurgery,ifindicated,isgenerallynotcontraindicated,exceptwhenextensivebraindamageorintracranialhaemorrhageispresent.9.2Infectiousaneurysms Infectious(mycotic)aneurysmsresultfromsepticarterialembolismtotheintraluminalspaceorvasavasorumorfromsubsequentspreadofinfectionthroughtheintimalvessels.Infectiousaneurysmsaretypicallythinwalledandfriableand,assuch,exhibitahightendencytoruptureandhaemorrhage.Nopredictorofrupturehasbeenidentifiedand,incontrasttonon-infectiousaneurysms,sizedoesnotappeartobeareliablepredictorofpotentialrupture.268,269Anintracraniallocationismostcommonandthereportedfrequencyof2–4%isprobablyanunderestimationsincesomeinfectiousaneurysmsareclinicallysilent.267,270Earlydetectionandtreatmentofinfectiousaneurysmsisessentialgiventhehighmorbidityandmortalityratesecondarytorupture.Clinicalpresentationishighlyvariable(i.e.focalneurologicaldeficit,headache,confusion,seizures),soimagingshouldbesystematicallyperformedtodetectintracranialinfectiousaneurysmsinanycaseofIEwithneurologicalsymptoms.268CerebralCTandMRIbothreliablydiagnoseinfectiousaneurysmswithgoodsensitivityandspecificity.271However,conventionalangiographyremainsthegoldstandardandshouldbeperformedwhennon-invasivetechniquesarenegativeandsuspicionremains.267Owingtothelackofrandomizedtrials,thereisnowidelyacceptedstandardmanagementforinfectiousaneurysms.ThusmanagementshouldbeprovidedbyanEndocarditisTeamandtailoredtotheindividualpatient.Someinfectiousaneurysmsmayresolveduringantibiotictreatment,whileothersrequiresurgicalorendovascularinterventiondependingontheoccurrenceofruptureandthelocationinthearterybed,aswellastheclinicalstatusofthepatient.268,269Regardingintracranialinfectiousaneurysms,rupturedaneurysmsmustbetreatedimmediatelybysurgicalorendovascularprocedures.Unrupturedinfectiousaneurysmsshouldbefollowedbyserialcerebralimagingunderantibiotictherapy.Ifthesizeoftheaneurysmdecreasesorresolvescompletely,surgicalorendovascularinterventionisusuallyunnecessary.However,ifthesizeoftheaneurysmincreasesorremainsunchanged,itislikelythatthepatientwillrequireintervention.Ontheotherhand,iftheinfectiousaneurysmisvoluminousandsymptomatic,neurosurgeryorendovasculartherapyisrecommended.272Finally,ifearlycardiacsurgeryisrequired,preoperativeendovascularinterventionmightbeconsideredbeforetheprocedure,dependingonassociatedcerebrallesions,thehaemodynamicstatusofthepatientandtheriskoftheprocedure.9.3Spleniccomplications Splenicinfarctsarecommonandveryoftenasymptomatic.Persistentorrecurrentfever,abdominalpainandbacteraemiasuggestthepresenceofcomplications(splenicabscessorrupture).Althoughsplenicemboliarecommon,splenicabscessesarerare.Persistentorrecurrentfeverandbacteraemiasuggestthediagnosis.ThesepatientsshouldbeevaluatedbyabdominalCT,MRIorultrasound.RecentlyPEThasprovedusefulforthediagnosisofsplenicmetastasicinfectioninpatientswithIE.273Treatmentconsistsofappropriateantibioticregimens.Splenectomymaybeconsideredforsplenicruptureorlargeabscesses,whichrespondpoorlytoantibioticsalone,andshouldbeperformedbeforevalvularsurgeryunlessthelatterisurgent.Rarely,splenectomyandvalvularsurgeryareperformedduringthesameoperativetime.Percutaneousdrainageisanalternativeforhigh-risksurgicalcandidates.274,2759.4Myocarditisandpericarditis Cardiacfailuremaybeduetomyocarditis,whichisfrequentlyassociatedwithabscessformationorimmunereaction.Ventriculararrhythmiasmayindicatemyocardialinvolvementandimplyapoorprognosis.MyocardialinvolvementisbestassessedusingTTEandcardiacMRI.Theinflammatoryresponse,HF,periannularcomplicationsorinfectionitselfcancausepericardialeffusion,whichcouldbeasignofmoresevereIE.Rarely,rupturedpseudoaneurysmsorfistulaemaycommunicatewiththepericardium,withdramaticandoftenfatalconsequences.Purulentpericarditisisrareandmaynecessitatesurgicaldrainage.276,2779.5Heartrhythmandconductiondisturbances ConductiondisordersareuncommoncomplicationsofIE.Accordingtodatafrompatientregistries,theirfrequencyisbetween1%and15%ofcasesandtheirpresenceisassociatedwithworseprognosisandhighermortality.278Conductionabnormalities(mainlyfirst-,second-,andthird-degreeatrio-ventricularblocks,rarelybundlebranchblocks)areduetospreadoftheinfectionbeyondtheendocardium,fromvalvestotheconductionpathways,andaregenerallyassociatedwithperivalvularcomplications.Completeatrio-ventricularblockismostoftenassociatedwithinvolvementoftheleft-sidedvalves(aortic,36%;mitral,33%).278Thisisbecauseoftheanatomicalrelationshipwiththeatrio-ventricularnode,whichisclosetothenon-coronaryaorticcuspandtheanteriormitralleaflet.InastudyofpatientswithIEandcompleteatrio-ventricularblock,pathologyworkuprevealedthepresenceofaninfection,frequentlyaccompaniedbyabscessesandfistulae,affectingtheconductionpathways;incasesofparoxysmalatrio-ventricularblock,inflammationwasobservedatthislevel,whichwouldexplainthereversibilityoftheevent.279Theoccurrenceofconductionabnormalitiesduringelectrocardiographicmonitoringinpatientswithendocarditiscanthereforealertphysicianstotheappearanceofperivalvularcomplications.Inthecaseofembolizationofvegetationfragmentsintoacoronaryartery,theresultingmyocardialischaemiacanbethesubstratefortheonsetoftachyarrhythmias.280AtrialfibrillationcanbeobservedinpatientswithIEandmaybepresentbeforeIEoroccurasacomplicationofIE.Atrialfibrillationhasbeenreportedtobemorefrequentintheelderlyandtobeassociatedwithapoorprognosis.281Morerecently,inalargeprospectiveseriesofIE,atrialfibrillationwasfoundtobeassociatedwithanincreasedembolicrisk,aswereotherfactors(age,diabetes,previousembolism,vegetationlengthandS.aureusinfection).222Consequently,atrialfibrillationhasthepotentialtoincreasetheriskofbothcongestiveHFandembolisminIE.However,thereisnospecificstudyonthissituationandnointernationalconsensusforthecareofthesepatients.ThemanagementofanticoagulationtherapyinthesepatientsshouldbetakenonanindividualbasisbytheEndocarditisTeam.9.6Musculoskeletalmanifestations Musculoskeletalsymptoms(arthralgia,myalgia,backpain)arefrequentduringIE.282,283RheumatologicalmanifestationsmaybethefirstmanifestationsofIEandcandelayitsdiagnosis,especiallywhenclassicmanifestationsarelessevidentandavarietyofantibodies(i.e.positiveantineutrophilcytoplasmicantibodytest)inducedbyinfections284,285arepresent.Arthralgiaoccursinabout10%ofpatients,whilemyalgiaispresentin12–15%.282,286Backpainisobservedinabout13%ofcases,andlumbarpainisthemostcommonsymptominpatientswithIEandvertebralosteomyelitis.282,283,287,288Peripheralarthritisoccursinabout14%ofcases.282TheprevalenceofspondylodiscitisinpatientswithIEisabout1.8–15%.282Pyogenicvertebralosteomyelitisoccursin4.6–19%ofIEpatientswithahighincidenceofstreptococcalandstaphylococcalbacteraemia.283,287IEcancomplicateorbecomplicatedbypyogenicosteomyelitis.TheprevalenceofIEinvertebralosteomyelitisishigher288,289inthepresenceofStreptococcusviridansIE.CT,butpreferablyMRI,ofthespineorwhole-body18F-FDG-PET/CT290shouldbeperformedinIEpatientswithbackorbonepain.Conversely,echocardiographyshouldbeperformedinpatientswithadefinitediagnosisofpyogenicspondylodiscitis/osteomyelitisandunderlyingcardiacconditionspredisposingtoIE.Indefinitespondylodiscitisandosteomyelitis,prolongedantibiotictherapyisgenerallyrequireduntilnosignsofinflammatoryactivityaredetectedby18FDGPET/CTorMRI.OthermusculoskeletalmanifestationsarelesscommoninIEandincludesacroiliitisinabout1%ofcases,aconditionmimickingpolymyalgiarheumaticawithpainandmorningstiffnessoftheshouldersandhips,proximalmuscleweaknessinabout0.9%ofcasesandcutaneousleucocytoclasticvasculitis(purpuricskinlesions)in3.6%ofcases.282,2899.7Acuterenalfailure AcuterenalfailureisacommoncomplicationofIEandmayworsentheprognosisofIE.Theonsetofrenaldysfunctionisindependentlyassociatedwithincreasedriskofin-hospitaldeath291,292andpostoperativeevents.293Acuterenaldysfunctionoccursinabout6–30%ofpatients.291,292,294,295Causesareoftenmultifactorial:296,297(i)immunecomplexandvasculiticglomerulonephritis;(ii)renalinfarction,mostlyduetosepticemboli,occurringatanytimeduringthecourseofthedisease;(iii)haemodynamicimpairmentincaseswithHForseveresepsisoraftercardiacsurgery;(iv)antibiotictoxicity(acuteinterstitialnephritis),notablyrelatedtoaminoglycosides,vancomycin(synergistictoxicitywithaminoglycosides)andevenhigh-dosepenicillin;and(v)nephrotoxicityofcontrastagentsusedforimagingpurposes.Haemodialysismayberequiredinsomepatientswithadvancedrenalfailureandisassociatedwithhighmortality.295Acuterenalfailureofamilderdegreeisoftenreversible.295Tomitigatethiscomplication,antibioticdosesshouldbeadjustedforcreatinineclearancewithcarefulmonitoringofserumlevels(aminoglycosidesandvancomycin).Imagingwithnephrotoxiccontrastagentsshouldbeavoidedwhenpossibleinpatientswithhaemodynamicimpairmentorpreviousrenalinsufficiency.10.Surgicaltherapy:principlesandmethods 10.1Operativeriskassessment FewstudieshaveevaluatedtheutilityofoperativeriskscoresinthesettingofIE.AlthoughEuroSCOREIIisfrequentlyused,298itwasdevelopedandvalidatedpredominantlyforcoronaryarterybypassgraftingandvalvesurgery.RiskscoresspecifictoIEsurgeryhavebeendeveloped:(i)fromtheSocietyofThoracicSurgeonsdatabaseusing13617patients299and(ii)anadditionalNVEriskscorefromasinglecentreusing440patientsbyDeFeoetal.300AstudycomparedtheprognosticutilityofthesecontemporaryriskscoresformortalityandmorbidityafterIEsurgeryin146patients.301Here,althoughEuroSCOREIIdiscriminatedmortalityandpostoperativemorbidity(inparticular,stroke),theSocietyofThoracicSurgeonsendocarditisscoreandtheDeFeoetal.score300performedbetteratpredictingoperativemortalityaftersurgeryforactiveIE.However,therelevanceofthesefindingsislimitedbythesmallnumberofpatientsinvolved.Similartopreviousstudies,preoperativeuseofinotropesoranintra-aorticballoonpump,priorcoronaryarterybypasssurgeryandrenalfailurerequiringdialysiswereindependentpredictorsofoperativeandlong-termmortality.Finally,althoughnosingleoperativeriskscoreisperfect,preoperativeassessmentofoperativeriskisofutmostimportance.AlthoughthetheoreticalindicationsforsurgeryinIEareclear(Table22),theirpracticalapplicationrelieslargelyontheclinicalstatusofthepatient,thepatient'sco-morbiditiesandthepatient'soperativerisk.10.2Preoperativeandperioperativemanagement 10.2.1Coronaryangiography CoronaryangiographyisrecommendedaccordingtotheESCGuidelinesonthemanagementofvalvularheartdisease55inmen>40years,inpost-menopausalwomenandinpatientswithatleastonecardiovascularriskfactororahistoryofcoronaryarterydisease.Exceptionsarisewhenthereareaorticvegetationsthatmaybedislodgedduringcatheterizationorwhenemergencysurgeryisnecessary.Inthesesituations,high-resolutionCTmaybeusedtoruleoutsignificantcoronaryarterydiseaseinhaemodynamicallystablepatients.5510.2.2Extracardiacinfection IfaprimaryfocusofinfectionlikelytoberesponsibleforIEhasbeenidentified,itmustbeeradicatedbeforecardiacsurgicalinterventionunlessvalvesurgeryisurgent.Inanycase,itshouldbeeradicatedbeforetheendofantibiotictherapy.10.2.3Intraoperativeechocardiography IntraoperativeTOEismostusefultodeterminetheexactlocationandextentofinfection,guidesurgery,assesstheresultandhelpinearlypostoperativefollow-up.7310.3Surgicalapproachandtechniques Thetwoprimaryobjectivesofsurgeryaretotalremovalofinfectedtissuesandreconstructionofcardiacmorphology,includingrepairorreplacementoftheaffectedvalve(s).Whereinfectionisconfinedtothevalvecuspsorleaflets,anymethodtorepairorreplacethevalvemaybeused.However,valverepairisfavouredwheneverpossible,particularlywhenIEaffectsthemitralortricuspidvalvewithoutsignificantdestruction.302Perforationsinasinglevalvecusporleafletmayberepairedwithanuntreatedorglutaraldehyde-treatedautologousorbovinepericardialpatch.Isolatedormultiplerupturedchordaemaybereplacedbypolytetrafluoroethyleneneo-chordae.Moreextensivedestructionofasingleleafletorthepresenceofanabscessisnotnecessarilyacontraindicationforvalverepair.302Rather,intraoperativeassessmentofthevalveafterdebridementisofparamountimportanceinordertoevaluatewhethertheremainingtissueisofsufficientqualitytoachieveadurablerepair.Theneedforapatchtoachieveacompetentvalve,whetherpericardial,tricuspidautograftoraflipped-overmitralpatch,hasnotbeenassociatedwithworseresultsintermsofrecurrenceofIEormitralregurgitationwhenperformedbyexperiencedsurgeons.303Toavoidparavalvularleaksincomplexcaseswithlocallyuncontrolledinfection,totalexcisionofinfectedanddevitalizedtissueshouldbefollowedbyvalvereplacementandrepairofassociateddefectstosecurevalvefixation.304Mechanicalandbiologicalprostheseshavesimilaroperativemortality.305ThereforetheTaskForcedoesnotfavouranyspecificvalvesubstitutebutrecommendsatailoredapproachforeachindividualpatientandclinicalsituation.Theuseofforeignmaterialshouldbekepttoaminimum.Smallabscessescanbecloseddirectly,butlargercavitiesshouldbeallowedtodrainintothepericardiumorcirculation.InmitralvalveIE,successfulvalverepaircanbeachievedbyexperiencedteamsinupto80%ofpatients,butsuchresultsmaynotbematchedinnon-specialistcentres.306Moreover,althoughsurgerymaybedeferredifcontroloftheinfectionbyantibiotictherapyappearsevidentintheabsenceofcardiacfailure,earlyoperationhasbeenassociatedinrecentreportswitharepairrateof61–80%andimprovedin-hospitalandlong-termsurvival.209,210,302,303,307ResidualmitralregurgitationshouldbeassessedusingintraoperativeTOE.Mitralsubannular,annularorsupraannulartissuedefectsarepreferablyrepairedwithautologousorbovinepericardium,aprostheticvalvethenbeingsecuredtothereconstructed/reinforcedannulus,ifnecessary.Thechoiceoftechniquedependsontheverticalextensionofthelesion/tissuedefect.308–310Theuseofmitralvalvehomograftsandpulmonaryautografts(RossIIprocedure)hasbeensuggested,311,312buttheirapplicationislimitedbypooravailabilityanddifficultyofthesurgicaltechnique,andtheresultshavenotbeenconsistent.InaorticIE,replacementoftheaorticvalveusingamechanicalorbiologicalprosthesisisthetechniqueofchoice.Nevertheless,incentreswithgreatexpertise,aorticvalverepairinIEcanbeachievedinupto33%ofpatients.However,experiencewithaorticvalverepairinthissettingisstillverylimitedandthereisnoevidencethatrepairisassociatedwithimprovedoutcomescomparedwithreplacement.313,314Owingtotheirnaturalbiocompatibility,theuseofcryopreservedorsterilizedhomograftshasbeensuggestedtoreducetheriskofpersistentorrecurrentinfection,especiallyinthepresenceofannularabscesses.315,316Itisexpertopinionandstandardstrategyinmanyinstitutionsthattheuseofahomograftistobefavouredovervalveprostheses,particularlyinthepresenceofrootabscess.316,317However,mechanicalprosthesesandxenograftshaveledtosimilarresultsintermsofpersistentorrecurrentinfectionandsurvivalifassociatedwithcompletedebridementofannularabscesses.313,318HomograftsorstentlessxenograftsmaybepreferredinPVEorincaseswherethereisextensiveaorticrootdestructionwithaorto-ventriculardiscontinuity.315,319Theanteriormitralleafletoftheaortichomograftcanbeeffectivelyusedforreconstructionoftheoutflowtract.Amonoblockaorto-mitralhomografthasbeensuggestedasasurgicaloptionforextensivebivalvularIE.320Inexperiencedhands,theRossproceduremaybeusedinchildrenoradolescentstofacilitategrowthandinyoungadultsforextendeddurability.321,322CardiactransplantationmaybeconsideredinextremecaseswhererepeatedoperativeprocedureshavefailedtoeradicatepersistentorrecurrentPVE.32310.4Postoperativecomplications Postoperativepatientmanagementshouldfollowtheusualrecommendationsaftervalvularsurgery324butshouldalsotakeintoaccountthespecificitiesofIE.Postoperativefollow-upshouldbeparticularlycautiousgiventhein-hospitalmortalityofpatientsoperatedonforacuteIEonanemergencyorurgentbasis,whichrangesfrom10%to20%inmostseries,1andtheincreasedriskofpostoperativecomplications.Amongthemostfrequentcomplicationsareseverecoagulopathyrequiringtreatmentwithclottingfactors,re-explorationofthechestforbleedingortamponade,acuterenalfailurerequiringhaemodialysis,stroke,lowcardiacoutputsyndrome,pneumoniaandatrio-ventricularblockfollowingradicalresectionofanaorticrootabscesswiththeneedforpacemakerimplantation.325Apreoperativeelectrocardiogramdemonstratingleftbundlebranchblockpredictstheneedforapostoperativepermanentpacemaker.23Whenapatientdoesnotsurvivesurgery,thecauseofdeathisoftenmultifactorial.32511.Outcomeafterdischarge:follow-upandlong-termprognosis Followingin-hospitaltreatment,themaincomplicationsincluderecurrenceofinfection,HF,needforvalvesurgeryanddeath.57,326,32711.1Recurrences:relapsesandreinfections TheactualriskofrecurrenceamongsurvivorsofIEvariesbetween2%and6%.57,326–332Twomaintypesofrecurrencearedistinguishable:relapseandreinfection.Althoughnotsystematicallydifferentiatedintheliterature,theterm‘relapse’referstoarepeatepisodeofIEcausedbythesamemicroorganism,while‘reinfection’describesaninfectioncausedbyadifferentmicroorganism.38WhenthesamespeciesisisolatedduringasubsequentepisodeofIE,thereisoftenuncertaintyastowhethertherepeatinfectionisarelapseoftheinitialinfectionoranewinfection(reinfection).Inthesecases,molecularmethodsincludingstrain-typingtechniquesshouldbeemployed.8,38Whenthesetechniquesortheidentityofbothisolatesisunavailable,thetimingofthesecondepisodeofIEmaybeusedtodistinguishrelapsefromreinfection.Thus,althoughvariable,thetimebetweenepisodesisusuallyshorterforrelapsethanforreinfection.Generallyspeaking,arecurrencecausedbythesamespecieswithin6monthsfollowingtheinitialinfectionrepresentsrelapse,whereaslatereventssuggestreinfection.38Forthesepurposes,storageofIEisolatesforatleast1yearisrecommended.8,38FactorsassociatedwithanincreasedrateofrelapsearelistedinTable24.Relapsesaremostoftenduetoinsufficientdurationoforiginaltreatment,suboptimalchoiceofinitialantibioticsorapersistentfocusofinfection.Whenthedurationoftherapyhasbeeninsufficientorthechoiceofantibioticincorrect,relapseshouldbetreatedforafurther4–6weeksdependingonthecausativemicroorganismanditsantibioticsusceptibility(rememberingthatresistancemaydevelopinthemeantime). Table24Factorsassociatedwithanincreasedrateofrelapse  BCNIE=bloodculture-negativeinfectiveendocarditis;IE=infectiveendocarditis;IVDA=intravenousdrugabuser. Openinnewtab Table24Factorsassociatedwithanincreasedrateofrelapse  BCNIE=bloodculture-negativeinfectiveendocarditis;IE=infectiveendocarditis;IVDA=intravenousdrugabuser. Openinnewtab PatientswithpreviousIEareatriskofreinfection,332andprophylacticmeasuresshouldbeverystrict.ReinfectionismorefrequentinIVDAs(especiallyintheyearaftertheinitialepisode),332,333inPVE,334inpatientsundergoingchronicdialysis326,332andinthosewithmultipleriskfactorsforIE.8Patientswithreinfectionareathigherriskofdeathandneedforvalvereplacement.325,332Paravalvulardestructionisassociatedwithahigherrateofrecurrenceandahigheroperativemortality.331InalargeseriesofsurgicallymanagedNVE(358cases),21%hadparavalvulardestruction,andfreedomfromrecurrentPVEat15yearswas78.9%.331ThetypeofvalveimplantedhasnoeffectontheriskofrecurrentIE.325,331Aorticvalveandrootreplacementwithaprostheticconduityieldsresultssimilartothoseforhomograftrootreplacement.335,33611.2Short-termfollow-up AfirstepisodeofIEshouldnotbeseenasanendingoncethepatienthasbeendischarged.Residualseverevalveregurgitationmaydecompensateleftventricularfunction,orvalvedeteriorationmayprogressdespitebacteriologicalcure,usuallypresentingwithacuteHF.Aftercompletionoftreatment,recommendationsforsurgeryfollowconventionalguidelines.55Asaconsequenceofincreasingratesofsurgeryduringtheactivephaseofinfection,theneedforlatevalvesurgeryislow,rangingfrom3%to8%inrecentseries.326–328PatientsshouldbeeducatedaboutthesignsandsymptomsofIEafterdischarge.TheyshouldbeawarethatrecurrencecouldoccurinIEandthatnewonsetoffever,chillsorothersignsofinfectionmandateimmediateevaluation,includingprocurementofbloodculturesbeforeempiricaluseofantibiotics.TomonitorthedevelopmentofsecondaryHF,aninitialclinicalevaluationandbaselineTTEshouldbeperformedatthecompletionofantimicrobialtherapyandrepeatedserially,particularlyduringthefirstyearoffollow-up.Clinicalfollow-upshouldbedonebytheEndocarditisTeamorbyaHeartValveClinicspecialist.11,337Regularclinicalandechocardiographicfollow-upshouldbeperformedduringthefirstyearfollowingcompletionoftreatment.8,12ThisTaskForcealsorecommendstotakebloodsamples(i.e.whitecellcount,CRP,etc.),andbloodculturessystematicallyattheinitialvisit,andotherwiseifthereisclinicalsuspicion.Goodoralhealthmaintenance,preventivedentistryandadviceaboutskinhygiene,includingtattoosandskinpiercing,aremandatory.DeficienciesindentalsurveillancecontributetothecontinuousgradualincreaseintheincidenceofIE.30,337ThisincreaseunderlinestheneedforrepeatingtheprinciplesofIEpreventionateachfollow-upvisit.11.3Long-termprognosis Inrecentseries,thecrudelong-termsurvivalratesafterthecompletionoftreatmentwereestimatedtobe80–90%at1year,70–80%at2yearsand60–70%at5years.57,326–332Themainpredictorsoflong-termmortalityareolderage,co-morbidities,recurrencesandHF,especiallywhencardiacsurgerycannotbeperformed.57,327,330Comparedwithanage-andsex-matchedgeneralpopulation,patientssurvivingafirstepisodeofIEhaveasignificantlyworsesurvival.57ThisexcessmortalityisespeciallyhighwithinthefirstfewyearsafterhospitaldischargeandcanbeexplainedbylatecomplicationssuchasHF,higherriskofrecurrencesandhigherpatientvulnerability.57,329Infact,mostrecurrencesandlatecardiacsurgeriesoccurredduringthisperiodoftime.57,328,329Insummary,recurrencesarerarefollowingIEandmaybeassociatedwithinadequateinitialantibiotictherapy,resistantmicroorganisms,persistentfocusofinfection,i.v.drugabuseandchronicdialysis.PatientswithIEmustbeinformedoftheriskofrecurrenceandeducatedabouthowtodiagnoseandpreventanewepisodeofIE.Theneedforlatevalvesurgeryislow.12.Managementofspecificsituations 12.1Prostheticvalveendocarditis PVEisthemostsevereformofIEandoccursin1–6%ofpatientswithvalveprostheses,338withanincidenceof0.3–1.2%perpatient-year.216,233,339,340PVEaccountsfor10–30%ofallcasesofIE341andaffectsmechanicalandbioprostheticvalvesequally.PVEwasobservedin16%ofcasesofIEinaFrenchsurvey,122in26%ofcasesintheEuroHeartSurvey54andin20%of2670patientswithdefiniteIEintheICEProspectiveCohortStudy.340PVEisstillassociatedwithdifficultiesindiagnosis,determinationoftheoptimaltherapeuticstrategyandpoorprognosis.12.1.1Definitionandpathophysiology EarlyPVEisdefinedasIEoccurringwithin1yearofsurgeryandlatePVEasIEoccurringbeyond1year,becauseofsignificantdifferencesbetweenthemicrobiologicalprofilesobservedbeforeandafterthistimepoint.3,342However,thisisanartificialdistinction.WhatisimportantisnotthetimefromthevalvereplacementproceduretotheonsetofIE,butwhetherIEisacquiredperioperativelyandwhichmicroorganismisinvolved.Arecentlarge,prospective,multicentre,internationalregistryreportedthat37%ofPVEcaseswereassociatedwithnosocomialinfectionornon-nosocomialhealthcare-associatedinfectionsinoutpatientswithextensivehealthcarecontact.340ThepathogenesisofPVEdiffersaccordingtoboththetypeofcontaminationandthetypeofprostheticvalve.Incaseswithperioperativecontamination,theinfectionusuallyinvolvesthejunctionbetweenthesewingringandtheannulus,leadingtoperivalvularabscess,dehiscence,pseudo-aneurysmsandfistulae.339,343,344InlatePVE,additionalmechanismsmayexist.Forexample,inlatebioprostheticPVE,infectionisfrequentlylocatedontheleafletsoftheprosthesis,leadingtovegetations,cuspruptureandperforation.PVEhasrecentlybeenreportedaftertranscatheteraorticbioprostheticvalveimplantation,whichshouldbemanagedinthesamemannerasotherprostheticvalves.345,346Theriskofprostheticvalveimplantationendocarditisincreaseswiththeuseoforotrachealintubationandaself-expandablevalvesystem.TheconsequenceofPVEisusuallynewprostheticregurgitation.Lessfrequently,largevegetationsmaycauseprostheticvalveobstruction,whichcanbediagnosedbyTOEandsometimesbyTTEorfluoroscopy.12.1.2Diagnosis DiagnosisismoredifficultinPVEthaninNVE.Clinicalpresentationisfrequentlyatypical,particularlyintheearlypostoperativeperiod,inwhichfeverandinflammatorysyndromesarecommonintheabsenceofIE.However,persistentfevershouldtriggerthesuspicionofPVE.AsinNVE,diagnosisofPVEisbasedmainlyontheresultsofechocardiographyandbloodcultures.However,botharemorefrequentlynegativeinPVE.100AlthoughTOEismandatoryinsuspectedPVE(Figure3),itsdiagnosticvalueislowerthaninNVE.AnegativeechocardiogramisfrequentlyobservedinPVE2anddoesnotruleoutthediagnosis,butidentificationofanewperiprostheticleakisamajorcriterion,inwhichcaseanadditionalimagingmodalitycouldbeconsidered(suchasCTornuclearimaging).InPVE,staphylococcalandfungalinfectionsaremorefrequentandstreptococcalinfectionlessfrequentthaninNVE.Staphylococci,fungiandGram-negativebacilliarethemaincausesofearlyPVE,whilethemicrobiologyoflatePVEmirrorsthatofNVE,withstaphylococci,oralstreptococci,S.bovisandenterococcibeingthemostfrequentorganisms,morelikelyduetocommunity-acquiredinfections.Staphyloccociandenteroccociarethemostcommonagentsinprostheticvalveimplantationendocarditis.345,346TheDukecriteriahavebeenshowntobehelpfulforthediagnosisofNVE,withasensitivityof70–80%,100,347butarelessusefulinPVEbecauseoftheirlowersensitivityinthissetting.348,349Recently,nucleartechniques,particularly18F-FDGPET/CT,havebeenshowntobeusefulforthediagnosisofPVE.93TheadditionofabnormalFDGuptakeasanovelmajorcriterionforPVEhasthusbeenpointedout.AnalgorithmforevaluationofpatientswithsuspectedPVE,includingechocardiographyandPET/CThasbeensuggested(seeFigure3).9312.1.3Prognosisandtreatment Averyhighin-hospitalmortalityrateof20–40%hasbeenreportedinPVE.338,341AsinNVE,prognosticassessmentisofcrucialimportanceinPVE,asitallowsidentificationofhigh-risksubgroupsofpatientsinwhomanaggressivestrategymaybenecessary.SeveralfactorshavebeenassociatedwithpoorprognosisinPVE,161,216,350–353includingolderage,diabetesmellitus,healthcare-associatedinfections,staphylococcalorfungalinfection,earlyPVE,HF,strokeandintracardiacabscess.Amongthese,complicatedPVEandstaphylococcalinfectionarethemostpowerfulmarkers.Thesepatientsneedaggressivemanagement,consistingofantibiotictherapyandearlyradicalsurgery.AntimicrobialtherapyforPVEissimilartothatforNVE.AnexceptionisS.aureusPVE,whichrequiresamoreprolonged(≥6weeks)antibioticregimen(particularlyinassociationwithaminoglycosides)andfrequentuseofrifampin.SurgeryforPVEfollowsthegeneralprinciplesoutlinedforNVE.Radicaldebridementinthesecasesmeansremovalofallinfectedforeignmaterial,includingtheoriginalprosthesis,andanycalciumremainingfromprevioussurgery.Homografts,stentlessxenograftsorautograftsmaybeconsideredinaorticPVE,andhomograftorxenograftrootreplacementisindicatedforanyabnormalityoftheaorticrootthatdistortstheaorticsinuses.Alternatively,avalvedDacronconduit336canbeused.ThebesttherapeuticoptioninPVEisstilldebated.221,354–359AlthoughsurgeryisgenerallyconsideredthebestoptionwhenPVEcausessevereprostheticdysfunctionorHF,220itwasperformedinonly50%ofpatientswithPVEintheEuroHeartSurvey,54asimilarrateasforpatientswithNVE.Othergroupshavereportedsimilardata.221,340Earlysurgerywasassociatedwithlowerin-hospitaland1-yearmortalityinalargecohortof4166patientsincludingbothnativeandprostheticvalveIEcomplicatedbyHF.216Conversely,afteradjustmentfordifferencesinclinicalcharacteristicsandsurvivalbias,earlyvalvereplacementwasnotassociatedwithlowermortalitycomparedwithmedicaltherapyinalargeinternationalcohort.37However,intheseseries,surgerywasbeneficialinthesubgroupofpatientswiththegreatestneedforsurgery,includingvalveregurgitation,vegetationanddehiscenceorparavalvularabscess/fistula.37ThereforeasurgicalstrategyisrecommendedforPVEinhigh-risksubgroupsidentifiedbyprognosticassessment,i.e.PVEcomplicatedbyHF,severeprostheticdysfunction,abscessorpersistentfever(Table22).EmergencysurgeryisindicatedonlyincaseswithrefractorycongestiveHFleadingtopulmonaryoedemaorshock,asinNVE.Conversely,patientswithuncomplicatednon-staphylococcalandnon-fungallatePVEcanbemanagedconservatively.350,357,358However,patientswhoareinitiallytreatedmedicallyrequireclosefollow-upbecauseoftheriskoflateevents.Insummary,PVErepresents20%ofallcasesofIE,withanincreasingincidence.ThediagnosisofPVEismoredifficultthanforNVE.ComplicatedPVEandstaphylococcalPVEareassociatedwithaworseprognosisiftreatedwithoutsurgery.TheseformsofPVEmustbemanagedaggressively.Patientswithuncomplicated,non-staphylococcallatePVEcanbemanagedconservativelywithclosefollow-up.12.2Infectiveendocarditisaffectingcardiacimplantableelectronicdevices 12.2.1Introduction Infectionofcardiacimplantableelectronicdevices(CIEDs)isaseverediseaseassociatedwithhighmortality.360TheincreasedratesofCIEDimplantationcoupledwithincreasedimplantationinolderpatientswithmoreco-morbiditieshavesetthestageforhigherratesofCIEDinfectionandtheincreasingfrequencyofIEinthesepatients.361Thereportedincidenceofpermanentpacemakerinfectionvarieswidelyamongstudies.362,363Apopulation-basedstudyfoundanincidenceofCIEDinfectionof1.9per1000device-yearsandahigherprobabilityofinfectionafterimplantablecardioverterdefibrillatorscomparedwithpermanentpacemakers.364Bothdiagnosisandtherapeuticstrategyareparticularlydifficultinthesepatients.36512.2.2Definitionsofcardiacdeviceinfections Adistinctionshouldbemadebetweenlocaldeviceinfectionandcardiacdevice-relatedIE(CDRIE).Localdeviceinfectionisdefinedasaninfectionlimitedtothepocketofthecardiacdeviceandisclinicallysuspectedinthepresenceoflocalsignsofinflammationatthegeneratorpocket,includingerythema,warmth,fluctuance,wounddehiscence,erosion,tendernessorpurulentdrainage.366CDRIEisdefinedasaninfectionextendingtotheelectrodeleads,cardiacvalveleafletsorendocardialsurface.However,differentiatinglocaldeviceinfectionandCDRIEisfrequentlydifficult.Inonestudy,367cultureofintravascularleadsegmentswaspositivein72%of50patientswithmanifestationsstrictlylimitedtotheimplantationsite.However,thepossibilityofintraoperativecontaminationoftheleadtipcannotbeexcludedinthesepatients.12.2.3Pathophysiology Thepocketmaybecomeinfectedatthetimeofimplantation,duringsubsequentsurgicalmanipulationofthepocketorifthegeneratororsubcutaneouselectrodeserodethroughtheskin.Pocketinfectionmaytrackalongtheintravascularportionoftheelectrodetoinvolvetheintracardiacportionofthepacemakerorimplantablecardioverterdefibrillator.Alternatively,thepocketorintracardiacportionoftheelectrodemaybecomeinfectedasaresultofhaematogenousseedingduringabacteraemiasecondarytoadistantinfectedfocus.Theconsequencemaybeformationofvegetations,whichcanbefoundanywherefromtheinsertionveintothesuperiorvenacava,ontheleadoronthetricuspidvalve,aswellasontherightatrialandventricularendocardium.SepticpulmonaryembolismisaveryfrequentcomplicationofCDRIE.12.2.4Riskfactors SeveralfactorshavebeenassociatedwithCIEDinfections.366,367Patientfactorsincluderenalfailure,corticosteroiduse,congestiveHF,haematomaformation,diabetesmellitusandanticoagulationuse.368–370Inaddition,proceduralcharacteristicsmayalsoplayanimportantroleinthedevelopmentofCIEDinfection.Thefactorsassociatedwithanincreasedriskofinfectionincludethetypeofintervention,371,372devicerevisions,thesiteofintervention,theamountofindwellinghardware,theuseofpre-proceduraltemporarypacing,failuretoadministerperioperativeantimicrobialprophylaxis,373feverwithinthe24hbeforeimplantationandoperatorexperience.37412.2.5Microbiology Staphylococci,andespeciallyCoNS,accountfor60–80%ofcasesinmostreportedseries.375,376AvarietyofCoNSspecieshavebeendescribed.366,377Methicillinresistanceamongstaphylococcivariesamongstudies,376,378butalowfrequencyofmethicillin-resistantCoNShasbeenreportedamongindividualswithnohealthcarecontact,whereasahighrateofmethicillinresistanceinCoNSisassociatedwithahealthcareenvironmentsource.379PolymicrobialinfectionsometimesinvolvesmorethanonespeciesofCoNS.376,380,381Corynebacteriumspp.,Propionibacteriumacnes,Gram-negativebacilliandCandidaspp.arerarelyidentifiedaspathogensinCIEDinfection.366,376,37712.2.6Diagnosis Clinicalpresentationisfrequentlymisleading,withpredominantrespiratoryandrheumatologicalsymptomsaswellaslocalsignsofinfection.382CDRIEmustbesuspectedinthepresenceofunexplainedfeverinapatientwithaCIED.Feverisfrequentlyblunted,particularlyinelderlypatients.AsinotherformsofIE,echocardiographyandbloodculturesarethecornerstonesofdiagnosis.S.aureusbacteraemiamightbethesolemanifestationofdeviceinfection.EchocardiographyplaysakeyroleinCDRIEandishelpfulforthediagnosisofbothleadvegetationsandtricuspidinvolvement,quantificationoftricuspidregurgitation,sizingofvegetationsandfollow-upafterleadextraction.SeveralprognosticfeaturesmaybebetterdefinedonTTEthanonTOE,suchaspericardialeffusion,ventriculardysfunctionandpulmonaryvascularpressureestimations.TOEhassuperiorsensitivityandspecificitytoTTEfordiagnosisoflead-relatedendocarditis.381–385TOEallowsvisualizationoftheleadinatypicallocations,suchastheproximalsuperiorvenacava,andofregionsthataredifficulttovisualizebyTTE.Inaddition,thesensitivityofTOEforleft-sidedinvolvementandforperivalvularextensionofinfectionissuperiortothatofTTE.Consideringtheircomplementaryrole,itisrecommendedtoperformbothinvestigationsinsuspectedCDRIE.Inthepresenceofinfectivematerialalongtheleadcoursenotprovidingtypicalvegetationsofmeasurablesize,bothTTEandTOEmaybefalselynegativeinCDRIE.Intracardiacechocardiographywasrecentlyfoundtobefeasibleandeffectiveincardiacdevicepatients386andtohaveasuperiorsensitivityforthedetectionofvegetationsincardiacdevices.386–388AnormalechographicexaminationdoesnotruleoutCDRIE.Indifficultcases,othermodalitiessuchasradiolabelledleucocytescintigraphy389and18F-FDGPET/CTscanning108,390havebeendescribedasadditivetoolsinthediagnosisofCDRIEandrelatedcomplications,includingpulmonarysepticembolism.TheDukecriteriaaredifficulttoapplyinthesepatientsbecauseoflowersensitivity.347ModificationsoftheDukecriteriahavebeenproposed,382,391includinglocalsignsofinfectionandpulmonaryembolismasmajorcriteria.38212.2.7Treatment CDRIEmustbetreatedbyprolongedantibiotictherapyassociatedwithcompletehardwareremoval.360,39112.2.8Antimicrobialtherapy AntimicrobialtherapyforCDRIEshouldbeindividualizedandbasedoncultureandsusceptibilityresultsifpossible(seesection7).BecausemostCDRIEinfectionsaresecondarytostaphylococcalspeciesand,ofthose,upto50%aremethicillin-resistant,376,392vancomycinshouldbeadministeredinitiallyasempiricalantibioticcoverageuntilmicrobiologicalresultsareknown.Daptomycin,approvedforright-sideIEandbacteraemiaattributabletoS.aureus,168isapromisingmoleculetotreatCIEDinfection.393–395Beforehardwareremoval,butafterbloodcultures,i.v.antibioticsshouldbeinitiated.Therearenoclinicaltrialdatatodefinetheoptimaldurationofantimicrobialtherapy.Thedurationoftherapyshouldbe4–6weeksinmostcases.362Atleast2weeksofparenteraltherapyisrecommendedafterextractionofaninfecteddeviceforpatientswithbloodstreaminfection.Patientswithsustained(>24h)positivebloodculturesdespiteCIEDremovalandappropriateantimicrobialtherapyshouldreceiveparenteraltherapyforatleast4weeks.362,36612.2.9Completehardwareremoval(deviceandleadextraction) InthecaseofdefiniteCDRIE,medicaltherapyalonehasbeenassociatedwithhighmortalityandriskofrecurrence.360,363,391Forthisreason,CIEDremovalisrecommendedinallcasesofprovenCDRIEandshouldalsobeconsideredwhenCDRIEisonlysuspectedinthecaseofoccultinfectionwithoutanyapparentsourceotherthanthedevice.396CompleteremovalofthesystemistherecommendedtreatmentforpatientswithestablishedCDRIE.363,391,396Consideringtheinherentriskofanopensurgicalprocedure,380transvenousleadextractionhasbecomethepreferredmethod.Itisessentialtoremoveallhardwaretoavoidtherecurrenceofinfection.368,397Inexperiencedcentres,proceduralmortalityrateshavebeenshowntobebetween0.1%and0.6%.396,398Long-termmortalityvariesamongsubgroups,butratesarehigherinsystemicinfections.399Transvenousextractionsarenotwithoutrisk,andproceduralcomplexitymayvarysignificantlyaccordingtoleadtypeandfeatures.TypicallyICDleadsaremoredifficulttoremovethancoronarysinusleads,whichareusuallyremovedbysimplemanualtraction.400–402Transvenousleadextractionshouldbeperformedonlyincentrescommittedtoaproceduralvolumeallowingthemaintenanceofskillsofadequatelytrainedteamsandabletoprovideimmediatecardiothoracicsurgerybackupintheeventofemergencythoracotomyorsternotomy.396,403Pulmonaryembolismasaresultofvegetationdisplacementduringextractionoccursfrequently,particularlywhenvegetationsarelarge.367,404However,theseepisodesarefrequentlyasymptomatic,andpercutaneousextractionremainstherecommendedmethodevenincasesoflargevegetations,360,391,404asoverallrisksareevenhigherwithsurgicalextraction.367,380Someauthorsrecommendsurgeryinpatientswithverylargevegetations.405Untiladditionaldataareavailable,decisionsregardingpercutaneousversussurgicalremovalofleadswithvegetations>2cmindiametershouldbeindividualized.OtherindicationsforasurgicalapproachtoleadremovalincludepatientswhoneedacontemporaryvalvereplacementorrepairforIEorpatientswhohavesignificantretainedhardwareafterattemptsatpercutaneousremoval.However,mortalityassociatedwithsurgicalremovalishighinthesefrequentlyelderlypatientswithassociatedco-morbidities.38012.2.10Reimplantation Thefirststepbeforereimplantationisare-evaluationoftheindicationforCIEDimplantation.377,403Inasignificantnumberofcases,reimplantationisnotnecessary.366,398Thedeviceshouldbereimplantedonthecontralateralside.Thereisnoclearrecommendationconcerningtheoptimaltimingofreimplantation.Factorssuchaspersistentbacteraemia,persistentvegetationandpacemakerandimplantablecardioverterdefibrillatordependencyshouldbeconsideredandthedecisionadaptedtotheindividualpatient.Immediatereimplantationshouldbeavoided,owingtotheriskofnewinfection.366,377,398,403Bloodculturesshouldbenegativeforatleast72hbeforeplacementofanewdevice.Incasesofevidenceofremnantvalvularinfection,implantationshouldbedelayedforatleast14days.366,406Temporarypacingisariskfactorforsubsequentcardiacdeviceinfection367andshouldbeavoidedifpossible.Inpacing-dependentpatients,temporaryuseofactivefixationleadsconnectedtoexternaldevicesisdescribedasa‘bridge’,407permittingearliermobilizationwithareducedriskofpacing-relatedadverseevents.408–41012.2.11Prophylaxis Althoughtherearenolargecontrolledstudiesonthistopic,antibioticprophylaxisisrecommendedbeforeimplantation.367,368,373Afirst-generationcephalosporin,suchascefazolin(6g/dayfor24–36haftertheintervention),isusuallyusedasprophylaxisandshouldbeparenterallyadministered1hbeforetheprocedure.Vancomycin,teicoplaninanddaptomicinmaybeconsideredinsteadofcefazolinincentreswhereoxacillinresistanceamongstaphylococciishigh,inhigh-riskpatientsorinpatientswithcontraindicationstocephalosporins.Theyshouldalwaysbestartedbeforetheprocedureaccordingtothedrugpharmacokinetics.Insummary,CDRIEisoneofthemostdifficultformsofIEtodiagnoseandmustbesuspectedinthepresenceoffrequentlymisleadingsymptoms,particularlyinelderlypatients.Prognosisispoor,probablybecauseofitsfrequentoccurrenceinelderlypatientswithassociatedco-morbidities.Inthemajorityofpatients,CDRIEmustbetreatedbyprolongedantibiotictherapyanddeviceremoval.Table25summarizesthemainfeaturesconcerningdiagnosis,treatmentandpreventionofCDRIE. Table25Cardiacdevice-relatedinfectiveendocarditis:diagnosis,treatmentandprevention  CDRIE=cardiacdevice-relatedinfectiveendocarditis;CIED=cardiacimplantableelectronicdevice;FDG=fluorodeoxyglucose;IE=infectiveendocarditis;NVE=nativevalveendocarditis;PET=positronemissiontomography;PVE=prostheticvalveendocarditis;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab Table25Cardiacdevice-relatedinfectiveendocarditis:diagnosis,treatmentandprevention  CDRIE=cardiacdevice-relatedinfectiveendocarditis;CIED=cardiacimplantableelectronicdevice;FDG=fluorodeoxyglucose;IE=infectiveendocarditis;NVE=nativevalveendocarditis;PET=positronemissiontomography;PVE=prostheticvalveendocarditis;TOE=transoesophagealechocardiography;TTE=transthoracicechocardiography.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations. Openinnewtab 12.3Infectiveendocarditisintheintensivecareunit Admissiontotheintensivecareunit(ICU)isfrequentlyapartofthenormalpatientpathwayfollowingsurgeryforIE.Inaddition,patientswithIEmaybeadmittedtotheICUduetohaemodynamicinstabilityrelatedtoseveresepsis,overtHFand/orseverevalvularpathologyororganfailurefromIE-relatedcomplications.411,412TheincidenceofnosocomialinfectionisincreasingandpatientsmaydevelopIEasaresultofhealthcare-associatedinfectionacquiredduringhospitalorintensivecareadmission.Finally,thediagnosisofIEcanbechallenging,beingmadeonlypost-morteminanumberofpatients.413Despiteadvancesindiagnosisandtreatment,mortalityremainsparticularlyhighincriticallyillpatients,rangingfrom29%to84%.411,414,415EstimationofthenumberofpatientsrequiringICUadmissionforIEischallenging.Inaretrospective,multicentre,observationalstudyof4106patientsadmittedtofourmedicalICUs,IEwasidentifiedin0.8%ofadmissions.416ReasonsforadmissiontotheICUwerecongestivecardiacfailure(64%),septicshock(21%),neurologicaldeterioration(15%)andcardiopulmonaryresuscitation(9%).416Criticalcaremorbidityishigh,withupto79%ofpatientsrequiringmechanicalventilation,73%inotropicsupportand39%developingrenalfailure.12.3.1Organisms LimiteddataareavailableregardingcausativeorganismsforIEintheICU.CaseserieshaverevealedStaphylococcispp.tobethemostcommoncausativeagent,accountingfor74%ofallnosocomialIEcases.Streptococciarethesecondmostcommoncausativeorganisms.FungalIEisanincreasingproblemintheICU,withCandidaIEoccurringsignificantlymoreofteninICUthannon-ICUhospitalizedpatients.417ThereshouldbeahighindexofsuspicionforfungalIEintheICUsetting,inparticularwherethereisfailuretorespondtoempiricalantimicrobialtherapy.12.3.2Diagnosis ThediagnosticcriteriaforIEintheICUareidenticaltothoseforthenon-ICUpatientpopulation.However,clinicalmanifestationsmaybeatypicalandtheclassicfeaturesmaybemaskedbyconcomitantpathologyandcriticalcareinterventions.Thuspyrexiamaybeattributedtoco-existinghospital-acquiredinfections,neurologicalmanifestationsmaskedbytheconfoundingfactorsofsedation,ICU-relateddelirium,concomitantmultiplepathologiesandacutekidneyinjuryascribedtoco-existingpathologies.Echocardiographycanbechallengingintheintensivecaresetting,withareducedsensitivityofTTEforthediagnosisofIE.ThereshouldbearelativelylowthresholdforTOEincriticallyillpatientswithS.aureuscatheter-relatedbloodstreaminfectionbecauseofitshighpropensitytocauseIE,andalso,ifnegative,thismayallowshortantibiotictreatment.12.3.3Management Patientswithseveresepsisorsepticshockshouldbemanagedaccordingtoprotocolisedinternationalguidelines.418AntimicrobialmanagementandindicationsforsurgeryinpatientswithIEaredescribedinsections7and10,respectively.However,emergency/salvagestatusaccountsforthehighestmortalityratesinregistrydataforpatientsoperatedonforIE,299andpatientswithSOFAscores>15onthedayofsurgeryhaveextremelypooroutcomes.125Decisionmakinginthismostcriticallyillpatientpopulationwhereindicationsandcontraindicationsforcardiacsurgeryco-existischallengingandshouldbeundertakeninthecontextofthemultiprofessional,multidisciplinaryEndocarditisTeamenvironment.12.4Right-sidedinfectiveendocarditis Right-sidedIEaccountsfor5–10%ofIEcases.419,420Althoughitmayoccurinpatientswithapacemaker,ICD,centralvenouscatheterorCHD,thissituationismostfrequentlyobservedinIVDAs,especiallyinpatientswithconcomitanthumanimmunodeficiencyvirus(HIV)seropositivityorinimmunosuppressedpatients.420–422S.aureusisthepredominantorganism(60–90%ofcases),419,423withmethicillin-resistantstrainsbecomingmoreprevalent.414Thefrequencyofpolymicrobialinfectionsisalsorising.424Thetricuspidvalveismostfrequentlyaffected,butothervalves—includingleft-sided—mayalsobecomeinfected.425In-hospitalmortalityisapproximately7%.426–42912.4.1Diagnosisandcomplications Theusualmanifestationsofright-sidedIEarepersistentfever,bacteraemiaandmultiplesepticpulmonaryemboli,whichmaymanifestaschestpain,coughorhaemoptysis.Whensystemicembolioccur,paradoxicalembolismorassociatedleft-sidedIEshouldbeconsidered.IsolatedrightHFisrare,butcanbecausedbypulmonaryhypertensionorsevereright-sidedvalvularregurgitationorobstruction.425Pulmonaryhypertensioncanbesecondarytoleft-sidedIE.TTEusuallyallowsassessmentoftricuspidinvolvementbecauseoftheanteriorlocationofthisvalveandusuallargevegetations.430,431Eustachianandpulmonaryvalvesshouldalwaysbeassessed.TOEismoresensitiveinthedetectionofpulmonaryvegetations432andassociatedleft-sidedinvolvement.12.4.2Prognosisandtreatment Vegetationlength>20mmandfungalaetiologywerethemainpredictorsofdeathinalargeretrospectivecohortofright-sidedIEinIVDAs.433InHIV-infectedpatients,aCD4count<200cells/μLhasahighprognosticvalue.420,42112.4.2.1Antimicrobialtherapy Thechoiceofempiricantimicrobialtherapydependsonthesuspectedmicroorganism,typeofdrugandsolventusedbytheaddictandtheinfectionlocation.424Inanycase,S.aureusmustalwaysbecovered.Initialtreatmentincludespenicillinase-resistantpenicillins,vancomycinordaptomycin,dependingonthelocalprevalenceofMRSA,424incombinationwithgentamicin.Ifthepatientisapentazocineaddict,anantipseudomonasagentshouldbeadded.434IfanIVDAusesbrownheroindissolvedinlemonjuice,Candidaspp.(notCandidaalbicans)shouldbeconsideredandantifungaltreatmentadded.435Oncethecausativeorganismshavebeenisolated,therapyhastobeadjusted.Consistentdatashowthat2-weektreatmentmaybesufficientandthattheadditionofanaminoglycosidemaybeunnecessary.436Two-weektreatmentwithoxacillin(orcloxacillin)withoutgentamiciniseffectiveformostpatientswithisolatedtricuspidIEifallthefollowingcriteriaarefulfilled: ecauseoflimitedbactericidalactivity,poorpenetrationintovegetationsandincreaseddrugclearanceinIVDAs,glycopeptides(vancomycin)shouldnotbeusedina2-weektreatment.Thestandard4–6-weekregimenmustbeusedinthefollowingsituations: lternatively,whenconventionali.v.routetherapyisnotpossible,right-sidedS.aureusIEinIVDAsmayalsobetreatedwithoralciprofloxacin[750mgbisindie(b.i.d.)]plusrifampicin(300mgb.i.d.)providedthatthestrainisfullysusceptibletobothdrugs,thecaseisuncomplicatedandpatientadherenceismonitoredcarefully.439Onerandomizedcontrolledstudyhasdemonstratedthenon-inferiorityofdaptomycincomparedwithstandardtherapyinthetreatmentofS.aureusinfections,includingright-sidedIE.168Whenusingdaptomycin,mostauthorsrecommendusinghighdoses(10mg/kg/24h)andcombiningitwithcloxacillinorfosfomycintoavoidthedevelopmentofresistancetothisdrug.174Glycopeptides(e.g.vancomycin)ordaptomycinaretheagentsofchoiceforMRSAinfections.VancomycinmayhavealowerefficacyininfectionscausedbyMRSAstrainswithavancomycinMIC>1μg/mL.171,172,440Inthesecases,daptomycinwouldbethedrugofchoice.FororganismsotherthanS.aureus,therapyinIVDAsdoesnotdifferfromthatinnon-IVDAs.MSSA,Goodresponsetotreatment,Absenceofmetastaticsitesofinfectionorempyema,Absenceofcardiacandextracardiaccomplications,Absenceofassociatedprostheticvalveorleft-sidedvalveinfection,<20mmvegetation,andAbsenceofsevereimmunosuppression(<200CD4cells/μL)withorwithoutacquiredimmunedeficiencysyndrome(AIDS).Slowclinicalormicrobiologicalresponse(>96h)toantibiotictherapy;426Right-sidedIEcomplicatedbyrightHF,vegetations>20mm,acuterespiratoryfailure,septicmetastaticfocioutsidethelungs(includingempyema)orextracardiaccomplications,e.g.acuterenalfailure;426Therapywithantibioticsotherthanpenicillinase-resistantpenicillins;437IVDAwithsevereimmunosuppression(CD4count<200cells/μL)withorwithoutAIDS;438orAssociatedleft-sidedIE.12.4.2.2Surgery GiventhehighrecurrencerateofIEduetocontinueddrugabuse,surgeryshouldgenerallybeavoidedinIVDAswithright-sidednativeIE,butithastobeconsideredinthefollowingsituations(Table26):ardiacsurgeryinHIV-infectedIVDAswithIEdoesnotworsentheprognosisofeithertheIEortheHIV.RightHFsecondarytoseveretricuspidregurgitationwithpoorresponsetodiuretictherapy;IEcausedbyorganismsthataredifficulttoeradicate(e.g.persistentfungi)orbacteraemiaforatleast7days(e.g.S.aureus,Pseudomonasaeruginosa)despiteadequateantimicrobialtherapy;441andTricuspidvalvevegetations>20mmthatpersistafterrecurrentpulmonaryemboliwithorwithoutconcomitantrightHF.426,433 Table26Indicationsforsurgicaltreatmentofright-sidedinfectiveendocarditis  HF=heartfailure.aClassofrecommendation.bLevelofevidence. Openinnewtab Table26Indicationsforsurgicaltreatmentofright-sidedinfectiveendocarditis  HF=heartfailure.aClassofrecommendation.bLevelofevidence. Openinnewtab RecentnationwidedatahaveshownthatthethreemostfrequentsurgicalstrategiesfortricuspidvalveIEarevalvectomy,valverepairandvalvereplacement.429Tricuspidvalvereplacementaccountedforthemajorityofcases,withmostreceivingabioprostheticvalve.Someauthorsprefervalverepair(avoidingartificialmaterialwheneverpossible)overvalvereplacement,buttheformerdidnotimproveoutcomesovervalvereplacementorvalvectomy.429Valvectomywithoutprostheticreplacementcanbedoneinextremecases,butmaybeassociatedwithseverepostoperativerightHF,particularlyinpatientswithpulmonaryhypertension.Inthesecases,thevalvecanbesubsequentlyreplacedonceinfectionhasbeencuredanddrugusediscontinued.Pulmonaryvalvereplacementshouldbeavoided,butifjudgednecessary,useofapulmonaryhomograft(or,ifunavailable,axenograftvalve)ispreferred.Insummary,right-sidedIEisprimarilyadiseasethataffectsIVDAsandpatientswithCHD.Diagnosticfeaturesincluderespiratorysymptomsandfever.S.aureusisresponsibleformostcases.TTEisofmajorvalueinthesepatients.Despiterelativelylowin-hospitalmortality,right-sidedIEhasahighriskofrecurrenceinIVDAsandsurgeryisrecommendedonlyforintractablesymptoms,failureofmedicaltherapy,recurrentsepticembolitothelungsorparadoxicalemboli.12.5Infectiveendocarditisincongenitalheartdisease ThepopulationofchildrenandadultswithCHDisexpanding,andthisisthemajorsubstrateforIEinyoungerpatients.However,ourknowledgeofIEinthissettingislimitedsincesystematicstudiesarefewandoftenretrospectiveandselectionbiasassociatedwithstudiesfromhighlyspecializedcentreshampersuniversalapplication.ThereportedincidenceofIEinCHDis15–140timeshigherthanthatinthegeneralpopulation(thehighestestimateoriginatingfromahighlyspecializedunit).442,443Theincidenceislowerinchildren(0.04%peryear)thaninadultswithCHD(0.1%peryear).444,445ThereportedproportionofCHDinpatientswithIEvaries(probablyduetoselectionbias)bybetween2%and60%,446–450withaconsistentminormaledominance.443,451,452Somesimplelesions,suchassecundumatrialseptaldefectandpulmonaryvalvedisease,carryalowriskofIE,whileothers,suchasbicuspidaorticvalve,carryhigherrisk.However,CHDoftenconsistsofmultiplecardiaclesions,eachcontributingtothetotalriskofIE.Forexample,theincidenceofIEisconsiderablyhigherinpatientswithaventricularseptaldefectwhenthereisassociatedaorticregurgitation.453Thedistributionofcausativeorganismsdoesnotdifferfromthepatternfoundinacquiredheartdisease,withstreptococciandstaphylococcibeingthemostcommonstrains.443,451,452Asinothergroups,thediagnosisofIEisoftenmadetoolate,highlightingtheneedtoconsiderthediagnosisofIEinanypatientwithCHDpresentingwithongoingfeverorothersignsofongoinginfection.Bloodculturesshouldbetakenbeforestartingantibiotictreatment.Theprincipalsymptoms,complicationsandbasisfordiagnosisdonotdifferfromIEingeneral.However,right-sidedIEismorefrequentinCHDthaninacquiredcardiacdisease.ThesuperiorityofTOEoverTTEhasnotbeensystematicallystudiedinthissetting.Nevertheless,complexanatomyandthepresenceofartificialmaterialmayreducetherateofdetectionofvegetationsandotherfeaturesofIE,thusfavouringtheadditionofTOE,particularlyintheadultgroup.443However,anegativestudydoesnotexcludethediagnosis.CareofCHDpatientswithIE,fromdiagnosistotreatment,isbestprovidedbyspecializedCHDcentreswithexpertiseinimaging,surgeryandintensivecare.Cardiacsurgeryisappropriatewhenmedicaltherapyfails,whenserioushaemodynamiccomplicationsariseandwhenthereisahighriskofdevastatingsepticembolism.IEinCHDcarriesamortalityrateof4–10%.443,451,452,454Thisbetterprognosiscomparedwithacquiredheartdiseasemayreflectthehigherproportionofright-heartIEorthebettercareinCHDcentres.Primarypreventionisvital.455Theimportanceofgoodoral,dentalandskinhygienehasalreadybeenemphasized,andantibioticprophylaxisisindicatedinhigh-riskgroupsasdefinedinsection3.However,thereisalsoaneducationalproblem,especiallyinpatientsnotfollowedinspecialistCHDcentres,andawarenessoftheriskofIEandtheneedforpreventivemeasuresarenotsatisfactorilyhighlightedinthepopulationwithCHD.456Cosmetictattooingandpiercing,atleastinvolvingthetongueandmucousmembranes,shouldbediscouragedinthisgroup.SurgicalrepairofCHDoftenreducestheriskofIE,providedthereisnoresiduallesion.447,457However,inothercaseswhenartificialvalvesubstitutesareimplanted,theproceduremayincreasetheoverallriskofIE.Therearenoscientificdatajustifyingcardiacsurgeryorpercutaneousinterventions(e.g.closureofapatentductusarteriosus)withthesolepurposeofeliminatingtheriskofIE.458CardiacrepairasasecondarypreventivemeasuretoreducetheriskofrecurrentIEhasbeendescribedbutnotsystematicallystudied.Insummary,IEinCHDisrareandmorefrequentlyaffectstherightheart.CareofCHDpatientswithIE,fromdiagnosistotreatment,isbestprovidedbyspecialistCHDcentreswithexpertiseinimaging,surgeryandintensivecare.ThisappliestomostpatientswithCHD.Complexanatomymakesechocardiographicassessmentdifficult.However,thediagnosisshouldbeconsideredinallCHDpatientswithongoinginfectionorfever.PrognosisisbetterthaninotherformsofIE,withamortalityrateof<10%.Preventivemeasuresandpatienteducationareofparticularimportanceinthispopulation.12.6Infectiveendocarditisduringpregnancy Achallengeforthephysicianduringpregnancyinthecardiacpatientisthechangingcardiovascularphysiology,whichcanmimiccardiacdiseaseandconfusetheclinicalpicture.459,460TheincidenceofIEduringpregnancyhasbeenreportedtobe0.006%.196TheincidenceofIEinpatientswithcardiacdiseaseis0–1.2%andishigherinwomenwithamechanicalprostheticvalve.461–464ThereforeIEinpregnancyisextremelyrareandiseitheracomplicationofapre-existingcardiaclesionortheresultofi.v.drugabuse.Maternalmortalityapproaches33%,withmostdeathsrelatingtoHForanembolicevent,whilefoetalmortalityisreportedtobeabout29%.196Closeattentionshouldbepaidtoanypregnantwomanwithunexplainedfeverandacardiacmurmur.RapiddetectionofIEandappropriatetreatmentisimportantinreducingtheriskofbothmaternalandfoetalmortality.196Despitethehighfoetalmortality,urgentsurgeryshouldbeperformedduringpregnancyinwomenwhopresentwithHFduetoacuteregurgitation.12.7Antithrombotictherapyininfectiveendocarditis IndicationsforanticoagulantandantiplatelettherapyarethesameinIEpatientsasinotherpatients,andevidencedoesnotsupporttheinitiationofmedicationsinterferingwiththecoagulationsystemasadjunctivetherapyforIE.258Thrombolytictherapyisgenerallycontraindicatedandhassometimesresultedinsevereintracranialhaemorrhage,465butthrombectomycouldbeanalternativeinselectedpatientswithischaemicstrokerelatedtoIE(seesection9.1).TheriskofintracranialhaemorrhagemaybeincreasedinpatientsalreadyonoralanticoagulantswhenIEisdiagnosed,especiallyinpatientswithS.aureusPVE.113,466Ontheotherhand,ongoingoralanticoagulantsduringIEdevelopmentmaydiminishearlyembolictendencies.467TherecommendationsformanagementofanticoagulanttherapyinIEpatientsarebasedonalowlevelofevidence,anddecisionsshouldbemadeonanindividualbasisbytheEndocarditisTeam.TheroleofbridgingtherapywithunfractionatedorlowmolecularweightheparinhasnotbeenstudiedinpatientswithIE,butmayhavereasonableadvantagesinspecialsituations(i.e.inunstablepatients)beforesurgicaldecisionsaremadeortoavoiddruginteractions.EvidencedoesnotsupportinitiationofantiplatelettherapyinpatientsdiagnosedwithIE,258despitepromisingresultsinexperimentalstudies.468Somecohortstudiesindicateapossiblereductionintherateofemboliccomplications257orIEdevelopmentinsubgroupsofpatientsalreadyonantiplatelettherapy,469butthedataarecontradictory.470,471 Table27Recommendationsfortheuseofantithrombotictherapy  IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations.dThereisverylimitedexperiencewithneworalanticoagulanttreatmentinthefieldofIE. Openinnewtab Table27Recommendationsfortheuseofantithrombotictherapy  IE=infectiveendocarditis.aClassofrecommendation.bLevelofevidence.cReference(s)supportingrecommendations.dThereisverylimitedexperiencewithneworalanticoagulanttreatmentinthefieldofIE. Openinnewtab 12.8Non-bacterialthromboticendocarditisandendocarditisassociatedwithcancers 12.8.1Non-bacterialthromboticendocarditis Non-bacterialthromboticendocarditis(NBTE)(i.e.maranticendocarditis,Libman–Sacksendocarditisorverrucousendocarditis)ischaracterizedbythepresenceofsterilevegetationsconsistingoffibrinandplateletaggregatesoncardiacvalves.Thesevegetationsareassociatedwithneitherbacteraemianorwithdestructivechangesoftheunderlyingvalve.472ItisalsoquiterelevanttodifferentiatetrueNBTEversuspatientswithnegativebloodculturesduetopreviousantibiotictherapy.473NBTEisaconditionassociatedwithnumerousdiseasessuchascancer,connectivetissuedisorders(i.e.systemiclupuserythematosuspatientspossessingantiphospholipidantibodies,calledLibman–Sacksendocarditis),autoimmunedisorders,hypercoagulablestates,septicaemia,severeburnsorchronicdiseasessuchastuberculosis,uraemiaorAIDS.Itisapotentiallylife-threateningsourceofthromboembolism,itsmainclinicalmanifestation.ItisessentialtodifferentiateNBTEfromIE.ThesameinitialdiagnosticworkupusedforIEisrecommended.ThediagnosisofNBTEisdifficultandreliesonstrongclinicalsuspicioninthecontextofadiseaseprocessknowntobeassociatedwithNBTE,thepresenceofaheartmurmur,thepresenceofvegetationsnotrespondingtoantibiotictreatmentandevidenceofmultiplesystemicemboli.474Thepresenceofanewmurmurorachangeinapre-existingmurmur,althoughinfrequent,inthesettingofapredisposingdiseaseshouldalertthecliniciantoconsiderNBTE.ValvularvegetationsinNBTEareusuallysmall,broadbasedandirregularlyshaped.Theyhavelittleinflammatoryreactionatthesiteofattachment,whichmakethemmorefriableanddetachable.Followingembolization,smallremnantsonaffectedvalves(≤3mm)mayresultinfalse-negativeechocardiographyresults.TOEshouldbeorderedwhenthereisahighsuspicionofNTBE.Left-sided(mitralmorethanaortic)andbilateralvegetationsaremoreconsistentwithNTBEthanwithIE.475WhenanearlyTOEexaminationisperformed,theprognosisofNTBEisimproved.476Comprehensivehaematologicalandcoagulationstudiesshouldbeperformedtosearchforapotentialcause.MultiplebloodculturesshouldbeundertakentoruleoutIE,althoughnegativebloodculturescanbeobservedinIE(i.e.previousantibiotictherapy,HACEKgroup,fungi,etc.).Immunologicalassaysforantiphospholipidsyndrome(i.e.lupusanticoagulant,anticardiolipinantibodies,andanti-β2-glycoprotein1antibodies;atleastonemustbepositiveforthediagnosisofantiphospholipidsyndromeonatleasttwooccasions12weeksapart)shouldbeundertakeninpatientspresentingwithrecurrentsystemicemboliorknownsystemiclupuserythematous.477NTBEisfirstmanagedbytreatingtheunderlyingpathology.Ifthereisnocontraindication,thesepatientsshouldbeanticoagulatedwithunfractionedorlowmolecularweightheparinorwarfarin,althoughthereislittleevidencetosupportthisstrategy.InNTBE,theuseofdirectthrombinorfactorXainhibitorshasnotbeenevaluated.Inantiphospholipidsyndrome,lifelonganticoagulationisindicated.Atrialcomparingrivaroxaban(afactorXainhibitor)andwarfarininpatientswiththromboticantiphospholipidsyndromeiscurrentlyinprogress.478However,anticoagulationisassociatedwithariskofhaemorrhagicconversionofembolicevents.CTofthebrainshouldbeperformedinpatientswithNBTEandcerebralattackbeforeanticoagulationtoruleoutintracranialhaemorrhage.Surgicalintervention,valvedebridementand/orreconstructionareoftennotrecommendedunlessthepatientpresentswithrecurrentthromboembolismdespitewell-controlledanticoagulation.OtherindicationsforvalvesurgeryarethesameasforIE.Inthecontextofcancer,amultidisciplinaryapproachisrecommended(EndocarditisTeam).12.8.2Infectiveendocarditisassociatedwithcancer IEmaybeapotentialmarkerofoccultcancers.Inalarge,Danish,nationwide,population-basedcohortstudy,997cancerswereidentifiedamong8445IEpatientswithamedianfollow-upof3.5years.TheriskofabdominalandhaematologicalcancerswashighsoonafterIEdiagnosis(withinthefirst3months)andremainedhigherthanexpectedinthelong-termfollow-up(>12months)forabdominalcancer.479Severalbacteriahavebeenreportedinassociationwithcoloniccancer,withthestrongestandbest-documentedrelationshipwithS.bovisinfection,specificallytheS.gallolyticussubspecies;S.bovisinfectionhasbeenrelatedtothepresenceofgastrointestinalneoplasia,whichinmostcasesiscolonicadenomaorcarcinoma.480However,itisstillasourceofdebatewhethertheassociationofS.bovis/S.gallolyticusIEwithcolorectaltumoursismerelyaconsequenceofthegastrointestinallesionorcouldtriggerorpromotecolorectalcancer.481InthesettingofS.bovisIE,thereisaneedforpropermicrobiologicalclassification.IncaseofS.bovis/S.gallolyticusIE,itisrecommendedtoruleoutoccultcoloncancerduringhospitalization.Intheabsenceofanytumour,schedulinganannualcolonoscopyishighlysuggested.482Asforothertests(i.e.faecaloccultblood),theserology-baseddetectionofcolorectalcancer—serumIgGconcentrationsagainstS.bovisantigens—isneithersensitive(notallcolorectaltumoursarecolonizedbyS.bovis)norspecific.483FDGPET/CTisincreasinglyusedinthediagnosticworkupofIE.Itmayplayaninterestingroleindetectinggastrointestinalpathologicalactivityandguidecolonoscopy.However,negativePET/CTdoesnotruleoutsignificantcolonicpathology.NostudyhasexamineditsclinicalvalueforthedetectionofoccultcolorectalcancerinpatientswithS.bovis/S.gallolyticusIE.13.Todoandnottodomessagesfromtheguidelines    Openinnewtab    Openinnewtab 14.Appendix ESCCommitteeforPracticeGuidelines(CPG):JoseLuisZamorano(Chairperson)(Spain),VictorAboyans(France),StephanAchenbach(Germany),StefanAgewall(Norway),LinaBadimon(Spain),GonzaloBarón-Esquivias(Spain),HelmutBaumgartner(Germany),JeroenJ.Bax(TheNetherlands),HéctorBueno(Spain),ScipioneCarerj(Italy),VeronicaDean(France),ÇetinErol(Turkey),DonnaFitzsimons(UK),OliverGaemperli(Switzerland),PaulusKirchhof(UK/Germany),PhilippeKolh(Belgium),PatrizioLancellotti(Belgium),GregoryY.H.Lip(UK),PetrosNihoyannopoulos(UK),MassimoF.Piepoli(Italy),PiotrPonikowski(Poland),MarcoRoffi(Switzerland),AdamTorbicki(Poland),AntonioVazCarneiro(Portugal),StephanWindecker(Switzerland).ESCNationalCardiacSocietiesactivelyinvolvedinthereviewprocessofthe2015ESCGuidelinesonthemanagementofinfectiveendocarditis:Austria:AustrianSocietyofCardiology,BernhardMetzler;Azerbaijan:AzerbaijanSocietyofCardiology,TofigJahangirov;Belarus:BelarusianScientificSocietyofCardiologists,SvetlanaSudzhaeva;Belgium:BelgianSocietyofCardiology,Jean-LouisVanoverschelde;Bosnia&Herzegovina:AssociationofCardiologistsofBosnia&Herzegovina,AmraMacić-Džanković;Bulgaria:BulgarianSocietyofCardiology,TemenugaDonova;Croatia:CroatianCardiacSociety,BoškoSkorić;Cyprus:CyprusSocietyofCardiology,GeorgiosC.Georgiou;CzechRepublic:CzechSocietyofCardiology,KaterinaLinhartova;Denmark:DanishSocietyofCardiology,NielsEskeBruun;Egypt:EgyptianSocietyofCardiology,HusseinRizk;Estonia:EstonianSocietyofCardiology,SirjeKõvask;Finland:FinnishCardiacSociety,AnuTurpeinen,FormerYugoslavRepublicofMacedonia:MacedonianSocietyofCardiology,SilvanaJovanova;France:FrenchSocietyofCardiology,FrançoisDelahaye;Georgia:GeorgianSocietyofCardiology,ShalvaPetriashvili;Germany:GermanCardiacSociety,ChristophK.Naber;Greece:HellenicCardiologicalSociety,GeorgiosHahalis;Hungary:HungarianSocietyofCardiology,AlbertVarga;Iceland:IcelandicSocietyofCardiology,ThórdísJ.Hrafnkelsdóttir;Israel:IsraelHeartSociety,YaronShapira;Italy:ItalianFederationofCardiology,EnricoCecchi;Kyrgyzstan:KyrgyzSocietyofCardiology,AlinaKerimkulova;Latvia:LatvianSocietyofCardiology,GintaKamzola;Lithuania:LithuanianSocietyofCardiology,ReginaJonkaitiene;Luxembourg:LuxembourgSocietyofCardiology,KerstinWagner;Malta:MalteseCardiacSociety,DanielaCassarDemarco;Morocco:MoroccanSocietyofCardiology,JamilaZarzur;Norway:NorwegianSocietyofCardiology,SvendAakhus;Poland:PolishCardiacSociety,JaninaStepinska;Portugal:PortugueseSocietyofCardiology,CristinaGavina;Romania:RomanianSocietyofCardiology,DragosVinereanu;Russia:RussianSocietyofCardiology,FilippPaleev;Serbia:CardiologySocietyofSerbia,BiljanaObrenovic-Kircanski;Slovakia:SlovakSocietyofCardiology,VasilHricák;Spain:SpanishSocietyofCardiology,AlbertoSanRoman,Sweden:SwedishSocietyofCardiology,UlfThilén;Switzerland:SwissSocietyofCardiology,BeatKaufmann;TheNetherlands:NetherlandsSocietyofCardiology,BertoJ.Bouma;Tunisia:TunisianSocietyofCardiologyandCardio-VascularSurgery,HediBaccar;Turkey:TurkishSocietyofCardiology,NeclaOzer;UnitedKingdom:BritishCardiovascularSociety,ChrisP.Gale;Ukraine:UkrainianAssociationofCardiology,ElenaNesukay.15.References 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DocumentReviewers:ÇetinErol(CPGReviewCoordinator)(Turkey),PetrosNihoyannopoulos(CPGReviewCoordinator)(UK),VictorAboyans(France),StefanAgewall(Norway),GeorgeAthanassopoulos(Greece),SaideAytekin(Turkey),WernerBenzer(Austria),HéctorBueno(Spain),LidewijBroekhuizen(TheNetherlands),ScipioneCarerj(Italy),BernardCosyns(Belgium),JulieDeBacker(Belgium),MicheleDeBonis(Italy),KonstantinosDimopoulos(UK),ErwanDonal(France),HeinzDrexel(Austria),FrankArnoldFlachskampf(Sweden),RogerHall(UK),SigrunHalvorsen(Norway),BrunoHoenb(France),PaulusKirchhof(UK/Germany),MitjaLainscak(Slovenia),AdelinoF.Leite-Moreira(Portugal),GregoryY.H.Lip(UK),CarlosA.Mestresc(Spain/UnitedArabEmirates),MassimoF.Piepoli(Italy),PrakashP.Punjabi(UK),ClaudioRapezzi(Italy),RaphaelRosenhek(Austria),KaatSiebens(Belgium),JuanTamargo(Spain),andDavidM.Walker(UK)ESCCommitteeforPracticeGuidelines(CPG)andNationalCardiacSocietiesdocumentreviewers:listedintheAppendixESCentitieshavingparticipatedinthedevelopmentofthisdocument:ESCAssociations:AcuteCardiovascularCareAssociation(ACCA),EuropeanAssociationforCardiovascularPrevention&Rehabilitation(EACPR),EuropeanAssociationofCardiovascularImaging(EACVI),EuropeanHeartRhythmAssociation(EHRA),HeartFailureAssociation(HFA).ESCCouncils:CouncilforCardiologyPractice(CCP),CouncilonCardiovascularNursingandAlliedProfessions(CCNAP),CouncilonCardiovascularPrimaryCare(CCPC).ESCWorkingGroups:CardiovascularPharmacotherapy,CardiovascularSurgery,Grown-upCongenitalHeartDisease,MyocardialandPericardialDiseases,PulmonaryCirculationandRightVentricularFunction,Thrombosis,ValvularHeartDisease.ThecontentoftheseEuropeanSocietyofCardiology(ESC)Guidelineshasbeenpublishedforpersonalandeducationaluseonly.Nocommercialuseisauthorized.NopartoftheESCGuidelinesmaybetranslatedorreproducedinanyformwithoutwrittenpermissionfromtheESC.PermissioncanbeobtaineduponsubmissionofawrittenrequesttoOxfordUniversityPress,thepublisheroftheEuropeanHeartJournalandthepartyauthorizedtohandlesuchpermissionsonbehalfoftheESC.Disclaimer.TheESCGuidelinesrepresenttheviewsoftheESCandwereproducedaftercarefulconsiderationofthescientificandmedicalknowledgeandtheevidenceavailableatthetimeoftheirpublication.TheESCisnotresponsibleintheeventofanycontradiction,discrepancyand/orambiguitybetweentheESCGuidelinesandanyotherofficialrecommendationsorguidelinesissuedbytherelevantpublichealthauthorities,inparticularinrelationtogooduseofhealthcareortherapeuticstrategies.HealthprofessionalsareencouragedtotaketheESCGuidelinesfullyintoaccountwhenexercisingtheirclinicaljudgment,aswellasinthedeterminationandtheimplementationofpreventive,diagnosticortherapeuticmedicalstrategies;however,theESCGuidelinesdonotoverride,inanywaywhatsoever,theindividualresponsibilityofhealthprofessionalstomakeappropriateandaccuratedecisionsinconsiderationofeachpatient'shealthconditionandinconsultationwiththatpatientand,whereappropriateand/ornecessary,thepatient'scaregiver.NordotheESCGuidelinesexempthealthprofessionalsfromtakingintofullandcarefulconsiderationtherelevantofficialupdatedrecommendationsorguidelinesissuedbythecompetentpublichealthauthorities,inordertomanageeachpatient'scaseinlightofthescientificallyaccepteddatapursuanttotheirrespectiveethicalandprofessionalobligations.Itisalsothehealthprofessional'sresponsibilitytoverifytheapplicablerulesandregulationsrelatingtodrugsandmedicaldevicesatthetimeofprescription.ThedisclosureformsofallexpertsinvolvedinthedevelopmentoftheseguidelinesareavailableontheESCwebsitehttp://www.escardio.org/guidelines.aRepresentingtheEuropeanAssociationofNuclearMedicine(EANM);bRepresentingtheEuropeanSocietyofClinicalMicrobiologyandInfectiousDiseases(ESCMID);andcRepresentingtheEuropeanAssociationforCardio-ThoracicSurgery(EACTS).©TheEuropeanSocietyofCardiology2015.Allrightsreserved.Forpermissionspleaseemail:[email protected] Topic: antibiotics endocarditis echocardiography bacterialendocarditis heartfailure surgicalprocedures,operative infections diagnosis guidelines heart surgeryspecialty embolism prevention IssueSection: ESCguidelines Downloadallslides Comments 2Comments Comments(2) Re:"2015ESCGuidelinesforthemanagementofinfectiveendocarditis"Habib,etal.,36(44):3075-3128doi:10.1093/eurheartj/ehv319 29February2016 SarahMillot,OdontologyDepartment,Marie-LaureColombier,Professor,BernardIung,CardiologyDepartment,PatrizioLancellotti,UniversityofLiègeHospital,GilbertHabib,Professor CharlesFoixHosp,APHP,France;ParisDescartesUni,Fr;APHP,BichatHosp,DHUFire,Paris-DiderotUni,Fr;DivCardiol,HeartValveClinic,GigaCardiovascularSci,Belgium;Aix-MarseilleUni,Fr WethankDizetal.fortheirfeedbackandinsightfulcommentsonthe2015ESCguidelinesininfectiveendocarditis(IE)(1).WeagreethatimplanttherapymaybeapreciousoptionfororalrehabilitationinpatientsathighriskofIE,despitethelackofdata(2). SeveralargumentshaveguidedthepositiontakenbytheTaskForce.First,dentalimplantsbelongtothecategoryof«atriskproceduresinvolvingmanipulationofthegingivalorperiapicalregionoftheteethorperforationoftheoralmucosa»,whichremainanindicationforantibioticprophylaxis(1).Theriskofbacteraemiaduringimplantplacementislowandcanbefurtherreducedwiththeuseof0,2%chlorhexidinedigluconaterinsebeforeimplant(3);bacteraemiainducedbyotherdentalinvasiveprocedures(extractions,scaling,intra-ligamentaryanaesthesia…)aremorefrequent(4,5).Secondly,theriskofdevelopingbacteraemiaisrelatedtotissuetrauma,localinflammation,densityoforalbacteriaandoralhygiene.Maintenanceofgooddentalandperiodontalhealthiscrucialtoreducetheriskofbacteraemiaandthisappliesevenmoretopatientswithdentalimplants(6,7). AsmentionedbyDizetal.,differencesinvascularanatomyaroundimplantsandteethhaveclinicalimplications.Indeed,periodontaltissuesarerichlyvascularised,originatedfromthreesourcesanastomosedtogether(alveolarbone,gingiva,periodontalligament).Thiscomplexvasculararchitecture(capillarynetwork,plexusofvessels)allowsthedevelopmentofdefencemechanismsagainstbacteria.Thecorrespondingsiteintheperi-implanttissueisalmostdevoidofvascularsupply,duetotheabsenceofperiodontalligament.However,ouropinionisthatthecrevicularspacethatsurroundsboththenaturalteethandthedentalimplantrepresentsacriticalregionforthedevelopmentofinfectiouslesionsthatmayresultinbacteraemia.Withplaqueaccumulationaroundimplants,intheabsenceofconnectivetissue,theinflammatorylesionsarenotencapsulatedbycollagenfibersandthenprogressrapidlytothealveolarboneanditsassociatedvessels.Asperiodontallesions,peri-implantlesionscanleadtotransientbacteraemia.Inaddition,therearefewervascularplexusbeneathperi-implantjunctionalepitheliuminvolvedinanti-bacterialdefence(8). Thishighlightsthatimplanttherapymustnotbelimitedtothesurgicalprocedureandshouldimplyaclosefollowupandamaintenanceprogramtopreventtheinfectiouscomplicationsthatcanoccurseveralyearsafterplacement,especiallyperi-implantitis(6).WhenimplantsareusedinpatientsatriskofIE,itismandatorytomaintainhealthyperi-implanttissuewithoutinflammatoryprocess. Weagreethattheuseofclindamycinreliesonlowlevelofevidencewithregardstodentalcare.Clindamycinisindicatedinthesecasesbecauseofthespectrumofitsantimicrobialeffect. Inconclusion,wesharetheopinionofDizetal.thatdentistsshouldbecloselyinvolvedinthepreventionofIE,inparticulargiventheharmfuleffectofbacteraemiaduetoimproperdentalhygiene.ThepossibilitytouseimplantsinpatientsatriskofIEisclearlystatedinthenewESCguidelines,butshouldbeassociatedwithclosefollow-up. References 1.HabibG,LancellottiP,AntunesMJ,BongiorniMG,CasaltaJP,DelZottiF,DulgheruR,ElKhouryG,ErbaPA,IungB,MiroJM,MulderBJ,Plonska-GosciniakE,PriceS,Roos-HesselinkJ,Snygg-MartinU,ThunyF,TornosMasP,VilacostaI,ZamoranoJL.2015ESCGuidelinesforthemanagementofinfectiveendocarditis:TheTaskForcefortheManagementofInfectiveEndocarditisoftheEuropeanSocietyofCardiology(ESC)Endorsedby:EuropeanAssociationforCardio-ThoracicSurgery(EACTS),theEuropeanAssociationofNuclearMedicine(EANM).EurHeartJ2015;26:3075-3128. 2.FindlerM,ChackartchiE,RegevE.Dentalimplantsinpatientsathighriskforinfectiveendocarditis:apreliminarystudy.IntJOralMaxillofacialSurg2014;43:1282-1285. 3.PiñeiroA,TomásI,BlancoJ,AlvarezM,SeoaneJ,DizP.Bacteraemiafollowingdental implants'placement.ClinOralImplantsRes2010;21:913-918. 4.BarbosaM,Prada-LópezI,ÁlvarezM,AmaralB,delosAngelesCD,TomásI.Post-toothextractionbacteraemia:arandomizedclinicaltrialontheefficacyofchlorhexidineprophylaxis.PLoSOne2015;10:e0124249 5.ZhangW,DalyCG,MitchellD,CurtisB.Incidenceandmagnitudeofbacteraemiacausedbyflossingandbyscalingandrootplaning.JClinPeriodontol2013;40:41-52. 6.LockhartPB,BrennanMT,SasserHC,FoxPC,PasterBJ,Bahrani-MougeotFK.Bacteremiaassociatedwithtoothbrushinganddentalextraction.Circulation2008;117:3118-3125. 7.MonjeA,ArandaL,DiazKT,AlarcónMA,BagramianRA,WangHL,CatenaA.Impactofmaintenancetherapyforthepreventionofperi-implantdiseases:asystematicreviewandmeta-analysis.JDentRes2015Dec23.pii:0022034515622432.[Epubaheadofprint] 8.LindheJ,LangNP,KarringT.FiftheditioneditionBlackwellMunksgaard.Clinicalperiodontologyandimplantdentistry,2008. Submittedon29/02/201612:00AMGMT Re:"2015ESCGuidelinesforthemanagementofinfectiveendocarditis"Habib,etal.,36(44):3075-3128doi:10.1093/eurheartj/ehv319 28September2015 PedroDiz,ProfessorinSpecialNeedsDentistry,JavierF.Feijoo,AssistantProfessorinSpecialNeedsDentistry,JacoboLimeres,SeniorLecturerinSpecialNeedsDentistry OMEQUIResearchGroup,SchoolofMedicineandDentistry,SantiagodeCompostelaUniversity,Spain Sir, Wereadwithinterestthelatestrecommendationsforthepreventionofinfectiveendocarditis(IE)recentlypublishedbytheESC(1).Theirrelevanceisindisputable,giventhecontroversygeneratedbythesystematicsuppressionofantibioticprophylaxisinhigh-riskpatientsundergoingdentaltreatment(2).However,thedocumentmakescertainproposalsrelatingtodentalproceduresthatweconsidershouldbediscussedfromtheperspectiveofthedentist. TheTaskForcestatedthat“At-riskproceduresinvolvemanipulationofthegingivalorperiapicalregionoftheteethorperforationoftheoralmucosa”,that“Theuseofdentalimplantsraisesconcernwithregardtopotentialriskduetoforeignmaterialattheinterfacebetweenthebuccalcavityandblood”,andthat“Thereisnoevidencetocontraindicateimplantsinallpatientsatrisk”.WeagreethatdentalimplantsmaybeanoptionfororalrehabilitationinpatientsathighriskofIE.However,inouropinion,thereisnoreasontofocusourattentionontheoralcavity-dentalimplant-bloodvesselinterfaceasthebloodsupplyaroundthedentalimplantsislessdevelopedthanaroundnaturaldentitionbecauseoftheabsenceoftheperiodontalligamentandadynamicprocessofboneremodelling.Theperiodontalspacethatsurroundsthenaturalteethdoesrepresentacriticalregionfortheentryoforalbacteriaintothebloodstream,asconfirmedbythehighprevalenceofbacteraemiageneratedbydentalproceduresthatrequiremanipulationofthiszone.Agoodexampleistoothextraction(3);however,intraligamentousanaesthesiaisalsorelevant(4),although,paradoxically,antibioticprophylaxisisnotrecommendedforthisprocedureinthenewESCguidelines(1).Perforationoftheoralmucosaisconsideredanat-riskprocedure,thoughwehaveobservedthatimplantplacementviaamucoperiostealflapdoesnotcarryasignificantriskofdevelopingbacteraemiaandthatthisriskpracticallydisappearswithasinglechlorhexidinemouthrinsebeforestartingthesurgicaltreatment(5). Anotherdebatablerecommendationisthecontinueduseofclindamycinastheantibioticofchoiceforpatientswithallergytotheβ-lactamantibiotics.Veryfewstudieshavebeenpublishedontheadministrationofclindamycintopreventbacteraemiafollowingdentalmanipulationsandtheirresultsdonotconfirmtheefficacyofthisantibiotictoreducethepercentageofpositivepost-extractionbloodcultures(6-8).Furthermore,theuseofclindamycinforantibioticprophylaxisisassociatedwithsignificantratesofadversedrugreactionsincluding,inparticular,Clostridiumdifficileinfection. Insummary,greaterattentionshouldperhapsbepaidtotheopinionofdentistswhendrawingupnewantibioticprophylaxisguidelinesapplicabletodentalprocedures. References 1.HabibG,LancellottiP,AntunesMJetal.2015ESCGuidelinesforthemanagementofinfectiveendocarditis:TheTaskForcefortheManagementofInfectiveEndocarditisoftheEuropeanSocietyofCardiology(ESC)Endorsedby:EuropeanAssociationforCardio-ThoracicSurgery(EACTS),theEuropeanAssociationofNuclearMedicine(EANM).EurHeartJ,2015;Aug29.pii:ehv319. 2.DayerMJ,JonesS,PrendergastB,BaddourLM,LockhartPB,ThornhillMH.IncidenceofinfectiveendocarditisinEngland,2000-13:aseculartrend,interruptedtime-seriesanalysis.Lancet,2015;385(9974):1219-28. 3.LockhartPB,BrennanMT,SasserHC,FoxPC,PasterBJ,Bahrani-MougeotFK.Bacteremiaassociatedwithtoothbrushinganddentalextraction.Circulation.2008;117:3118-25. 4.RobertsGJ,SimmonsNB,LonghurstP,HewittPB.Bacteraemiafollowinglocalanaestheticinjectionsinchildren.BrDentJ1998;185:295-8. 5.PiñeiroA,TomásI,BlancoJ,ÁlvarezM,SeoaneJ,DizP.Bacteraemiafollowingdentalimplants'placement.ClinOralImplRes2010;21:913-8. 6.GökerK,GüvenerO.Antibacterialeffectsofofloxacin,clindamycinandsultamicillinonsurgicalremovalofimpactedthirdmolars.JMarmaraUnivDentFac1992;1:237-49. 7.DizDiosP,TomásCarmonaI,LimeresPosseJ,MedinaHenríquezJ,FernándezFeijooJ,ÁlvarezFernándezM.Comparativeefficaciesofamoxicillin,clindamycin,andmoxifloxacininpreventionofbacteremiafollowingdentalextractions.AntimicrobAgentsChemother2006;50:2996-3002. 8.MaharajB,CoovadiaY,VayejAC.Acomparativestudyofamoxicillin,clindamycinandchlorhexidineinthepreventionofpost-extractionbacteraemia.CardiovascJAfr2012;23:491-4. 9.ThornhillMH,DayerMJ,PrendergastB,BaddourLM,JonesS,LockhartPB.Incidenceandnatureofadversereactionstoantibioticsusedasendocarditisprophylaxis.JAntimicrobChemother2015.pii:dkv115.[Epubaheadofprint] Submittedon28/09/201512:00AMGMT Advertisement 1,038,589 Views 2,061 Citations ViewMetrics × Emailalerts Articleactivityalert Advancearticlealerts Newissuealert ReceiveexclusiveoffersandupdatesfromOxfordAcademic Moreonthistopic 2021ESC/EACTSGuidelinesforthemanagementofvalvularheartdisease:DevelopedbytheTaskForceforthemanagementofvalvularheartdiseaseoftheEuropeanSocietyofCardiology(ESC)andtheEuropeanAssociationforCardio-ThoracicSurgery(EACTS) One-monthresultsfromaprospectiveexperienceonCASusingC-GUARDstentsystem:theIRONGUARD-2study DeterminantsofoutcomesfollowingsurgeryfortypeAacuteaorticdissection:theUKNationalAdultCardiacSurgicalAudit Conservative,surgical,andpercutaneoustreatmentformitralregurgitationshortlyafteracutemyocardialinfarction Relatedarticlesin WebofScience GoogleScholar RelatedarticlesinPubMed Neurologicaleventpredictionforpatientswithsymptomaticcerebralcavernousmalformation:theBLED2score. 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