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25/11/2015

Croup: Pharmacologic and supportive interventions

OfficialreprintfromUpToDate
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Croup:Pharmacologicandsupportiveinterventions
Author
CharlesRWoods,MD,MS

SectionEditor
SheldonLKaplan,MD

DeputyEditor
CarrieArmsby,MD,MPH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2015.|Thistopiclastupdated:Jan30,2014.
INTRODUCTIONCroup(laryngotracheitis)isarespiratoryillnesscharacterizedbyinspiratorystridor,
barkingcough,andhoarseness.Ittypicallyoccursinchildrensixmonthstothreeyearsofageandiscaused
byparainfluenzavirus.(See"Croup:Clinicalfeatures,evaluation,anddiagnosis".)
Thetreatmentofcrouphaschangedsignificantlysincethe1980s.Glucocorticoidsandnebulized
epinephrinehavebecomethecornerstonesoftherapy.Substantialclinicalevidencesupportstheefficacyof
theseinterventions[15].Theimpactalsoisevidentinthedecreaseinannualhospitaladmissionsforcroup
inchildrenintheUnitedStatesbetween1979to1982and1994to1997(from2.8to2.1per1000for
children<1yearandfrom1.8to1.2per1000childrenforchildren1to4years)[6].
Treatmentofcroupmayinvolveavarietyofpharmacologicandnonpharmacologicinterventions.Itmay
occurentirelyathome,orintheoffice,emergencydepartment(ED),orhospitalsetting.Supportiveand
pharmacologicinterventionswillbediscussedbelow.Theclinicalfeaturesandevaluationofcroupandthe
approachtomanagementarediscussedseparately.(See"Croup:Clinicalfeatures,evaluation,and
diagnosis"and"Croup:Approachtomanagement".)
GLUCOCORTICOIDSGlucocorticoidsprovidelonglastingandeffectivetreatmentofmild,moderate,and
severecroup[3,79].Theantiinflammatoryactionsofglucocorticoidsarethoughttodecreaseedemainthe
laryngealmucosaofchildrenwithcroup.Improvementisusuallyevidentwithinsixhoursofadministration
butseldomisdramatic[7,10].
Treatmentwithglucocorticoidsatvariousdosesandbyvariousrouteshasbeenshowntoimprovecroup
scoresandtodecreaseunscheduledmedicalvisits,lengthofstayintheemergencydepartmentorhospital,
andtheuseofepinephrine[7].Amongtheavailableglucocorticoids,dexamethasonehasbeenusedmost
frequently,istheleastexpensive,hasthelongestdurationofaction,andistheeasiesttoadminister.
EfficacyIntramuscular(IM),intravenous(IV),oral,andinhaledroutesofadministrationofglucocorticoids
havebeenshowntobeeffectiveincroupofalllevelsofseverity[7,8].Dexamethasone(oralorIM)and
budesonide(inhaled)weretheagentsusedinthemajorityofstudies.Asystematicreviewincluded24trials
(withcollectiveenrollmentof2878children)thatobjectivelymeasuredtheeffectivenessofglucocorticoid
treatmentforcroupcomparedwithplacebo[7].Fourteenothertrialscompareddifferentglucocorticoid
agentsordifferentroutesordosagesofthesameagent[7].Comparedwithtreatmentwithplacebo,
treatmentwithglucocorticoidwasassociatedwith:
Improvementinthecroupscoreatsixhourswithaweightedmeandifferenceof1.2(95%CI1.6to
0.8)andat12hours1.9(95%CI2.4to1.3)at24hoursthisimprovementwasnolongersignificant
(1.3,95%CI2.70.2)
Fewerreturnvisitsand/or(re)admissions(relativerisk0.50,95%CI0.30.7)
Decreasedlengthoftimespentinemergencydepartmentorhospital(weightedmeandifference12
hours,95%CI519hours)
Decreaseduseofepinephrine(riskdifference10percent95%CI120percent)
Therewerenosignificantdifferencesinclinicalefficacybetweentheroutesoragents,andthe
combinationoforalorIMdexamethasonewithinhaledbudesonidewasnotsuperiortoeitheragent

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alone[11,12].
Anothersystematicreviewofeightrandomizedcontrolledtrialscomparedtheadministrationofnebulized
glucocorticoidswithplacebo.Childrentreatedwithnebulizedglucocorticoidsweresignificantlymorelikelyto
showimprovementincroupscoreatfivehours(combinedrelativerisk(RR)1.48,95%CI1.271.74)and
significantlylesslikelytoneedhospitaladmission(combinedRR0.56,95%CI0.420.75)[13].
AdverseeffectsFewseriousadverseeffectshavebeenreportedinthestudiesevaluatingtheefficacyof
asingledoseofglucocorticoidsincroup[14].However,mostofthesestudiesweretoosmalltosufficiently
evaluaterare(<1percent)adverseeffects[15,16].
Theprimaryconcernispotentialriskofprogressiveviralinfectionorsecondarybacterialinfection,which
havebeenreportedinpatientswhoreceivedglucocorticoidtreatmentoverseveraldays[16],orreceived
nebulizeddexamethasoneandhadneutropenia[17].Thesecomplicationshavenotbeendescribedin
childrenwhohavereceivedsingledosesoforal,intramuscular,orintravenousglucocorticoidsforcroup.
Glucocorticoidusemayexacerbateactivevaricellaandtuberculosisandshouldbeavoidedinchildrenwith
theseinfectionsandinthoserecentlyexposedto,andpossiblyincubating,varicella[18,19].(See"Clinical
featuresofvaricellazostervirusinfection:Chickenpox".)
Administrationofglucocorticoidsmaymaskthepresentationofsteroidresponsiveupperairwaylesions,
suchashemangiomas,whichalsocanpresentwithstridor,particularlyduringaviralupperrespiratorytract
infection[20].(See"Epidemiology,pathogenesis,clinicalfeatures,andcomplicationsofinfantile
hemangiomas".)
Agents
DexamethasoneDexamethasonemaybeadministeredIM,IV,ororally.Todate,noclinically
significantdifferenceincroupoutcomesbetweenIMororallyadministereddexamethasonehasbeen
demonstrated[7].WhendexamethasoneisadministeredIMorIV,asingledoseof0.6mg/kg(maximum
doseof10mg)isusedmostfrequently.Smallerdosesappeartobeequallyeffectiveformildcroupwhen
administeredorally,asillustratedbelow:
Inonestudy,100childrenwithmildcroupwererandomlyassignedtoreceiveoraldexamethasone
(0.15mg/kg)orplacebointheemergencydepartment[21].Eightchildrenintheplacebogroup,and
noneinthedexamethasonegroup,returnedformedicalcare(astatisticallysignificantdifference).
Inanotherstudy,120hospitalizedchildrenwithcroupwererandomlyassignedtoreceiveasingleoral
doseofdexamethasone(0.15mg/kg,0.3mg/kg,0.6mg/kg)orplacebo[22].Therewasnodifferencein
durationofhospitalization,reductionincroupscore,orepinephrineuseamongthethreegroups
receivingdexamethasone.
Thesecondstudydescribedabove[22]includedasmallnumberofchildrenwithrelativelymildcroupand
consequentlymayhavebeenunderpowered(unable)todetectaclinicallyimportantdifference,particularly
inchildrenwithmoreseveresymptoms[14].
Childrenwithmildcroupwhocantolerateoralmedicationscanbegiveneitherdexamethasone0.15mg/kg
ordexamethasone0.6mg/kgorally,toamaximumtotaldoseof10mg.Althoughthelower0.15mg/kgdose
appearstobeefficacious[21],wecontinuetosuggestthehigherdose[23,24].
Theoralpreparationofdexamethasone(1mgpermL)hasafoultaste.Theintravenouspreparationismore
concentrated(4mgpermL)andcanbegivenorallymixedwithsyrup[11,25,26].
Studiesofnebulizeddexamethasoneinchildrenwithcrouphavemixedresults.Onestudyfoundnebulized
dexamethasonetobelesseffectivethanoraldexamethasoneinpreventingtheneedforsubsequent
treatmentwithglucocorticoidorepinephrineinchildrenwithmildcroup[27].Anotherstudyfoundthat
treatmentwithnebulizeddexamethasoneinchildrenwithmoderatecroupimprovedcroupscoresatfour
hoursbutdidnotaffecttherateofhospitalization[17].Inaddition,twopatientswithneutropeniawhowere

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treatedwithdexamethasonedevelopedbacterialtracheitis.
BudesonideNebulizedbudesonidehasbeenshowntobemoreeffectivethanplaceboandas
effectiveasIMororaldexamethasoneforthetreatmentofcroup[7,28].However,nebulizedbudesonideis
moreexpensiveandmoredifficulttoadministerthanIMororaldexamethasoneandisnotroutinelyindicated
inthetreatmentofcroup.However,nebulizedbudesonidemayprovideanalternativetoIMorIV
dexamethasoneforchildrenwithvomitingorsevererespiratorydistress[24].Inchildrenwithsevere
respiratorydistress,asingledoseofbudesonidemaybemixedwithepinephrineandadministered
simultaneously.(See"Croup:Approachtomanagement",sectionon'Moderatetoseverecroup'.)
PrednisoloneSomeauthoritiessuggestthatforchildrenwhoaretreatedasoutpatients,oral
prednisolone(2mg/kgperdayforthreedays)isanalternativetooraldexamethasone[29].Theuseof
prednisoloneinthetreatmentofcrouphasbeenevaluatedinalimitednumberofstudies.
A2011metaanalysisoftwotrials[30,31]thatcomparedasingledoseoforaldexamethasone(0.6mg/kgor
0.15mg/kg)withasingledoseoforalprednisolone(1mg/kg)showednodifferenceincroupscores,but
childrenrandomizedtoreceivedexamethasonehadfewerreturnvisitsand/orsubsequentadmissions(9.6
versus29.7percent,RR0.3,95%CI0.20.6)[7].
Asubsequentrandomizedtrialcomparedoraldexamethasone(0.6mg/kgonthefirstdayfollowedby
placeboonthenexttwodays)withoralprednisolone(2mg/kgperdayforthreedays)in87childrenwith
mildormoderatecroupwhoweretreatedasoutpatients[29].Therewerenodifferencesbetweengroupsin
additionalhealthcarevisits(2versus7percent[notsignificant]),durationofsymptoms(2.8versus2.2
days),durationofnonbarkycough(6.1versus5.9days),nightswithdisturbedparentalsleep(0.7versus
1.2),ordayswithstress(1.6versus1.4).
Anotherstudyof70childrencomparedprednisolone(1mg/kgevery12hours)withplaceboinchildrenwith
croupwhowerealreadyintubated[8].Childrenwhoreceivedprednisolonehadashortermediandurationof
intubationthanthoseintheplacebogroup(98versus138hours).Inaddition,fewerchildreninthe
prednisolonegrouprequiredreintubation(5versus34percent).
PrednisoneTheuseofprednisoneinthemanagementofcrouphasnotbeenevaluatedinclinical
trials.However,ithasequivalentpotencytoprednisoloneand,intheory,shouldhavesimilareffects.Despite
itslackofprovenbenefit,prednisoneiswidelyusedintheoutpatientmanagementofcroup[32].
Ifprednisoneistobeused,itisimportanttoadministeradosethatisequivalentinstrengthtothedosesof
glucocorticoidsthathavebeenbetterstudied.Dexamethasonehas6.67timestheglucocorticoidpotencyof
prednisone(4mg/kgofprednisone=0.6mg/kgofdexamethasone2mg/kgofprednisone=0.3mg/kgof
dexamethasoneand1mg/kgofprednisone=0.15mg/kgofdexamethasone).Ifchoosingtousethehigher
dose(ie,4mg/kgofprednisone),thevolumerequiredmaybeprohibitivegiventhattheconcentrationofthe
oralsolutionofprednisoneis1mg/1mL.
BetamethasoneApilotstudycomparedtheeffectivenessofasingleoraldoseofbetamethasone(0.4
mg/kg)withasingledoseofIMdexamethasone(0.6mg/kg)in52children(sixmonthstosixyears)withmild
tomoderatecroupwhoweretreatedintheemergencydepartment[33].Despiterandomization,mean
baselinecroupscoreswerehigherinthedexamethasonegroup(3.6versus2).Croupscoresdeclined
significantlyinbothgroups,andtherewerenodifferencesbetweengroupsinmeancroupscoresfourhours
aftertreatment,rateofhospitalization,timetoresolutionofsymptoms,needforadditionaltreatment,or
numberofreturnvisitstotheemergencydepartment.
RepeateddosingThemajorityofclinicaltrialsoforalandIMglucocorticoidsincrouphaveusedasingle
dose.Repeatdosesarenotnecessaryonaroutinebasis.Althoughrepeatdosesmaybereasonableinthe
occasionalchildwhohaspersistentsymptoms,theyshouldbeusedwithcaution.Theanecdotalcasesof
progressionofviralillnessandsecondarybacterialinfectionthathavebeenreportedwithuseof
glucocorticoidsforcroupoccurredwithrepeateddosingoverseveraldays[34],orinneutropenicpatients
[17].(See'Adverseeffects'above.)

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Moderatetoseveresymptomsthatpersistformorethanafewdaysshouldpromptinvestigationforother
causesofairwayobstruction.(See"Croup:Clinicalfeatures,evaluation,anddiagnosis",sectionon
'Differentialdiagnosis'.)
NEBULIZEDEPINEPHRINETheadministrationofnebulizedepinephrinetopatientswithmoderateto
severecroupoftenresultsinrapidimprovementofupperairwayobstruction.Epinephrineconstricts
precapillaryarteriolesintheupperairwaymucosaanddecreasescapillaryhydrostaticpressure,leadingto
fluidresorptionandimprovementinairwayedema[18].Evenamodestincreaseinairwaydiametercanlead
tosignificantclinicalimprovement.
BenefitsSeveralsmallrandomizedcontrolledtrialsandametaanalysishavedemonstratedthebenefit
ofracemicepinephrinecomparedwithplaceboinreducingthecroupscores30minutesaftertreatmentin
childrenintheemergencydepartment,hospital,andintensivecareunit[1,3537].Themagnitudeof
reductioninmeancroupscorefrombaselinerangedfrom2.2to3.6at20to30minutes(comparedwith
approximately1intheplacebogroup).However,by120minutes,croupscoresreturnedtobaselineornear
baseline[1,36].Inonetrial,treatmentwithIMdexamethasoneandnebulizedepinephrinewasassociated
withdecreaseddurationofhospitalizationcomparedwithIMdexamethasoneandplacebo(32hours,95%
CI59.1to4.9)[38,39].
Administrationofepinephrinedoesnotalterthenaturalhistoryofcroupintheshort(>2hours)orlongerterm
(24to36hours)[1,36,39].
Inthestudiesdescribedabove,racemicepinephrinewasadministeredeitherbynebulizationaloneorby
nebulizationcombinedwithintermittentpositivepressurebreaths[1,35,36].Anotherstudycomparedthese
twomethodsofadministrationandfoundthemtobesimilarlyeffective[2].
RacemicversusLepinephrineRacemicepinephrine,whichisa1:1mixtureoftheDandLisomers,
wasinitiallythoughttoproducefewersystemicsideeffects,suchastachycardiaandhypertension[18].
However,arandomizeddoubleblindstudycomparingracemicepinephrineandLepinephrineinchildren
withcroupfoundnodifferencebetweenthetwopreparationsin30minutecroupscore,heartrate,blood
pressure,respiratoryrate,fractionofinspiredoxygen,oroxygensaturation[40].Thisfindingisparticularly
importantoutsideoftheUnitedStates,whereracemicepinephrineisnotreadilyavailable.Eitherformof
epinephrineisacceptabletouseintheUnitedStates.
Dose
Racemicepinephrineisadministeredas0.05mL/kgperdose(maximumof0.5mL)ofa2.25percent
solutiondilutedto3mLtotalvolumewithnormalsaline.Itisgivenvianebulizerover15minutes.
Lepinephrineisadministeredas0.5mL/kgperdose(maximumof5mL)ofa1:1000dilution[40].Itis
givenvianebulizerover15minutes.
Nebulizedepinephrinetreatmentsmayberepeatedevery15to20minutesifwarrantedbytheclinical
course.Childrenwhorequirerepeatedfrequentdosing(eg,threeormoredoseswithintwotothreehours)to
achievestabilizationoftheirrespiratoryfunctiongenerallyshouldbeadmittedtoanintensivecareunitor
intermediatecaresetting(dependingontheseverityofpersistingsigns).
PrecautionsTheclinicaleffectsofnebulizedepinephrinelastfornomorethantwohours.Afterthe
effectshavewornoff,symptomsmayreturntobaseline(anapparentworsening,sometimesreferredtoas
the"reboundphenomenon").Childrenwhoreceiveevenasingledoseofnebulizedepinephrineshouldbe
observedintheemergencydepartmentorhospitalsettingforatleastthreetofourhoursafteradministration
toensurethatsymptomsdonotreturntobaseline.
Seriousadverseeffectsfromnebulizedepinephrineareexceedinglyrare.However,acaseofmyocardial
infarctioninachildwithcroupwhoreceivedthreedosesofracemicepinephrinewithin60minuteshasbeen
reported[41].Thus,itseemsprudenttoplacechildrenwhorequireongoingepinephrinetreatmentsmore
frequentlythaneveryonetotwohoursoncardiacmonitors(bothbecauseoftheseverityofillnessandthe

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potentialsystemicimpactofnebulizedepinephrine).Continuouselectrocardiographicmonitoring(or
equivalentcardiacmonitoring)alsoshouldbeconsideredinthesecases.
OXYGENOxygenisnotknowntohaveanydirectimpactonthesubglotticedemaorairwaynarrowing,
butshouldbeadministeredtochildrenwhoarehypoxemic(oxygensaturationof<92percentinroomair)
and/orinmoderatetosevererespiratorydistress[14,24].Supplementaloxygenshouldbehumidifiedto
decreasedryingeffectsontheairways,sincedryingmayimpedethephysiologicremovalofairway
secretionsviamucociliaryandcoughmechanisms.(See"Continuousoxygendeliverysystemsforinfants,
children,andadults".)
HelioxHeliumisinert,nontoxic,andofverylowdensity.Helioxisamixtureofhelium(70to80percent)
andoxygen(20to30percent).Itcanflowthroughairwayswithlessturbulenceandresistancethanpure
oxygen.(See"Physiologyandclinicaluseofheliox".)
Helioxdecreasestheworkofrespirationinchildrenwithcroupandtheoreticallycouldbeusedasa
temporizingmeasure,topreventtheneedforintubationwhilewaitingforglucocorticoidstodecreaseairway
edema[42].However,inclinicaltrials,helioxhasnotdefinitivelybeenshowntobemoreeffectivethan
humidifiedoxygenorracemicepinephrineinreducingcroupscores[4345].A2013systematicreviewfound
onlythreemethodologicallylimitedtrials(91patients)evaluatinghelioxinchildrenwithcroupandconcluded
thatalargertrialisneededbeforerecommendationsregardingtheuseofhelioxinchildrenwithcroupcan
bemade[45].
MISTTHERAPYHumidifiedairisfrequentlyusedinthetreatmentofcroup,althoughtherehavebeenno
studiessupportingitsefficacyinreducingsymptoms[46].Tworandomizedtrials(onecomparingmistversus
nomistandtheothercomparingnomist,lowhumidity,and100percenthumidity)amongchildrenbroughtto
anemergencydepartmentforcroupdemonstratednosignificantchangeincroupscoresfrombaseline
betweenthegroups[47,48].
Althoughhumidifiedairdoesnotreducesubglotticedema,itmayprovideotherbenefits.Inhalationofmoist
air,relativetodryair,maydecreasedryingofinflamedmucosalsurfacesandreduceinspissationof
secretions[49].Inaddition,amistsourcemayprovideasenseofcomfortandreassurancetoboththechild
andfamily[5052].Inmedicalsettings,misttherapymaybeprovidedbyblowbyorsalinenebulization
treatments.Crouptentsshouldbeavoided,sincetheycanaggravateachild'sanxietyandmakevitalsigns
andothervisualassessmentsofthechildmoredifficult.Someguidelinesrecommendagainsttheuseofmist
therapyforchildrenwhoarehospitalizedwithcroup[24].Certainlyifthechildisagitatedbytheprovisionof
mist,misttherapyshouldbediscontinued.
OTHERTHERAPIES
AntibioticsAntibioticshavenoroleintheroutinemanagementofuncomplicatedcroup,sincemost
casesarecausedbyviruses[14].Antibioticsshouldbeusedonlytotreatspecificbacterialcomplications,
suchastracheitis.
AntitussivesNonprescriptionantitussiveagentsareofunprovenbenefitforcroup(orotherrespiratory
tractinfections).Codeine,whichisamorepotentcoughsuppressant,canalterthechild'ssensorium,
makingitdifficulttofollowtheclinicalcourse.
DecongestantsDecongestantsalsoareofunprovenbenefitforcroup[14,24].
SedativesTheroutineuseofsedativeagentsinefforttoimproveairwayobstructionbyrelievinganxiety
andapprehensionisnotrecommended.Sedativesmaytreatthesymptomofagitationwhilemaskingthe
underlyingcausesofairhungerandhypoxia.Theyalsomaydecreaserespiratoryeffort(andthereforecroup
scores),withoutimprovingventilation[14,53].
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasics
andBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven

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condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easyto
readmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmore
detailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowant
indepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremail
thesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsby
searchingonpatientinfoandthekeyword(s)ofinterest.)
Basicstopic(see"Patientinformation:Croup(TheBasics)")
BeyondtheBasicstopic(see"Patientinformation:Croupininfantsandchildren(BeyondtheBasics)")
SUMMARY
Treatmentwithglucocorticoids(oral,intramuscular,ornebulized)hasbeenshowntodecreasecroup
scores,unscheduledmedicalvisits,lengthofstayintheemergencydepartmentorhospital,andthe
useofepinephrine.Asingledoseoforalorintramusculardexamethasoneisappropriateandadequate
formostchildren.(See'Glucocorticoids'aboveand"Croup:Approachtomanagement",sectionon
'Initialtreatment'.)
Treatmentwithnebulizedepinephrineresultsinrapidimprovementofupperairwayobstruction,butthe
durationofeffectislessthantwohours.RacemicepinephrineandLepinephrineappeartobeequally
effective.(See'Nebulizedepinephrine'above.)
Humidifiedairisfrequentlyusedasasupportivetreatmentforcrouphowever,therehavebeenno
studiessupportingitsefficacyinreducingsymptoms.(See'Misttherapy'above.)
Humidifiedoxygenshouldbeadministeredtochildrenwhoarehypoxemicand/orinmoderatetosevere
respiratorydistress.(See'Oxygen'above.)
Helioxhasnotdefinitivelybeenshowntobemoreeffectivethanhumidifiedoxygenorracemic
epinephrineinreducingcroupscores.(See'Heliox'above.)
Antibioticsshouldbeusedonlytotreatspecificbacterialcomplicationsofcroup.(See'Antibiotics'
aboveand"Croup:Approachtomanagement",sectionon'Complications'.)
Antitussivesanddecongestantsareofunprovenbenefitinthemanagementofcroup.Sedativesmay
decreasetheworkofbreathingandimproveagitationwithoutactuallyimprovingventilationor
addressingtheunderlyingcauseofagitation(hypoxemia).(See'Othertherapies'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic6008Version18.0

Disclosures
Disclosures:CharlesRWoods,MD,MSOtherFinancialInterest:Cerexa[Epiglottitis(DataSafetyMonitoringBoardforpediatric
trialsoftheantibioticagentceftaroline)].SheldonLKaplan,MDGrant/Research/ClinicalTrialSupport:Pfizer[vaccine(PCV13)]
ForestLab[antibiotic(Ceftaroline)]Optimer[antibiotic(fidaxomicin)].Consultant/AdvisoryBoards:Pfizer[vaccine(PCV13)].Carrie
Armsby,MD,MPHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately

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