Azithromycin, Clarithromycin, and Telithromycin

26/10/2015 Azithromycin,clarithromycin,andtelithromycin
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Azithromycin,clarithromycin,andtelithromycin
Author SectionEditor DeputyEditor

AmyLGraziani,PharmD DavidCHooper,MD AnnaRThorner,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Oct06,2014.
INTRODUCTIONAzithromycin(Zithromax)andclarithromycin(Biaxin)aremacrolideantibioticsthatare
usedinthetreatmentofcommunityacquiredrespiratorytractinfections,particularlypneumonia.Theyare
derivativesoftheoldermacrolideantibiotic,erythromycin.Structuralmodificationsoferythromycincausea
changeinthespectrumofactivity,dosing,andadministrationofthenewermacrolidesandketolides.
Telithromycin(Ketek)isthefirstmemberoftheketolideclassofantimicrobials,whichisrelatedtothe
macrolideclass.Concernsaboutpostmarketingreportsofhepatotoxicityandexacerbationsofmyasthenia
gravishaveledtosignificantrestrictionsontheuseoftelithromycin.(See'Warningsabouttelithromycin'
below.)
Thespectrumofactivity,mechanismsofactionandresistance,pharmacokinetics,interactionswithother
drugs,andadverseeffectsofthesenewermacrolideantibioticswillbereviewedhere.Theuseofthesedrugs
forcommunityacquiredpneumoniaisdiscussedseparately.(See"Treatmentofcommunityacquired
pneumoniainadultsintheoutpatientsetting"and"Treatmentofcommunityacquiredpneumoniainadultswho
requirehospitalization".)
Themacrolidesaresometimesusedfortheirantiinflammatoryeffects.Thisisdiscussedindetailseparately.
(See"Cysticfibrosis:Overviewofthetreatmentoflungdisease",sectionon'Macrolideantibiotics'and
"Chroniclungtransplantrejection:Bronchiolitisobliterans",sectionon'Treatment'and"Diffuse
panbronchiolitis",sectionon'Macrolideantibiotics'.)
MECHANISMOFACTIONANDCHEMICALSTRUCTUREThemechanismofactionofthenewer
macrolidesissimilartothatoferythromycin.Theybindtothe50Ssubunitofbacterialribosomes,leadingto
inhibitionoftranspeptidation,translocation,chainelongation,and,ultimately,bacterialproteinsynthesis[1,2].
Clarithromycinhasthesamemacrolide,14memberedlactoneringaserythromycintheonlydifferenceisthat,
atpositionsix,amethoxygroupreplacesthehydroxylgroup[1].Azithromycin,incomparison,hasa15
memberedringandamethylsubstitutednitrogenreplacingthe9Acarbonylgroup.Forthisreason,
azithromycinismorepreciselyreferredtoasanazalideratherthanamacrolide[24].
Thesestructuralchangeshavemadethenewermacrolidesmoreacidstablethanerythromycin,providing
improvedoralabsorption,tolerance,andpharmacokineticproperties.Thenewermacrolidesalsohaveabroader
spectrumofantibacterialactivitythanerythromycin[1,2].
Theketolide,telithromycin,wasdesignedtospecificallytargetmacrolideresistantrespiratorytractpathogens.
IthasaketogroupsubstitutedfortheLcladinoseatC3,amethoxygroupatC6,andanNsubstituted
carbamateatC11/C12.ThesemodificationsenabletelithromycintobindmoretightlytoribosomalRNA,which
increasesitspotency,decreasestheselectionofbacterialresistance,increasesitsactivityagainst
erythromycinresistantstrains,andimprovesthepharmacokinetics.
RESISTANCEAcquiredmacrolideresistanceisanincreasingproblem.Aswithresistancetootherdrugs,
antibioticusehasbeenassociatedwithdevelopmentofresistance.Thisrelationshipwasdirectlydemonstrated
inarandomized,doubleblindtrialinwhich224healthyvolunteerswereassignedtoazithromycin,
clarithromycin,orplacebotheendpointwasthedevelopmentofpharyngealcarriageofmacrolideresistant
streptococci[5].Theproportionofmacrolideresistantstreptococciwas26to30percentatbaseline.Both
macrolidessignificantlyincreasedtheproportionofmacrolideresistantstreptococcicomparedwithplacebo,
peakingatdayfourtoeight,withameanincreaseofabout50percent(toanabsoluteproportionofover80
percent)comparedwitha4percentincreasewithplacebo.Theincreaseinresistancewasgreaterwith
azithromycin,apossiblereflectionofitsmuchlongerhalflife.
http://www.uptodate.com/contents/azithromycinclarithromycinandtelithromycin?topicKey=ID%2F474&elapsedTimeMs=0&source=search_result&sea 1/17
Twomainmechanismsofacquiredmacrolideresistancehavebeendescribed[68]:
Methylasesencodedbytheerm(erythromycinribosomemethylase)genes(ermA,ermB,ermC)alterthe
macrolidebindingsiteonthebacterialribosomalRNA,usuallyconferringahighdegreeofmacrolide
resistance[9].Inastudyofselectedresistanceinvolunteers,clarithromycinbutnotazithromycin
selectedforthistypeofresistance[5].Thismechanismalsousuallyconfersresistancetoclindamycin.
(See"Clindamycin:Anoverview",sectionon'Resistance'.)
Activemacrolideeffluxpumps,encodedbythemef(macrolideefflux)msrAandmsrBgenes,confera
lowtomoderatedegreeofmacrolideresistance[911].
Thesemechanismsareresponsibleforerythromycinresistanceinmostgrampositivecocci(eg,
Staphylococcusaureus,Streptococcuspneumoniae,otherstreptococci).Incontrastwiththemechanismsof
acquiredresistance,intrinsicresistanceexhibitedbyEnterobacteriaceae,Pseudomonasspp,and
Acinetobactersppisduetodecreasedpermeabilityoftheoutercellenvelope.
Mechanismsofresistancetoazithromycinorclarithromycinarethesameasorsimilartothoseof
erythromycin.Thereiscompletecrossresistancebetweenerythromycin,azithromycin,andclarithromycinfor
grampositiveorganismsbythealterationinribosomalRNAmechanism.Incontrast,resistanceto
telithromycinbythismechanismisasyetuncommonasaresult,telithromycinisactiveagainstmany
erythromycinresistantrespiratorypathogens.However,resistanceduetoketolideeffluxpumpscancause
resistancetotelithromycin[12].Telithromycinresistantisolateshavebeenisolatedinvitro,andacasereport
hasdocumentedatelithromycinresistantS.pneumoniaeisolaterecoveredfrombloodfollowingtelithromycin
treatment[13].
TheincidenceofmacrolideresistantS.pneumoniaeisolatesincreasedfrom10.6percentin1995to20.4
percentin1999.However,incitiesintheUnitedStateswherepneumococcalvaccinationofchildrenhasbeen
widespread,therewasadistinctreductionintheoverallprevalenceofmacrolideresistanceamonginvasive
isolatesin2002.(See"ResistanceofStreptococcuspneumoniaetothemacrolides,azalides,lincosamines,
andketolides",sectionon'Prevalenceofresistance'.)
Azithromycin,clarithromycin,andtelithromycinhaveenhancedgramnegativeactivitycomparedwith
erythromycin.Asaresult,selectederythromycinresistantgramnegativeorganismsmaybesensitivetothe
newerdrugs.
Increasingresistancetoazithromycinhasbeendescribedinpatientswithsyphilisthefrequencyvarieswith
geographicarea.(See"Pathogenesis,clinicalmanifestations,andtreatmentofearlysyphilis",sectionon
'Macrolides'.)
SPECTRUMOFACTIVITYAzithromycin,clarithromycin,andtelithromycinhaveabroaderspectrumof
activitythanerythromycin[14].
Thegreatestuseofthemacrolidesisinupperrespiratorytractinfectionsazithromycin,clarithromycin,and
telithromycinhaveactivityagainsterythromycinsensitiveStreptococcuspneumoniae,Haemophilusspp,
Moraxellacatarrhalis,andatypicalpneumoniapathogens,includingLegionellapneumophila,Chlamydia
pneumoniae,andMycoplasmapneumoniae.Telithromycinalsohasactivityagainstmanyerythromycin
resistantS.pneumoniae.AzithromycinismoreeffectiveinvitroagainstmoststrainsofH.influenzaeandhas
morerapidkillingandalongerpostantibioticeffectthanclarithromycin[14,15].Despitethefactthat
clarithromycins14hydroxymetabolitehasactivityagainstH.influenzae,inonestudy,only63percentofH.
influenzaeisolatesweresusceptibletoclarithromycin,whereas96percentweresusceptibletoazithromycin
[16].Forthisreason,azithromycinispreferredoverclarithromycininoutpatientswithcommunityacquired
pneumoniawhohavecomorbidities,suchaschronicobstructivepulmonarydisease[15].Erythromycindoes
nothaveactivityagainstH.influenzae.(See"Treatmentofcommunityacquiredpneumoniainadultsinthe
outpatientsetting"and"Antibioticstudiesforthetreatmentofcommunityacquiredpneumoniainadults",
sectionon'Macrolideresistance'.)
TheseantibioticsarealsousuallyactiveagainstothergrampositiveorganismsincludingStaphylococcus
aureus(exceptformethicillinresistantS.aureus)andgroupA,B,C,andGStreptococcus.
Resistancetoeitherazithromycinorclarithromycinbygrampositiveorganismsresultsincrossresistanceto
theothermacrolideshowever,thiscrossresistanceisnotnecessarilytruewithtelithromycin.Asanexample,
telithromycinisactiveagainstmanyerythromycinresistantS.pneumoniaeandStreptococcuspyogenesandis
moreactivethanazithromycinandclarithromycininvitroagainsterythromycinsensitiveS.aureus[14].
Thenewermacrolideshaveenhancedgramnegativeactivitycomparedwitherythromycin.Asaresult,an
erythromycinresistantgramnegativeorganismmaybesensitivetoazithromycin,clarithromycin,and/or
telithromycin.ThegramnegativespectrumincludesactivityagainstEscherichiacoli,Salmonellaspp,Yersinia
enterocolitica,Shigellaspp,Campylobacterjejuni,Vibriocholerae,Neisseriagonorrhoeae,andHelicobacter
pylori.
ClarithromycinandazithromycinaretheprimaryagentsusedtotreatMycobacteriumaviumcomplex
infections.(See"Mycobacteriumaviumcomplex(MAC)infectionsinHIVinfectedpatients"and"Treatmentof
nontuberculousmycobacterialinfectionsofthelunginHIVnegativepatients".)
METABOLISMANDPHARMACOKINETICSClarithromycin,azithromycin,andtelithromycinhave
improvedoralabsorption,longerserumhalflives,andbettertissueandintracellularpenetrationthan
erythromycin.Onlyazithromycinisavailableinanintravenousformulation.
AcidstabilityandfoodAzithromycin,clarithromycin,andtelithromycinarestableatgastricpH.Asa
result,theirbioavailabilityisbetterthanthatoferythromycinbase(37versus25percent),andentericcoatingis
notrequired.Allofthenewertabletformulationsandoralsuspensions,exceptforextendedrelease
clarithromycin,canbetakenwithorwithoutfood[1,4,17].
Theserumconcentrationsattainedwithoralazithromycinaremuchlowerthanthoseofclarithromycin.
Aregimenof500mgondayonefollowedby250mg/dayforninedaysleadstoanaverageplasma
azithromycinconcentrationof0.21mcg/mL[24,18,19].
Theextendedreleaseoralsuspensionofazithromycin(Zmax,givenasasingledoseperweek)resultsin
ahigherpeakserumconcentrationandmoresystemicexposurethancanbeachievedwithstandard
regimensofimmediatereleaseazithromycin[20].
Theoralbioavailabilityoftheoriginalclarithromycin(dosedevery12hours)tabletsisapproximately50
percentthemeansteadystatepeakserumconcentrationfollowing500mgorallyevery12hoursis2to3
mcg/mL[21].
Thenewerextendedreleaseclarithromycintablets(BiaxinXL,dosedoncedaily)haveinactiveingredients
inthetabletthatbindtoclarithromycinandslowgastricabsorption.Thepeakserumconcentrationis
lowerthantheoriginalclarithromycintabletsandisdelayeduntilfivetoeighthoursfollowingthedose.
Patientsshouldbeinstructedtotaketheextendedreleasetabletswithfoodbecausefastingdecreases
theareaundertheplasmaconcentrationtimecurve(AUC)by30percent.
Telithromyciniswellabsorbedfromthegastrointestinaltract(90percent),butathirdofthedoseismetabolized
viafirstpassmetabolismbytheliverandintestine,resultinginanoralbioavailabilityof57percent[12].Peak
plasmalevelsonetotwohoursafteran800mgoraldoseare1.8to2.2mcg/mL.Theplasmahalflifeis9.8
hoursatsteadystate[22].Fooddoesnotaffecttherateorextentofabsorptionoftelithromycin.
TissueandintracellularpenetrationAllmacrolidesandketolidesdistributeandconcentratewellinmost
bodytissuesandphagocyticcells.Thus,thetissuelevels,epithelialliningfluid,andalveolarmacrophage
concentrationsareusuallyhigherthanthoseintheplasma[1,4].
Telithromycinisthemosthighlyconcentratedintissue,followedbyazithromycin,clarithromycin,and
erythromycin[1,21].Telithromycinachievesconcentrationsinlowerrespiratorytractinfectionsitesthatare
higherthantheminimuminhibitoryconcentrations(MICs)ofmostrespiratorypathogens[17].Asanexample,
telithromycinconcentratesintracellularlyinalveolarmacrophages(atleast400foldhigherthanconcomitant
serumconcentrations)andinpolymorphonuclearcells(200to300foldhigherthanconcomitantserum
concentrations)[14,23].
Azithromycinlevelsinsputumandlungare10to100timesthoseintheplasmaalveolarmacrophageand
neutrophilconcentrationsarealsohigher[2,4,21].Incomparison,clarithromycinlevelsinthelungareonlysix
toeighttimeshigherthantheplasmaconcentration[19].
Thesedifferencesinintracellularpenetrationandplasmaconcentrationaretworeasonsthatcomparisonof
theseagentsbytraditional,invitromethods(suchasminimuminhibitoryconcentration)isdifficult.Theclinical
significanceofthebettertissuepenetrationbutlowerplasmalevelsoftelithromycinandazithromycinisnot
known.
ActivemetabolitesAzithromycinisexcretedinthebileandthenthefeces,withverylittleunchangeddrug
appearingintheurine[2,4].Severalazithromycinmetaboliteshavebeenidentified,butnoneisknowntobe
biologicallyactive[4,24].
Clarithromycinishydroxylated,Ndemethylated,andhydrolyzedintheliver,utilizingthecytochromeP450
enzymesystem.Themajormetabolite,14hydroxyclarithromycin,ismicrobiologicallyactive[1,2],anditis
moreactivethantheparentcompoundagainstsomespecies.Asanexample,amongH.influenzaeisolates
frompatientswithcommunityacquiredpneumonia,theconcentrationatwhich90percentoforganismsare
inhibited(MIC90)ofthe14OHmetabolitewas3mcg/mLcomparedwith9mcg/mLfortheparentcompound
[16].Thisactiveclarithromycinmetaboliteisanothervariablethatmakesacomparisonbetweenclarithromycin
andazithromycindifficultinvitro.Twentyto30percentofclarithromycinisexcretedunchangedintheurine
[25].
Telithromycinhasmultipleroutesofelimination:7percentiseliminatedinthefeces,13percentisexcreted
unchangedintheurine,andtheremainderismetabolizedbyhepaticCYP450andnonCYP450pathways.Up
tofourmajormetabolitesappeartohaveantibacterialactivity,althoughtheactivityisweak,onlyabout6
percentaspotentastelithromycin[23].
DOSINGANDADMINISTRATION
AzithromycinComparedwithclarithromycin,azithromycinistypicallygivenforashorterperiodbecauseof
thelongintracellularhalflife(40to68hours)andslowreleasefromtissuesites.Thus,formanyinfections,a
oncedaily,fivedayregimenisaseffectiveas10daycoursesoftheothermacrolides.
Azithromycinisavailableinseveraldifferentformulations,including250,500,and600mgtabletsanda100
mg/5mLor200mg/5mLpediatricpreparation.
Azithromycinisalsoavailableasanintravenousformulation.Theinfusionvolumesarerelativelylarge(250mL
to500mL)andtheinfusionratesarelong(threehoursforthe1mg/mLconcentrationandonehourforthe2
mg/mLconcentration).
The2gextendedreleaseoralsuspensionofazithromycin(Zmax)hasanevenshorterregimen,asitisgiven
asasingledose,becauseofthelonghalflife[20].
ClarithromycinClarithromycinisavailableintheoriginaltablets(250and500mg)andextendedrelease
tablets(BiaxinXL,500mg).Thereisnointravenousformulation.
Apediatricformulationisavailableincludingtabletsorgranulesfororalsuspension(125mg/5mLand250mg/5
mL)[24].Thesuspensionshouldnotberefrigeratedbecauseitcanbecomeveryviscousanddifficulttoshake
adequately.
WarningsabouttelithromycinTelithromycinisavailablein400mgtablets.Thereisnointravenous
formulation.
Becauseofreportsofpotentiallyfatalhepatotoxicity,potentiallyfatalexacerbationsofmyastheniagravis,and
visualdisturbances,theUSFoodandDrugAdministration(FDA)concludedinFebruary2007thattherisks
associatedwithtelithromycinoutweighitsbenefitsforminorillnessesandthattelithromycinshouldnotbe
usedtotreatsinusitisorbronchitis[26].Evenamongpatientswithmildtomoderatecommunityacquired
pneumonia,theFDAconcludedthattelithromycinshouldbeasecondaryalternativetootherantimicrobial
drugs.Aboxedwarningwasaddedtothelabelstatingthattelithromycinshouldnotbeusedinpatientswith
myastheniagravis.Therehasbeensomecontroversyoverthereviewandmonitoringofthehepatotoxicitypre
andpostmarketing[26,27].
SPECIALPOPULATIONS
RenalinsufficiencyAzithromycindosingdoesnotrequireadjustmentwithdecreasedcreatinineclearance.
Inpatientswithacreatinineclearancebelow30mL/min,thedoseofclarithromycinshouldbereducedbyhalf
orthedosingintervalshouldbedoubled.
Telithromycindosingdoesnotrequireadjustmentwithmildtomoderaterenalimpairment(creatinineclearance
30mL/min).Nodosehasbeenestablishedforpatientswithsevererenalimpairment,butthedrug
accumulateswithdecreasedrenalfunction.Asaresult,doseadjustmentshouldbeconsideredinthese
patients.
PregnancyErythromycinshouldbeconsideredthesafestmacrolideinpregnantwomenbecauseofthe
manyyearsofclinicalexperience.Ofthenewermacrolides,thereismoreexperienceduringpregnancywith
azithromycinthanclarithromycinortelithromycin.
AzithromycinAzithromycinisaUSFoodandDrugAdministration(FDA)pregnancycategoryBdrug
(ie,noevidenceofriskinpregnanthumans),thesamecategoryasforerythromycin(table1)[24,28].
Thereareseveralreportsoftheuseofazithromycininpregnantwomen[2931].Intwostudies,patientswith
cervicalchlamydialinfectionreceiveda1gdoseofazithromycinandwerefollowedforefficacyandtoxicity
[29,30].Teratogeniceffectswerenotnoted,althoughitisnotclearifneonatalexaminationandfollowupwere
required.Morerecently,123pregnantwomentakingazithromycinwereprospectivelyfollowedalongwithtwo
groupsofmatchedcontrols[31].Theincidenceofmajormalformationswassimilarintheazithromycin
exposedandunexposedgroupsandwasnotmorethanthe1to3percentthatwouldbeexpectedinthe
generalpopulation.Allthreeofthemalformationsoccurredintheinfantsofazithromycinexposedwomenwho
weretreatedforfivedaysforupperrespiratorytractinfections.Thisstudywasunderpoweredtodetecta
differencebetweentheazithromycinexposedandunexposedgroups.Thesafetyofthisagentinpregnant
womenisnotdefinitivelyknown.
ClarithromycinClarithromycinisapregnancycategoryCdrug(ie,riskcannotberuledout)(table1)
[32].Teratogeniceffects(includingcleftpalate,cardiovascularanomalies,andfetalgrowthrestriction)have
occurredinmonkeys,rats,mice,andrabbitswithplasmaclarithromycinconcentrations2to17timesthe
levelsnormallyachievedinhumans.Thelabelingstatesthatnoadequateandwellcontrolledtrialsinpregnant
womenhavebeenperformedasaresult,clarithromycinshouldbeusedinpregnantwomenonlyifthepotential
benefitjustifiesthepotentialrisktothefetus[32].
TelithromycinTelithromycinisapregnancycategoryCdrug(table1).Inratsandrabbitsathighdoses,
maternaltoxicitymayresultindelayedfetalmaturationinrats,itisexcretedinbreastmilk[33].
ADVERSEREACTIONSThenewermacrolidesaregenerallybettertoleratedthanerythromycin.Because
ofitsmorefrequentgastrointestinalsideeffectsandriskofQTprolongationandsuddendeath,erythromycinis
nowrarelyrecommended.ErythromycinwasthefirstmacrolidetobeassociatedwithQTprolongation,but
subsequentreportsandstudieshavealsodescribedQTprolongationwithclarithromycinandazithromycinas
wellastheketolide,telithromycin.
Thefollowingprovidesabriefsummaryofsomeofthemajoradverseeffectsassociatedwiththesedrugs.
DetailaboutspecificinteractionsisavailablebyusingtheLexiInteractprogramincludedwithUpToDate.
Hepatotoxicity
AzithromycinPostmarketingreportshaveidentifiedvarioushepaticabnormalitiesinpatientsreceiving
azithromycin,includingabnormalliverfunctiontests,hepatitis,cholestaticjaundice,hepaticnecrosis,and
hepaticfailuresomeofthesecaseshaveresultedindeath[34].Azithromycinisthereforecontraindicatedin
patientswithahistoryofcholestaticjaundiceorhepaticdysfunctionassociatedwithpriorazithromycinuse.It
shouldbediscontinuedimmediatelyifsignsorsymptomsofhepatitisoccur.
TelithromycinSeverehepatotoxicityreportedinthreepatientsreceivingtelithromycinpromptedanUS
FoodandDrugAdministration(FDA)PublicHealthAdvisory[35].Allthreepatientsdevelopedjaundiceand
abnormalliverfunction.Onepatientrecovered,onerequiredanorgantransplant,andonedied.Liverhistology
inthelattertwopatientsshowedmassivetissuedeath.Althoughtwopatientsreportedsomealcoholuse,all
threehadbeenpreviouslyhealthyandwerenotusingotherprescriptiondrugs.Therehavebeenadditional
reportsofhepatotoxicity,42ofwhichwerereviewedindetailandpublished[36].Theonsetwasshort(median
10days)andmortalitywashigh.
Cliniciansarecautionedtomonitorpatientstakingtelithromycinforsignsandsymptomsofliverdysfunction
andareadvisedtostopthemedicationinanypatientwhodevelopsevidenceofliverdisease.Telithromycin
shouldnotbereadministeredtopatientswithaprevioushistoryofhepatitisand/orjaundiceassociatedwiththe
useoftelithromycinoranymacrolideantibiotic.
Duetopostmarketingreportsofhepatotoxicityandothertoxicities,theFDArescindeditsapprovalof
telithromycinforbronchitisandsinusitis.Itisstillapprovedforthetreatmentofmildtomoderatecommunity
acquiredpneumonia(CAP),buttheFDAconcludedthattelithromycinshouldbeasecondaryalternativeto
otherantimicrobialdrugs.(See'Warningsabouttelithromycin'above.)
GastrointestinaltoxicityGastrointestinalsideeffects(nausea,diarrhea,abdominalpain)occurin2to5
percentofpatientswithoralazithromycinandclarithromycinandabout12percentwithtelithromycin[14,33].
Clarithromycindoesnotformtheanhydrohemiketaldegradationproductthoughttoberesponsibleforsomeof
thegastrointestinalsideeffectsassociatedwitherythromycin[19].Macrolideshaveadoserelatedeffecton
motilinreceptorsandcantherebystimulatethesmoothmuscleofthegastrointestinaltract.Infact,theyhave
beenusedclinicallytostimulategastricmotility[37].
Theintravenousformulationofazithromycinalsocausesgastrointestinalsideeffectsincludingnausea(4to7
percent),vomiting(1.4percent),diarrhea(4to9percent),andabdominalpain(2to3percent).
Theresponsetoonedrugdoesnotnecessarilypredictthattotheother.Somepatients,forexample,have
intolerablesideeffectswithclarithromycinbutnotazithromycinandviceversa.Abdominalcrampingwith
subsequentloosestoolsiscommonwithhighdosesofazithromycin[4,19].
Dysgeusiaseemstobearelativelyfrequentcomplaintinpatientswhoaretreatedwithclarithromycin,lessso
withtelithromycin,andnotwithazithromycin.Theclarithromycinpediatricsuspensionisbittertasting.
QTintervalprolongationandcardiovasculareventsErythromycinwasthefirstmacrolidetobe
associatedwithQTintervalprolongation,butsubsequentreportsandstudieshavealsodescribedQTinterval
prolongationwithclarithromycinandazithromycinaswellastheketolide,telithromycin.Cliniciansshould
assesstheriskoftorsadesdepointeswhenconsideringamacrolideandotherantibiotictreatmentoptionsfor
patientsatriskforcardiovascularevents[38].Inadditiontomacrolides,certainnonmacrolides,suchas
fluoroquinolones,alsohavethepotentialforprolongingtheQTinterval.(See"Fluoroquinolones",sectionon'QT
intervalprolongationandarrhythmia'and"AcquiredlongQTsyndrome",sectionon'Incidencewithspecific
drugs'.)
Eachpatient'smedicationlistshouldbereviewedtodetermineifheorsheistakinganotherdrugthatcan
prolongtheQTinterval(eg,methadone)sincepatientsreceivingmorethanonesuchagentareatincreased
riskoftorsadesdepointes(table2).
InformationregardingtheriskofQTprolongationwitheachmacrolideandtelithromycinissummarizedas
follows:
ErythromycinErythromycinisassociatedwithanapproximatetwofoldincreaseintheriskofsudden
cardiacdeathoverallandafivefoldincreaseinpatientsalsotakingCYP3A4inhibitors[39].
AzithromycinTherearecasereports,postmarketingsurveillancedata,andlargecohortstudies
suggestinganassociationbetweenazithromycinandanincreasedriskofcardiovascularmorbidityand
mortalityinpatientstreatedwithazithromycin[40,41].However,somelargecohortstudieshavenot
shownanincreasedrisk.Althoughnotallreportshavebeenpoweredtodetectlowtomoderateincreases
inrisk,anincreasedriskhasbeenseeninpatientswithcomorbidities,includingolderadultpatientsand
thosereceivingothermedicationsthataffecttheQTinterval.Anincreasedriskinotherpopulations
cannotberuledout.
In2013,theUSFoodandDrugAdministration(FDA)issuedawarningabouttheriskofQTinterval
prolongationandpotentiallyfataltorsadesdepointesamongpatientstakingazithromycin[38].Patientsat
particularriskincludethosewithexistingQTintervalprolongation(includingcongenitallongQT
syndrome),ahistoryoftorsadesdepointes,hypokalemia,hypomagnesemia,significantbradycardia,
bradyarrhythmias,uncompensatedheartfailure,andthosereceivingcertainantiarrhythmicdrugs(eg,
classIA[quinidine,procainamide]orclassIII[dofetilide,amiodarone,sotalol]antiarrhythmicdrugs)
[38,42,43].OlderadultpatientsmayalsobemoresusceptibletodrugassociatedQTintervalprolongation.
Thewarningwasbasedonareviewthatfollowedthepublicationofastudythatshowedanincreased
riskofdeathinpatientsreceivingazithromycin[44]:
Inalargedatabaseanalysisofadultsaged30to74yearsenrolledinMedicaidinTennessee,
patientsreceivingafivedaycourseofazithromycinhadanincreasedriskofcardiovascular
mortality(hazardratio[HR]2.88,95%CI1.794.63)andallcausemortality(HR1.85,95%CI1.25
2.75)comparedwiththosewhotooknoantibiotics[44].Patientsreceivingazithromycinalsohadan
increasedriskofcardiovascularmortality(HR2.49,95%1.384.50)andallcausemortality(HR
2.02,95%CI1.243.30)comparedwiththosereceivingamoxicillin.Incontrast,therewasno
increaseintheriskofdeathinpatientsreceivingamoxicillinorciprofloxacin.Theriskof
cardiovascularmortalityandallcausemortalityweresimilarforazithromycinandlevofloxacin.
Theabsoluteincreaseincardiovascularmortalitywassmallpatientswhoreceivedazithromycin
hadanestimated47additionalcardiovasculardeathspermillioncoursesoftherapycomparedwith
amoxicillin[44].Theriskofcardiovascularmortalitywashighestamongpatientswithelevated
cardiovascularriskscorescomparedwithpatientsreceivingamoxicillin,inpatientsreceiving
azithromycin,therewerenineexcesscardiovasculardeathspermillionfivedaycoursesof
antibioticsamongthoseinthelowestcardiovascularriskcategoryversus245excess
cardiovasculardeathsamongthoseinthehighestcategory.Amongthe29cardiovasculardeaths
thatoccurredduringafivedaycourseofazithromycin,22weresuddencardiacdeaths.Althoughthe
investigatorsusedpropensityanalysistoadjustforbaselinerisk,residualconfoundingremainsa
concernsincepatientsprescribedazithromycinmayhavehadahigherriskofdeathbecauseoftheir
underlyingdiseaseand/orcomorbidities.
Inadatabaseanalysisof1.7millionUnitedStatesveteranswhoreceivedoutpatientprescriptions
forazithromycin,levofloxacin,oramoxicillin,therewasanincreasedriskofmortalityandarrhythmia
inpatientswhoreceivedazithromycinorlevofloxacin,butnotamoxicillin[45].
Otherstudieshaveshownconflictingresults:
AlargecohortstudyusedDanishnationalhealthcaredatatoevaluatetheassociationbetween
azithromycinuseandcardiovasculardeathinadultsbetweentheagesof18and64[46].Theriskof
deathfromcardiovascularcauseswassignificantlyincreasedwithcurrentuseofazithromycin
(definedasafivedaycourse)comparedwithnouseofantibiotics(rateratio[RR]2.85,95%CI
1.137.24).However,inapropensityadjustedanalysis,currentazithromycinusewasnot
associatedwithanincreasedriskofdeathfromcardiovascularcausescomparedwithpenicillinV
(RR0.93,95%CI0.561.55).Theseresultssuggestthattheincreasedriskofcardiovasculardeath
observedinpatientsreceivingazithromycincomparedwithnoantibioticusewasattributableto
underlyingpatientfactorsthatledtotheprescriptionofantibiotics.
Becausetherewerefewevents,therewaslimitedpowertoexaminetheriskofcardiovascular
deathinsubgroups,includingthesubgroupofpatientswithknowncardiovasculardisease(RR1.35,
95%CI0.692.64)[46].Ofnote,thepopulationinthisstudywashealthierthantheMedicaid
populationevaluatedinthedatabaseanalysisdescribedabove[40,44].Thecardiovascularmortality
rateintheMedicaidpopulationwas85.2deathspermillioncoursesofazithromycincomparedwith
15.4deathspermillioncoursesintheDanishpopulation.Thisstudysuggeststhatazithromycin
doesnotincreasetheriskofcardiovasculardeathinyoungandmiddleagedmembersofthegeneral
population,atleastthosewithoutpreexistingcardiovasculardisease.
AlargecohortstudyusedDepartmentofVeteransAffairsadministrativedatatoevaluatethe
associationbetweenazithromycinuseandallcausemortalityandcardiovasculareventsinpatients
65yearsofagewhowerehospitalizedwithpneumonia[47].Ninetydaymortalitywassignificantly
lowerinthosewhoreceivedazithromycinversusthosewhoreceivedotherguidelineconcordant
antibiotics(17versus22percentoddsratio[OR]0.73,95%CI0.700.76).Comparedwithpatients
whodidnotreceiveazithromycin,thosewhoreceivedazithromycinwereslightlymorelikelytohave
amyocardialinfarction(5.1versus4.4percentOR1.17,95%CI1.081.25),butnotarrhythmias,
heartfailure,oranycardiacevent.Basedonthepropensitymatchedanalysis,thenumberneeded
totreatwithazithromycinwas21topreventonedeathwithin90days.Thenumberneededtoharm
was144formyocardialinfarction.Theseresultscorrespondtoanetbenefitofapproximatelyseven
deathsavertedforonenonfatalmyocardialinfarctioninduced.
AreviewofpublichealthdatabasesinOregonandWashingtondidnotshowanassociation
betweenazithromycinuseandcardiovascularmortalityinayoung(meanage24years),healthy
population[48].Inthereport,162,385peopleweretreatedforChlamydiaorgonorrheawithasingle
doseof1gramofazithromycinandtherewerenocardiovasculardeathswithin10daysof
treatment.Therewerethreenoncardiovasculardeathsintheazithromycingroup,andtwo
noncardiovasculardeathsinthe97,663patientcontrolgroupthatdidnotreceiveazithromycin.The
studywasonlypoweredtodetectlargeincreasesinrisk.
AninstitutionwidecomputerbasedQTalertsystemhasbeendevelopedthatscreensallelectrocardiogramsin
theelectronicmedicalrecord(EMR)andalertsthephysicianiftheQTcis500msinanattempttoreducethe
incidenceoftorsadesdepointes[49,50].Suchelectronicmethodsareimportantinstrumentsforthesafeuseof
medicationsand,ifnotalreadyintegrated,shouldbeaddedtoavailableEMRs.(See"AcquiredlongQT
syndrome".)
ClarithromycinClarithromycinhasalsobeenassociatedwithQTintervalprolongation[5154]andis
metabolizedbyCYP3A4.Torsadesdepointeshasprimarilybeendescribedwhenclarithromycinisgiven
withotherdrugsthatprolongtheQTinterval.Afewcasereportshavedescribedtorsadesdepointeswith
clarithromycinalone[55].
Inanobservationalstudythatincludedpatientswithacuteexacerbationsofchronicobstructive
pulmonarydisease(COPD),clarithromycinwasindependentlyassociatedwithanincreasedriskof
cardiovascularevents(HR1.50,95%CI1.131.97),acutecoronarysyndromes(HR1.67,95%CI1.04
2.68),andcardiovascularmortality(adjustedHR1.52,95%CI1.022.26)butnotallcausemortality[53].
Inpatientswithcommunityacquiredpneumonia,clarithromycinusewasindependentlyassociatedwith
anincreasedriskofcardiovascularevents(HR1.68,95%CI1.182.38)butnotacutecoronary
syndrome,cardiovascularmortality,orallcausemortality.Bothinpatientswithacuteexacerbationsof
COPDandinthosewithCAP,adurationofclarithromycin>7dayswasassociatedwithcardiovascular
events,whereasaduration<3dayswasnot.
InalargecohortstudythatassessedtheriskofcardiacdeathinDanishadultsaged40to74yearswho
receivedasevendaycourseofclarithromycin,roxithromycin(anothermacrolide),orpenicillin,useof
clarithromycinwasassociatedwithanincreasedriskofcardiacdeath(5.3per1000personyearsadjustedrate
ratio1.76,95%CI1.082.85)comparedwithpenicillin,butroxithromycinwasnot[54].Forclarithromycin,the
associationwasmorepronouncedinwomen(adjustedrateratio2.83,95%CI1.505.36)anddidnotreach
statisticalsignificanceinmen(adjustedrateratio1.09,95%CI0.512.35).
TelithromycinTelithromycincanalsoprolongtheQTinterval.Theproductlabelingspecifiesthat
telithromycinshouldbeavoidedinpatientswithcongenitallongQTsyndrome,ongoingproarrhythmic
conditions,significantbradycardia,andthosetakingclass1AorIIIantiarrhythmicagents(eg,quinidine,
procainamide,dofetilide).
OtherSeverereactionsarerarebutpossiblewithallthreemacrolides.Theseincludeanaphylaxis,Stevens
Johnsonsyndrome,andpseudomembranouscolitis[24,32].Aseverereactiontoazithromycinmaypersistfor
severaldaysduetoitslonghalflife.Irreversiblehearinglosshasbeenreportedwithazithromycin,
clarithromycin,anderythromycin[56,57].Reversiblehearinglosshasalsobeenreportedfollowingmacrolide
use,especiallywhentheyhavebeengivenathighdoses[5861].Interstitialnephritishasbeenreportedwith
erythromycin[62].
Inaddition,severalotherraresideeffectshaveoccurredwithtelithromycin,includingfatalhepatotoxicity,fatal
exacerbationofmyastheniagravis,lossofconsciousness,andacuteinterstitialnephritis[33,6366].Visual
disturbances(eg,blurryvision,diplopia,difficultyfocusing)canalsooccurandmayberelatedto
telithromycin'seffectsonnicotinicacidreceptors[67].Telithromyciniscontraindicatedinpatientswith
myastheniagravis.(See'Warningsabouttelithromycin'above.)
DRUGINTERACTIONSThemacrolideshaveavarietyofdruginteractions,manyofwhicharemediated
byinhibitionofhepaticcytochromeCYP(P450)3Aenzymes[68].Incontrastwiththeothermacrolides,
azithromycindoesnotappeartoaffecthepaticenzymessignificantly,leadingtofewerdocumenteddrug
interactions.However,severalclinicallyimportantdruginteractionshavebeenreportedwithallofthese
agents.Asanexample,fatalitieshavebeenreportedinpatientsreceivingclarithromycinandcolchicine,and
specificcolchicinedosereductionrecommendationshavebeenpublished[69,70].
Inapopulationbasedretrospectivecohortstudyofolderadults(meanage76years),coprescribing
clarithromycinwithacalciumchannelblocker(comparedwithazithromycinplusacalciumchannelblocker)
wasassociatedwithasmallbutstatisticallysignificantincreaseinriskofhospitalizationwithacutekidney
injury(absoluteriskincrease0.22percent,95%CI0.160.27percent)[71].Coprescriptionwithclarithromycin
wasalsoassociatedwithahigherriskofhospitalizationwithhypotension(absoluteriskincrease0.04percent,
95%CI0.020.07percent)andallcausemortality(absoluteriskincrease0.43percent,95%CI0.350.51
percent).Althoughtherisksassociatedwiththecombineduseofclarithromycinandcalciumchannelblockers
appeartobesmall,theyshouldbeconsideredwhendecidingwhethertousetheseagentsincombinationin
olderpatientsorotherpatientsatriskforacutekidneyinjury.
Specificinteractionsbetweenanytwomedicationsmaybedeterminedusingthedruginteractiontool(Lexi
InteractOnline).ThistoolcanbeaccessedfromtheUpToDateonlinesearchpageorthroughtheindividual
druginformationtopics,sectiononDruginteractions.
SUMMARY
Azithromycin(Zithromax)andclarithromycin(Biaxin)aremacrolideantibioticsthatareusedinthe
treatmentofcommunityacquiredrespiratorytractinfections.Theyarederivativesoftheoldermacrolide
antibiotic,erythromycin.Telithromycin(Ketek)isthefirstmemberoftheketolideclassofantimicrobials,
whichisrelatedtothemacrolideclass.Concernsaboutpostmarketingreportsofhepatotoxicityand
exacerbationsofmyastheniagravishaveledtosignificantrestrictionsontheuseoftelithromycin.(See
'Introduction'aboveand'Warningsabouttelithromycin'above.)
Themechanismofactionofthenewermacrolidesissimilartothatoferythromycin.Theybindtothe50S
subunitofbacterialribosomes,leadingtoinhibitionoftranspeptidation,translocation,chainelongation,
and,ultimately,bacterialproteinsynthesis.(See'Mechanismofactionandchemicalstructure'above.)
Structuralchangeshavemadethenewermacrolidesmoreacidstablethanerythromycin,providing
improvedoralabsorption,tolerance,andpharmacokineticproperties.Thenewermacrolidesalsohavea
broaderspectrumofantibacterialactivitythanerythromycin.(See'Mechanismofactionandchemical
structure'aboveand'Dosingandadministration'above.)
Twomainmechanismsofacquiredmacrolideresistancehavebeendescribed:
Methylasesencodedbytheerm(erythromycinribosomemethylase)genes(ermA,ermB,ermC)
alterthemacrolidebindingsiteonthebacterialribosomalRNA,usuallyconferringahighdegreeof
macrolideresistanceaswellasresistancetoclindamycin.
Activemacrolideeffluxpumps,encodedbythemef(macrolideefflux)msrAandmsrBgenes,confer
alowtomoderatedegreeofmacrolideresistanceThesemechanismsareresponsiblefor
erythromycinresistanceinmostgrampositivecocci(eg,Staphylococcusaureus,Streptococcus
pneumoniae,Staphylococcusaureus,otherstreptococci).Incontrastwiththemechanismsof
acquiredresistance,intrinsicresistanceexhibitedbyEnterobacteriaceae,Pseudomonasspp,and
Acinetobactersppisduetodecreasedpermeabilityoftheoutercellenvelope.(See'Resistance'
above.)
Azithromycinandclarithromycinhaveabroaderspectrumofactivitythanerythromycinandinclude
activityagainstrespiratorytractpathogenssuchasStreptococcuspneumoniae,Haemophilusspp,
Moraxellacatarrhalis,andatypicalpneumoniapathogens,aswellasagainstvariousothergramnegative
bacteriaandMycobacteriumaviumcomplex.(See'Spectrumofactivity'above.)
BecauseofitsmorefrequentgastrointestinalsideeffectsandtheearlierappreciationoftheriskofQT
prolongationandsuddendeath,erythromycinisrarelyrecommended.However,subsequentreportsand
studieshavealsodescribedQTprolongationwithclarithromycinandazithromycinaswellastheketolide,
telithromycin.Postmarketingreportshavealsoidentifiedvarioushepaticabnormalitiesinpatients
receivingazithromycin,includingcasesthathaveresultedindeath.(See'Adversereactions'above.)
Themacrolideshaveavarietyofdruginteractions,manyofwhicharemediatedbyinhibitionofhepatic
cytochromeCYP(P450)3Aenzymes.Incontrasttotheothermacrolides,azithromycindoesnotappear
toaffecthepaticenzymessignificantly,leadingtofewerdocumenteddruginteractions.(See'Drug
interactions'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic474Version21.0
GRAPHICS
Drugratingsinpregnancy(USFoodandDrugAdministration)
Category Interpretation
A Controlledhumanstudiesshownorisk
Controlledstudiesinpregnantwomenfailtodemonstratearisktothefetus
inthefirsttrimesterwithnoevidenceofriskinlatertrimesters.The
possibilityoffetalharmappearsremote.
B Noevidenceofriskinstudies
Eitheranimalreproductionstudieshavenotdemonstratedafetalriskbut
therearenocontrolledstudiesinpregnantwomen,oranimalreproduction
studieshaveshownanadverseeffect(otherthanadecreaseinfertility)that
wasnotconfirmedincontrolledstudiesinwomeninthefirsttrimesterand
thereisnoevidenceofariskinlatertrimesters.
C Riskcannotberuledout
Eitherstudiesinanimalshaverevealedadverseeffectsonthefetus
(teratogenicorembryocidaleffectsorother)andtherearenocontrolled
studiesinwomen,orstudiesinwomenandanimalsarenotavailable.Drugs
shouldbegivenonlyifthepotentialbenefitsjustifythepotentialrisktothe
fetus.
D Positiveevidenceofrisk
Thereispositiveevidenceofhumanfetalrisk,butthebenefitsfromusein
pregnantwomenmaybeacceptabledespitetherisk(eg,ifthedrugisneeded
inalifethreateningsituationorforaseriousdiseaseforwhichsaferdrugs
cannotbeusedorareineffective).
X Contraindicatedinpregnancy
Studiesinanimalsorhumanbeingshavedemonstratedfetalabnormalitiesor
thereisevidenceoffetalriskbasedonhumanexperience,orboth,andthe
riskoftheuseofthedruginpregnantwomenclearlyoutweighsanypossible
benefit.Thedrugiscontraindicatedinwomenwhoareormaybecome
pregnant.
In2015,theUSFoodandDrugAdministration(FDA)beganoverseeingthephaseoutof
pregnancyriskcategories(A,B,C,D,andX)fromprescriptiondruglabelingandbegan
requiringinformationfromavailablehumanandanimalstudiesof(1)knownorpotential
maternalorfetaladversereactions,and(2)doseadjustmentsneededduringpregnancy
andthepostpartumperiod.AdditionalinformationisavailableattheFDAwebsite:
PregnancyandLactationLabelingFinalRule.
Reproducedwithpermissionfrom:LexicompOnline.Copyright19782015Lexicomp,Inc.All
RightsReserved.
Graphic50021Version23.0
SomereportedcausesandpotentiatorsofthelongQTsyndrome*
Congenital Acquired(continued)
JervellandLangeNielsensyndrome Antihistamines
(including"channelopathies")
Astemizole ,hydroxyzine,terfenadine
RomanoWardsyndrome
Antineoplasticdrugs
Idiopathic
Arsenictrioxide,ceritinib,cesium
Acquired chloride , crizotinib,dasatinib,eribulin,
nilotinib,lapatinib,
Metabolicdisorders
panobinostat,pazopanib,romidepsin,
Hypokalemia sorafenib,sunitinib,toremifene,
vandetanib,vemurafenib,vorinostat
Hypomagnesemia
Analgesicandsedativedrugs
Hypocalcemia
Chloralhydrate
Starvation
Methadone
Anorexianervosa
Propofol
Liquidproteindiets
Diuretics
Hypothyroidism
Viaelectrolytechanges(especially
Bradyarrhythmias
hypokalemiaorhypomagnesemia)
Sinusnodedysfunction
Gastrointestinaldrugs
Atrioventricular(AV)blocksecondor
Antiemetics:ondansetron,granisetron,
thirddegree
dolasetron,droperidol(maybesafeatthe
Antiarrhythmicdrugs lowdosesusedbyanesthesiologists
Quinidine,procainamide,disopyramide [0.625to1.25mg]),hydroxyzine,
tropisetron
Flecainide,propafenone
Promotility:cisapride(restricted
Amiodarone,dronedarone
availability),domperidone ,
Sotalol metoclopramide
Dofetilide,ibutilide Protonpumpinhibitors:chronicuse
leadingtohypomagnesemia
Androgendeprivationtherapy
Neurologicdrugs
Gonadotropinreleasinghormoneagonists
andantagonists:buserelin,degarelix, Apomorphine,donepezil,
goserelin,histrelin,leuprolide,triptorelin fingolimod,tetrabenazine
Antianginaldrugs Psychotropicdrugs
Ranolazine,ivabradine Antipsychotics
Knownrisk:chlorpromazine,haloperidol,
Antiinfectivedrugs
pimozide,sulpiride ,thioridazine
Antimalarial
Possiblerisk:aripiprazole,
Higherrisk:artemetherlumefantrine, clozapine,iloperidone,
chloroquine,halofantrine, olanzapine,paliperidone,
quinidine,quinine pipamperone ,risperidone,sertindole
Lower/conditionalrisk: Conditionalrisk:amisulpride ,asenapine,
hydroxychloroquine,mefloquine, quetiapine,ziprasidone
primaquine
Tricyclicandtetracyclicantidepressants

Antituberculous:bedaquiline (TCAs)
Azoleantifungals:fluconazole,
Selectiveserotoninreuptakeinhibitors
itraconazole,ketoconazole(systemic),
(lowerriskthanTCAs):citalopram,
posaconazole,voriconazole
fluoxetine
Fluoroquinolones(systemic):ciprofloxacin, Others:atomoxetine,trazodone
gatifloxacin ,levofloxacin,moxifloxacin,
ofloxacin,sparfloxacin Vasodilatordrugs
HIVantiretrovirals(some):lopinavir, Bepridil ,cilostazol

nelfinavir,saquinavir Otherdrugsandherbs
Macrolideantibiotics:azithromycin, Miscellaneous:anagrelide,alfuzosin,
erythromycin,clarithromycin, arformoterol,cocaine,formoterol,
telithromycin mifepristone,papaverine,pasireotide,
Metronidazole probucol ,terlipressin
Pentamidine(intravenous) Herbs:cinchona(containsquinine),
licoriceextract(glycyrrhizin)inoveruse
Telavancin leadingtoelectrolytechanges
Otherfactors
Myocardialischemiaorinfarction,
especiallywithprominentTwave
inversions
Intracranialdisease
HIVinfection
Hypothermia
Toxicexposure:organophosphate
insecticides
Connectivetissuediseaseswithanti
Ro/SSAantibodies
*ThelongandgrowinglistofmedicationsandotherfactorscapableofprolongingtheQTrepresents
anevolvingareaofclinicalresearch.InsomecasesoflongQT,twoormorefactorsmaybeinvolved.
ThisisnotacompletelistofalldrugsassociatedwithQTprolongation.Additionalclinicalinformationis
providedattheArizonaCenterforEducationandResearchonTherapeutics(CERT)website:
http://crediblemeds.org/.
NotavailableintheUnitedStates.
Removedfrommarketinmostcountriesduetoadversecardiovasculareffects.
ThoughamoxapineandprotriptylinearenotincludedontheArizonaCERTlistofdrugsassociated
withacquiredQTprolongation,overdoseofthesetricyclicantidepressantshasbeenassociatedwith
cardiovasculartoxicityandfatalities.
Datafrom:
1. NielsenJ,GraffC,KantersJ,etal.AssessingQTintervalprolongationanditsassociatedrisks
withantipsychotics.CNSDrugs201125:473.
2. LiE,EsterlyJ,PohlS,etal.DruginducedQTintervalprolongation:Considerationsfor
clinicians.Pharmacotherapy201030:684.
3. CredibleMedsQTdrugslistwesbsitesponsoredbyScienceFoundationoftheUniversityof
Arizona.Availableathttp://crediblemeds.org/(AccessedSeptember17,2015)
4. LexicompOnline.Copyright19782015Lexicomp,Inc.AllRightsReserved.
Graphic57431Version46.0
Disclosures
Disclosures:AmyLGraziani,PharmDEquityOwnership/StockOptions(Spouse):BristolMyersSquibbJohnsonandJohnson
[Antiretrovirals(Efavirenz,rilpivirine,darunavir,Darunavir/cobicistat,etravirine,atazanavir,atazanavir/cobicistat,didanosine,
stavudine,efavirenz/emtricitabine/tenofovir,rilpivirine/emtricitabine/tenofovir)].DavidCHooper,MDConsultant/AdvisoryBoards:
Bacterioscan[Antimicrobials(Urinediagnosticunderdevelopment)]Cubist[Antimicrobials(Daptomycin,fidaxomycin,tedizolid,
ceftolozanetazobactam)]Shionogi[Antimicrobials(Antigramnegativebetalactamunderdevelopment)]Melinta[Antimicrobials
(Antimicrobialsunderdevelopment)]Cepheid[Antimicrobials(rapidgeneticdiagnostics)]FabPharma[Antimicrobials(Antimicrobial
underdevelopment)].AnnaRThorner,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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HIVantiretrovirals(some):lopinavir, Bepridil ,cilostazol

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