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Antimalarialdrugs:Anoverview
Authors: MarkTravassos,MD,MSc,MiriamKLaufer,MD,MPH
SectionEditor: JohannaDaily,MD,MSc
DeputyEditor: ElinorLBaron,MD,DTMH

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Sep27,2016.
INTRODUCTIONAntimalarialdrugsareusedforthetreatmentandpreventionofmalariainfection.Most
antimalarialdrugstargettheerythrocyticstageofmalariainfection,whichisthephaseofinfectionthatcauses
symptomaticillness(figure1).Theextentofpreerythrocytic(hepaticstage)activityformostantimalarialdrugs
isnotwellcharacterized.
Treatmentoftheacutebloodstageinfectionisnecessaryformalariacausedbyallmalariaspecies.In
addition,forinfectionduetoPlasmodiumovaleorPlasmodiumvivax,terminalprophylaxisisrequiredwitha
drugactiveagainsthypnozoites(whichcanremaindormantintheliverformonthsand,occasionally,years
aftertheinitialinfection).
Themechanismsofaction,resistance,andtoxicitiesofantimalarialdrugswillbereviewedhere.Useofthese
agentsforpreventionandtreatmentofmalariaisdiscussedindetailseparately.(See"Preventionofmalaria
infectionintravelers"and"Treatmentofseveremalaria"and"Treatmentofuncomplicatedfalciparummalaria
innonpregnantadultsandchildren".)
QUINOLINEDERIVATIVESQuinolinederivativesincludechloroquine,amodiaquine,quinine,quinidine,
mefloquine,primaquine,lumefantrine,andhalofantrine.Thesedrugshaveactivityagainsttheerythrocytic
stageofinfectionprimaquinealsokillsintrahepaticformsandgametocytes(figure1).Thedrugsactby
accumulatingintheparasitefoodvacuoleandformingacomplexwithhemethatpreventscrystallizationinthe
Plasmodiumfoodvacuole.Hemepolymeraseactivityisinhibited,resultinginaccumulationofcytotoxicfree
heme.
4aminoquinolines
ChloroquineChloroquinewasthefirstdrugproducedonalargescalefortreatmentandpreventionof
malariainfection.ChloroquinehasactivityagainstthebloodstagesofPlasmodiumovale,P.malariae,and
susceptiblestrainsofP.vivaxandP.falciparum[1].Widespreadresistanceinmostmalariaendemiccountries
hasledtodeclineinitsuseforthetreatmentofP.falciparum,althoughitremainseffectivefortreatmentofP.
ovale,P.malariae,and,inmostregions,P.vivax.(See"Overviewofnonfalciparummalariainnonpregnant
adultsandchildren".)
Chloroquinepenetratesintomosttissuesandthereforehasalargevolumeofdistribution.Asaresult,serum
druglevelsmaybemaintainedforuptotwomonths[2].Sideeffectsofchloroquineincludeheadaches,
dizziness,abdominaldiscomfort,vomiting,anddiarrhea.Chloroquinemayalsoproducepruritusinsome
patientsthishasbeennotedtooccurmostfrequentlyinAfricanpopulations[3].Thepruritusistransient,
lasting48to72hours,andisnotresponsivetoantihistamines.
Severeadversereactionsareextremelyrare.Someareassociatedonlywithprolongeduse,suchas
neuromyopathywithlongtermprophylaxisandretinopathywithhighdoseadministrationfortreatmentof
rheumatologicdiseases(totaldosesof1g/kgorprophylaxisforgreaterthanoneyear).Rarecasesof
idiosyncraticreactions,suchaserythemamultiformeandbonemarrowtoxicity,havebeenreported[4].
Chloroquineisonlyadministeredorallyintravenousinfusionisassociatedwithsignificanttoxicity[5,6].
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Amongchloroquineresistantparasites,thereisdecreasedaccumulationofdrugwithinthefoodvacuole.
Mutationsinthegeneencodingthechloroquineresistancetransporterprotein(PfCRT),locatedinthefood
vacuole,areassociatedwithchloroquineresistancebothinvitroandinvivo[7,8].Tracingthespreadofthis
genemutationhasledtothecurrentunderstandingthatchloroquineresistancedevelopedindependentlyin
Asia,PapuaNewGuinea,andSouthAmerica.ThechloroquineresistantgenethatemergedinSoutheast
AsiaspreadacrosstheAsiancontinentandreachedAfricainthelate1970s[9,10].Mutationsinthehomolog
ofthemajormultidrugtransporterP.falciparummultidrugresistanceprotein1(pfmdr1)maymodulatethe
extentofchloroquineresistanceaswellasresistancetootherantimalarials[11].
AmodiaquineAmodiaquineissimilarinstructuretochloroquine,andthereiscrossresistancebetween
thetwodrugs,althoughamodiaquineretainssomeactivityagainstchloroquineresistantparasitesinvivoand
invitro[1214].
AmodiaquinehasbeentakenoffthemarketintheUnitedStatesduetotheriskoftoxicityassociatedwith
prolongedadministrationforprophylaxis.Themostseriousadverseeffectsofamodiaquineare
agranulocytosisandhepatotoxicity,whichhavebeenreportedinEuropeantravelersusingamodiaquineto
preventmalaria.BasedonprescriptiondatafromtheUnitedKingdom,thefrequencyofneutropeniawith
amodiaquineprophylaxiswas1:2200,whilethatofhepatictoxicitywas1:15,650[15].Casereportshave
linkedsuchadverseeventswithtotaldosesofamodiaquineinexcessof1.5gorwithadministrationoverat
leastonemonth[16,17].
Amodiaquineiscommonlyusedinmalariaendemiccountriesasoneofthefewdrugsavailabletotreat
chloroquineresistantinfectionsandisavailableincoformulationwithartesunate[18].Amodiaquineiswell
toleratedwhenadministeredasasinglecourseoftreatmentoverthreedays.Trialsevaluatingathreeday
treatmentcourseofamodiaquineforuncomplicatedmalarianotedmildtomoderateadverseeffects(including
nausea,emesis,andpruritus),withnosignificanthepatotoxicity[13,19].Adverseeventrateswerethesame
asothercommonlyusedantimalarialdrugs[19,20].Declinesinneutrophilcountsbelow1000/mm3havebeen
notedwithamodiaquineusedfortherapyofmalariainfection,althoughtheclinicalsignificanceisnotcertain
[21].Suchneutropeniahasnotbeenobservedwithartesunateamodiaquinetreatment[22].
PiperaquinePiperaquineisabisquinolinethatiscloselyrelatedtochloroquineandamodiaquine.
Piperaquineisusedincombinationwithdihydroartemisininascombinationtherapyfortreatmentofmalaria
previously,itwasusedinChinaandSoutheastAsiaforthetreatmentandpreventionofmalariaduringthe
secondhalfofthe20thcentury.Piperaquineiseffectiveagainstchloroquineresistantparasites[23].Thehalf
lifeistwotothreeweeks,whichislongerthanotherdrugsthatarecombinedwithartemisininderivativesin
artermisininbasedcombinationtherapytherefore,itprovidesanextendedperiodofposttreatment
prophylaxis[24,25].SomestudiessuggestpiperaquinecancauseaprolongedQTintervalintheabsenceof
clinicalsymptoms[26,27].
4methanolquinolines
QuinineandquinidineQuinineisaderivativefromthebarkoftheSouthAmericanCinchonatreeand
existsinoralandparenteralforms.Itisacommonlyusedparenteralantimalarialdruginmalariaendemic
regions.Quinidineisastereoisomerofquinineavailableinparenteralformulationandisveryeffectivefor
treatmentofseveremalaria[28].
Theadverseeffectsofquinineandquinidineincludeacomplexofsymptomsreferredtoascinchonism:
tinnitus,nausea,headaches,dizziness,anddisturbedvision.Theseeffectsareobservedtosomeextentinall
patientsreceivingtreatmentandtypicallyresolvewithcessationofthemedication.Thesesymptomsdonot
warrantchangeindrugdose.However,toxicityofteninterfereswithcomplianceincompletingthecourseof
therapy.Lesscommonly,hypersensitivityreactionwithbronchospasmandcutaneousmanifestations,suchas
flushingandurticaria,mayoccur.
Quininehasashorthalflife.Whengivenorally,itmustbeadministeredthreetimesperdaywhen
administeredtogetherwithoneweekoftetracyclineantibioticsorclindamycin,thedurationoftherapyisthree
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tosevendays.Thedrugshouldbegivenforsevendaysiftheinfectionisacquiredinanareawhere
decreasedquininesusceptibilityhasbeenreported,suchasSoutheastAsia[29].
Forseveredisease,quininecanbeadministeredintravenouslyorintramuscularly.Intravenousadministration
ofquinidineandquinineshouldbeasaninfusionbecauserapidbolusesareassociatedwithhypotension.To
hastenparasiteclearancetime,aninitialloadingdoseofparenteralquinineorquinidineisappropriateifthe
patienthasnotreceivedtreatmentwiththeseagentsrecently[30].Afterinitialimprovementonparenteral
therapy,patientscanbeswitchedtooralmedication.Whiletherapeuticapproachescanincludecompletinga
courseoforalquinineplusanantibiotic(eg,tetracycline,doxycycline,orclindamycin),itmaybepreferableto
giveafullcourseofanotheroralantimalarialwithbettertolerabilitythanquinine.(See'Antimicrobials'below
and"Treatmentofseveremalaria".)
Quinineandquinidinehaveanarrowtherapeuticwindowoverdosagemayleadtocardiotoxicity,including
arrhythmiasandhypotension,blindness,ordeafness.Quinidineisthemostcardiotoxicoftheseagents:
cardiacmonitoringincludingserialbloodpressuremeasurementsshouldalwaysbeinplacewhenquinidineis
administeredtomonitorforprolongationoftheQTintervalandventriculartachycardia.Bloodsugarlevels
shouldbemonitoredwithintravenousinfusion,asbothquinineandquinidinestimulateinsulinproduction[31].
ReducedquinineefficacyhasbeendescribedinSoutheastAsia[29].Themechanismforquinineresistanceis
complexandpoorlyunderstood[32].Thecombinationofquininewithanantibiotic(tetracycline,doxycycline,
orclindamycin)remainseffectiveinareaswheredecreasedquininesusceptibilityhasbeenobserved.
BecausequinidineisnolongerusedroutinelyasanantiarrhythmicmedicationintheUnitedStates,itmaynot
bereadilyavailableinsuchcircumstances,themanufacturerEliLillymaybecontacteddirectlytoarrange
shipment(telephone8008210538).
MefloquineMefloquineisavailableasanoralformulationandmaybeusedastreatmentorprophylaxis
forallsusceptiblemalariaspecies.
Adverseeffectsofmefloquineincludevomitinganddizziness.Liketheotherdrugsinthisclass,mefloquine
canalsointerferewithcardiacconductionandthereforeshouldnotbeusedinindividualswithcardiac
conductionabnormalities.
Mefloquineiscontraindicatedforindividualswithneurologicandpsychiatricdisordersthosewithsignificant
familyhistoryofseizuresandmajorpsychiatricdisordersshouldalsoavoidtakingmefloquine.Seizures,
encephalopathy,andpsychosisoccurin0.1to5percentofpatientstreatedformalaria[33].Theextentto
whichmefloquineisassociatedwithseriousneuropsychiatricsideeffectsinthesettingofweeklyprophylaxisis
anareaofcontroversy.Theriskofpsychosisandpanicattackswithmefloquinecomparedwithother
antimalarialsisincreasedtwofold,althoughtheabsoluteriskislow(1to3episodesper1000personyearsof
exposure)[34,35].Thereisnoevidenceofanincreasedriskofdepressioncomparedwithotherantimalarials.
Mefloquineusersmayexperiencesleepdisturbances,includingstrangedreamsandinsomnia[34].
Mefloquineinducedpneumonitisisaninfrequentlyreportedbutseriousadverseeventinthesettingofboth
prophylacticandtherapeuticuse[3640].Onethirdofthepatientsimprovedfollowingtreatmentwith
corticosteroids,andmostpatientsfullyrecoveredupondiscontinuationofthedrug.
Splittingthe25mg/kgdoseinto15mg/kgand10mg/kgovera6to24hourperiodmaybehelpfultoreduce
mildadverseeffects.Whenusedforprophylaxis,itisbeststartedtwotothreeweekspriortodepartureto
assesstolerability,thoughsideeffectscandeveloplongintotheprophylacticcourseorevenifithasbeenwell
toleratedinthepast.
MefloquineresistanceisfoundprimarilyinareasofSoutheastAsia.Mefloquinetreatmentfailureisassociated
withanincreaseincopynumberofpfmdr1,whichencodesaproteinonthedigestivevacuolemembranethat
appearstoplayaroleinregulatingtrafficacrossthemembrane[41].Resistancetothecombinationof
mefloquineplusartesunateappearstohaveemergedinsomeregionsofSoutheastAsia[42].However,
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mefloquinesusceptibleinfectionsmaybemorecommoninthatregionaftertheintroductionof
dihydroartemisininpiperaquine,anartemisininbasedcombinationtherapyforthetreatmentofmalaria[43].
(See'Artemisininderivatives'below.)
8aminoquinolines
PrimaquinePrimaquineistheonly8aminoquinolineinclinicaluseitsmechanismofactionisnot
known.ItismostcommonlyusedtopreventrelapseofP.vivaxandP.ovalemalariabyeliminatingdormant
hypnozoites.PrimaquinealsohasactivityagainstthepreerythrocyticstageandgametocytesofP.falciparum
[44].
Primaquinecancausehemolyticanemiainthosewithglucose6phosphatedehydrogenase(G6PD)
deficiency.Therefore,patientsshouldreceiveprimaquineonlyifG6PDdeficiencyhasbeenexcluded.In
addition,electrocardiogrammonitoringiswarrantedwhenusingprimaquineinpatientswithcardiacdisease,
longQTsyndrome,ahistoryofventriculararrhythmias,uncorrectedhypokalemiaand/orhypomagnesemia,or
bradycardia(<50bpm)andduringconcomitantadministrationwithQTintervalprolongingagents[45].
Primaquinemayalsocausegastrointestinalupsetthatcanbeminimizediftakenwithfood.Primaquineis
contraindicatedinpregnancyandbreastfeeding,eveninthesettingofanormalmaternalG6PDlevel.
Hypnozoiteresistancetoprimaquineisdifficulttoassess.Parasitemiawithinthefirstfourtosixweeksofan
initialinfectionmaybeduetofailureofthebloodstagetreatment,inadequateadherence,orprimaquine
failure.
Aspartofamalariaeliminationcampaign,theWorldHealthOrganizationsuggestsconsiderationofasingle
doseofprimaquinefollowinganartemisininbasedcombinationtherapy(ACT)regimentoreducegametocyte
carriage[46].AsinglelowdoseisbelievedtobesafeeveninindividualswithG6PDdeficiency.WhileACTs
havesomeactivityagainstgametocytes,theadditionofprimaquinemayfurthershortenanindividual'speriod
ofinfectivity[47,48].
ANTIFOLATESAntifolatesincludesulfonamides,pyrimethamine,proguanil,anddapsone.Thesedrugsact
synergisticallytotargetenzymesinvolvedinfolatesynthesis,apathwayrequiredforparasiteDNAsynthesis
[49].
SulfadoxinepyrimethamineSulfadoxineandpyrimethaminetargetenzymesinvolvedinfolatesynthesis
pyrimethaminetargetsdihydrofolatereductase(DHFR),andsulfadoxineactsondihydropteroatesynthase
(DHPS).Sulfadoxinepyrimethamine(SPbrandnameFansidar)isavailableinafixeddosetabletbecause
thecomponentsactonenzymesinthesamepathway,itisnotconsideredacombinationtherapy.
Mildadverseeffectsincludegastrointestinalupsetandheadache.Mildbonemarrowsuppressionmayoccur,
andsulfadoxinecanprecipitatehemolysisinpatientswithglucose6phosphatedehydrogenase(G6PD)
deficiency.Severecutaneoustoxicityduetothesulfamoietycanoccur,includingerythemamultiforme,
StevensJohnsonsyndrome,andtoxicepidermalnecrosis[50,51].
ResistancetosulfadoxinepyrimethamineoccursviamutationsinthetargetenzymesDHFRandDHPS.P.
falciparumresistancetosulfadoxinepyrimethamineiswidespreadinmostmalariaendemicregions.Theuse
ofsulfadoxinepyrimethamineisusuallyrestrictedtothepreventionofmalariainpregnantwomeninmalaria
endemiccountries.Duetohighlevelsofresistance,especiallyineasternandsouthernAfrica,uncertainty
regardingitseffectivenesshasbeenraised[52].
AtovaquoneproguanilAtovaquoneproguanilinterfereswithtwoseparatepathwaysinvolvedinthe
biosynthesisofpyrimidines,whichareessentialfornucleicacidreplication.Atovaquoneblockstheparasite
mitochondrialelectrontransportchain,andproguanilinhibitsparasitedihydrofolatereductasethroughits
activemetabolite,cycloguanil.Proguanilalsoappearstoactviaadirectmechanismoutsidethefolate
pathway,enhancingatovaquone'smitochondrialmembranetoxicity[53,54].

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Adverseeffectsincludeabdominalpain,vomiting,diarrhea,headache,andpruritis.AmongadultsinThailand,
mildasymptomaticincreasesintransaminaseswereobservedshortlyafterinitiatingtherapy,althoughthey
normalizewithintwoweeks[55,56].
Resistancetoatovaquoneismediatedbymutationsinthecytochromebgene.Thepolymorphismassociated
withresistancehasbeenfoundinparasitepopulationsevenintheabsenceofdrugpressureandcanarise
rapidlywhenthedrugisused[57,58].However,thecombinationretainsexcellentclinicalefficacyfortreatment
andpreventionthroughouttheworldeveninthepresenceofantifolateresistance[59,60].
ANTIMICROBIALSTetracycline,doxycycline,andclindamycintargetprokaryoticproteinsynthesis.In
malariaparasites,thesedrugsappeartotargettheapicoplast,anorganellederivedfromprokaryotic
ancestors[49].Antimicrobialshaverelativelyslowantimalarialactivitybecausetheyexerttheirtoxiceffectsin
thesubsequentcycleofcelldivision[49,61].Theyaretypicallypairedwithfastactingantimalarials(usually
quinine).Doxycyclinehasalongerhalflifethantetracyclinesoisusedmorecommonly.Resistancehasnot
beendetectedtotetracycline,doxycycline,orclindamycin.
Adverseeffectsarecommonwiththetetracyclinesandinterferewithadherence.Gastrointestinaldiscomfort
andcandidiasisarethemostfrequentcomplaints.Doxycyclinetherapyalsoposesariskofesophageal
ulceration[62].Photosensitivitycanoccurwithdoxycycline,whichcanbeconcerningforfairskinnedtravelers
usingitasprophylaxisfortraveltothetropics.
Tetracyclinesshouldnotbegiventopregnantwomenorchildrenlessthaneightyearsoldbecauseoftherisk
ofdepositioningrowingbonesandteeth.Clindamycinisthepreferredalternativeinthesegroupsfor
treatmentclindamycinshouldnotbeusedinchemoprophylacticregimenstopreventmalaria.
ARTEMISININDERIVATIVESTheartemisininsarederivedfromtheleavesoftheChinesesweet
wormwoodplant,Artemisiaannua.TheyhavebeenusedinChinaforthetreatmentofmalariaforover2000
yearsandcametoattentionoutsideofChinainthe1970sand1980s.Artemisininformulationsinclude
artemether,arteether,dihydroartemisinin,andartesunate.Theyaremarketedaspartofcombinationtherapy
throughouttheworld.
Artemisininsappeartoactbybindingiron,breakingdownperoxidebridges,leadingtothegenerationoffree
radicalsthatdamageparasiteproteins[63].Theyactrapidly,killingbloodstagesofallPlasmodiumspecies
andreducingtheparasitebiomass[64].Artemisininshavethefastestparasiteclearancetimesofany
antimalarial[65].Artemisininsareactiveagainstgametocytes,theparasiteformthatisinfectiousto
mosquitoes,andtheirusehasbeenassociatedwithreducedmalariatransmissionwhentheywereintroduced
inThailand[66,67].
Intravenousartesunateisfirstlinetherapyforthetreatmentofseveremalaria.Itissuperiortoquininefor
treatmentofseveremalariawithrespecttoclearingparasitemiaandreducingmortalityinbothchildrenand
adults[68,69].IntravenousartesunatehasbeenmadeavailableintheUnitedStatesthroughtheCentersfor
DiseaseControlandPrevention[70].Rectalartesunateisusedinremoteareasofmalariaendemiccountries
forstabilizingseverelyillpatientspriortohealthfacilitytransportforfurthermanagement[71].
Giventheshorthalflifeofartemisinins,intravenoustherapymustbefollowedbyalongeractingagentonce
thepatientisabletotolerateoralmedication.Ifusedalone(viatheparenteral,rectal,ororalroute),
artesunatemustbeadministeredforfivetosevendays.Treatmentforlessthanfivedaysresultsinrecurrent
parasitemiaseveralweeksaftertherapyduetotheveryshortdurationofactionratherthantoartemisinin
resistance.
Artemisininsaregenerallywelltolerated[66,72,73].Type1hypersensitivitytotheartemisinincompoundshas
beenreported(incidence1:3000)[74].Alargescalestudyontheadverseeffectsoforallyadministered
artemisininsdemonstratedtransientneurologicalabnormalities,includingnystagmusanddisturbancesin
balancetheseeffectsresolvedwithoutlastingsequelae[73].Transientneutropeniahasbeenobservedin
individualsreceivingoralartesunateatdoseshigherthanthattypicallyprescribed[75].
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Therehavebeenconcernsabouttheuseofartemisininsduringthefirsttrimesterofpregnancy.Animal
studieshavesuggestedthattheartemisininderivativesmaybeteratogenicduringorganogenesis[76,77].A
limitednumberofwomenintheirfirsttrimesterhavebeenstudiedwithoutevidenceofadverseevents.In
observationalstudies,artemisininsadministeredinthefirsttrimesterhavenotbeenassociatedwithadverse
pregnancyoutcomes[78,79].
ArtemisininbasedcombinationtherapiesIngeneral,artemisininsshouldnotbeusedasasingleagent
topreventemergenceofdrugresistanceandtoavoidtheneedforprolongedtherapy.Artemisininbased
combinationtherapy(ACT)combinesthehighlyeffectiveshortactingartemisininswithalongeractingpartner
toprotectagainstartemisininresistanceandtofacilitatedosingconvenience.ACTsaretypicallyadministered
forthreedaysandareoftenavailableinfixeddosetablets.
FiveACTsarerecommendedbytheWorldHealthOrganizationforthetreatmentofuncomplicatedmalaria:
artemetherlumefantrine,artesunateamodiaquine,artesunatemefloquine,artesunatesulfadoxine
pyrimethamine,anddihydroartemisininpiperaquine[46].Artemetherlumefantrineisthemostwidelyadopted
ACTinAfrica,followedbyartesunateamodiaquine[80].Dihydroartemisininpiperaquineisbeingwidelyused
inresearchstudiesandpilotprogramsforintermittenttreatmentandtargetedparasiteeliminationprograms.
ArtemisininresistanceReducedsusceptibilitytoartemisinins,asevidencedbydelayedparasite
clearancetime,hasbeendemonstratedinSoutheastAsiabutnotsubSaharanAfrica[8183].Point
mutationsinthekelchproteinK13areassociatedwiththisreducedsusceptibility[8386]theunderlying
mechanismisnotknown.ManyofthesemutationshavearisenindependentlyinSoutheastAsia,but
resistancehasalsospreadwithintheregion[85].
Decreasedsusceptibilitytoartemisininsmayincreasethelikelihoodofdevelopingresistancetopartnerdrugs.
DihydroartemisininpiperaquinetreatmentfailuresinCambodiahaveoccurredwhereartemisininresistanceis
emergingthemechanismforpiperaquineresistancehasnotyetbeenidentified[8789].
Becausetheartemisininsarethecornerstoneofnearlyallnewcombinationtherapies,theWorldHealth
Organizationhascalledforthebanningofallmanufacturinganddistributionoforalartemisininmonotherapy
todeterresistance.
INVESTIGATIONALDRUGSAgentsfortreatmentofmalariaunderstudyordevelopmentincludeKAE609
(asyntheticantimalarialspiroindoloneanalog)[90],pyronaridine(anacridinederivative)[91],ferroquine[92],
tafenoquine[93],malarialproteaseinhibitors,macrolides[94],andarterolane[95].
KAE609(cipargamin)targetsaparasiteplasmamembraneNa+ATPaseandhasbeenshowntohavepotent
dosedependentactivityagainstasexualandsexualstageparasites[96].InaphaseIIstudyinThailand,three
daysoftreatment(30mgdaily)clearedparasitemiarapidlyin11adultswithuncomplicatedP.falciparum
malariaand10adultswithP.vivaxmalaria[90].
Pyronaridinewasoneofthefirstsyntheticallydevelopedantimalarialdrugsafterchloroquine.Itisactive
againstchloroquineresistantinfectionsbothinvitroandinvivo,althoughtherehasbeenconcernaboutthe
emergenceofresistanceifusedasmonotherapy[97,98].Itisbeingdevelopedasanartemisininbased
combinationtherapyincombinationwithartesunate[99].Pyronaridineartesunatehasbeenshowntohave
similarefficacytoartemetherlumefantrineandartesunatemefloquinefortreatmentofuncomplicatedP.
falciparummalaria[100,101]butmaycausehepatotoxicity[91].However,riskofhepatotoxicitydoesnot
appeartoincreasewithpyronaridineartesunateretreatment[102].Advantagesofpyronaridineincludeits
structuraldissimilaritytootherantimalarialdrugs,longshelflife,andoncedailydosing.
Ferroquine,a4aminoquinoline,issimilarinstructuretochloroquineandhasactivityagainstchloroquine
resistantP.falciparum.InaphaseIIstudyinsubSaharanAfrica,athreedaycourseofferroquinein
combinationwithartesunatewaseffectiveintreatinguncomplicatedP.falciparummalaria[92].Thepotential
useofferroquineincombinationwithotherantimalarialdrugsindevelopmentisbeingexplored.

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DRUGQUALITYCounterfeitandlowqualityantimalarialmedicationsaresignificantconcernsworldwide,
withimplicationsfortreatmentfailureamongindividualpatientsandpublichealthconcernsrelatedto
developmentofdrugresistance.InsurveysofantimalarialmedicationspurchasedinSoutheastAsia,30to50
percentofmedicationswerecounterfeit,containingasubtherapeuticorundetectableamountofactive
ingredient[103105].Thesesampleswerepurchasedinarangeofdifferentvenues,includinginformalshops,
pharmacies,andhospitals.Thereisincreasingevidenceofpoorqualityandcounterfeitingofantimalarial
drugsinAfrica,especiallythosepurchasedoutsidetheformalhealthcaresystem[106,107].
SUMMARY
Antimalarialdrugsareusedforthetreatmentandpreventionofmalariainfection.Mostantimalarialdrugs
targettheerythrocyticstageofmalariainfection,whichisthephaseofinfectionthatcausessymptomatic
illness(figure1).Treatmentoftheacutebloodstageinfectionisnecessaryformalariacausedbyall
malariaspecies.(See'Introduction'above.)
FortreatmentofinfectionduetoP.ovaleorP.vivax,terminalprophylaxisisalsorequiredwithadrug
activeagainsthypnozoites,whichcanotherwiseremaindormantintheliverformonthstoyearsafter
infection.Primaquineistheonlymedicationlicensedforeliminationofhypnozoites.(See'Introduction'
above.)
Quinolinederivatives(chloroquine,amodiaquine,piperaquine,quinine,quinidine,mefloquine,primaquine,
lumefantrine,andhalofantrine)haveactivityagainsttheerythrocyticstageofinfectionprimaquinealso
killsintrahepaticformsandgametocytes(figure1).
Widespreadresistanceinmostmalariaendemiccountrieshasledtodeclineinuseofchloroquine
forthetreatmentofP.falciparum,althoughitremainseffectivefortreatmentofP.ovale,P.malariae,
and,inmostregions,P.vivax.(See'Chloroquine'above.)
Quinineexistsinoralandparenteralforms.Inmalariaendemicregions,itisthemostcommonly
usedparenteralantimalarialdrug,and,inmanyregions,itistheonlyavailableagentforsevere
malaria,although,intheUnitedStates,quinineisonlyavailableinitsoralform.(See'Quinineand
quinidine'above.)
Mefloquineisavailableasanoralformulationandmaybeusedastreatmentorprophylaxisforall
susceptiblemalariaspecies.However,sideeffectscanlimittolerability.(See'Mefloquine'above.)
PrimaquineisusedtopreventrelapseofP.ovaleandP.vivaxmalariabyeliminatingdormant
hypnozoites,anditalsohasactivityagainstthepreerythrocyticstageandgametocytesofP.falciparum.
(See'Primaquine'above.)
Antifolates(sulfonamides,pyrimethamine,proguanil,anddapsone)actsynergisticallytotargetenzymes
involvedinfolatesynthesis,apathwayrequiredforparasiteDNAsynthesis.Atovaquoneproguanil
interfereswithtwoseparatepathwaysinvolvedinthebiosynthesisofpyrimidinesessentialfornucleicacid
replication.(See'Antifolates'above.)
Tetracycline,doxycycline,andclindamycintargetprokaryoticproteinsynthesis.Theyaretypicallypaired
withfastactingantimalarials(usuallyquinine).(See'Antimicrobials'above.)
Intravenousartesunateissuperiortoquininefortreatmentofseveremalariawithrespecttoclearing
parasitemiaandreducingmortality.Artemisininbasedcombinationtherapycombinesthehighlyeffective
shortactingartemisininswithalongeractingpartnertoprotectagainstartemisininresistanceandto
facilitatedosingconvenience.(See'Artemisininderivatives'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS
LifecycleofPlasmodium*

(1)PlasmodiuminfectedAnophelesmosquitobitesahumanandtransmitssporozoitesintothe
bloodstream.(2)Sporozoitesmigratethroughthebloodtotheliverwheretheyinvadehepatocytes
anddividetoformmultinucleatedschizonts(preerythrocyticstage).Atovaquoneproguaniland
primaquinehaveactivityagainsthepaticstageschizonts.(3)Hypnozoitesareaquiescentstageinthe
liverthatexistonlyinthesettingofP.vivaxandP.ovaleinfection.Thisliverstagedoesnotcause
clinicalsymptoms,butwithreactivationandreleaseintothecirculation,lateonsetorrelapseddisease
canoccuruptomanymonthsafterinitialinfection.8aminoquinolinesareactiveagainstthequiescent
hypnozoitesofP.vivaxandP.ovale.(4)Theschizontsruptureandreleasemerozoitesintothe
circulationwheretheyinvaderedbloodcells.Withinredcells,merozoitesmaturefromringformsto
trophozoitestomultinucleatedschizonts(erythrocyticstage).Bloodstageschizonticidesinterrupt
schizogonywithinredcells.(5)Somemerozoitesdifferentiateintomaleorfemalegametocytes.These
cellsareingestedbytheAnophelesmosquitoandmatureinthemidgut,wheresporozoitesdevelop
andmigratetothesalivaryglandsofthemosquito.Themosquitocompletesthecycleoftransmission
bybitinganotherhost.
*Thereisstrongevidencethatdrugslistedinparenthesesareactiveagainstdesignatedstageofparasitic
lifecycle.
Quinolinederivativesarebloodstageschizonticideswiththeexceptionofprimaquine.
PrimaquineisabloodstageschizonticidewithactivityagainstschizontsofP.vivaxbutnotthoseofP.
falciparum.Quinolinederivativesincludechloroquine,amodiaquine,quinine,quinidine,mefloquine,
primaquine,lumefantrine,andhalofantrine.Antifolatesincludesulfadoxinepyrimethamineandatovaquone
proguanil.Antimicrobialsincludetetracycline,doxycycline,andclindamycin.
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