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Transcript of WHO Guidelines for-2
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WHO Guidelines forthe treatment of malaria
. .Dr Ramya k- -
07 02 2011
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Road mapIntroduction
Clinical Disease-malariaAnti malarial drugsWHO strategiesDiagnosis
Objectives of treatmentResistence to antimalarial drugsAnti malarialial treatment policiesTreatment for p.falciparum
Treatment for other speciesResistence to anti malarial drugsTreatment failuresconclusion
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u
Malaria: an important cause of death &illness in children & adults, especially intropical countries
Disease now affects more than half abillion in world and kills more than amillion people every year
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Clinical disease &epidemiology
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Clinical disease &
epidemiologyCaused by parasites of the
species Plasmodium
vP. falciparum (highest mortality)
vP. vivax (most common)
vP. ovale
vP. malariaev
vP.knowlesi
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plapppLife cycle of
Plasmodium
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Drugs classificationTrue casual prophylactics
Casual prophylactics hepatic cycle-primary tissue schizonticidesPrimaquine, pyrimethamine, proguanil
Suppressives-erythrocytic stage-schizonticidesQuinine, 4-aminoquinolines, mefloquine,
artemisinin, proguanil, pyrimethamine,tetracycline
Radical curatives- both phases
primaquine, proganil
Gametocytocidal drugsPrimaquine-all species
Chloroquine, quinine, artesunate(exceptfalciparum)
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Clinical Manifestations
Malaria parasites multiply rapidly in the liver,then in red blood cells.
Symptoms commonly include:
FeverHeadacheChillsMalaise
Joint painVomiting
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manifestations
If not treated promptly with effective medicines,malaria may cause mortality by infecting &destroying red blood cells which clog thecapillaries carrying blood to the brain or othervital organs potentially causing the following:
Renal failureHypoglycemia
AnemiaPulmonary edemaShock and coma
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Cerebral malariaSeizuresFatal if untreated; mortality 20% with Rx
10% treated have neurologic sequelae
Risk factors: - Young & old - Pregnancy - Poor nutrition
- HIV
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WHO strategiesMalaria control requires an integrated
approach, includingPrevention (primarily vector control)Prompt treatment with effective
antimalarials
WHO urges 4 main strategies to tacklemalaria
PreventionTreatmentSpecial effort-young children , pregnant
woman
Pre empting epidemics by detecting them
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WHOstrategiesWHO Guidelines for the treatment of
malaria-first published in 2006
Provide global, evidence-basedrecommendations on the casemanagement of malaria
Targeted policy-makers at country level
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Recommendations on
parasitological diagnosisPrompt parasitological confirmation by
microscopy, or RDT s, is recommended inall patients suspected of malaria beforetreatment is started
Treatment solely on the basis of clinical
suspicion should only be considered whena parasitological diagnosis is notaccessible
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Objectives of treatment-Uncomplicated malaria
Objective: Cure the infection as rapidly aspossible
Cure: defined as elimination of parasites thatcaused illness from the bodyPrevents progression to severe disease &
additional morbidity associated withtreatment failure
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Objectives of treatment-Uncomplicated malaria
Public health goal of treatment:To reduce transmission of the infection to
othersTo reduce the infectious reservoirTo prevent the emergence and spread of
resistance
Other considerations:
Adverse effect profileTolerability of antimalarial medicinesSpeed of therapeutic response
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-malaria
Primary objective: prevent death
Cerebral malaria: prevention of neurological deficit
Severe malaria in pregnancy-saving the life of themother
Secondaryobjective:
In all cases -prevention of recrudescence,avoidance of minor adverse effects are
secondary
di i
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medicines
Resistance: Major threat to malaria control
Indiscriminate use of antimalarials exerts astrong selective pressure on malaria parasites
Resistance: prevented by
Combining antimalarials with differentmechanisms of action
Full adherence to correct dose regimens
Drug resistance with Plasmodium falciparum:lethalChloroquine resistance does occur in P. vivax,Very few reports of resistance in P. malariae or P.
ovale
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policy
Aims to offer highly effective antimalarials
Main determinants of antimalarial treatmentpolicy:
Therapeutic efficacy of antimalarial medicineChanging patterns of malaria-associated
morbidity and mortalityConsumer and provider dissatisfaction with the
current policyAvailability of alternative medicines, strategies
and approaches
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treatment policy
Duration of post-treatment follow-up is based
on: Elimination half-life antimalarial medicine
Current recommended duration of follow-up:
Minimum of 28 days for all antimalarialmedicines
Extended for longer duration depending on
elimination half-life42 days for combinations with
mefloquine and piperaquine
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WHO GU IDELINES FOR THE TREATMENTOF MALARIA
2nd Edition, 2010
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Treatment of uncomplicatedP. falciparum malaria
Uncomplicated malaria : Defined asSymptomatic malaria without signs of
severity or evidence (clinical orlaboratory) of vital organ dysfunction
The signs and symptoms ofuncomplicated malaria arenonspecific.
Malaria is, therefore, suspectedclinically mostly on the basis offever or a history of fever
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Rationale for antimalarialcombination therapy
Antimalarial combination therapy:Simultaneous use of two or more blood
schizontocidal medicines with independentmodes of action
Rationale is twofold:Combination is often more effectiveIf a mutant parasite resistant to one of the
medicines arises de novo during the courseof the infection, this resistant parasite will bekilled by the other antimalarial medicine
This mutual protection is thought to prevent orto delay the emergence of resistance
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uncomplicatedP. falciparum malaria
Artemisinin-based combination therapies(ACTs) - recommended treatments
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combination therapy
Artemisinins produce rapid clearance of
parasitaemia and rapid resolution ofsymptoms, by reducing parasite numbers100- to 1000-fold per asexual cycle of theparasite
7-day course is required:Artemisinin and its derivatives are
eliminated rapidly, when given alone or in
combination with rapidly eliminatedcompounds (tetracyclines, clindamycin)
3-day course can be used:
In combination with slowly eliminated
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combination therapy
Additional advantage from: ability of theartemisinins to reduce gametocyte carriage transmissibility of malaria malariacontrol in areas of low-to-moderateendemicity
Shorter courses of 12 days notrecommended:Leads to a larger proportion of
parasitaemia for clearance by the partnermedicineLess efficacious (except when the partner
drug is highly effective)
Less effect on gametocyte carriageProvide less rotection of the slowl
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Artemisinin-basedcombination therapy
The choice of ACT - based on the level ofresistance of the partner medicine in thecombination
Artemisinin and its derivatives should not beused as monotherapy
Non-artemisinin based combinationtherapy: inferior in efficacy: hence nolonger recommended
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Fixed dose combinations
Fixed-dose combination (FDC) formulations
are strongly preferred and recommendedover blistered co-packaged or loose tabletscombinations to
Promote adherence to treatmentTo reduce the potential selective use of the
medicines as monotherapy
Fixed-dose combination formulations arenow available for all recommended ACTs,except artesunate plus SP.
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Second-line antimalarialtreatment
Alternative ACT known to be effective in theregion
Artesunate plus tetracycline or doxycyclineor clindamycin-7 days
Quinine plus tetracycline or doxycycline orclindamycin-7 days
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Additional considerations forclinical management
Can the patient take oral medication?
Use of antipyretics
Use of antiemetics
Management of seizures
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Operational issues intreatment management
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-malariaRecommended to improve access to prompt
and effective treatment of malaria-trainedcommunity members
Coverage of the health services for malaria to
extend beyond the reach of health facilities
Effective and appropriate treatment withfirst-line ACTs- guidance on referral criteria-
provided at the community level
Rectal artesunate and RDTs recommended
HMM?
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HMM?...Trained community providers (CHWs,
Medicine Sellers or Retailers) should
be provided with:
ACTs for treatment of
uncomplicated malaria
Rectal artemisinin
suppositories for pre-referral
treatment of severe malaria
Rapid diagnostic tests where
applicable
Information, Education and
Treatment of uncomplicated
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Treatment of uncomplicatedP. falciparum malaria inspecial risk groups
Pregnancy
First trimester:
Quinine plus clindamycin - 7 days(artesunate plus clindamycin - 7 daysindicated if fails)
During pregnancy, infection with P.falciparum, (in p.vivax also)reducesbirth weight and increases the risk ofneonatal death due to
Chronic anaemia
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P. falciparum malaria inPregnancy
An ACT is indicated If this is the only treatment immediately
availableIf treatment with 7-day quinine plus
clindamycin failsUncertainty of compliance with a 7-day
treatment
Second and third trimesters:
ACTs known to be effective in thecountry/region
Artesunate lus clindam cin-7 da s
rea men o uncomp ca e .
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rea men o uncomp ca e .falciparum malaria
Lactating women
Lactating women - standard antimalarialtreatment (including ACTs) except fordapsone, Primaquine and tetracyclines
Infants and young children:ACTs - first-line treatment - accurate
dosing and ensuring -administered doseretained
Travellers returning to non-endemiccountries
Atovaquone-proguanil;
Artemether-lumefantrine;
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HIV infection-uncomplicated P.falciparum malaria
Treatment or intermittent preventive treatmentwith sulfadoxine-pyrimethamine should not begiven to HIV patients receiving cotrimoxazole(trimethoprim plus sulfamethoxazole)prophylaxis
Treatment in HIV patients on zidovudine orefavirenz should, if possible, avoidamodiaquine-containing ACT regimens
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Malaria - Treatment
.
Artemisinin
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TREATMENT OF SEVERE P.FALCIPARUMMALARIA
S f l i l i
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Severe falciparum malariaPresence of one or more of the following
clinical or laboratory features
Clinical features: Impaired consciousness Generalized weakness, failure to feed
multiple convulsions more than 2 in24 h
respiratory distress (acidotic breathing) circulatory collapse or shock
clinical jaundice, other vital organdysfunction
haemoglobinuria abnormal spontaneous bleeding
pulmonary oedema (radiological)
l i
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malariaLaboratory findings:
hypoglycaemia (blood glucose < 40 mg/dl) metabolic acidosis (bicarbonate < 15
mmol/l)
severe normocytic anaemia (Hb < 5 g/dl)
haemoglobinuria hyperparasitaemia (> 2%/100 000/l )
hyperlactataemia (lactate > 5 mmol/l)
renal impairment (s.creatinine > 265mol/l)
Treatment of severe P
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Treatment of severe P.falciparum malaria
Severe malaria -medical emergency
Full doses of parenteral antimalarialtreatment without delay
Adults Artesunate IV or IM
Quinine an alternative
Children ( endemic areas of africa) Artesunate IV or IM
Quinine (IV infusion or divided IM )
Artemether IM ( absorption - erratic)
T t t f P
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Treatment of severe P.falciparum malaria
Give parenteral antimalarials - for a minimumof 24 h, once started
Complete treatment by giving a completecourse of:An ACT;Artesunate plus clindamycin or
doxycycline;Quinine plus clindamycin or doxycycline.
Treatment of severe P
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Treatment of severe P.falciparum malaria
If complete treatment is not possible,patients should be given pre-referraltreatment
Referred to an appropriate facility forfurther treatment
Options for pre-referral treatment :
rectal artesunate, quinine IM,artesunate IM, artemether IM
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Treatment ofPlasmodium
vivax, P. ovale and P.malariae infections
Treatment of p vivax malaria
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Treatment of p.vivax malariaPlasmodium vivax
Objectives of treatment of vivax malaria are
two fold:To terminate the acute blood infection
To cure the clinical symptoms
To clear hypnozoites from the liver toprevent future relapses-radical cure
Standard oral regimen
Chloroquine monotherapy (25 mg base/kgbody weight over 3 days) is recommendedas the standard treatment for vivaxmalaria
malaria
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malaria
Primaquine (0.25 or 0.5 mg base/kg body
weight in a single daily dose for 14 days) isused as a supplement to the standardtreatment for the purpose of eradicatingdormant parasites in the liver and
preventing relapses
14-day regimen of primaquine is superior in
preventing relapses
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Treatment of uncomplicatedP. vivaxmalaria
Chloroquine with primaquine-treatment of choice -chloroquine-sensitive infections
In mild-to-moderate G6PD deficiency,primaquine 0.75 mg base/kg bodyweight - once a week for 8 weeks
In severe G6PD deficiency,primaquine is contraindicated
Treatment of uncomplicated P
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Treatment of uncomplicated P.vivaxmalaria
ACT (exception AS+SP) -adopted asfirst-line treatment for P. falciparum
May also be used for P. vivaxmalaria
in combination with primaquine forradical cure
Artesunate plus sulfadoxine-
pyrimethamine is not effectiveagainst P. vivaxin many places
Treatment of chloroquine-
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Treatment of chloroquineresistant P. vivaxAntimalarials that are effective against P.
falciparum are generally effective againstthe other human malarias
The exception to this is sulfadoxine-pyrimethamine to which P. vivaxiscommonly resistant
Owing to the high prevalence ofdhfrmutations in P. vivax(Pvdhfr), resistance to
sulfadoxine-pyrimethamine develops faster
.i
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.vivax
Artemisinins, combined with an effectivepartner medicine-excellent cure rates inboth chloroquine sensitive & resistantstrains ofP. vivax
In areas of CQ resistance, twoACTs,DHA+PPQ and AS+AQ , incombination with primaquine, have
provided high cure rates
ACTs with partner medicines that havelonger half-lives, such as DHA+PPQ, are
more effective in reducing relapses than
chloroquine- resistant P
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chloroquine- resistant P.vivax
Mild nausea,vomiting and abdominal painare the commonly reported adversereactions
Mefloquine (15 mg base/kg body weight asa single dose) has been found to be highlyeffective with a treatment success of 100%
Doxycycline alone (100 mg twice a day for7 days) provides poor cure rates in P. vivax
hl i i P
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chloroquine- resistant P.vivax
Artemisinin derivatives, such asmonotherapy for 37 days, have shown poorefficacy in vivax malaria The addition ofprimaquine to these regimes improved the day
28 cure rates to 100%
Quinine (10 mg salt/kg body weight threetimes a day for 7 days) is also effectiveagainst CQ resistant P. vivax, but it is not anideal treatment because of its toxicity andconsequent poor adherence to this regimen
Treatment of chloroquine-
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Treatment of chloroquineresistant P. vivax
Wide a range treatment of vivax malariawith quinine leads to early relapses
This may be because quinine has a short
half-life, and no antihypnozoite activity
The best combinations for the treatment ofP. vivaxare those containing primaquine
when given in antihypnozoite doses
The recommended treatments for CQresistant P. vivaxare, therefore, ACTs (with
the exception of AS+SP) combined with
Treatment of chloroquine
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Treatment of chloroquine-resistant P. vivax
If the recurrence appears within 16 days ofstarting treatment of the primary infection,it is almost certainly a recrudescence due
to therapeutic failure
A recurrence between days 17 and 28 maybe either a recrudescence by chloroquine-
resistant parasites or a relapse
Beyond day 28, any recurrence probablyrepresents a relapse in an infection ofchloro uine-sensitive P. vivax
relapses
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relapses
Primaquine is the only available and marketed drugthat can eliminate the latent hypnozoite reservoirsofP. vivaxand P. ovale that cause relapses
Hypnozoites of many strains ofP. vivaxare
susceptible to a total dose of 210 mg ofprimaquine
unsupervised 14-day primaquine therapy can be
overcome effectively through patient education
relapses
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relapses
Alternative drugs are much needed for theradical treatment ofP. vivaxmalariaresistant to chloroquine and/or primaquine
New drugs, tafenoquine and bulaquine, arecurrently being evaluated as an alternativeto primaquine in the prevention of relapses
-this too has haemolytic potential in G6PD-deficient individuals
Treatment of severe and
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Treatment of severe andcomplicated vivax malaria
Prompt and effective management shouldbe the same as for severe and complicated
falciparum malaria
Treatment of malaria caused
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Treatment of malaria causedby P. ovale and P. malariae
The recommended treatment for radicalcure ofP. ovale, relapsing malaria, is thesame as that for P. vivax, i.e. withchloroquine and primaquine
P. malariae forms no hypnozoites, and so it
does not require radical cure withprimaquine
verse e ec s ant i di ti
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contraindications
Chloroquine is generally well tolerated.Common side effects include milddizziness, nausea, vomiting, abdominalpain and itching
Primaquine can induce a life-threatening
haemolysis in those who are deficient inthe enzyme G6PD
Adverse effects and
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contraindications
Abdominal pain and/or cramps arecommonly reported when primaquine istaken on an empty stomach.
Gastrointestinal toxicity is dose-related, andit is improved by taking primaquine withfood. Primaquine may cause weakness,uneasiness in the chest, haemolytic
anaemia, leukopenia, and suppression ofmyeloid series
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Mixed malaria infections
ACTs are effective against all malariaspecies, and they are the treatment ofchoice
Radical treatment with primaquine should begiven to patients with confirmed P. vivaxand P. ovale infections, except in hightransmission settings where the risk of re-
infection is high
ract ca aspects o
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ptreatment withrecommended ACTs
Artemether plus lumefantrine
Fixed-dose formulation with dispersible orstandard tablets containing 20 mg of
artemether and 120 mg of lumefantrineTherapeutic dose. 6-dose regimen over a 3-dayperiod
Dosing based on the number of tablets per doseaccording to pre-defined weight bands (514 kg:1 tab; 1524 kg: 2 tabs; 2534 kg: 3 tabs; > 34kg: 4 tabs) given twice a day for 3 days
Drugs Therapeutic dose Duration
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mg/kgartesunate + 4 once a day for
amodiaquine 10 3 days
Artesunate + 4 once a day for
mefloquine 8.3 3 days
Artesunate + 4 OD 3 days
Sulphadoxinepyrimethamine 25/1.25 Single administrationon day 1st
Dihydroartemisinin + 4 OD for 3
piperaquine 18 days
Artesunate 2 OD For
Tetracycline/Doxycycline/clindamycin
43.510
QID 7OD daysBID
Management of treatment
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gfailuresRecurrence - P. falciparum malaria-re-
infection, or a recrudescence(i.e. failure)
If fever and parasitaemia fail to resolve orrecur within two weeks of treatment-failure
of treatment
Treatment failures-drug resistance, pooradherence or inadequate drug exposure,substandard medicines
Patients history- confirmed parasitologically
blood slide examination (as P. falciparum- -
.Management oft t t f il
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treatment failures
Failure within 14 days
Treatment failures within 14 days of initialtreatment should be treated with a second-line antimalarial
Failure after 14 daysRecurrence - more than two weeks after
treatment could result either fromrecrudescence or new infection
This distinction can only be made throughparasite genotyping by PCR.
Management of
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Management oftreatment failures
Treatment failures after two weeks of initialtreatment - new infections-treated with thefirst-line ACT
If failure is a recrudescence, then the first-line treatment should still be effective inmost cases
Reuse of mefloquine within 60 days of firsttreatment is associated with an increasedrisk of neuropsychiatric reactions
In cases where the initial treatment was
recommendations
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recommendations
For the radical cure of chloroquine-sensitive
P. vivaxmalaria in patients with no G6PDdeficiency
The standard oral regimen of
Chloroquine of 25 mg base/kg body weight-3 days
PlusPrimaquine at either a low (0.25 mg base/kg
body weight per day for 14 days) or
High (0.50.75 mg base/kg body weight per
day for 14 days) dose is effective and safe
recommendations
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Where infections of drug-resistant P.falciparum and/or P. vivaxare common,
An artemisinin-based combination treatment(dihydroartemisinin +piperaquine) thatdoes not include sulfadoxine-pyrimethamine would be a good choice
Use of high-dose primaquine (0.50.75 mgbase/kg body weight/day -14 days), with
either chloroquine or another effectiveantimalarial, to prevent relapses ofprimaquine-resistant or primaquine-tolerant P. vivax
recommendations
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A primaquine regimen of 0.75 mg base/kg
body weight once per week for 8 weeks isrecommended as anti-relapse therapy forP. vivaxand P. ovale malaria in patientswith mild G6PD deficiency
Increased efforts are needed to evaluatealternative treatments for P. vivaxstrainsthat are resistant to chloroquine
Malaria Prevention
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Malaria - Prevention
References
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Guidelines for the treatment of malaria, WHO, 2nd ed.Geneva:world press; 2010. p.1-210.(http://whqlibdoc.who.int/publications/2010/9789241547925_en
g.pdf)
Vinetz JM, ClainJ, Bounkeua V, Eastman RT, Fidock D.Chemotherapy of Malaria. In: Hardman.J.G, Limbird.L.E,Gilman.A.J Editors. Goodman & Gilmans The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill;2011.P.1383-1418.
Satoskar RS, Bhandarkar SD, Rege NN. Chemotherapy of Malaria.In: Pharmacology and pharmacotherapeutics. Revised 21st ed.
Mumbai: Popular prakashan private limited; 2010. p.758-776.
references
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Tripathi KD. Antimalarial drugs. In:Essentials of medicalpharmacology. 6th ed. New delhi:Jaypee brothers medicalpublishers (p)ltd,2009.p.780-96.
Rosenthal .P.J. Antiprotozoal Drugs. In: Katzung BG, Masters SB,Trevor AJ, editors.Basic and clinical pharmaclogy.11th edition.
New york: Tata McGraw-Hill,2009.p.899-912.
Valuha.N. Drug therapy of Malaria. In:Seth SD, Seth.V. Textbook ofPharmacology. 3rd edition. New Delhi:Elsevier;2009.p.XI.5-XI.19.
Park K.Epidemiology of communicable diseases.In: Parks textbook
of preventive & social medicine. 20th ed. Jabalipur: BanaridasBhanot Publishers,2009. p.222-32.
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Thank you