WHO Guidelines for-2

8/7/2019 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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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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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

chloroquineresistant P


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chloroquineresistant 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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chloroquineresistant 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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