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Malaria treatment (Current WHO

recommendations & guidelines)


Copenhagen 31 January 2006
7.3

Malaria distribution and reported


case of resistance or treatment failure

First demonstration project


in Thailand
Treatment efficacy at Thai-Burmese border

Cured (%)
100

Mefloquine +
artesunate

80

Mefloquine25
60

Mefloquine15

40

Year

Adoption of ACT as first-line


treatment in 2000

Countries with falciparum malaria


Few countries deployed ACTs
in selected provinces/districts

ACT as first-line malaria treatment


in 2006

Countries with falciparum malaria


Countries which adopted ACT
as 1st-line treatment

56 countries have adopted ACTs


Continent

AFRICA

ASIA

SOUTH
AMERICA

Updated
15 Jan.
2006

Countries

Drug

Line

Burundi, Cameroon, Cte d'Ivoire, DRC, Eq.Guinea, Gabon, Ghana, Guinea,


Liberia, Madagascar, Senegal, ST&P, Sierra Leone, Sudan (S), Zanzibar

AS + AQ

1st

Angola, Benin, Burkina Faso, Comoros, Ethiopia, Gambia, Guinea Bissau, Kenya
Mali, Namibia, Niger, Nigeria, Rwanda, Uganda, S. Africa, Tanzania, Togo, Zambia

AL

1st

Cte d'Ivoire, Gabon, Mozambique, Sudan (N), ST&P, Zanzibar

AL

2nd

Mozambique, Sudan (N), South Africa (Mpumalanga)

AS + SP

1st

Cambodia, Thailand

AS + MQ

1st

Bangladesh, Bhutan, Laos, Myanmar

AL

1st

Indonesia

AS + AQ

1st

Afghanistan, India (5 Provinces), Iran, Tajikistan, Yemen

AS + SP

1st

Viet Nam

DP

1st

Papua New Guinea

AS + SP

2nd

Philippines, Iran

AL

2nd

Ecuador, Peru

AS + SP

1st

Bolivia, Peru, Venezuela

AS + MQ

1st

Brazil, Guyana, Suriname

AL

1st

AQ=amodiaquine; AL=artemether/lumefantrine; AS=artesunate; DP=dihydroartemisinin/piperaquine; MQ=mefloquine;


SP=sulfadoxine/pyrimethamine

26 countries are deploying ACTs


Continent

AFRICA

Updated
15 Jan.
2006

Countries

Drug

Line

Burundi, Cameroon, Cte d'Ivoire, DRC, Eq.Guinea, Gabon, Ghana, Guinea, Liberia,
Madagascar, Senegal, ST&P, Sierra Leone, Sudan (S), Zanzibar

AS + AQ

1st

Angola, Benin, Burkina Faso, Comoros, Ethiopia, Gambia, Guinea Bissau, Kenya
Mali, Namibia, Niger, Nigeria, Rwanda, Uganda, S. Africa, Tanzania, Togo, Zambia

AL

1st

Cte d'Ivoire, Gabon, Mozambique, Sudan (N), ST&P, Zanzibar

AL

2nd

Mozambique, Sudan (N), South Africa (Mpumalanga)

AS + SP

1st

Cambodia, Thailand

AS + MQ

1st

Bangladesh, Bhutan, Laos, Myanmar

AL

1st

Indonesia

AS + AQ

1st

Afghanistan, India (5 Provinces), Iran, Tajikistan, Yemen

AS + SP

1st

Viet Nam

DP

1st

Papua New Guinea

AS + SP

2nd

Philippines, Iran

AL

2nd

29% deploying

ASIA

60% deploying
SOUTH
AMERICA

Ecuador, Peru

AS + SP

1st

Bolivia, Peru, Venezuela

AS + MQ

1st

71% deploying

Brazil, Guyana, Suriname

AL

1st

AQ=amodiaquine; AL=artemether/lumefantrine; AS=artesunate; DP=dihydroartemisinin/piperaquine; MQ=mefloquine; SP=sulfadoxine/pyrimethamine

WHO definition of Antimalarial CombinationTherapy


(Use of Antimalarial Drugs - Nov 2000)
Antimalarial Combination Therapy = simultaneous use
of two or more blood schizonticidal drugs with
independent modes of action and different biochemical
targets in the parasite: fixed-dose or multiple-therapy
What is NOT antimalarial combination therapy:
antimalarial drug with a drug that enhances its action
(e.g. CQ plus chlorpheniramine)
use of a blood schizonticidal drug with a gametocytocidal drug
(CQ plus primaquine)
combinations in which components have no significant
schizonticidal effect (e.g. SP, chlorproguanildapsone,
atovaquoneproguanil)

WHO Technical consultation on Antimalarial


Combination Therapy (April 2001)
Combinations reviewed:
Chloroquine + Sulphadoxine-pyrimethamine
Amodiaquine + Sulphadoxine-pyrimethamine
Mefloquine + Sulphadoxine-pyrimethamine
Quinine + Tetracycline or doxycycline
Artemisinin based combination
Artesunate +chloroquine
Artesunate + amodiaquine
Artesunate + suphadoxine-pyrimethamine
Artesunate + mefloquine
Artemether-lumefantrine

Which combination
therapies ?
WHO Technical Consultation on Antimalarial
Combination Therapy April 2001
Based on available safety and efficacy data the
following therapeutic options, currently available,
have the potential for deployment (in priority order)
regardless of cost:

artemether-lumefantrine
artesunate (3 days) + amodiaquine
artesunate (3 days) + SP where SP is still effective
amodiaquine + SP where amodiaquine and SP are
still efficacious
artesunate (3 days) + mefloquine in areas of low
transmission

THERAPEUTIC OPTIONS
NOT RECOMMENDED BY WHO
WITH OBJECTIVE OF DELAYING RESITANCE

chloroquine based combinations (CQ + SP


and CQ + artesunate)
one day treatment of artesunate + SP
mefloquine based combinations (e.g.
mefloquine + artesunate) in areas of high
malaria transmission
one day treatment of artesunate + mefloquine
in the acute phase of complex emergencies
chlorproguanil/dapsone as monotherapy in
Africa

Malaria diagnosis
Parasitological confirmation
(microscopy or RDT) before treatment
Exceptions:
children under 5 years of age, from areas
of high transmission where treatment is
based on clinical diagnosis
suspected severe malaria where
parasitological confirmation is not
immediately possible

Changing
antimalarial treatment policy
Treatment failure of >10% (as assessed
through monitoring of therapeutic efficacy
at 28 days)
New treatment an average cure rate
of > 95% as assessed in clinical trials

ANTIMALARIALS DEVELOPED SO FAR

Quinine Chloroquine Amodiaquine Primaquine


Pamaquine Mepacrine
Proguanil Pyrimethamine Pyrimeth-sulfa
<1930

1930s

1940s

1950s

1960s

Artemisinin

Artesunate
Artemether
Mefloquine
Pyronaridine
Halofantrine

Artemether-lumefantrine
Atovaquone-proguanil

1970s

1980s

1990s

Treatment of uncomplicated
falciparum malaria
Artemisinin-based combination therapies
(ACT) are the treatments recommended
for all cases of uncomplicated falciparum
malaria including:
in infants,
in people living with HIV/AIDS
for home-based management of malaria
pregnant women in the 2nd and 3rd
trimesters
Exception:
1st trimester of pregnancy

Treatment of uncomplicated
falciparum malaria
The following ACTs are presently
recommended:
artemether-lumefantrine
artesunate + amodiaquine
artesunate + mefloquine
artesunate + sulfadoxine-pyrimethamine
Efficacy of ACTs depend on the efficacy
of the partner medicine
The artemisinin derivatives
(oral formulations) and partner
medicines of ACTs are not
recommended as monotherapy

Treatment of uncomplicated
falciparum malaria
Second-line treatment:
alternative ACT
quinine + tetracycline
or doxycycline
or clindamycin

Treatment of severe
falciparum malaria
Any of the following antimalarial medicines
are recommended
Artesunate i.v. or i.m
artemether i.m.
quinine (i.v. infusion or i.m. injection).
Full course of ACT or quinine + clindamycin
or doxycycline when patient can tolerate
oral treatment

Dosage and administration Coartem (Artemether 20


mg/Lumefantrine 120 mg) for uncomplicated malaria
falciparum
Age group

4 months
5 years

6 11 years

12 14
years

> 14 years

Weight
group

5 14 kg

15 -24 kg

25 34 kg

>34 kg

Blister
color

Yellow

(Day 1)

(Day 2)

(Day 3)

1 tb R,

1 tb R,

1 tb R,

1 tb Z

1 tb Z

1 tb Z

2 tb R,

2 tb R,

2 tb R,

2 tb Z

2 tb Z

2 tb Z

3 tb R,

3 tb R,

3 tb R,

3 tb Z

3 tb Z

3 tb Z

4 tb R,

4 tb R,

4 tb R,

4 tb Z

4 tb Z

4 tb Z

Blue

Orange

Green

Source: Guideline for the treatment of malaria, WHO; 2006

Coartem Dosage Schedule

Source: WHO, 2007

Artesunate+Amodiaquine
Amodiaquine
A tablet contains:
153.1mg of base as Chlorohydrate or
200mg of base as Hydrochloride
Artesunate
A tablet contains:
50mg of Sodium Artesunate
Dosing Schedule
The total recommended treatment is as follow:
4mg/kg body weight of Artesunate
10mg/kg body weight of Amodiaquine
Both must be given once a day, at the same time, for three days

Artesunate+Amodiaquine
Age

Dose in mg (No of tablets)


Artesunate

Amodiaquine

Day 1

Day 2

Day 3

Day 1

Day 2

Day 3

5 mnt
11 mnts

25 mg

25 mg

25 mg

76 mg

76 mg

76 mg

16
years

50 mg

50 mg

50 mg

153 mg

153 mg

153 mg

7 13
years

100 mg

100 mg

100 mg

306 mg

306 mg

306 mg

Over 13
years

200 mg

200 mg

200 mg

612 mg

612 mg

612 mg

MECHANISM OF ACTION
Exerts antimalarial activity by iron-mediated cleavage
of the peroxide bridge and generation of an organic
free radical.
The interaction of artemisinin with haem in the parasite
may turn out to be essential.
Haem bound iron (but also free iron) may serve as a
catalyst.
The artemisinin radical binds subsequently to
membrane proteins, and alkylation reactions
eventually cause destruction of the parasite.
(Vries et al, Drugs, 1996

ANTIMALARIAL EFFICACY

Rapidly acting blood schizontocidal antimalarials


against chloroquine sensitive and chloroquine resistant
falciparum as well as vivax malaria
They quickly arrest the ring or the trophozoite
development and also prevent pathological sequelae
Fever subsides and parasites are cleared rapidly
Defervescence occurs within 2-3 days after drug
administration
Ninety percent clearance of asexual erythrocytic
parasitaemia is usually observed within 4 hours
(Valecha N. et al., Indian Journal of Pharmacology, 1997)

ARTEMISININ DERIVATIVES EFFECTS ON


ROSETTING AND CYTOADHERANCE
The process whereby erythrocytes containing mature forms of
P. falciparum ahdere to microvascular endothelium is called
cytoadherance. It thus disappears from circulation, known as
sequestration.
Erythrocytes containing mature parasites also adhere to
uninfected parasites, leading to the formation of rosettes.
Cytoadherance and rosetting lead to microcirculatory
obstruction in falciparum malaria, the consequence of which
are reduced oxygen and substrate supply, anaerobic
glycolysis and lactic acidosis, finally leading to complications
of malaria. (Manson, 1997)
All artemisinin drugs prevent the development of ring stage
parasites to the more mature pathogenic stages that rosette
and cytoadhere to capillaries

(The use of artemisinin and its derivatives as antimalarial drugs - Report of


a Joint CTD/DMP/TDR- WHO, 1998)

EFFICACY OVER OTHER


ANTIMALARIALS
Artesunate and artemether have been shown to clear
parasitaemias more effectively than chloroquine and
sulfadoxine/pyrimethamine
Meta analysis of mortality in trials indicated that a patient
treated with artemether had at least an equal chance of
survival as a patient treated with quinine
Artemisinin drugs cleared parasites faster than quinine in
patients with severe malaria but fever clearance was
similar
Parenteral artemether and artesunate are easier to use
than quinine and do not induce hypoglycaemia
(The use of artemisinin and its derivatives as antimalarial drugs Report of a Joint CTD/DMP/TDR- WHO, 1998)

Treatment of other malaria cases


During Pregnancy
ORAL QUININE ALL TRIMESTERS
It safe in all trimesters
It is a 7-day treatment
It is taken as 10mg/kg to a maximum of 600mg or 2 tablets, three
times daily.
Can reduce doses to 5 7.5mg/kg (i.e 2 tablets twice daily) after
three days

ACTs 2ND AND 3RD TRIMESTERS ONLY


The use of ACTs in the second and third trimester have not been
found to be associated with any teratogenic or mutagenic effect.

Children less than 5 kg


Oral Quinine 10mg/kg 8 hourly for 7 days
(No enough evidence on the use of ACTs)

Chemoprophylaxis
Sickle Cell Anaemia
Daily Proguanil

Non Immune Visitors


Mefloquine
Doxycycline
Atovaquone-Proguanil

Dosage and administration of Chloroquine and


Primaquine for malaria vivax.
CHLOROQUINE
(150 mg base) 10 mg/kg on the first two
days.
5 mg/kg on day 3

Age Group

Give for 3 days

* Weight
group (Kg)

PRIMAQUINE
(15 mg base)
0.5 mg/kg bw
Start
concurrently
with CQ and
give daily for
14 days

Day 1

Day 2

Day 3

4 months up
to 12 months

4 - <10

13 months up
to 5 years

10 - <19

6 - 7 years

19 - < 24

8 - 11 years

24 - <35

12 - 14 years

35 - < 50

15 +

50 or more

Specific severe malaria


treatment
Artesunate (60 mg): 2.4 mg/kg body weight
(bw) IV or IM on admission (time=0), followed
by 2.4 mg/kg at 12 and 24 hours, followed by
once daily for seven days. Once the patient
can tolerate oral therapy, treatment should be
switched to a complete dosage of coartem
for three days as recommended in the national
treatment guidelines for uncomplicated
malaria .
The congenital malaria is also treated with
Artesunate, where 2.4 mg/kg is initially
given through IV, followed by 1.2 mg/kg at
12 and 24 hr then every 24 hr for 3 -5 days.

Specific severe malaria


treatment
Artemether (80mg for adult and 40 mg for
children and the newborn): 3.2 mg/kg bw IM
on the first day followed by 1.6 mg/kg bw
daily for seven days. Once the patient can
tolerate oral therapy, treatment should be
switched to a complete dosage of coartem.
Arteether (150 mg): 3.2 mg/kg bw IM on the
first day, followed by 1.6 mg/kg bw for the
next 4 days. Once the patient can tolerate
oral therapy, may switch to a complete
dosage of coartem.

If Coartem is not available, quinine


should be administered in
combination with tetracycline or
doxycycline or clindamycin, to
complete the seven-day treatment,
except for pregnant women and
children under eight years of age for
whom tetracycline/doxycycline is
contraindicated

Quinine
Loading dose:
Quinine dihydrochloride 20 mg salt/ kg bw
diluted in 10 ml/kg bw of 5% dextrose or
dextrose saline administered by IV infusion
over a period of four hours for both adult and
children. In severe Childhood falciparum
malaria, if patient received quinine or quinidine
or mefloquine in 48 hrs before arrival, give 10
mg/kg over 2 hours.

Maintenance dose: Quinine dihydrochloride 10 mg


salt/ kg body weight diluted in 10 ml/kg body weight of
5% dextrose or dextrose saline administered by IV
infusion. In adults, the maintenance dose is infused
over a period of four hours and repeated every eight
hours.
Similarly in children including congenital malaria,
it is infused over a period of two hours and
repeated every eight hours (calculated from the
beginning of the previous infusion) until the
patient can swallow. To complete the seven-day to
eight-day treatment in children, give Quinine
sulfate 10 mg/kg per oral three times in a day.
Increase the dosage of Quinine sulfate to 15-20
mg/kg after 4 days or add tetracycline 5 mg/kg
twice a day for children above 7 years.

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