Plasmodium species Tables

Table 1. Currently Available Antimalarial Drugs

Arylaminoalcohols
4-aminoquinolones:	Chloroquine Amodiaquine Amopyraquine
Structurally Related Compounds	Pyronaridine Piperaquine Quinine Quinidine Mefloquine Halofantrine Lumefrantrine (Benflumetol)
8-aminoquinolones	Primaquine Tafenoquine (Etaquine)
Dihydrofolate reductase inhibitors	Pyrimethamine Proguanil Chlorproguanil Pyrimethamine-sulfadoxine Chlorproguanil-dapsone
Artemisinin and deriatives	Artemisinin Artemether Artesunate Artemotil Dihydroartemisinin
Hydroxynaphthaquinones	Atovaquone Atovaquone-proguanil
Antibiotics with antimalarial activity	Sulfonamides Tetracyclines Chloramphenicol Fluoroquinolones (weak) Rifamycins (weak) Macrolides Clindamycin Lincomycin

Drugs in italics are either still investigational, or are not widely available

Table 2. Dosing Schedule for Artesunate plus Amodiaquine

Age	Dose in mg (no. of tablets)
	Artesunate			Amodiaquine (base)
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5–11 months	25 (½)	25	25	76 (½)	76	76
1–6 years	50 (1)	50	50	153 (1)	153	153
7–13 years	100 (2)	100	100	306 (2)	306	306
>13 years	200 (4)	200	200	612 (4)	612	612

Table 3. Dosing Schedule for Artesunate plus Sulfadoxine-Pyrimethamine

Age	Dose in mg (no. of tablets)
	Artesunate			Sulfadoxine-pyrimethamine
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5–11 months	25 (½)	25	25	250/12.5 (½)	–	–
1–6 years	50 (1)	50	50	500/25 (1)	–	–
7–13 years	100 (2)	100	100	1000/50 (2)	–	–
>13 years	200 (4)	200	200	1500/75 (3)	–	–

Table 4. Dosing Schedule for Artemether-Lumefantrine

Body weight in kg (age in years)	No. of tablets recommended at approximate timing of dosing^a
Body weight in kg (age in years)	0 h	8 h	24 h	36 h	48 h	60 h
5–14 (<3)	1	1	1	1	1	1
15–24 (3–9)	2	2	2	2	2	2
25–34 (9–14)	3	3	3	3	3	3
>34 (>14)	4	4	4	4	4	4

^a Co-Artem: 1 Tablet contains 20mg Artemether and 120mg Lumefantrine. The drug should be taken with food or milk as. Bioavailability is significantly enhanced with coadministartion of fat, each dosage should be taken with milk or fatty snack.

Table 5. Dosing Schedule for Artesunate plus Mefloquine*

Age	Dose in mg (no. of tablets)
	Artesunate			Mefloquine (base)
	Day 1	Day 2	Day 3	Day 1	Day 2	Day 3
5–11 months	25 (½)	25	25	–	125 (½)	–
1–6 years	50 (1)	50	50	–	250 (1)	–
7–13 years	100 (2)	100	100	–	500 (2)	250 (1)
>13 years	200 (4)	200	200	–	1000 (4)	500 (2)

*alternatively the total dose of mefloquine may be split into three, with one third of the dose being taken on days 1, 2 and 3.

Table 6. Recommendations on the Treatment of Falciparum Malaria in Non-immune Travellers

For travelers returning to non-endemic countries:¹

Artemether-lumefantrine (1.5 mg/12 mg/kg twice daily for 3 days)
Atovaquone-proguanil (1 g/400 mg once daily for 3 days)
Quinine (10 mg salt/kg 8-hourly) plus Doxycycline² (3.5 mg/kg once daily) or
Clindamycin (10 mg/kg 12-hourly); all drugs to be given for 7 days.

For severe malaria:

– Antimalarial treatment of severe malaria in travelers is the same as the general recommendation
(table 7)

– Travellers with severe malaria should be managed in an intensive care unit

– Haemofiltration or haemodialysis should be started early in acute renal failure or severe
metabolic acidosis

– Positive pressure ventilation should be started in case of respiratory distress and coma with breathing
abnormalities

¹ Halofantrine is not recommended as first-line treatment for uncomplicated malaria because of cardiotoxicity.

² Doxycycline should not be used in children under 8 years of age and in pregnancy.

Table 7. Antimalarial Treatment of Severe Malaria

Artesunate¹	2.4 mg/kg i.v. or i.m. on admission, at 12, 24 hours, then daily. Artesunic acid (60mg) is dissolved in 1ml of 5% sodium bicarbonate and further diluted into 5ml with 5% dextrose or normal saline for intravenous injection (given as a bolus over 2 min). 1 ampoule=60mg
Artemether	3.2 mg/kg i.m. on admission followed by 1.6 mg/kg daily. NOT for i.v. administration. 1 ampoule = 80mg. Injections to the anterior thigh.
Quinine	20mg /kg of dihydrochloride salt by intravenous infusion over 4 hrs followed by 10 mg/kg infused over 2 - 8 hrs every 8 hours. If intravenous route not possible then give by intramuscular injection to the anterior thigh. The first dose should be divided; 10mg salt/kg to each thigh. Quinine should be diluted, inject no more than 180mg/ml.
Quinidine	10 mg base/kg infused at constant rate over 1-2 hr followed by 0.02 mg/kg/min as constant infusion, with electrocardiographic monitoring.

¹ Parenteral artesunate is the drug of choice for the treatment of severe malaria in adults. For children in high transmission areas there is as yet insufficient evidence to recommend any of the above antimalarial medicines over another.

Table 8. Treatment of Uncomplicated Vivax and Ovale Malaria.

· Chloroquine 25 mg base/kg bw divided over 3 days, combined with primaquine 0.25 mg base/kg bw, taken with food once daily for 14 days is the treatment of choice for chloroquine-sensitive infections. In Oceania and South-East Asia the dose of primaquine should be 0.5 mg/kg bw.

· Amodiaquine (30 mg base/kg bw divided over 3 days as 10mg/kg bw single daily doses) combined with primaquine should be given for chloroquine-resistant vivax malaria.

· In moderate G6PD deficiency, primaquine 0.75 mg base/kg bw should be given once a week for 8 weeks. In severe G6PD deficiency, primaquine should not be given.

· Where ACT has been adopted as the first-line treatment for P. falciparum malaria, it may also be used for P. vivax malaria in combination with primaquine for radical cure. Artesunate plus sulfadoxine-pyrimethamine is the exception as it will not be effective against P. vivax in many places.

Table 9. Treatment of Malaria in Pregnancy

Falciparum Malaria in Pregnancy

Treatment group

Transmission region

Trimester

Current Treatment regimens

Uncomplicated malaria

P. falciparum

Parasitemia <4% and no signs of severity

Chloroquine-sensitive

As this is only valid for a very limited number of regions in the world, we do not advise the use of this drug during pregnancy, unless reliable information on drug resistance is available.

Treat as for Chloroquine-resistant or unknown resistance (see below)

Chloroquine-resistant or unknown resistance

1^st

Supervised Oral Quinine plus Clindamycin

Quinine sulfate: 10 mg salt/kg/dose 8 hourly for 7 days plus Clindamycin: 10 mg/kg
12-hourly for 7 days

2^nd & 3^rd

1. Supervised Oral Artemisinin Combination Therapy¹

ACT should be known to be effective in the region.

For dosages see Tables 2, 3, 4

Since mefloquine has been associated with stillbirth, it should only be used if no safer alternative is available.

2. Supervised Oral Artesunate plus Clindamycin¹

Artesunate 2 mg/kg once daily for 7 days plus Clindamycin 10 mg/kg 12-hourly p.os full 7 days

3. Supervised Oral Quinine plus Clindamycin

Quinine sulfate: 10 mg salt/kg/dose 8 hourly for 7 days plus Clindamycin: 10 mg/kg 12-hourly for 7 days

4. Supervised Artesunate-Atovaquone-Proguanil (AAP)^1,2

can be used in case of recrudescence²

3 day oral regimen: Artesunate 4 mg/kg/day, Atovaquone 20 mg/kg/day and Proguanil 8 mg/kg/day

Severe Malaria

P. falciparum

One or more criteria for severity!

(see Table 13)

All

1. Artesunate i.v. initial dose 2.4mg/kg, then 2.4mg/kg at 12h and 24h after admission, then once daily until patient can tolerate oral medication. Total course 7 days.

If artesunate is not available;

2a. Artemether i.m. initial dose 3.2mg/kg i.m. anterior thigh day 1, then 1.6mg/kg i.m. once daily from day 2-7, or until patient can tolerate oral artesunate³

2b. Quinine i.v. loading dose 20mg/kg i.v. over 4h on admission, then 10mg/kg i.v. over 2 to 4h, 8-hourly for a total of 7 days, or until patient can tolerate oral medication.

¹ oral Artesunate 1 Tablet contains 50mg, a suspension is made by dissolving 1 tablet in 5ml of water, 1ml equals 10mg, using a syringe

² Malarone (AQ/PG) - one tablet contains 250 mg Atovaquone and 100 mg Proguanil. Give Atovaquone-Proguanil with food. If patient vomits within 30 minutes of taking a dose, then repeat the whole dose. If vomiting occurs after 30–60mins of taking a dose, repeat half the dosage.

³ to prevent recrudesence follow-on treatment should be given, when the patient is able to take oral medication. Follow-on treatment can be a full course of the ACT of choice in the region (see text).

Malaria in Pregnancy, other than Falciparum

Uncompl. malaria

P. vivax

Chloroquine-sensitive

(P. vivax and
P. ovale)

All

Oral Chloroquine; initial dose 10 mg base/kg then10 mg base/kg after 24 hours, followed by 5 mg base/kg after 48 hours (total dose 25 mg/kg).

(for radical treatment see below)

Chloroquine-resistant or unknown resistance

1^st

No studies available but we would consider:

Quinine sulphate: 10 mg salt / kg every 8h for 7 days

2^nd and 3^rd

Artesunate –amodiaquine or other ACT available in the region (see treatment of uncomplicated falciparum malaria during pregnancy)

Uncompl. malaria

P. ovale

Chloroquine-sensitive

Chloroquine (dosage see above)

Uncompl. malaria

P. malariae

All regions

Chloroquine (dosage see above)

Radical treatment of hypnozoites

P. vivax & ovale

Primaquine is contraindicated during pregnancy. It is used for eradication of hypnozoites, dormant in the liver to prevent relapses, in P. vivax and P. ovale infections. During pregnancy radical treatment of hypnozoites is not possible. Pregnant patients with P. vivax and P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The chemoprophylactic dose for chloroquine sulphate is 300 mg base (=500 mg salt) orally once per week. Radical treatment with primaquine can then be startyed a few months after delivery.

After delivery; because primaquine can cause hemolytic anemia in persons with G6PD deficiency, patients must be screened for G6PD deficiency prior to starting treatment with primaquine. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given 45mg orally one time per week for 8 weeks; consultation with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons.

ETF	Early treatment failure; one or more of the following A) Development of danger signs or severe malaria on Day 1, Day 2 or Day 3, in the presence of parasitaemia; B) Parasite count on day 2 higher than day 0 irrespective of temperature C) Axillary temperature ≥ 37.5^oC on Day 3 in the presence of parasitaemia; For areas of low to moderate transmission that there must be a measured increase in axillary temperature on day 3. D) Parasitaemia on Day 3 ≥ 25% of count on Day 0
LTF	Late treatment failure, one of the following A) Development of danger signs or severe malaria in the presence of parasitaemia on any day from Day 4 to Day 14, without previously meeting any of the criteria of early treatment failure; B) In areas of intense transmission; axillary temperature ≥ 37.5^oC in the presence of parasitaemia on any day from day 4 to day 14, without previously meeting any of the criteria of early treatment failure. In areas of low to moderate transmission; presence of parasitaemia on any day from day 4 to day 28, and a measured axillary temperature > 37.5^oC , without previously meeting any of the criteria of early treatment failure. If history of fever, rather than measured fever was accepted as an entry criterion for the study, then parasitaemia with history of fever suffices for LTF.
LPF	Late Parasitological Failure, in high transmission settings, defined as “presence of parasitaemia on day 14, and a measured axillary temperature <37.5^oC without previously meeting any of the criteria of early or late treatment failure”. In low to moderate transmission settings the definition is the same, except that parasitaemia at any time from Day 7 to Day 28 qualifies.
ACR	Adequate clinical response; one of the following during the follow-up period from day 4 to 14 A) Absence of parasitaemia on day 14 irrespective of axillary temperature, without previously meeting any of the criteria of early or late treatment failure; B) Axillary temperature < 37.5^oC irrespective of the presence of parasitaemia, without previously meeting any of the criteria of early or late treatment failure.
ACPR	Adequate clinical and parasitological response. In a high transmission setting this is defined as above (A), but in low to moderate transmission settings the assessment is made on day 28.