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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Serge Korjian, Yazan Daaboul

Overview

Active malaria infection with P. falciparum is a medical emergency requiring hospitalization. Infection with P. vivax, P. ovale or P. malariae can often be treated on an outpatient basis. Treatment of malaria involves supportive measures as well as specific antimalarial drugs. When properly treated, someone with malaria can expect a complete cure.

Medical Therapy

The treatment approach in patients with suspected or confirmed malaria varies according to several factors namely travel history, species of Plasmodium, severity of presentation, and availability of certain therapeutic agents.

Initial Assessment & Severe Malaria

The first step in the management of patients with malaria is to conduct a clinical assessment of status and disease severity, as well as determination of the degree of parasitemia. Signs of severe malarial disease include any of the following: Prostration, impaired consciousness/coma, respiratory distress, convulsions, shock, pulmonary edema, acute respiratory distress syndrome (ARDS), jaundice, abnormal bleeding, severe anemia, hemolysis, hemoglobinuria, acute kidney injury, metabolic acidosis, disseminated intravascular coagulopathy, parasitemia >5%. Patients with severe disease require rapid resuscitation and medical therapy. The most vital step in the management is immediate initiation of appropriate parenteral treatment. Unlike patients who appear stable clinically, patients with severe malaria do not require speciation prior to initiation of medical therapy.

The therapeutic regimen in patients with severe malaria consists of intravenous quinidine gluconate plus either tetracycline, doxycycline, or clindamycin. Other supportive measures include admission to the intensive care unit, continuous monitoring of cardiac function, glycemia, parasitemia, hemoglobin and electrolytes. Exchange transfusions may also be considered in patients with a degree of parasitemia >10%.

Uncomplicated Malaria

In patients with clinically and bacteriologically uncomplicated malaria, speciation is required to tailor medical therapy. For most non-falciparum species, chloroquine remains the first line therapeutic agent. It is important to add primaquine to the treatment regimen in patients with documented P. vivax and P. ovale infections to eradicate liver hypnozoites (dormant liver spores that are responsible for recurrence). Care should be taken in patients with G6PD deficiency as large doses of primaquine can cause significant hemolysis. Patients infected with P. malaria do not require primaquine as the species is not capable of forming hypnozoites. Patients diagnosed with P. falciparum malaria require hospitalization given the risk of progression to severe malaria. These patients have to be monitored on daily basis with a blood film and a full physical exam. The choice of drug in these patients depends on two main factors: the area of acquisition of the parasite, and the center at which the patient is being treated.

Despite being the mainstay of therapy since its introduction, empiric treatment with chloroquine in patients with P. falciparum is no longer recommended due to a sharp increase in resistance. A detailed travel history is important to determine where the infection was acquired. Most malaria endemic countries have reported chloroquine resistant strains, with the exception of Central America west of Panama Canal, Mexico, Hispaniola, certain parts of China, and the Middle East (see figure below). If acquired in any of the latter sites then treatment with chloroquine is adequate. Acquisition from all other endemic countries requires other therapeutic regimens such as oral quinine with either tetracycline, doxycycline, or clindamycin as a first line therapy in the United States, otherwise atovaquone-proguanil or mefloquine if the primary regimen is unavailable.

Worldwide, the treatment of both complicated and uncomplicated P. falciparum malaria requires a combination therapy that includes artemisinin derivatives. According to the 2010 WHO guidelines on the treatment of malaria, the following regimens are first line for the treatment of uncomplicated P. falciparum: artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, and artesunate plus sulfadoxine-pyrimethamin. It is important to note that artemisin monotherapy in not recommended due to increasing resistance. For patients with severe P. falciparum malaria, artesunate IV or IM is first line followed by IV quinidine. The artemisinin derivatives clear parasites very rapidly have been shown to reduce mortality in severe malaria compared with parenteral quinine. Artemisins are not widely available in the United States and their use is not common practice. Only oral artemether plus lumefantrine is available, while IV atresunate can be obtained through the CDC part of an investigational drug protocol.

Antimicrobial Regimen

• 1. Plasmodium falciparum

• 1.1 Treatment of uncomplicated P. falciparum malaria

• 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)

• Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days.

• Note: The first two doses should, ideally, be given 8 h apart.
• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
• Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
• Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
• Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days

• Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days

• Note: A total therapeutic dose range of 6–30 mg/kg/day artesunate and 22.5–45 mg/kg/day per dose amodiaquine is recommended.
• Dosage regimen based on Body weight (kg)
• Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
• Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
• Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days

• Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 9- Artesunate 25 mg PO qd AND Mefloquine 55 mg PO qd for 3 days
• Body weight (kg)-9to < 18- Artesunate 50 mg PO qd AND Mefloquine 110 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Mefloquine 220 mg PO qd for 3 days
• Body weight (kg)- ≥ 36 - Artesunate 200 mg PO qd AND Mefloquine 440 mg PO qd for 3 days

• Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 10- Artesunate 25 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 250/12 mg PO given as a single dose on day 1
• Body weight (kg)-10 to < 25- Artesunate 50 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 500/25 mg PO given as a single dose on day 1
• Body weight (kg)-25 to < 50- Artesunate 100 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1000/50 mg PO given as a single dose on day 1
• Body weight (kg)- ≥50- Artesunate 200 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1500/75 mg PO given as a single dose on day 1

• Preferred regimen (5): Dihydroartemisinin 2–10 mg/kg/day PO qd AND Piperaquine16–27 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 8- Dihydroartemisinin 20 mg PO qd AND Piperaquine 160 mg PO qd for 3 days
• Body weight (kg)-8 to < 11- Dihydroartemisinin 30 mg PO qd AND Piperaquine 240 mg PO qd for 3 days
• Body weight (kg)-11 to < 17 - Dihydroartemisinin 40 mg PO qd AND Piperaquine 320 mg PO qd for 3 days
• Body weight (kg)-17 to < 25- Dihydroartemisinin 60 mg PO qd AND Piperaquine 480 mg PO qd for 3 days
• Body weight (kg)-25 to < 36- Dihydroartemisinin 80 mg PO qd AND Piperaquine 640 mg PO qd for 3 days
• Body weight (kg)-36 to < 60- Dihydroartemisinin 120 mg PO qd AND Piperaquine 960 mg PO qd for 3 days
• Body weight (kg)-60 < 80 - Dihydroartemisinin 160 mg PO qd AND Piperaquine 1280 mg PO qd for 3 days
• Body weight (kg)- >80- Dose of Dihydroartemisinin 200 mg PO qd AND Piperaquine 1600 mg PO qd for 3 days

• 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Preferred regimen: Single dose of 0.25 mg/kg Primaquine with ACT

• 1.2 Recurrent Falciparum Malaria

• 1.2.1 Failure within 28 days

• Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.

• 1.2.2 Failure after 28 days

• Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.

• 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Note: Single dose of 0.25 mg/kg bw Primaquine with ACT

• 1.4 Treating uncomplicated P. falciparum malaria in special risk groups

• 1.4.1 Pregnancy

• First trimester of pregnancy : Quinine AND Clindamycin 10mg/kg/day PO bid for 7 days
• Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
• Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
• Note (2): Primaquine and tetracyclines should not be used in pregnancy.

• 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
• 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving efavirenz or zidovudine.
• 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
• 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
• 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
• 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.

• 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi

• 2.1 Blood Stage infection

• 2.1.1. Uncomplicated malaria caused by P. vivax

• 2.1.1.1 In areas with chloroquine-sensitive P. vivax

• Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day.

• 2.1.1.2 In areas with chloroquine-resistant P. vivax

• Note: ACTs containing Piperaquine, Mefloquine OR Lumefantrine are the recommended treatment, although Artesunate + Amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, Dihydroartemisinin + Piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (Artemether + Lumefantrine, Artesunate + Amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.

• 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria

• Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.

• 2.1.3 Mixed malaria infections

• Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

• 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale

• Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]

• 2.2.1 Primaquine for preventive relapse

• Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days

• 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency

• Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks.
• Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.

• 2.2.3 Prevention of relapse in pregnant or lacating women and infants

• Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient).

• 3. Treatment of severe malaria

• 3.1 Treatment of severe falciparum infection with Artesunate

• 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-

• Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).

• 3.1.2 Young children weighing < 20 kg

• Preferred regimen:Artesunate 3 mg/kg per dose IV/IM q24h
• Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria

• 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)

• 3.2.1 Adults and children

• Preferred regimen: Artesunate IM q24h
• Alternative regimen: Artemether IM OR Quinine IM

• 3.2.2 Children < 6 years

• Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
• Note: Do not use rectal artesunate in older children and adults.

• 3.3 Pregancy

• Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.

• 3.4 Treatment of severe P. Vivax infection

• Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.

• 3.5 Additional aspects of management in severe malaria

• Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
• Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
• Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.

Anti-malarial Agents

Recommended Indications and Doses of Common Anti-malarial Agents

Anti-malarial Agent	Indication	Dosing
Chloroquine phosphate	P. falciparum from chloroquine-sensitive areas P. vivax from chloroquine-sensitive areas All P. ovale All P. malariae	1g oral load, followed by 500 mg orally at 6, 24, and 48 h
Hydroxychloroquine	Same as chloroquine (second line agent)	800 mg oral load, followed by 400 mg orally at 6, 24, and 48 h
Atovaquone-Proguanil	P. falciparum from chloroquine-resistant areas	250 mg atovaquone/100 mg proguanil (1 tab) orally 4 times daily for 3 days
Primaquine phosphate	Cure of P. vivax and P. ovale (to eliminate hypnozoites)	30 mg orally once daily for 14 days
Clindamycin*	P. falciparum or P. vivax from chloroquine-resistant areas	20 mg/kg/day orally for 3 days or 10 mg/kg IV load, followed by 5 mg/kg IV every 8 hours
Doxycycline*	P. falciparum or P. vivax from chloroquine-resistant areas	100 mg orally twice daily for 7 days or 100 mg IV every 12 hours for 7 days (can switch from IV to PO)
Tertacycline*	P. falciparum or P. vivax from chloroquine-resistant areas	250 mg orally 4 times daily for 7 days or 250 mg IV 4 times daily for 7 days (can switch from IV to PO)
Mefloquine	P. falciparum or P. vivax from chloroquine-resistant areas except Thailand-Burmese and Thailand-Cambodian border regions	750 mg oral load, followed by 500 mg orally 6-12 hours after initial dose
Quinine sulfate	P. falciparum or P. vivax from chloroquine-resistant areas	650 mg orally 3 times daily for 3 days or 7 days if acquired from Southeast Asia
Quinidine gluconate	Severe malaria (all species Unable to tolerate oral agents Parasitemia>10%	10 mg/kg IV load over 1-2 hours, then 0.02 mg/kg/min continuous infusion for at least 24 hours
Artemether-lumefantrine	All P. falciparum (outside USA)	1.5 mg/kg - 9 mg/kg orally twice daily for 3 days
Dihydroartemisinin–piperaquine	All P. falciparum (outside USA)	2·5 mg/kg – 20 mg/kg orally once daily for 3 days
Artesunate	All P. falciparum (outside USA) First line IV agent for severe malaria (outside USA)	In severe malaria: 2.4 mg/kg IV or IM load, followed by 2.4 mg/kg at 12 h and 24 h; continue injection once daily if necessary In uncomplicated malaria: Monotherapy not recommended, 4mg/kg orally once daily for 3 days combined with a single oral dose of sulfadoxine–pyrimethamine 25/1.25 mg/kg or mefloquine 8 mg/kg orally daily for 3 days

^{*Used in combination with quinine or quinidine}

Antimicrobial Regimen

• 1. Plasmodium falciparum

• 1.1 Treatment of uncomplicated P. falciparum malaria

• 1.1.1 Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACT (artemisinin-based combination therapy)

• Preferred regimen (1): Artemether 5–24 mg/kg/day PO bid AND Lumefantrine 29–144 mg/kg/day PO bid for 3 days.

• Note: The first two doses should, ideally, be given 8 h apart.
• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 15- Artemether 20 mg PO bid AND Lumefantrine 120 mg PO bid for 3 days
• Body weight (kg)-15 to < 25- Artemether 40 mg PO bid AND Lumefantrine 240 mg PO bid for 3 days
• Body weight (kg)-25 to < 35- Artemether 60 mg PO bid AND Lumefantrine 360 mg PO bid for 3 days
• Body weight (kg) ≥ 35- Artemether 80 mg PO bid AND Lumefantrine 480 mg PO bid for 3 days

• Preferred regimen (2): Artesunate 2–10 mg/kg/day PO qd AND Amodiaquine 7.5–15 mg/kg/day PO qd for 3 days

• Note: A total therapeutic dose range of 6–30 mg/kg/day artesunate and 22.5–45 mg/kg/day per dose amodiaquine is recommended.
• Dosage regimen based on Body weight (kg)
• Body weight (kg)-4.5 to < 9- Artesunate 25 mg PO qd AND Amodiaquine 67.5 mg PO qd for 3 days
• Body weight (kg)-9 to < 18 - Artesunate 50 mg PO qd AND Amodiaquine 135 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Amodiaquine 270 mg PO qd for 3 days
• Body weight (kg) ≥ 36 - Artesunate 200 mg PO qd AND Amodiaquine 540 mg PO qd for 3 days

• Preferred regimen (3): Artesunate 2–10 mg/kg/day PO qd AND Mefloquine 2–10 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 9- Artesunate 25 mg PO qd AND Mefloquine 55 mg PO qd for 3 days
• Body weight (kg)-9to < 18- Artesunate 50 mg PO qd AND Mefloquine 110 mg PO qd for 3 days
• Body weight (kg)-18 to < 36- Artesunate 100 mg PO qd AND Mefloquine 220 mg PO qd for 3 days
• Body weight (kg)- ≥ 36 - Artesunate 200 mg PO qd AND Mefloquine 440 mg PO qd for 3 days

• Preferred regimen (4): Artesunate 2–10 mg/kg/day PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1.25 (25–70 / 1.25–3.5) mg/kg/day PO given as a single dose on day 1

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 10- Artesunate 25 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 250/12 mg PO given as a single dose on day 1
• Body weight (kg)-10 to < 25- Artesunate 50 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 500/25 mg PO given as a single dose on day 1
• Body weight (kg)-25 to < 50- Artesunate 100 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1000/50 mg PO given as a single dose on day 1
• Body weight (kg)- ≥50- Artesunate 200 mg PO qd for 3 days AND Sulfadoxine-Pyrimethamine 1500/75 mg PO given as a single dose on day 1

• Preferred regimen (5): Dihydroartemisinin 2–10 mg/kg/day PO qd AND Piperaquine16–27 mg/kg/day PO qd for 3 days

• Dosage regimen based on Body weight (kg)
• Body weight (kg)-5 to < 8- Dihydroartemisinin 20 mg PO qd AND Piperaquine 160 mg PO qd for 3 days
• Body weight (kg)-8 to < 11- Dihydroartemisinin 30 mg PO qd AND Piperaquine 240 mg PO qd for 3 days
• Body weight (kg)-11 to < 17 - Dihydroartemisinin 40 mg PO qd AND Piperaquine 320 mg PO qd for 3 days
• Body weight (kg)-17 to < 25- Dihydroartemisinin 60 mg PO qd AND Piperaquine 480 mg PO qd for 3 days
• Body weight (kg)-25 to < 36- Dihydroartemisinin 80 mg PO qd AND Piperaquine 640 mg PO qd for 3 days
• Body weight (kg)-36 to < 60- Dihydroartemisinin 120 mg PO qd AND Piperaquine 960 mg PO qd for 3 days
• Body weight (kg)-60 < 80 - Dihydroartemisinin 160 mg PO qd AND Piperaquine 1280 mg PO qd for 3 days
• Body weight (kg)- >80- Dose of Dihydroartemisinin 200 mg PO qd AND Piperaquine 1600 mg PO qd for 3 days

• 1.1.2 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Preferred regimen: Single dose of 0.25 mg/kg Primaquine with ACT

• 1.2 Recurrent Falciparum Malaria

• 1.2.1 Failure within 28 days

• Note:The recommended second-line treatment is an alternative ACT known to be effective in the region. Adherence to 7-day treatment regimens (with artesunate or quinine both of which should be co-administered with + tetracycline, or doxycycline or clindamycin) is likely to be poor if treatment is not directly observed; these regimens are no longer generally recommended.

• 1.2.2 Failure after 28 days

• Note: all presumed treatment failures after 4 weeks of initial treatment should, from an operational standpoint, be considered new infections and be treated with the first-line ACT. However, reuse of mefloquine within 60 days of first treatment is associated with an increased risk for neuropsychiatric reactions, and an alternative ACT should be used.

• 1.3 Reducing the transmissibility of treated P. falciparum infections In low-transmission areas in patients with P. falciparum malaria (except pregnant women, infants aged < 6 months and women breastfeeding infants aged < 6 months)

• Note: Single dose of 0.25 mg/kg bw Primaquine with ACT

• 1.4 Treating uncomplicated P. falciparum malaria in special risk groups

• 1.4.1 Pregnancy

• First trimester of pregnancy : Quinine AND Clindamycin 10mg/kg/day PO bid for 7 days
• Second and third trimesters : Mefloquine is considered safe for the treatment of malaria during the second and third trimesters; however, it should be given only in combination with an artemisinin derivative.
• Note (1): Quinine is associated with an increased risk for hypoglycaemia in late pregnancy, and it should be used (with clindamycin) only if effective alternatives are not available.
• Note (2): Primaquine and tetracyclines should not be used in pregnancy.

• 1.4.2 Infants less than 5kg body weight : with an ACT at the same mg/kg bw target dose as for children weighing 5 kg.
• 1.4.3 Patients co-infected with HIV: should avoid Artesunate + SP if they are also receiving Co-trimoxazole, and avoid Artesunate AND Amodiaquine if they are also receiving efavirenz or zidovudine.
• 1.4.4 Large and Obese adults: For obese patients, less drug is often distributed to fat than to other tissues; therefore, they should be dosed on the basis of an estimate of lean body weight, ideal body weight. Patients who are heavy but not obese require the same mg/kg bw doses as lighter patients.
• 1.4.5 Patients co-infected with TB: Rifamycins, in particular rifampicin, are potent CYP3A4 inducers with weak antimalarial activity. Concomitant administration of rifampicin during quinine treatment of adults with malaria was associated with a significant decrease in exposure to quinine and a five-fold higher recrudescence rate
• 1.4.6 Non-immune travellers : Treat travellers with uncomplicated P. falciparum malaria returning to nonendemic settings with an ACT.
• 1.4.7 Uncomplicated hyperparasitaemia: People with P. falciparum hyperparasitaemia are at increased risk of treatment failure, severe malaria and death so should be closely monitored, in addition to receiving an ACT.

• 2. Treatment of uncomplicated malaria caused by P. vivax, P. ovale, P. malariae or P. knowlesi

• 2.1 Blood Stage infection

• 2.1.1. Uncomplicated malaria caused by P. vivax

• 2.1.1.1 In areas with chloroquine-sensitive P. vivax

• Preferred regimen: Chloroquine total dose of 25 mg/kg PO. Chloroquine is given at an initial dose of 10 mg/kg, followed by 10 mg/kg on the second day and 5 mg/kg on the third day.

• 2.1.1.2 In areas with chloroquine-resistant P. vivax

• Note: ACTs containing Piperaquine, Mefloquine OR Lumefantrine are the recommended treatment, although Artesunate + Amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, Dihydroartemisinin + Piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (Artemether + Lumefantrine, Artesunate + Amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up.

• 2.1.2 Uncomplicated malaria caused by P. ovale, P. malariae or P. knowlesi malaria

• Note: Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or Chloroquine, as for vivax malaria.

• 2.1.3 Mixed malaria infections

• Note: ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

• 2.2 Liver stages (hypnozoites) of P. vivax and P. ovale

• Note: To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged < 6 months, women breastfeeding infants < 6 months, women breastfeeding older infants unless they are known not to be G6PD deficient and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings. Strong recommendation, high-quality evidence In people with G6PD deficiency, consider preventing relapse by giving primaquine base at 0.75 mg base/kg bw once a week for 8 weeks, with close medical supervision for potential primaquine-induced adverse haematological effects.]

• 2.2.1 Primaquine for preventive relapse

• Preferred regimen: Primaquine 0.25–0.5 mg/kg/day PO qd for 14 days

• 2.2.2 Primaquine and glucose-6-phosphate dehydrogenase deficiency

• Preferred regimen: Primaquine 0.75 mg base/kg/day PO once a week for 8 weeks.
• Note: The decision to give or withhold Primaquine should depend on the possibility of giving the treatment under close medical supervision, with ready access to health facilities with blood transfusion services.

• 2.2.3 Prevention of relapse in pregnant or lacating women and infants

• Note: Primaquine is contraindicated in pregnant women, infants < 6 months of age and in lactating women (unless the infant is known not to be G6PD deficient).

• 3. Treatment of severe malaria

• 3.1 Treatment of severe falciparum infection with Artesunate

• 3.1.1 Adults and children with severe malaria (including infants, pregnant women in all trimesters and lactating women):-

• Preferred regimen: Artesunate IV/IM for at least 24 h and until they can tolerate oral medication. Once a patient has received at least 24 h of parenteral therapy and can tolerate oral therapy, complete treatment with 3 days of an ACT (add single dose Primaquine in areas of low transmission).

• 3.1.2 Young children weighing < 20 kg

• Preferred regimen:Artesunate 3 mg/kg per dose IV/IM q24h
• Alternatives regimen: use Artemether in preference to quinine for treating children and adults with severe malaria

• 3.2.Treating cases of suspected severe malaria pending transfer to a higher-level facility (pre-referral treatment)

• 3.2.1 Adults and children

• Preferred regimen: Artesunate IM q24h
• Alternative regimen: Artemether IM OR Quinine IM

• 3.2.2 Children < 6 years

• Preferred regimen: Where intramuscular injections of artesunate are not available, treat with a single rectal dose (10 mg/kg) of Artesunate, and refer immediately to an appropriate facility for further care.
• Note: Do not use rectal artesunate in older children and adults.

• 3.3 Pregancy

• Note: Parenteral artesunate is the treatment of choice in all trimesters. Treatment must not be delayed.

• 3.4 Treatment of severe P. Vivax infection

• Note: parenteral artesunate, treatment can be completed with a full treatment course of oral ACT or chloroquine (in countries where chloroquine is the treatment of choice). A full course of radical treatment with primaquine should be given after recovery.

• 3.5 Additional aspects of management in severe malaria

• Fluid therapy: It is not possible to give general recommendations on fluid replacement; each patient must be assessed individually and fluid resuscitation based on the estimated deficit.
• Blood Transfusion :In high-transmission settings, blood transfusion is generally recommended for children with a haemoglobin level of < 5 g/100 mL(haematocrit < 15%). In low-transmission settings, a threshold of 20% (haemoglobin,7 g/100 mL) is recommended.
• Exchange blood transfusion: Exchange blood transfusion requires intensive nursing care and a relatively large volume of blood, and it carries significant risks. There is no consensus on the indications, benefits and dangers involved or on practical details such as the volume of blood that should be exchanged. It is, therefore, not possible to make any recommendation regarding the use of exchange blood transfusion.