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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}

mx 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.