How to treat uncomplicated malaria

Are you treating a patient with malaria? Check out this article on the gold-standard for treating uncomplicated malaria.
Last update29th Apr 2021

Now that we have reviewed how to diagnose malaria using microscopy as well as rapid diagnostic tests and polymerase chain reaction, let’s turn our attention to treating malaria. Treatment should be delayed until a malaria diagnosis is confirmed through laboratory testing except in cases where there is a strong clinical suspicion or severe disease and prompt testing is not available.

Typically, patients diagnosed with malaria are categorized as having either uncomplicated malaria or severe malaria.

Patients diagnosed with uncomplicated malaria—usually caused by P. vivax, P. ovale, or P. knowlesi—can be effectively treated with oral anti-malarials. The treatment of uncomplicated malaria usually involves chloroquine.

How is chloroquine used to treat uncomplicated malaria?

Remember that once the Plasmodium parasite invades a red blood cell (RBC) it takes in hemoglobin by pinocytosis, and breaks it down into heme and hematin, two pigments that are actually lethal to the parasite. But the parasite has heme polymerase, which detoxifies heme and hematin, turning them into hemozoin which it uses to build essential amino acids and replicate.

Heme polymerase is the target of a family of drugs known as 8-aminoquinolones. The most common one is chloroquine. It blocks the parasite’s heme polymerase, allowing toxic heme and hematin to build up and kill the parasite.

Figure 1. Inside a red blood cell (RBC), the drug chloroquine blocks heme polymerase in a Plasmodium parasite to prevent the detoxification of heme and hematin which accumulate and kill the parasite.

How is primaquine used to treat uncomplicated malaria?

In almost all patients with P. ovale and P. vivax, a small number of parasites called hypnozoites, remain dormant inside liver cells. So in these two types, even if we treat and kill active malaria in the red blood cells with chloroquine, we may not be able to kill the hypnozoites and the patient may have a relapse.

Two cases to avoid using primaquine

  1. Primaquine can cause massive hemolysis if given to patients who have glucose-6-phosphatase dehydrogenase (G6PD) deficiency. So test for the presence of G6PD deficiency before giving primaquine, especially if treating persons of African descent.
  2. Primaquine is contraindicated in pregnancy because it has been shown to cause developmental abnormalities. In addition, if the fetus is G6PD deficient, massive hemolysis can occur, which can be fatal. Instead, treat with chloroquine first, then wait until after delivery and treat the mother and baby with primaquine.
Figure 2. Primaquine should not be used to treat malaria in persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency and in pregnant women.

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Can chloroquine be used to treat P. falciparum?

Milder cases of falciparum malaria may occur in individuals who were previously infected and have antibodies to the disease—known as uncomplicated P. falciparum malaria. We know that chloroquine can be used to treat uncomplicated forms of malaria. But some strains of P. falciparum will be resistant to chloroquine so it can only be used in some of the areas where P. falciparum is found.

For uncomplicated P. falciparum infections acquired in areas without chloroquine-resistant strains, like Central America west of the Panama Canal, Haiti, and the Dominican Republic, patients can be treated with oral chloroquine.

For uncomplicated P. falciparum infections acquired in areas with chloroquine resistance, four treatment options are available:

  1. Artemether-lumefantrine
  2. Atovaquone-proguanil
  3. Quinine sulfate + doxycycline, tetracycline, or clindamycin
  4. Mefloquine


If it’s readily available, artemether-lumefantrine is the preferred treatment. Artemether works by disrupting the mitochondrial membrane and the energy production of the mitochondrion, causing the parasite to die. Lumefantrine's precise mechanism of action is unknown, but available data suggests that it inhibits nucleic acid and protein synthesis.

Figure 3. Artemether-lumefantrine disrupts the mitochondrial membrane, inhibits nucleic acid and protein synthesis of the Plasmodium parasite.


The second option is a combination of atovaquone and proguanil. Atovaquone disrupts the mitochondria electron transport system while proguanil inhibits the synthesis of folic acid in the parasite.

Figure 4. Atovaquone-proguanil treats Plasmodium infections by disrupting mitochondrial electron transport and folic acid synthesis in the parasite.

Quinine sulfate + doxycycline, tetracycline, or clindamycin

The third option is Quinine sulfate + doxycycline, tetracycline, or clindamycin.

Quinine is one of the 8-aminoquinolones which block heme polymerase.

Doxycycline, tetracycline, and clindamycin all inhibit protein synthesis in the parasite. Doxycycline or tetracycline are preferred to clindamycin because there is more evidence to support their efficacy.

Figure 5. Quinine sulfate, a member of the 8-aminoquinolone family of drugs, blocks heme polymerase, killing the Plasmodium parasite. Doxycycline, tetracycline, and clindamycin all inhibit protein synthesis in Plasmodium. A combination of these drugs is used to treat uncomplicated falciparum malaria.


The fourth option is mefloquine. Mefloquine acts as a blood schizonticide. However, its exact mechanism of action is not known.

Figure 6. To treat Plasmodium infection, mefloquine targets red blood cell (RBC) schizonts.

That’s it for now. If you want to improve your understanding of key concepts in medicine, and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and downloads. We’ll help you make the right decisions for yourself and your patients.

Recommended reading

  • Ashley, EA, Phyo, AP, and Woodrow, CJ. 2018. Malaria. Lancet391: 1608­–1621. PMID: 29631781
  • Fairhurst, RM and Wellems, TE. 2014. “Malaria (Plasmodium Species)”. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Bennett, JE, Dolin, R, Blaser, MJ. 8th edition. Philadelphia: Elsevier Saunders. (Fairhurst and Wellems 2014, 3070–3090)
  • Phillips, MA, Burrows, JN, Manyando, C, et al. 2017. Malaria. Nat Rev Dis Primers3: 17050 PMID: 28770814
  • World Health Organization. 2015. Guidelines for treatment of malaria third edition. World Health Organization. World Health Organization
  • World Health Organization. 2019. World malaria report 2019. World Health OrganizationWorld Health Organization

About the author

John F. Fisher, MD MACP FIDSA
John is a Professor of Medicine (Infectious Diseases) at the Medical College of Georgia, Augusta University, USA.
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