Malaria Treatment & Management

The treatment of malaria is predicated on the severity of the patient’s illness, the infecting species, geographic knowledge of anti-malarial drug resistance, and knowledge of prior antimalarials given to the patient (it is not recommended to use the same prophylactic medication for treatment).

CDC Criteria for Severe Malaria (1 or more of the following):

• Impaired consciousness/coma
• Severe anemia (hemoglobin < 7 g/dL)
• Acute kidney injury
• Acute respiratory distress syndrome
• Circulatory collapse/shock
• Disseminated intravascular coagulation
• Acidosis
• Jaundice (along with at least one other sign of severe malaria)
• Percent parasitemia of ≥5%

Mixed infections involving more than 1 species of Plasmodium may occur in areas of high endemicity and multiple circulating malarial species. In these cases, clinical differentiation and decision making will be important; however, the clinician should have a low threshold for including the possible presence of P falciparum in the treatment considerations.

Occasionally, morphologic features do not permit distinction between P falciparum and other Plasmodium species. In such cases, patients from a P falciparum –endemic area should be presumed to have P falciparum infection and should be treated accordingly.

In patients from Southeast Asia, consider the possibility of P knowlesi infection. This species frequently causes hyperparasitemia and the infection tends to be more severe than infections with other non– P falciparum plasmodia. It should be treated as P falciparum infection.

P falciparum is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America, and parts of the Middle East. Resistance is rare in P vivax infection, and P ovale and P malariae remain sensitive to chloroquine. Primaquine or tafenoquine is required in the treatment of P ovale and P vivax infection in order to eliminate the hypnozoites (liver phase).

In the United States, patients with P falciparum infections often are treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment.

Pregnancy

Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria have a greater tendency to develop severe malaria. Unlike malarial infection in nongravid individuals, pregnant individuals with P vivax are at high risk for severe malaria, and those with P falciparum have a greatly increased predisposition for severe malaria as well.

For these reasons, it is especially important that nonimmune pregnant persons in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.

If a pregnant individual becomes infected, they should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for the mother and the fetus. Therefore, the medications should be used, since the benefits of these drugs greatly outweigh the risks associated with leaving the infection untreated.

In the United States, treatment options for uncomplicated chloroquine-resistant P falciparum and P vivax malaria in pregnant individuals are limited to mefloquine or quinine plus clindamycin. Although the limited availability of quinine and increasing resistance to mefloquine limit these options, strong evidence demonstrates that artemether-lumefantrine (Coartem) is effective and safe in the treatment of malaria in pregnancy. These data are supported by the World Health Organization.

The CDC recommends the use of artemether/lumefantrine as an additional treatment option for uncomplicated malaria in pregnant patients in the United States during the second and third trimester of pregnancy at the same doses recommended for nonpregnant patients. During the first trimester of pregnancy, mefloquine or quinine plus clindamycin should be used as treatment; however, when neither of these options is available, artemether-lumefantrine should be considered. ^[45]

Pediatrics

In children, malaria has a shorter course, often rapidly progressing to severe malaria. Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.

Cerebral malaria results in neurologic sequelae in 9-26% of children, but of these sequelae, approximately one half completely resolve with time.

Most antimalarial drugs are very effective and safe in children, provided the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults.

Diet and activity

Patients with malaria should continue intake and activity as tolerated.

Monitoring

Patients with non– P falciparum malaria who are well usually can be treated on an outpatient basis. Obtain blood smears every day to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health.

​Treatment options for uncomplicated malaria not meeting severe criteria  (see CDC malaria treatment guideline for dosing specifics) ^[14]  

P falciparum or Species Not Identified from area with chloroquine resistance

• Artemether/lumefantrine
• Atovaquone/proguanil
• Quinine (extended duration if infection acquired in SE Asia) + doxycycline (doxycycline is preferred, but tetracycline or clindamycin also are options)
• Mefloquine (not recommended in certain regions of SE Asia due to resistance)

P falciparum from area without chloroquine resistance or other Species Not Identified (P vivax, ovale, malariae, knowlesi)

• Chloroquine
• Hydroxychloroquine
• Any regimen listed for chloroquine-resistant P falciparum malaria

*P vivax chloroquine resistance has been noted with high prevalence in Papua New Guinea and Indonesia, and cases arising from these areas should not be treated with chloroquine.

• Otherwise, P vivax initially may be treated with chloroquine with potential transition to a regimen reserved for chloroquine resistance, as rare cases of chloroquine resistance also have been found in Burma, India, and South America.

P vivax & P ovale hypnozoite eradication (must test for G6PD Deficiency)

• Primaquine daily for 14 days (can start with treatment of acute infection)
• Tafenoquine single dose only in patients >16 years who received chloroquine for treatment of acute infection                                                 

Treatment recommendations for tafenoquine:

In July 2018, the FDA approved tafenoquine, an antiplasmodial 8-aminoquinoline derivative indicated for the radical cure (prevention of relapse) of P vivax malaria in patients aged 16 years or older who are receiving appropriate antimalarial therapy for acute P vivax infection. The drug is active against all stages of the P vivax life cycle. Tafenoquine is administered as a single oral dose on the first or second day of appropriate antimalarial therapy (chloroquine) for acute P vivax malaria. Because tafenoquine increases the risk for hemolytic anemia in patients with G6PD deficiency, patients must be tested before initiating the drug. Tafenoquine is contraindicated in patients with G6PD deficiency (or unknown status), in patients who are breastfeeding an infant with G6PD deficiency (or unknown status), and in those with known hypersensitivity. ^[46]  In August 2018, tafenoquine gained a second indication for adults aged 18 years or older as prophylaxis when traveling to malarious areas. For this indication, the 100-mg tablet (Arakoda) is administered as a loading dose (before traveling to endemic area), a maintenance dose while in malarious area, and then a terminal prophylaxis dose in the week exiting the area. ^[47]

The recommendation to use tafenoquine for radical cure only in combination with chloroquine was made in 2020 following the unpublished results of a randomised trial of tafenoquine versus low-dose primaquine versus placebo in Indonesian soldiers returning from Papua (artemesinin combination therapy is the recommended blood stage therapy in Indonesia). The rationale for only using tafenoquine with chloroquine may be explained by either suboptimal dosing in the randomized trials or synergy of the 8-aminoquinolones with chloroquine. ^[48]

If G6PD testing indicates deficiency, moderate deficiency can be treated with a prolonged course of reduce-dosed primaquine with close monitoring for hemolysis. If G6PD deficiency is severe, chloroquine prophylaxis may be used for a 1 year duration after acute infection given that most reactivations occur in this period. ^[13]

Treatment options for severe/ complicated malaria (see CDC malaria treatment guideline for dosing specifics)

IV artesunate:

Obtain via ivartesunate.com as the CDC no longer provides this medication.

The preferred interim therapy is artemether/lumefantrine (secondary options are atovaquone/proguanil, quinine, and mefloquine).

A dose of of artesunate should be given at 0, 12, and 24 hours.

After the initial course of IV artesunate, the patient can transition to a full course of oral artemether/lumefantrine if parasitemia is reduced to < 1% and the patient tolerates oral therapy.

• If artemether/lumefantrine is unavailable, less preferred options are atovaquone/proguanil, quinine + doxycycline (or clindamycin), or mefloquine (last resort)
• If the patient cannot tolerate oral therapy at the end of the IV artesunate course, the patient can continue receiving artesunate for a duration not to exceed a total of 7 days
• Post-artemesinin hemolytic anemia is a rare adverse effect and is seen to a greater degree in patients with higher initial parasitemia. All patients who receive IV artesunate should be monitored weekly for up to 4 weeks after treatment for evidence of hemolytic anemia. 

In a 2010 randomized study done in 11 African centers, children (age < 15 years) with severe P falciparum malaria had reduced mortality after treatment with IV artesunate, as compared with IV quinine. Development of coma, seizures, and posttreatment hypoglycemia were each less common in patients treated with artesunate. ^[49]

Evidence from a meta-analysis including 7429 subjects from 8 trials shows a decreased risk for death using parenteral artesunate compared with quinine for the treatment of severe malaria in adults and children. ^[50]

P falciparum drug resistance is common in endemic areas, such as Africa. Standard antimalarials, such as chloroquine and antifolates (pyrimethamine/sulfadoxine), are ineffective in many areas. Because of this increasing prevalence of drug resistance and a high likelihood of resistance development to new agents, combination therapy is becoming the standard of care for treatment of P falciparum infection worldwide. In April 2009, the US Food and Drug Administration (FDA) approved the use of artemisinins, a new class of antimalarial agent. ^[51]

Despite the activity of artemisinin and its derivatives, monotherapy with these agents has been associated with high rates of relapse. This may be due to the temporary arrest of the growth of ring-stage parasites (dormancy) after exposure to artemisinin drugs. For this reason, monotherapy with artemisinin drugs is not recommended. ^[52] Rectal artesunate has been used for pretreatment of children in resource-limited settings as a bridge therapy until the patient can access health care facilities for definitive IV or oral therapy. ^[53]

Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia). ^[54]

Artesunate IV was officially approved by the FDA in May 2020 (it was previously available from the CDC through an IND protocol). Approval was based the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine Artesunate Malaria Trial (AQUAMAT). These 2 studies examined a total of 6,886 patients, including adults, children, and pregnant women. Artesunate IV reduced mortality by 34.7% (P = 0.0002) and 22.5% (P = 0.002) compared with quinine in the SEAQUMAT and AQUAMAT studies, respectively. ^{[49, 55]}

When making treatment decisions, it is essential to consider the possibility of coinfection with more than 1 species. Reports of P knowlesi infection suggest that coinfection is common. ^[56] It also has been demonstrated that up to 39% of patients infected with this species may develop severe malaria. In cases of severe P knowlesi malaria, IV therapy with quinine or artesunate is recommended. ^[57]

A note on mefloquine

In July 2013, the FDA updated its warning about mefloquine hydrochloride to include neurologic side effects, along with the already known risk for adverse psychiatric events such as anxiety, confusion, paranoia, and depression. The information, which is included in the patient medication guide and in a new boxed warning on the label, cautions that vestibular symptoms, which include dizziness, loss of balance, vertigo, and tinnitus, can occur. ^{[58, 59]}  The FDA also warns that vestibular side effects can persist long after treatment has ended and may become permanent. In addition, clinicians are warned against prophylactic mefloquine use in patients with major psychiatric disorders and are further cautioned that if psychiatric or neurologic symptoms arise while the drug is being used prophylactically, it should be replaced with another medication.

Pharmacologic treatment in pregnancy

Medications that can be used for the treatment of malaria in pregnancy include chloroquine, quinine, atovaquone-proguanil, clindamycin, mefloquine, sulfadoxine-pyrimethamine (avoid in first trimester) and the artemisinins (see below). Briand et al compared the efficacy and safety of sulfadoxine-pyrimethamine to mefloquine for intermittent preventive treatment during pregnancy. In their study, 1601 women of all gravidities received either sulfadoxine-pyrimethamine (1500 mg of sulfadoxine and 75 mg of pyrimethamine) or mefloquine (15 mg/kg) in a single dose twice during pregnancy. There was a small advantage for mefloquine in terms of efficacy, although the incidence of side effects was higher with mefloquine than with sulfadoxine-pyrimethamine. ^{[60, 61]}  

In addition to mefloquine and sulfadoxine/pyrimethamine, other medications have been used in the treatment of the pregnant patient with malaria. In a recent study in African patients, artemether/lumefantrine was as efficacious and as well tolerated as oral quinine in treating uncomplicated falciparum malaria during the second and third trimesters of pregnancy. ^[62]  Artesunate and other antimalarials also appear to be effective and safe in the first trimester of pregnancy, when development of malaria carries a high risk for miscarriage. ^[63]  Use of primaquine or tafenoquine to prevent relapse of P vivax malaria during pregnancy is not recommended. Use during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. In addition, tafenoquine use during lactation should be avoided if the infant is G6PD deficient or of unknown G6PD status. ^[46]

Patients meeting criteria for severe malaria or with P falciparum infection initially should be hospitalized until their condition improves and there is a noticeable decline in parasitemia.

Obtain blood smears every day to demonstrate a response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants also may prevent infection. Avoid wearing perfumes and colognes.

Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when the skin no longer is exposed to potential mosquito bites. Consider using bed nets that are treated with the insecticide permethrin. Although this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyrethroid resistance in Anopheles spp has been reported. ^[34] Seek out medical attention immediately upon contracting any tropical fever or flulike illness.

Consider chemoprophylaxis with antimalarials in patients traveling to endemic areas. Chemoprophylaxis is available in many different forms. The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.

Before traveling, people should consult their physician and the Malaria and Traveler's Web site of the CDC to determine the most appropriate chemoprophylaxis. ^[64] Travel Medicine clinics are a useful source of information and advice.

Malaria Vaccine

On 6 October 2021, the WHO recommended large-scale use of the RTS,S/AS01 (Mosquirix) malaria vaccine. ^{[1, 65]}  It is approved for children in sub-Saharan Africa and other areas with high malaria transmission based on trials involving 830,000 children in Ghana, Kenya, and Malawi. It is a recombinant protein vaccine based on an antigen found on the P falciparum sporozoite. After 30 years of research and development between GlaxoSmithKline and the US Walter Reed Army Institute of Research, its use has resulted in a 9% decrease in all-cause mortality and 30% reduction in hospital admissions of children with severe malaria. If optimal access to the vaccine can be achieved, it is estimated to be able to save the lives of 40,000 to 80,000 African children per year. 

Consider consulting an infectious disease specialist for assistance with malaria diagnosis, treatment, and disease management. The CDC is an excellent resource if no local resources are available. To obtain the latest recommendations for malaria prophylaxis and treatment from the CDC, call the CDC Malaria Hotline at (770) 488-7788 or (855) 856-4713 (M-F, 9 am-5 pm, Eastern time). For emergency consultation after hours, call (770) 488-7100 and ask to talk with a CDC Malaria Branch clinician. ^[66]

Pregnant patients with malaria are at increased risk for morbidity and mortality. ^[40] In addition, nonimmune mothers and immune primigravidas may be at an increased risk for low birth weight, fetal loss, and prematurity. Consult an expert in malaria to determine the safest and most effective prophylaxis or treatment in a pregnant individual.