Malaria Treatment & Management

Failure to consider malaria in the differential diagnosis of a febrile illness in a patient who has traveled to an area where malaria is endemic can result in significant morbidity or mortality, especially in children and in pregnant or immunocompromised patients.

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 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 infection are often 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 also have a greater tendency to develop severe malaria. Unlike malarial infection in nongravid individuals, pregnant women 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 women in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.

If a pregnant woman becomes infected, she 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 women are limited to mefloquine or quinine plus clindamycin. Although the limited availability of quinine and increasing resistance to mefloquine limit these options, strong evidence now 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 now recommends the use of artemether-lumefantrine as an additional treatment option for uncomplicated malaria in pregnant women in the United States during the second and third trimester of pregnancy at the same doses recommended for nonpregnant women. 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. ^[19]

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 that 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 can usually 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.

IV preparations of antimalarials are available for the treatment of severe complicated malaria, including artesunate and quinidine gluconate, which is used as a substitute for the IV quinine available in countries outside of the United States.

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. ^[20]

Evidence from a meta-analysis including 7429 subjects from 8 trials shows a decreased risk of death using parenteral artesunate compared to quinine for the treatment of severe malaria in adults and children. ^[21]

P falciparum drug resistance is common in endemic areas, such as Africa. Standard antimalarials, such as chloroquine and antifolates (sulfadoxine-pyrimethamine), 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 now 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. ^[22]

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. ^[23] 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. ^[24]

Despite their being a fairly new antimalarial class, resistance to artemisinins has been reported in some parts of southeast Asia (Cambodia). ^[25]

In the United States, artemether and lumefantrine tablets (Coartem) can be used to treat acute uncomplicated malaria. Artesunate IV, a form of artemisinin, is indicated for initial treatment of severe malaria in adults and children. Once the patient can tolerate oral therapy, a complete treatment course of an appropriate oral antimalarial regimen should always follow artesunate. Other combinations, such as atovaquone and proguanil HCL (Malarone) or quinine in combination with doxycycline or clindamycin, remain highly efficacious.

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 two 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. ^{[20, 26]}

Malaria vaccine production and distribution continues to be in the research and development stage. ^{[27, 28, 29]} In 2015, European Union (EU) regulators approved the world's first malaria vaccine for use outside the EU among children aged 6 weeks to 17 months. The new vaccine (Mosquirix, GlaxoSmithKline Biologicals), as of April 2019, is entering a large-scale pilot test in Malawi, followed by Kenya and Ghana. The vaccine is to be administered to 360,000 children aged 2 years or younger to evaluate efficacy and feasibility. In trials, the vaccine reduced malaria episodes by 40%. ^[30] Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver. ^[31]

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. ^[4] It has also 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. ^[5]

The following is a summary of general recommendations for the treatment of malaria:

• P falciparum malaria - Quinine-based therapy is with quinine (or quinidine) sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine; alternative therapies are artemether-lumefantrine, atovaquone-proguanil, or mefloquine

• P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the Middle East) - Chloroquine

• P vivax, P ovale malaria - Chloroquine plus primaquine; however, a 2012 study of Indonesian soldiers demonstrated that primaquine combined with newer nonchloroquine antimalarials killed dormant P vivax parasites and prevented malaria relapse; ^{[32, 33]} the combination of dihydroartemisinin-piperaquine with primaquine had 98% efficacy against relapse, suggesting that this regimen could become a useful alternative to primaquine plus chloroquine, the clinical utility of which is being threatened by worsening chloroquine resistance

• P malariae malaria - Chloroquine

• P knowlesi malaria – Recommendations same as those for P falciparum malaria.

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 (eg, chloroquine) for acute P vivax malaria. Approval was based on an international program of more than 4000 participants.

In one of the clinical trials, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 89.2% with tafenoquine 300 mg and 91.9% with tafenoquine 600 mg compared with chloroquine alone (37.5%). The results showed a significantly improved treatment difference compared with chloroquine alone of 51.7% (P< 0.0001) with tafenoquine 300 mg and 54.5% (P< 0.0001) with tafenoquine 600 mg. ^[34]

Because tafenoquine increases the risk of 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. ^[35]

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. ^[36]

In July 2013, the FDA updated its warning about mefloquine hydrochloride to include neurologic side effects, along with the already known risk of 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. ^{[37, 38]}

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. ^{[39, 40]}

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. ^[1]

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 of miscarriage. ^[2]

Use of 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. ^[35]

Patients with elevated parasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated.

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 may also 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 is no longer exposed to potential mosquito bite. Consider using bed nets that are treated with the insecticide permethrin. While 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. ^[9] 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. ^[41] Travel Medicine clinics are also a useful source of information and advice.

Investigational malaria vaccine

Malaria vaccine production and distribution continues to be in the research and development stage. ^{[27, 28, 29]} In 2015, European Union (EU) regulators approved the world's first malaria vaccine for use outside the EU among children aged 6 weeks to 17 months. The new vaccine (Mosquirix, GlaxoSmithKline Biologicals), as of April 2019, is entering a large-scale pilot test in Malawi, followed by Kenya and Ghana. The vaccine is to be administered to 360,000 children aged 2 years or younger to evaluate efficacy and feasibility. In trials, the vaccine reduced malaria episodes by 40%. ^[30] Mosquirix targets P falciparum. It limits the parasite's ability to infect, mature, and multiply in the liver. ^[31]

Interim phase 3 trial results were reported in 2011 for the malaria vaccine RTS,S/AS01. The results included 6000 African children aged 5-17 months who received the malaria vaccine or a comparator vaccine and were followed for 12 months. The incidence of malaria was 0.44 case per person-year in the RTS,S/AS01 group, compared with 0.83 case per person-year in the comparator vaccine group. The vaccine efficacy rate was calculated to be 55.8%. ^{[42, 43]}

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. ^[44]

Pregnant patients with malaria are at increased risk of morbidity and mortality. ^[45] In addition, nonimmune mothers and immune primigravidas may be at an increased risk of 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 woman.