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.

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 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.^[13]

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.^[14]

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.^[15] 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.^[16]

In the United States, artemether and lumefantrine tablets (Coartem) can be used to treat acute uncomplicated malaria. Artesunate, a form of artemisinin that can be used intravenously, is available from the Centers for Disease Control and Prevention (CDC). Other combinations, such as atovaquone and proguanil HCL (Malarone) or quinine in combination with doxycycline or clindamycin, remain highly efficacious. Malaria vaccine production and distribution continues to be in the research and development stage.^{[17, 18, 19]}

When making treatment decisions, it is essential to consider the possibility of co-infection with more than 1 species. Reports of P. knowlesi infection suggest that co-infection is common.^[2] 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.^[3]

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

Pharmacologic treatment in pregnancy

Medications that can be used for the treatment of malaria in pregnancy include chloroquine, quinine, atovaquone-proguanil, clindamycin, mefloquine (avoid in first trimester), 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.^{[20, 21]}

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.^[22]

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.^[5]

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 permethrin. While this is an effective method for prevention of malaria transmission in endemic areas, an increasing incidence of pyretrhoid resistance in Anopheles spp has been reported.^[23] 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.^[24] Travel Medicine clinics are also a useful source of information and advice.

Investigational malaria vaccine

Interim phase 3 trial results have been reported 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%.^{[25, 26]}

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.^[27]

Pregnant patients with malaria are at increased risk of morbidity and mortality.^[28] 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.