Treatment of Malaria: Guidelines For Clinicians (United States)
Malaria infection in pregnant women is associated with high risks of both maternal and perinatal morbidity and mortality. While the mechanism is poorly understood, pregnant women have a reduced immune response and therefore less effectively clear malaria infections. In addition, malaria parasites sequester and replicate in the placenta. Pregnant women are three times more likely to develop severe disease than non-pregnant women acquiring infections from the same area. Malaria infection during pregnancy can lead to miscarriage, premature delivery, low birth weight, congenital infection, and/or perinatal death.
For pregnant women diagnosed with uncomplicated malaria caused by P. malariae, P. vivax, P. ovale, or chloroquine-sensitive P. falciparum infection, prompt treatment with chloroquine (treatment schedule as with non-pregnant adult patients) is recommended. Alternatively, hydroxychloroquine, may be given instead. For women in their second or third trimesters, artemether-lumefantrine is an additional option. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, women in the second and third trimesters can be treated with artemether-lumfantrine, and for all trimesters, mefloquine or a combination of quinine sulfate and clindamycin is recommended. Quinine treatment should continue for 7 days for infections acquired in Southeast Asia and for 3 days for infections acquired elsewhere; clindamycin treatment should continue for 7 days regardless of where the infection was acquired. For pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. vivax infection, prompt treatment with artemether-lumfantrine (second and third trimesters) or mefloquine (all trimesters) is recommended.
Doxycycline and tetracycline are generally not indicated for use in pregnant women. However, in rare instances, doxycycline or tetracycline can be used in combination with quinine if other treatment options are not available or are not being tolerated, and the benefit of adding doxycycline or tetracycline is judged to outweigh the risks.
According to its U.S. labels, atovaquone/proguanil is not indicated for use in pregnant women because there are no adequate, well-controlled studies in pregnant women. However, for pregnant women diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, atovaquone-proguanil may be used if other treatment options are not available or are not being tolerated, and if the potential benefit is judged to outweigh the potential risks.
For P. vivax or P. ovale infections, primaquine phosphate and tafenoquine for radical treatment of hypnozoites should not be given during pregnancy. Pregnant patients with P. vivax or P. ovale infections should be maintained on chloroquine prophylaxis for the duration of their pregnancy. The chemoprophylactic dose of chloroquine phosphate is 300mg base (=500 mg salt) orally once per week. After delivery, for pregnant patients with P. vivax or P. ovale infections who do not have G6PD deficiency, subsequent treatment with primaquine phosphate or tafenoquine is needed, but will depend on breastfeeding. If not breastfeeding, either drug can be used. For women who are breastfeeding infants with normal G6PD activity, primaquine phosphate can be given. Tafenoquine is not recommended during breastfeeding. Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy as described below.
Patients who are considered to have manifestations of more severe disease should be treated aggressively with parenteral antimalarial therapy regardless of the species of malaria seen on the blood smear. If severe malaria is strongly suspected but a laboratory diagnosis cannot be made at that time, blood should be collected for diagnostic testing as soon as it is available and parenteral antimalarial drugs should be started.
All patients with severe malaria, regardless of infecting species, should be treated with intravenous (IV) artesunate. Clinicians caring for patients with suspected severe malaria should call CDC to obtain IV artesunate. The CDC Malaria Hotline (770-488-7788, or toll-free 855-856-4713) is available Monday–Friday 9am–5pm EST. Outside those hours, providers should call 770-488-7100 and ask to speak with a malaria expert.
Severe malaria can progress rapidly and must be treated as soon as possible. While timely delivery of IV artesunate is anticipated, health-care providers can consider treating the patient with an oral antimalarial while waiting for IV artesunate to arrive. Health-care providers will need to decide the most feasible route to administer the drug for patients unable to tolerate an oral antimalarial. For example, if this intolerance is due to nausea and vomiting, an anti-emetic preceding the antimalarial may help. For comatose patients, a nasogastric tube can be considered.
One of the antimalarials listed below can be administered. IV clindamycin and IV tetracyclines such as doxycycline are not recommended. These drugs are slow-acting antimalarials that would not take effect until well after 24 hours, and they are not effective antimalarials for treatment of severe malaria when used alone.
- Artemether/lumefantrine (Coartem®): 1 tablet=20 mg artemether and 120 mg lumefantrine. Give initial dose, then if still needed, follow with second dose 8 hours later.
- 5-14 kg: 1 tablet per dose
- 15-24 kg: 2 tablets per dose
- 25-34 kg: 3 tablets per dose
- ≥35 kg: 4 tablets per dose
- Atovaquone/proguanil (Malarone®): Adult (250 mg atovaquone/100 mg proguanil) and pediatric (62.5 mg atovaquone/25 mg proguanil) formulations are available.
- Adults: 4 adult tablets as one dose
- Children (≥5 kg only): Dosing based on weight
- 5–8 kg: 2 peds tabs
- 9–10 kg: 3 peds tabs
- 11–20 kg: 1 adult tab
- 21–30 kg: 2 adult tabs
- 31–40 kg: 3 adult tabs
- >40 kg: 4 adult tabs
- Quinine: Adults: 650 mg (salt) every 8 hours. Children: 10 mg (salt)/kg every 8 hours.
- Mefloquine (because of a risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if atovaquone/proguanil or quinine is not available, and based on health-care provider judgement that treatment is needed prior to the arrival of IV artesunate): Adults: 750 mg salt, initially, then 500 mg salt 6–12 hours after initial dose. Children: 15 mg salt/kg, initially, then 10 mg salt/kg 6–12 hours after initial dose.
When IV artesunate arrives, discontinue the oral medication. The dosing of IV artesunate is as follows:
- Adults and children ≥20 kg: 2.4 mg/kg at 0 hour, 12 hours, and 24 hours; and 48 hours
- Children <20 kg: 3.0 mg/kg at 0 hour, 12 hours, and 24 hours; and 48 hours
After the course of IV artesunate is completed, a follow-on drug must be administered. Options include the following:
- Artemether/lumefantrine (Coartem®): 1 tablet=20 mg artemether and 120 mg lumefantrine. A 3-day treatment schedule with a total of 6 oral doses as follows: initial dose, second dose 8 hours later, then 1 dose twice a day for the following 2 days. Dosing as above.
- Atovaquone/proguanil (Malarone®): One dose daily for 3 days. Dosing as above.
- Adults: 100 mg twice a day for 7 days.
- Children (8 years or older): 2 mg/kg twice a day for 7 days.
- Children under 8 years of age or pregnant women should instead receive clindamycin 20 mg base/kg/day divided three times a day for 7 days.
- Mefloquine (because of a risk of severe neuropsychiatric adverse events at treatment doses, mefloquine should only be used if other options are not available):
- Adults: 750 mg salt, initially, then 500 mg salt 6–12 hours after initial dose.
- Children: 15 mg salt/kg, initially, 10 mg salt/kg 6–12 hours after initial dose.
For those patients who still cannot tolerate oral medications after completing artesunate treatment, several treatment options are available, depending on the patient’s clinical and parasitological status. The most suitable course of treatment should be selected by the attending clinicians in consultation with CDC. Potential options include the following:
- Continue IV artesunate, 1 dose daily (see above for dosing) not to exceed a total course of 7 days.
- Switch to treatment with IV doxycycline (7 days) or IV clindamycin (7 days), dosing as above.
IV artesunate is safe in infants, children, and pregnant women in the second and third trimesters. There are limited clinical data on women taking IV artesunate in the first trimester of pregnancy; no harmful effects have been observed. Given that severe malaria is life threatening for pregnant women and their fetuses, and the lack of other treatment options for severe malaria in the United States, the benefits of treatment with IV artesunate outweigh the risks and IV artesunate should not be withheld. The only contraindication to IV artesunate is known allergy to IV artemisinins.
IV artesunate is well tolerated. While rare, delayed post-artemisinin hemolytic anemia has been noted in published case reports following treatment of severe malaria with IV artesunate in other non-endemic countries. Persons treated for severe malaria with IV artesunate should be monitored for up to 4 weeks after that treatment for evidence of hemolytic anemia. Persons with higher parasitemia seem to have a higher likelihood of delayed hemolytic anemia after treatment with IV artesunate. Depending on the amount of hemolysis, transfusion may be needed.
Previously, CDC recommended that exchange transfusion be considered for certain severely ill persons. However, exchange transfusion had not been proven beneficial in an adequately powered randomized controlled trial. In 2013 CDC conducted an analysis of cases of severe malaria treated with exchange transfusion and was unable to demonstrate a survival benefit of the procedure. CDC no longer recommends the use of exchange transfusion as an adjunct procedure for the treatment of severe malaria.