Severe malaria: Initial treatment^*

	Areas with no established artemisinin resistance	Areas with established artemisinin resistance^¶Δ
Initial treatment regimen (adults and children)	Treat with intravenous artesunate^◊§¥: Adults and children ≥20 kg: 2.4 mg/kg IV at 0, 12, and 24 hours. Children <20 kg^[1]: 3 mg/kg IV at 0, 12, and 24 hours. If IV artesunate is not readily available, administer interim treatment as outlined below.	In the United States^‡: Treat with intravenous artesunate (dosing outlined in preceding column). Outside the United States: Intravenous artesunate (dosing outlined in preceding column). plus Quinine dihydrochloride^†, dosed as follows: Loading dose: 20 mg salt/kg (= 16.4 mg base/kg) IV up to a maximum of 1400 mg salt (1150 mg base) in 5% dextrose over 4 hours^†,. Followed by: 10 mg salt/kg (= 8.2 mg base/kg) IV over 4 hours at 8- or 12-hour intervals (maximum 2100 mg base/day [= 1720 mg salt/day]), starting 8 hours after the beginning of the loading dose^†.
Interim treatment (if IV artesunate is not readily available)	In the United States^[2]: Administer oral antimalarial therapy^¶¶ while obtaining IV artesunate. If oral therapy is not tolerated, consider administration via nasogastric tube or following an antiemetic. Outside the United States^[3]: Administer one of the following: Artemether (3.2 mg/kg intramuscular injection [anterior thigh], followed by 1.6 mg/kg IM daily for 3 days, until artesunate is available, or until treatment can be completed orally). or Quinine dihydrochloride (salt)^†,: Loading dose: 20 mg salt/kg (= 16.4 mg base/kg) IV up to a maximum of 1400 mg salt (1150 mg base) in 5% dextrose over 4 hours^†,. Followed by: 10 mg salt/kg (= 8.2 mg base/kg) IV over 4 hours at 8- or 12-hour intervals (maximum 2100 mg salt/day [= 1720 mg base/day]), starting 8 hours after the beginning of the loading dose^†. Once IV artesunate arrives, discontinue interim treatment and initiate IV artesunate.	In the United States^[2]: Administer oral antimalarial therapy^¶¶ while obtaining IV artesunate. If oral therapy is not tolerated, consider administration via nasogastric tube or following an antiemetic. Outside the United States: Treat with intramuscular artemether plus IV quinine (dosing outlined in preceding column). Once IV artesunate arrives, discontinue interim treatment and treat with IV artesunate plus quinine (dosing outlined above).
Reassessment and follow-on treatment^ΔΔ	Reassess parasite density at least 4 hours after third dose of IV artesunate.	Reassess parasite density at least 4 hours after third dose of IV artesunate.
	For patients with parasite density ≤1% who are able to tolerate oral medication, administer a complete follow-on oral regimen^◊◊.	For patients with parasite density ≤1% who are able to tolerate oral medication, administer a complete follow-on oral regimen^◊◊.
	For patients with parasite density ≤1% who are unable to tolerate oral medication, continue parenteral therapy (artesunate 2.4 mg/kg IV once daily) until the patient is able to tolerate oral therapy (up to 6 more days). Then administer a complete follow-on oral regimen.	For patients with parasite density ≤1% who are unable to tolerate oral medication, continue parenteral therapy (artesunate 2.4 mg/kg IV once daily plus quinine dosed as outlined above) until the patient is able to tolerate oral therapy (up to 6 more days). Then administer a complete follow-on oral regimen.
	For patients with parasite density >1%, continue artesunate (2.4 mg/kg IV once daily) until parasite density ≤1% for up to 6 more days. Once parasite density ≤1%, and patient is able to tolerate oral therapy, administer a complete follow-on oral regimen^ΔΔ.	For patients with parasite density >1%, continue parenteral therapy (artesunate 2.4 mg/kg IV once daily plus quinine dosed as outlined above) until parasite density ≤1% for up to 6 more days. Once parasite density ≤1%, and patient is able to tolerate oral therapy, administer a complete follow-on oral regimen.

The above approach applies to treatment of severe malaria due to all species. In addition, for patients with Plasmodium vivax or Plasmodium ovale infection, antirelapse treatment should be administered (refer to the UpToDate content on treatment of non-falciparum malaria).

CDC: United States Centers for Disease Control and Prevention; IM: intramuscularly; IV: intravenous.

* Refer to the UpToDate text for the definition of severe malaria.

¶ Artemisinin resistance in Plasmodium falciparum is prevalent in parts of Cambodia, the Lao People's Democratic Republic, Myanmar, Thailand, and Vietnam.

Δ At the current levels of resistance, the artemisinin derivatives still provide significant antimalarial activity; therefore, longer courses of treatment with existing or new augmented combinations or treatment with new partner medicines (eg, artesunate + pyronaridine) may be effective. Studies to determine the best treatments for artemisinin-resistant malaria are needed.

◊ In the United States, IV artesunate is commercially available; if the drug is not in stock or available within 24 hours, contact the CDC malaria hotline (770-488-7788 Monday-Friday, 9 am-5 pm Eastern time; outside these hours, call 770-488-7100 and ask to speak with a CDC malaria expert). The CDC webpage provides options for emergency acquisition of IV artesunate for hospitals that do not have in stock or cannot obtain it readily from the commercial source.

§ Our approach is in alignment with WHO guidelines^[1,3] but differs from CDC^[2] and FDA guidance^[4] which favor 2.4 mg/kg for children and adults.

¥ Patients treated with intravenous artesunate should be monitored for delayed hemolytic anemia, with repeat hemoglobin testing at 7, 14, and 30 days after treatment.

‡ Artemisinin derivatives still provide significant antimalarial activity, even in the setting of resistance; in the United States, we use artesunate alone as IV quinine is not available.

† Quinine dihydrochloride salt contains approximately 82% quinine base; it should be given by rate-controlled intravenous infusion at a maximum rate of 5 mg salt/kg per hour and never by rapid intravenous injection (which can be lethal). Quinine dihydrochloride can also be administered via intramuscular injection if intravenous infusions cannot be given: the loading dose can be given as two injections of 10 mg salt/kg (each diluted in NaCl 0.9% to 60 to 100 mg salt/mL) administered four hours apart. Maintenance doses (ie, 10 mg salt/kg) are prepared in the same way and given IM every 8 to 12 hours. The anterior thigh is preferred over the gluteal region to minimize the risk of sciatic nerve damage. In patients with acute kidney injury or if parenteral therapy is required for more than 48 hours in patients who are not receiving hemodialysis or hemofiltration, the dose of intravenous quinine should be reduced by one-third to one-half (eg, to 10 mg salt/kg every 12 hours or 5 mg salt/kg every 8 hours). Dose adjustments are not necessary for patients receiving hemodialysis or hemofiltration.

** Important adverse effects of quinine include hypoglycemia, QT prolongation, tinnitus, reversible hearing loss, nausea, vomiting, dizziness, and visual disturbances. To avoid cardiotoxicity, a loading dose of quinine/quinidine should not be administered to patients who received mefloquine or other quinine derivatives within the previous 12 hours.

¶¶ Options for oral antimalarial therapy while obtaining IV artesunate include: artemether-lumefantrine (preferred), atovaquone-proguanil, quinine sulfate or mefloquine (only if no other options available); refer to separate UpToDate table for dosing. If an oral antimalarial agent was used for chemoprophylaxis, a different agent should be used for treatment.

ΔΔ Parasite density should be repeated every 12 to 24 hours until negative. For patients in endemic areas who have received at least 24 hours of parenteral therapy and are able to tolerate oral medications, treatment may be switched to oral therapy even if parasitemia is above 1%.

◊◊ Options for oral antimalarial therapy for follow-on treatment include artemether-lumefantrine (preferred), atovaquone-proguanil, quinine plus doxycycline [or quinine plus clindamycin for children <8 years old and pregnant women], or mefloquine (only if no other options available); refer to separate UpToDate table for dosing. If an oral antimalarial agent was used for chemoprophylaxis, a different agent should be used for treatment.

References:

Haghiri A, Price DJ, Fitzpatrick P, et al. Evidence based optimal dosing of intravenous artesunate in children with severe falciparum malaria. Clin Pharmacol Ther 2023; 114:1304.
Malaria in the United States: Treatment tables. Centers for Disease Control and Prevention. https://www.cdc.gov/malaria/resources/pdf/Malaria_Treatment_Table_202306.pdf (Accessed on October 4, 2023). World Health Organization.
WHO guidelines for malaria, 3 June 2022. https://www.who.int/publications/i/item/guidelines-for-malaria (Accessed on September 14, 2022).
Kitabi E, Bensman TJ, Earp JC, et al. Effect of body weight and age on the pharmacokinetics of dihydroartemisinin: Food and Drug Administration basis for dose determination of artesunate for injection in pediatric patients with severe malaria. Clin Infect Dis 2021; 73:903.

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Severe malaria: Initial treatment*

Severe malaria: Initial treatment^*