Treatment of Uncomplicated Malaria

Medication shortage

P. falciparum or species not identified - acquired in areas with chloroquine resistance

For P. falciparum infections acquired in areas with chloroquine resistance, four treatment options are available. These include artemether-lumefantrine (Coartem^®), which is the preferred option if readily available, and atovaquone-proguanil (Malarone™). These are fixed-dose combination therapies that can be used for pediatric patients ≥5 kg. Quinine sulfate plus doxycycline, tetracycline, or clindamycin is also a treatment option. For the quinine sulfate combination options, quinine sulfate plus either doxycycline or tetracycline is generally preferred to quinine sulfate plus clindamycin because there are more data on the efficacy of quinine sulfate plus doxycycline or tetracycline. Quinine should be given for three days, except for infections acquired in Southeast Asia where seven days of treatment is required. The fourth option, mefloquine, is associated with rare but potentially severe neuropsychiatric reactions when used at treatment dose. We recommend this option only when the other options cannot be used. In addition, mefloquine is not recommended for infections acquired in certain parts of Southeast Asia due to drug resistance. Once a treatment regimen is started, if it is being tolerated, there is no need to switch regimens even if a preferred regimen becomes available.

Options for treatment of pregnant women are presented in the Alternatives for Pregnant Women section below. Due to the risk of progression to severe disease, uncomplicated malaria treatment should be initiated as soon as possible with the regimen that is most readily available. In addition, clinicians should hospitalize patients with P. falciparum infection to monitor clinical response and check parasite density every 12 – 24 hours. Once clinical presentation improves and a decrease in parasite density becomes apparent, treating clinicians can consider outpatient completion of treatment.

For pediatric patients, the treatment options are the same as for adults except the drug dose is adjusted by patient weight, and artemether-lumefantrine (Coartem^®) and atovaquone-proguanil (Malarone™) can only be used in children ≥5 kg. The pediatric dose should never exceed the recommended adult dose. Pediatric dosing with quinine may be difficult due to unavailability of non-capsule forms of this antimalarial. If using a quinine-based regimen for children less than eight years old, doxycycline and tetracycline are generally not recommended; therefore, quinine can be given in combination with clindamycin as recommended above. In rare instances, doxycycline or tetracycline can be used in combination with quinine in children less than eight years old if other treatment options are not available or are not tolerated, and the benefit of adding doxycycline or tetracycline is judged to outweigh the risk.

For infections attributed to "species not identified" from areas with chloroquine resistance that are subsequently diagnosed as being due to P. vivax or P. ovale, additional treatment with primaquine or tafenoquine should be administered (see P. vivax and P. ovale section below).

P. falciparum of species not identified - acquired in areas without chloroquine resistance

For P. falciparum infections acquired in areas without chloroquine-resistant strains, which include Central America west of the Panama Canal, Haiti, and the Dominican Republic, patients can be treated with oral chloroquine, or, alternatively, hydroxychloroquine at recommended doses.

In addition, any of the regimens listed for the treatment of chloroquine-resistant malaria may be used for the treatment of chloroquine-sensitive P. falciparum malaria. Prompt initiation of an effective regimen is vitally important, so using any one of the effective regimens that is readily available would be the preferred strategy.

Due to the risk of progression to severe disease in patients with P. falciparum infection, patients should be hospitalized to monitor clinical response and check parasite density every 12 – 24 hours until clinical presentation improves and a decrease in parasite density becomes apparent. Then, treating clinicians can consider outpatient completion of treatment for patients with improved clinical symptoms and decreasing parasite density. If infections initially attributed to "species not identified" are subsequently diagnosed as being due to P. vivax or P. ovale, additional treatment with primaquine or tafenoquine should be administered (see P. vivax and P. ovale section below).

P. malariae and P. knowlesi

There has been no widespread evidence of chloroquine resistance in P. malariae and P. knowlesi species; therefore, chloroquine (or hydroxychloroquine) may still be used for both infections. In addition, any of the regimens listed above for the treatment of chloroquine-resistant P. falciparum may be used for the treatment of P. malariae and P. knowlesi infections. Due to the risk of complications among patients with P. knowlesi, clinicians should consider hospitalization to monitor clinical response and check parasite density every 12 – 24 hours until clinical presentation improves and a decrease in parasite density becomes apparent.

P. vivax and P. ovale

Chloroquine (or hydroxychloroquine) remains an effective choice for P. vivax and P. ovale infections except for P. vivax infections acquired in Papua New Guinea or Indonesia, countries with high prevalence of chloroquine-resistant P. vivax. Rare cases of chloroquine-resistant P. vivax have also been documented in Burma (Myanmar), India, and Central and South America. Persons acquiring P. vivax infections from regions other than Papua New Guinea or Indonesia should initially be treated with chloroquine. If chloroquine is given and the patient has an inadequate response, including persistence or worsening of clinical symptoms or no decrease in parasite density, treatment should be changed to one of the regimens recommended for chloroquine-resistant P. vivax infections (see below), and your state health department and CDC should be notified—(CDC Malaria Hotline: (770) 488-7788, Monday–Friday, 9 am to 5 pm EST; (770) 488-7100 after hours, weekends, and holidays).

If chloroquine is not available, or for persons acquiring P. vivax infections in Papua New Guinea or Indonesia, treatment with a regimen recommended for chloroquine-resistant P. vivax infections is appropriate. These include artemether-lumefantrine, atovaquone-proguanil, or quinine sulfate plus doxycycline or tetracycline (or clindamycin for pregnant women and children <8 years old) and are equally recommended. Mefloquine can be used if no other options are available, because of rare but potentially severe neuropsychiatric reactions when used at treatment dose.

Anti-relapse treatment

In addition to requiring treatment for the blood stage parasites, i.e., acute phase of malaria, P. vivax and P. ovale infections can relapse due to hypnozoites, which are dormant forms that remain in the liver. To eradicate the hypnozoites, patients should be treated with either primaquine phosphate or tafenoquine (Krintafel^TM). Primaquine phosphate can be used in combination with any of the drug options for treatment of the acute phase of infection. CDC recommends a primaquine phosphate dose of 30 mg (base) by mouth daily for 14 days. Due to reduced efficacy of primaquine in patients ≥70 kg, the total dose of primaquine should be adjusted in these patients to 6 mg/kg, then divided into daily doses of 30 mg for the number of days needed to complete the total dose. A daily dose >30 mg is not recommended due to safety concerns. Tafenoquine can be used only in patients who received chloroquine for treatment for the acute phase, and in patients who are at least 16 years old. Because both tafenoquine and primaquine can cause hemolytic anemia in persons with glucose-6-phosphate-dehydrogenase (G6PD) deficiency, quantitative G6PD testing must occur prior to starting treatment with these drugs, and only patients with normal activity should receive these drugs. G6PD quantitative testing varies greatly across laboratories and assays used, so clinicians should follow reference ranges provided by each laboratory.

For persons with intermediate G6PD deficiency, clinicians may consider giving primaquine at 45 mg (base) po once per week for eight weeks with close monitoring for hemolysis. Consultation with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in intermediate G6PD-deficient individuals. Primaquine and tafenoquine must not be used during pregnancy (see section on Alternatives for Pregnant Women below). Tafenoquine must not be used in children less than 16 years old, or in those with a history of a psychotic disorder. Patients with G6PD deficiency who are not expected to tolerate primaquine or tafenoquine should be put on chloroquine prophylaxis (300 mg [base] po once a week) for one year from the acute infection, as most of the relapses resulting from hypnozoite reactivation occur within this timeframe.

For pediatric patients ≥5 kg, the treatment options for the acute phase are the same as for adults except the drug dose is adjusted by patient weight. The pediatric dose should never exceed the recommended adult dose. In addition, for children <8 years of age, doxycycline and tetracycline are generally not recommended; therefore, the other treatment options should be used. For pediatric patients <5 kg, either mefloquine or quinine plus clindamycin are the only options. If those are not available or tolerated and if the treatment benefits outweigh the risks, atovaquone-proguanil or artemether-lumefantrine could be used in those instances. Primaquine should be given to pediatric patients only after they have been screened for G6PD deficiency, and tafenoquine can only be used in patients 16 years or older who received chloroquine.