Malaria Organism-Specific Therapy

Several antibody-based rapid diagnostic tests (RDTs) are available for diagnosing malaria, but they cover only four of the five species that cause human malaria (all except Plasmodium knowlesi). Symptomatic patients from areas where P knowlesi is present should be investigated as described below. All efforts should be made to confirm the diagnosis of malaria and to identify the species. Diagnosis is based on Giemsa-stained thick and thin peripheral blood smears.

Complications influence the choice of treatment. Complications of Plasmodium falciparum malaria include impaired consciousness, seizures, severe anemia, renal failure, pulmonary edema or acute respiratory distress syndrome (ARDS), refractory hypotension, and disseminated intravascular coagulation (DIC). Criteria for the diagnosis of severe malaria are provided by the World Health Organization (WHO) and should be used in the clinical management of the patient. ^{[1, 2, 3, 4]}

Conditions such as pregnancy also affect the choice of treatment. Resistance patterns at a regional level are currently less important, as the first choice for uncomplicated P falciparum malaria should always be artemisinin combination therapy. As chloroquine can be used for prophylaxis and for therapy in very limited circumstances, resistance patterns to this drug will also be covered.

Key points

If the patient meets the criteria for severe malaria and treatment must be initiated before the species is known, treat for P falciparum.

P falciparum should be presumed to be chloroquine-resistant, except in a few areas of Central America and the Middle East.

Primaquine should be given if Plasmodium vivax or Plasmodium ovale is suspected after checking for the presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Malaria resistance patterns

Chloroquine-resistant P falciparum

• Eastern hemisphere: Algeria, Western Sahara, all of sub-Saharan Africa, Bhutan, Saudi Arabia, Oman ,Yemen, Iran, Tajikistan, Pakistan, Afghanistan, Nepal, China, North Korea and all of Southeast Asia, Solomon Islands
• Western hemisphere: Argentina, Panama, Haiti, Peru, Bolivia, Colombia, Venezuela, Ecuador, Brazil, French Guyana, Guyana, Suriname Solomon Islands

Chloroquine-sensitive P falciparum

• Eastern hemisphere: Turkey, Azerbaijan.
• Western hemisphere: Belize, Paraguay, Mexico, Guatemala, Honduras, Nicaragua, El Salvador, Dominican Republic, South Korea

Mefloquine-resistant P falciparum

• Southeast Asia: Regions of Vietnam, Laos, Thailand, Burma, Cambodia, China

Chloroquine-resistant P vivax

• Papua New Guinea and Indonesia; All countries not present in the above list are malaria-transmission free

Treatment of uncomplicated Plasmodium falciparum malaria

The 2015 WHO malaria treatment guidelines ^[2] state that uncomplicated P falciparum malaria should always be treated with oral artemisinin combination therapy (ACT), as follows:

• Artemether plus lumefantrine (AL)
• Artesunate plus amodiaquine
• Artesunate plus mefloquine
• Dihydroartemisinin plus piperaquine (DHAP)
• Artesunate plus sulfadoxine-pyrimethamine

Not all of the above combinations are available in Europe or the United States. Available drugs include AL (United States) and AL or DHAP (Europe). Oral artesunate is unavailable in the United States, although IV artesunate is approved for initial therapy.

The 2016 British guidelines for the treatment of malaria ^[5] also signal the possibility to adopt other treatments (atovaquone plus proguanil or quinine sulphate) if artemisinin combination therapy is not available.

Dosages for uncomplicated P falciparum malaria are as follows: ^[5]

• Artemether plus lumefantrine: Doses are given twice daily for 3 days depending on body weight, as follows:

  • 5 to < 15 kg: 20 + 120 mg
  • 15 to < 25 kg: 40 + 240 mg
  • 25 to < 35 kg: 60 + 360 mg
  • More than 35 kg: 80 + 480 mg
• Dosing for dihydroartemisinin plus piperaquine depends on body weight, as follows:

  • 36-60 kg: 3 tablets daily for three days
  • >60 kg: 4 tablets daily for three days
  • Children who weight < 25 kg should receive a minimum of dihydroartemisinin 2.5 mg/kg/day and piperaquine 20 mg/kg/day for 3 days
• Atovaquone plus proguanil: 1 g/400 mg tablets daily for 3 days
• Oral quinine sulphate: 600 mg q8h for 5-7 days plus doxycycline 200 mg daily (or clindamycin 450 mg 8 hourly for pregnant women) for 7 days

Treatment of uncomplicated Plasmodium malariae, Plasmodium knowlesi, Plasmodium vivax, and Plasmodium ovale malaria

The 2015 WHO guidelines for the treatment of malaria ^[2] state that, if the species cannot be confirmed, the patient should be managed as if the infection is caused by P falciparum. This also applies to all patients who acquire malaria in regions with chloroquine-resistant infections.

In areas of chloroquine sensitivity, chloroquine should be used.

Co-infections (generally P falciparum and other species) should be actively ruled out in patients from areas where co-infections are known to occur. Treatment for P falciparum malaria is sufficient to eradicate both species. Primaquine should be added if P vivax or P ovale is present to avoid relapses caused by the permanence of hypnozoites in the liver.

Dosages for P malariae and P knowlesi malaria are as follows: ^[5]

• Chloroquine phosphate 1000 mg (10 mg/kg base) PO as the initial dose, then 300 mg (5 mg/kg) at 6 hours, 24 hours, and 48 hours or
• Hydroxychloroquine 800 mg PO as initial dose, then 400 mg PO at 6 hours, 24 hours, and 48 hours or
• Any of the treatments used for uncomplicated P falciparum malaria

Dosages for P vivax and P ovale malaria are as follows:

• Chloroquine phosphate 1000 mg (10 mg/kg base) PO as the initial dose, then 300 mg (5 mg/kg) at 6 hours, 24 hours, and 48 hours plus  primaquine 30 mg (0.5 mg/kg base) PO q24h for 14 days or
• Hydroxychloroquine 800 mg PO as the initial dose, then 400 mg PO at 6 hours, 24 hours, and 48 hours plus  primaquine 30 mg (0.5 mg/kg base) PO q24h for 14 days ^[5] or
• Any of the treatments used for P falciparum malaria plus primaquine 30 mg (0.5 mg/kg base) PO q24h for 14 day

Prevention of P vivax malaria relapse

Tafenoquine, an 8-aminoquinoline derivative, is 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 (eg, chloroquine) for acute P vivax infection.

A single 300-mg oral dose of tafenoquine is coadministered on the first or second day of the appropriate antimalarial therapy (eg, chloroquine) for acute P vivax malaria infection. Nearly 90% of patients were relapse-free at 6 months after treatment. ^[6]

Treatment of complicated malaria

According to the 2015 WHO guidelines for the treatment of malaria, complicated malaria should be treated first with intravenous artemether, followed by oral artemisinin combination therapy as soon as the patient is able to take oral medication (generally after at least 48 hours following intravenous therapy). If artemether is not available, quinine can be used as an alternative, followed by the oral phase of the therapeutic course.

Dosages are as follows: ^[2]

• Artesunate regimen: 2.4 mg/kg IV at 0 hours, 12 hours, and 24 hours and then daily thereafter. After completion of a minimum of 24 hours of therapy (maximum 5 days), a full course of oral artemisinin combination therapy should be administered when the patient can tolerate oral medication.
• Quinine: Loading dose of 20 mg/kg quinine dihydrochloride in 5% dextrose or dextrose saline over 4 hours, followed by 10 mg/kg every 8 hours for the first 48 hours (or until the patient can swallow). Frequency of dosing should be reduced to q12h if intravenous quinine continues for more than 48 hours.
• Parenteral quinine therapy should be continued until the patient can take oral therapy, when quinine sulphate 600 mg should be given three times a day to complete 5-7 days of quinine in total.
• Quinine treatment should always be accompanied by a second drug: doxycycline 200 mg (or clindamycin 450 mg 3 times a day in children or pregnant women), given orally for total of 7 days from when the patient can swallow.

Treatment in the United States

Approximate 2000 cases of malaria are diagnosed in the United States each year, with 300 of those infected having severe disease. ^[7] Artesunate IV is approved in the United States and is indicated for the initial treatment of severe malaria in adults and children. ^{[8, 9]} CDC guidelines for the treatment of malaria in the United States is determined by infection severity, country of infection origin, drug susceptibility (eg, chloroquine resistance), and the Plasmodium species identified. ^[10]

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 the mortality rate by 34.7% (P = 0.0002) and 22.5% (P = 0.002) compared with quinine in the SEAQUMAT and AQUAMAT studies, respectively. ^{[8, 9]}

Prophylaxis

Malaria prophylaxis relies on mosquito avoidance measures (which include wearing long-sleeved shirts and long pants, using DEET-based repellents, and sleeping under bed nets) and chemoprophylaxis. Several drugs can be used for chemoprophylaxis, but indications may vary depending on the country of destination. Updated information is available on websites such as that of the Centers for Disease Control and Prevention. ^[11]

Malaria chemoprophylaxis options

Atovaquone-proguanil

• Atovaquone-proguanil 1 tablet/day PO
• Begin 1-2 days before travel to malarial areas; discontinue 7 days after departure from malarial areas
• Not recommended for prophylaxis if creatinine clearance < 30 mL/min
• Atovaquone-proguanil should be taken with food or a milky drink

Chloroquine phosphate

• Chloroquine phosphate 300 mg base (500 mg salt) PO once weekly should be used as prophylaxis only in areas with chloroquine-sensitive malaria
• Begin 1-2 weeks before travel to malarial areas; discontinue 4 weeks after departure from malarial areas

Doxycycline

• Doxycycline 100 mg/day PO can be used as prophylaxis in all areas
• Begin 1-2 days before travel to malarial areas; discontinue 4 weeks after departure from malarial areas
• Contraindicated in children younger than 8 years and in pregnant women
• Significant risk for photosensitivity

Mefloquine

• Mefloquine 250 mg PO once weekly can be used as prophylaxis in areas with mefloquine-sensitive malaria
• Begin 1-2 weeks before travel to malarial areas; discontinue 4 weeks after departure from malarial areas
• Contraindicated in persons with active or recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or seizures ^[12]
• Prolongs QT interval; not recommended in persons with cardiac conduction abnormalities ^[12]

Primaquine ^[2]

• Primaquine 30 mg base/day PO can be used as prophylaxis for short-duration travel to areas with > 90% P vivax
• Begin 1-2 days before travel to malarial areas; discontinue 7 days after departure from malarial areas
• Not recommended in persons with G6PD deficiency (all persons who take primaquine should have a documented normal G6PD level before starting)
• Also not recommended during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level

Tafenoquine ^[13]

• Daily loading dose beginning 3 days before travel to malarious area; once weekly dose while in malarious area; and single terminal prophylaxis dose the week following exit from malarious area
• Not recommended in persons with G6PD deficiency (all persons who take tafenoquine should have a documented normal G6PD level before starting)
• Also not recommended during pregnancy and lactation unless the infant being breastfed has a documented normal G6PD level
• Contraindicated in patients with history of or current psychotic disorders (eg, hallucinations, delusions, grossly disorganized behavior)

Special considerations

Patients prescribed primaquine should be tested for G6PD deficiency.