Treatment of Malaria: Guidelines For Clinicians (United States)
Part 2: General Approach to Treatment and Treatment of Uncomplicated Malaria
General Approach to Treatment
It is preferable that treatment for malaria should not be initiated until the diagnosis has been established by laboratory investigations. “Presumptive treatment” without the benefit of laboratory confirmation should be reserved for extreme circumstances (strong clinical suspicion or, severe disease, in a setting where prompt laboratory diagnosis is not available).
Once the diagnosis of malaria has been made, appropriate antimalarial treatment must be initiated immediately. Treatment should be guided by three main factors:
- The infecting Plasmodium species
- The clinical status of the patient
- The drug susceptibility of the infecting parasites as determined by the geographic area where the infection was acquired and the previous use of antimalarial medicines
The infecting Plasmodium species: Determination of the infecting Plasmodium species for treatment purposes is important for three main reasons. Firstly, P. falciparum and P. knowlesi infections can cause rapidly progressive severe illness or death while the other species, P. vivax, P. ovale, or P. malariae, are less likely to cause severe manifestations. Secondly, P. vivax and P. ovale infections also require treatment for the hypnozoite forms that remain dormant in the liver and can cause a relapsing infection. Finally, P. falciparum and P. vivax species have different drug resistance patterns in differing geographic regions. For P. falciparum and P. knowlesi infections, the urgent initiation of appropriate therapy is especially critical.
The clinical status of the patient: Patients diagnosed with malaria are generally categorized as having either uncomplicated or severe malaria. Patients diagnosed with uncomplicated malaria can be effectively treated with oral antimalarials. However, patients who have one or more of the following clinical criteria (impaired consciousness/coma, severe normocytic anemia [hemoglobin < 7], acute kidney injury, acute respiratory distress syndrome, hypotension, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of ≥ 5%) are considered to have manifestations of more severe disease and should be treated aggressively with parenteral antimalarial therapy.
The drug susceptibility of the infecting parasites: Finally, knowledge of the geographic area where the infection was acquired provides information on the likelihood of drug resistance of the infecting parasite and enables the treating clinician to choose an appropriate drug or drug combination and treatment course. In addition, if a malaria infection occurred despite use of a medicine for chemoprophylaxis, that medicine should not be a part of the treatment regimen. If the diagnosis of malaria is suspected and cannot be confirmed, or if the diagnosis of malaria is confirmed but species determination is not possible, antimalarial treatment effective against chloroquine-resistant P. falciparum must be initiated immediately.
Malaria is a nationally notifiable disease and all cases should be reported to your state health department, which are forwarded onto the CDC.
CDC clinicians are on-call 24 hours to provide advice to clinicians on the diagnosis and treatment of malaria and can be reached through the Malaria Hotline 770-488-7788 (or toll free 855-856-4713) Monday – Friday, 9:00 am to 5:00 pm. Off-hours, weekends, and federal holidays, call 770-488-7100 and ask to have the malaria clinician on-call to be paged.
The three-page Treatment Guidelines [PDF, 125 KB, 3 pages] table can be used as a guide for treatment of malaria in the United States. The drug or drug combinations recommended for treatment are listed in bold on the first line of each box in the adult and pediatric “drug and dose” columns. Each drug and its recommended dose are then listed individually on the lines below in the same box. It is important to note that the base/salt conversions for antimalarials are a continual source of confusion and can contribute to treatment errors. In this treatment table (where appropriate), the antimalarial dose is expressed in base with the salt equivalency noted in parentheses.
After initiation of treatment, the patient’s clinical and parasitologic status should be monitored. In infections with P. falciparum or suspected chloroquine-resistant P. vivax, blood smears should be made to confirm adequate parasitologic response to treatment (decrease in parasite density).
Treatment of Uncomplicated Malaria
P. falciparum or 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. A chloroquine dose of 600 mg base (= 1,000 mg salt) should be given initially, followed by 300 mg base (= 500 mg salt) at 6, 24, and 48 hours after the initial dose for a total chloroquine dose of 1,500 mg base (=2,500 mg salt). Alternatively, hydroxychloroquine may be used at a dose of 620 mg base (=800 mg salt) po given initially, followed by 310 mg base (=400 mg salt) po at 6, 24, and 48 hours after the initial dose for a total hydroxychloroquine dose of 1,550 mg base (=2,000 mg salt).
In addition, any of the regimens listed below for the treatment of chloroquine-resistant malaria may be used for the treatment of chloroquine-sensitive malaria. Prompt initiation of an effective regimen is vitally important and so using any one of the effective regimens that is readily at hand would be the preferred strategy.
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. The first two treatment options are atovaquone-proguanil (Malarone) or artemether-lumefantrine (Coartem). These are fixed dose combination medicines that can be used for pediatric patients ≥5kg and for atoavaquone-proguanil, non-pregnant adults. Both of these options are very efficacious. Quinine sulfate plus doxycycline, tetracycline, or clindamycin is the next 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 plus doxycycline or tetracycline. Quinine treatment should continue for 7 days for infections acquired in Southeast Asia and for 3 days for infections acquired in Africa or South America. The fourth option, mefloquine, is associated with rare but potentially severe neuropsychiatric reactions when used at treatment doses. We recommend this fourth option only when the other options cannot be used.
For pediatric patients, the treatment options 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. Pediatric dosing may be difficult due to unavailability of non-capsule forms of quinine. If unable to provide pediatric doses of quinine, consider one of the other three options.
If using a quinine-based regimen for children less than eight years old, doxycycline and tetracycline are generally not indicated; 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 8 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.
If infections initially attributed to “species not identified” are subsequently diagnosed as being due to P. vivax or P. ovale, additional treatment with primaquine should be administered (see P. vivax and P. ovale, 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 of these infections. In addition, any of the regimens listed above for the treatment of chloroquine-resistant malaria may be used for the treatment of P. malariae and P. knowlesi infections.
P. vivax and P. ovale
Chloroquine (or hydroxychloroquine) remains an effective choice for all P. vivax and P. ovale infections except for P. vivax infections acquired in Papua New Guinea or Indonesia. The regimens listed for the treatment of P. falciparum are also effective and may be used. Reports have confirmed a high prevalence of chloroquine-resistant P. vivax in these two specific areas. 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 the patient does not respond to chloroquine, treatment should be changed to one of the two regimens recommended for chloroquine-resistant P. vivax infections, and your state health department and the CDC should be notified (CDC Malaria Hotline: (770) 488-7788 Monday-Friday 8am to 4:30pm EST; (770) 488-7100 after hours, weekends and holidays).
Persons acquiring P. vivax infections in Papua New Guinea or Indonesia should initially be treated with a regimen recommended for chloroquine-resistant P. vivax infections. The treatment regimens for chloroquine-resistant P. vivax infections are quinine sulfate plus doxycycline or tetracycline, or, atovaquone-proguanil, or artemether-lumefantrine, or mefloquine. These treatment options are equally recommended.
In addition to requiring blood stage treatment, infections with P. vivax and P. ovale can relapse due to hypnozoites that remain dormant in the liver. To eradicate the hypnozoites, patients should be treated with a 14-day course of primaquine phosphate. CDC recommends a primaquine phosphate dose of 30 mg (base) by mouth daily for 14 days. Because primaquine can cause hemolytic anemia in persons with glucose-6-phosphate-dehydrogenase (G6PD) deficiency, persons must be screened for G6PD deficiency prior to starting primaquine treatment. For persons with borderline G6PD deficiency or as an alternate to the above regimen, primaquine may be given at the dose of 45 mg (base) orally one time per week for 8 weeks; consultation with an expert in infectious disease and/or tropical medicine is advised if this alternative regimen is considered in G6PD-deficient persons. Primaquine must not be used during pregnancy.
For pediatric patients greater than 8 years old, the treatment options are the same as for adults except the drug dose is adjusted by patient weight. The pediatric dose should never exceed the adult recommended adult dose. For children less than 8 years old, doxycycline and tetracycline are generally not indicated; therefore the other treatment options should be used. For pediatric patients <5kg, mefloquine is the only option. If mefloquine is not available or is not being tolerated and if the treatment benefits outweigh the risks, atovaquone-proguanil or artemether-lumefantrine should be used instead. Primaquine should be given to pediatric patients only after they have been screened for G6PD deficiency.