There are two major classes of drugs available for parenteral treatment of severe malaria:
- the cinchona alkaloids (quinine and quinidine) and
- the artemisinin derivatives (artesunate, artemether and artemotil).
Data comparing quinine and artemisinins suggest that intravenous artesunate is preferable for treatment of adults and children with severe falciparum malaria (in areas where intravenous artesunate of reliable quality is readily available). If intravenous artensunate is not an option, intravenous quinine (or quinidine in the United States) remains the drug of choice.
1) Artemisinins
Artemisinin derivatives clear parasitemia more rapidly than quinine. They are active against a broader life-cycle range of blood stage parasites than quinine and they are active against gametocytes. Artemisinin derivatives include artesunate, artemether and artemotil. Artesunate is the preferred artemisinin; clinical experience with artemether and artemotil drugs is limited and they should not be used for treatment of severe disease.
Artesunate is the preferred therapy for treatment of severe falciparum malaria in adults and children in areas where intravenous artesunate is available. This approach is based on data suggesting that artesunate is superior to intravenous quinine for treatment of adults in Asia and children in Africa with severe malaria:
- Among 1461 patients in Bangladesh, India, Indonesia, and Myanmar randomized to receive artesunate or quinine, lower mortality was observed among those who received artesunate (15 versus 22 percent, respectively; risk reduction 34 percent). The life saving impact of artesunate was noted among patients who survived more than 24 hours after starting treatment. Artesunate was well tolerated, while quinine was associated with a threefold increased risk of hypoglycemia.
- Among 5425 children in Africa with severe malaria randomized to receive therapy artesunate or quinine, lower mortality was observed among those who received artesunate (8.5 versus 10.9 percent, respectively; risk reduction 22.5 percent). The life saving impact of artesunate was apparent throughout the course of treatment. Hypoglycemia was less frequent in the artesunate group than the quinine group (1.8 versus 2.8 percent). There were no differences in the rate of neurological sequelae between the two groups.
- A meta-analysis of seven randomized trials compared the survival rates among recipients of parenteral quinine and artesunate; artesunate was superior with respect to mortality (overall odds ratio 0.69, 0.57-0.84, p<0.00001), and there was no significant heterogeneity between results from Africa and Asia.
Intravenous artesunate of reliable quality is not yet available in many countries; in these areas, quinine remains the treatment of choice. In the United States intravenous artesunate is not approved by the Food and Drug Administration but is available for use under an investigational protocol by enrollment with the Centers for Disease Control (CDC Malaria Hotline: (770) 488-7788 Monday-Friday 8a to 4:30p EST; (770) 488-7100 after hours, weekends and holidays). Eligible patients include those with parasitemia ≥5 percent and/or other signs of severe malaria, as well as those with uncomplicated malaria who require parenteral therapy due to intolerance of oral medications. The CDC also requires that artesunate be available at least as rapidly as quinidine or that there be quinidine intolerance, failure or contraindication.
Artesunate is the most rapidly acting of the artemisinin compounds because of its water solubility. Administration of intravenous artesunate consists of 2.4 mg/kg as first dose, followed by 2.4 mg/kg at 12 and 24 hours, followed by 2.4 mg/kg once daily. Following four doses of intravenous artesunate, oral antimalarial treatment may be administered if the patient is able to tolerate oral therapy. Intravenous therapy for more than three days may be indicated in very ill patients. Artesunate can also be administered intramuscularly, orally, or via rectal suppository.
Artesunate dosing need not be adjusted for hepatic or renal failure, nor for concomitant or previous therapy with other medications (including mefloquine, quinine, or quinidine). The most common adverse effects associated with artemisinins include nausea, vomiting, anorexia and dizziness, although these may be due to malaria rather than drug toxicity. There is no convincing evidence of neurotoxic effects in humans due to oral or intravenous artemisinins, although neurotoxicity has been described in animals and attributed to fat soluble artemisinins more frequently than to artesunate. Limited data are available on the use of artesunate for severe malaria during pregnancy.
Emergence of artemisinin resistance is an important concern, and combination of artemisinins with other active agents may protect against the development of resistance to individual drugs. Pending further data, use of intravenous artesunate monotherapy remains appropriate for treatment of severe malaria. After the patient is no longer critically ill, oral combination therapy is typically used to complete the course of treatment.
2) Quinine/quinidine
Intravenous quinine remains the treatment of choice for areas where intravenous artesunate of reliable quality is not readily available.
In the United States, parenteral quinine was withdrawn by the CDC in 1991; intravenous quinidine is available for treatment of severe malaria.
Quinine (or quinidine) should be administered by intravenous infusion beginning with an initial loading dose:
- Intravenous quinine dihydrochloride 20 mg salt/kg (in 5 percent dextrose) loading dose over 4 hours, followed by 20 to 30 mg salt/kg divided into two to three equal administrations of 10 mg salt/kg (over 2 hours) at 8 or 12 hour intervals (maximum 1800 mg salt/day). Solutions diluted to 60 mg/mL quinine dihydrochloride are less painful than more concentrated preparations.
- Intravenous quinidine gluconate 10 mg salt/kg loading dose (maximum 600 mg salt) in normal saline over 1 hour, followed by 0.02 mg/kg/minute continuous infusion.
If intravenous infusions cannot be given, quinine can be administered via intramuscular injection. Two injections of 10 mg/kg quinine (diluted to 60 to 100 mg/mL) should be administered 4 hours apart. The anterior thigh is preferred over the gluteal region to minimize the risk of sciatic nerve damage.
Both quinine and quinidine can act as pancreatic secretagogues, leading to hyperinsulinemic hypoglycemia. Other toxic effects include tinnitus, reversible hearing loss, nausea, vomiting, dizziness, and visual disturbances. Quinidine can cause QT prolongation and should be administered with electrocardiographic monitoring. Infusions should be done with care and the rate should be reduced if the corrected QT interval becomes prolonged by more than 25 percent of the baseline value. Such monitoring is not necessary in the setting of quinine administration in patients without cardiac abnormalities.
The approach to parenteral treatment with quinine (or quinidine) depends on the clinical circumstances. For patients with malaria acquired in SE Asia, parenteral treatment with quinine (or quinidine) should be combined with one of the following: doxycycline, tetracycline or clindamycin. For children with malaria acquired in Africa, clinical management consists of administering parenteral quinine (at least three doses) until the child can swallow, followed by oral therapy with an artemisinin combination drug.
Prereferral treatment
The risk of death due to severe malaria is greatest in the first 24 hours of illness. In rural endemic areas where patients with severe malaria cannot begin intravenous therapy immediately, patients should be treated with a prereferral dose of intramuscular or intrarectal therapy and triaged to an acute care facility. Options include intramuscular administration of quinine or an artemisinin, or rectal administration of artesunate.
A single artesunate rectal suppository pending transport has been demonstrated to reduce mortality. This was illustrated in a randomized trial of over 12,000 patients in rural Bangladesh, Ghana and Tanzania with suspected severe malaria. Dosing consisted of 100 mg for children 6 months to 6 years of age and 400 mg for patients >6 years. Mortality was significantly lower among those who received prereferral rectal artesunate than among those who received placebo (1.9 versus 3.8 percent, respectively; risk ratio 0.49, 95 percent CI 0.32-0.77).
If referral is impossible, intramuscular or rectal treatment should be continued until the patient can tolerate oral medication, at which point a full course of oral therapy should be administered.
Completing therapy
In general, the total duration of therapy with quinine/quinidine for severe malaria is 7 days. The total duration of therapy with artemisinin based therapy is 3 days.
After the acute stage of illness has been treated with parenteral therapy and the patient can swallow, a course of oral therapy should be administered based on known susceptibility data to complete the treatment course. In general, the class of agent administered parenterally may be used for oral completion of therapy when feasible. Patients receiving parenteral quinine/quinidine can be transitioned to oral quinine, and those receiving parenteral artemisinin therapy can be transitioned to oral artemisinin combination chemotherapy.
Patients completing oral quinine treatment should also receive a second agent. Options for coadministration with quinine include 7 days of doxycycline or tetracycline (or clindamycin for children or pregnant women).
Alternatively, a full course of treatment with atovaquone-proguanil or mefloquine may be administered as for uncomplicated malaria.
Regimens containing mefloquine should be avoided if the patient presented with altered consciousness, since there is an increased incidence of neuropsychiatric toxic effects associated with mefloquine following cerebral malaria.
References: UTD