At present, quinine remains the drug of choice for the treatment of severe and complicated malaria in most parts of the world. It should always be given by rate-controlled infusion, never by bolus (“push”) intravenous injection. It may also be given intramuscularly diluted to 60-100 mg/ ml. Quinine is safe in pregnancy.
Mild side-effects are common, notably cinchonism (tinnitus, hearing loss, dizziness, nausea, uneasiness, restlessness and blurring of vision); serious cardiovascular and neurological toxicity is rare. Hypoglycaemia is the most serious frequent adverse side-effect. In suspected quinine poisoning, activated charcoal given orally or by nasogastric tube accelerates elimination.
Artemisinin and its derivatives may be administered intrarectally. Suppository formulations of artemisinin, developed originally in China, have proved highly effective in clinical trials in adults and children with severe malaria in Viet Nam in dosages ranging from 10 to 40 mg/kg of body weight. However, more studies are needed to determine the optimal dosage and schedule of administration. The therapeutic response has been as rapid as that following parenteral administration of artesunate and artemether, and the suppositories have been well tolerated. Artemisinin derivatives do not induce hypoglycaemia in pregnancy although there is still very little information on their use in pregnancy. To date there is no reason to withhold these drugs from pregnant women with severe malaria.
Artesunate is now becoming more widely used and is available in oral, intramuscular and intravenous formulations. It is rapidly absorbed with an accelerated parasite clearance time when compared with quinine. The drug is well tolerated with no attributable local or systemic adverse effects. Studies evaluating a suppository formulation of artesunate gel in a gelatin-covered capsule (rectocap) are currently in progress in which adult patients with severe malaria have been treated with 200-mg rectocaps in a total dose ranging from 1200 to 1600 mg over 60-72 hours. However, more studies are needed to determine the optimal dosage and schedule of administration.
Artemether is available in oral and intramuscular formulations. Its efficacy, side-effects and availability are similar to artesunate except that the parenteral formulation is oil-based and may be inadequately or erratically absorbed following intramuscular injection in severely ill patients. Studies evaluating the intrarectal administration of the parenteral formulation of artemether in a dosage of 10 mg/ kg of body weight are currently in progress.
Sulfadoxine-pyrimethamine (500 mg + 25 mg)
Sulfadoxine-pyrimethamine should preferably not be given in the first trimester of pregnancy. Sulfonamides should not be given directly to neonates because of the risk of ker-nicterus, but sulfonamide treatment of a lactating woman does not pose a threat to her breastfed neonate unless there is jaundice, prematurity or G6PD deficiency. Theoretically, there might be a risk of kernicterus if sulfonamides were administered in late pregnancy, just before delivery; however, there has been no documented case of this complication. An intramuscular preparation exists and may be useful for treatment of severe malaria if quinine or artemisinin derivatives are not available or cannot be given safely. When the contra-indications to the use of this drug are respected, and when this drug combination is used as a single-dose treatment for malaria in the prescribed manner, severe reactions are rare.
Chloroquine in tablet form is still the most widely prescribed antimalarial drug in the tropics. Despite parasite resistance, it provides symptomatic relief and reduces morbidity and mortality in many endemic areas where resistance is predominantly RI or RII. Its safe use in severe malaria is restricted to Central America where parasite resistance has not been demonstrated. In severe disease, chloroquine, like quinine, should always be given by slow, rate-controlled intravenous infusion and never by bolus (“push”) injection. It can also be given intramuscularly or subcutaneously at a lower dosage than that recommended for intravenous infusion (see inside front cover flap). Oral therapy should be substituted as soon as possible; crushed chloroquine tablets can be given by nasogastric tube if injection is not possible. Immediate side-effects include nausea, vomiting, headache, uneasiness, restlessness, blurred vision, hypotension and pruritus. Acute chloroquine poisoning is manifested by coma, convulsions, dysrhythmias and hypotension.
Mefloquine is effective against all malarial species including multidrug-resistant P. falciparum. Structurally, it resembles quinine. Naturally resistant parasite populations have been reported in various parts of the tropics. It is available only in tablet form. Toxic effects include nausea, abdominal discomfort, vertigo, insomnia and malaise. Acute psychosis and a transient encephalopathy with convulsions are serious but generally short-lived side-effects. In severe malaria a post-malarial neurological syndrome has been reported in Viet Nam, where mefloquine was used to complement parenteral therapy (with artesunate and artemether).