Pediatric Malaria

Malaria is an ancient scourge of humanity. Although almost eradicated from industrialized nations, malaria continues to extract a heavy toll of life and health in a substantial part of the world. Almost half the world's population lives in countries where the disease is endemic, and almost every country in the world encounters imported malaria. Children are the worst affected, especially children aged 6 months to 5 years. In parts of the world where malaria is endemic, it may cause as many as 10% of all deaths in children. (See Epidemiology.)

In the 1950s, the World Health Organization launched an ambitious plan to control or eradicate malaria. After initial successes, the plan foundered; malaria is now returning to areas where it was once controlled, and it is entering new areas. Because of plasmodial and mosquito resistance to drugs and insecticides, the danger of malaria has worsened, and the disease is now a major global problem. (See Deterrence and Prevention.)

Malaria is caused by Plasmodium species, which are protozoal blood parasites. The following 4 species can infect humans:

• P vivax

• P falciparum

• P malariae

• P ovale

The bite of an infected mosquito introduces asexual forms of the parasite, called sporozoites, into the bloodstream. Sporozoites enter the hepatocytes and form schizonts, which are also asexual forms. Schizonts undergo a process of maturation and multiplication known as preerythrocytic or hepatic schizogony. In P vivax and P ovale infection, some sporozoites convert to dormant forms, called hypnozoites, which can cause disease after months or years. The images below detail the various stages of the Plasmodium life cycle.

Preerythrocytic schizogony takes 6-16 days and results in the host cell bursting and releasing thousands of merozoites into the blood. Merozoites enter the erythrocytes and initiate another asexual reproductive cycle, known as erythrocytic schizogony. The parasite successively passes through the stages of trophozoite and schizont, ultimately giving rise to several merozoites. Upon maturation of these merozoites, the erythrocyte ruptures, releasing the merozoites and multiple antigenic and pyrogenic substances into the bloodstream.

These merozoites again infect new erythrocytes. After a few cycles of this erythrocytic schizogony, some merozoites differentiate into the sexual forms: the male and female gametocytes. A mosquito that takes a blood meal from a patient with gametocytemia acquires these sexual forms and plays host to the sexual stage of the plasmodial life cycle.

Rupture of a large number of erythrocytes at the same time releases a large amount of pyrogens, causing the paroxysms of malarial fever. The periodicity of malarial fever depends on the time required for the erythrocytic cycle and is definite for each species. P malariae needs 72 hours for each cycle, leading to the name quartan malaria. The other 3 species each take 48 hours for 1 cycle and cause fever on alternate days (tertian malaria). However, this periodicity requires all the parasites to be developing and releasing simultaneously; if this synchronization is absent, periodicity is not observed.

Most malaria acquired in Africa is due to P falciparum. P vivax dominates in Asia and the Americas. The bite of an infected female Anopheles mosquito transmits malaria. Species of mosquito capable of transmitting malaria are found in all 48 of the contiguous states of the United States.

Malaria can also be transmitted through blood transfusion. Among people living in malarious areas, semi-immunity to malaria allows donors to have parasitemia without any fever or other clinical manifestations. The malaria transmitted is by the merozoites, which do not enter the liver cells. Because the liver stage is not present, curing the acute attack results in complete cure. Organ transplantation is another malarial transmission route.

Transplacental malaria (ie, congenital malaria) can be significant in populations who are semi-immune to malaria. The mother may have placental parasitemia, peripheral parasitemia, or both, without any fever or other clinical manifestations. Vertical transmission of this infestation may be as high as 40% and is associated with anemia in the baby.

Zoonotic Malaria

There are several Plasmodium species that infect non-human primates. P. knowlesi is a malarial parasite of macaques, but it can be transmitted to humans and cause disease. This zoonotic disease was restricted to Malaysia and nearby parts of Asia, but is increasingly being seen in other parts of the world. P. cynomolgi is another zoonotic malaria infection, mainly reported from forest areas of Vietnam. Others are P. inui and P. coatneyi. These Plasmodium species are usually unable to infect humans because of inability to invade erythrocytes, but are overcoming these host barriers by producing the protein families required for erythrocyte invasion.

The disease can be cured by treatment with artemisinin combination therapy. These zoonotic malaria species are transmitted by non-usual mosquitoes. Two known species are Anopheles balabacensis and Anopheles dirus. The non-human reservoir and non-usual vectors have the potential to impede malaria control efforts.

Risk factors

Risk factors for malaria include the following:

• Residence in, or travel through, a malarious area

• No previous exposure to malaria (hence no immunity)

• No chemoprophylaxis or improper chemoprophylaxis

Approximately 1300 cases of malaria are diagnosed every year in the United States, most of them acquired outside the country. Only about 1% of patients acquire the infection in the United States; over half of the cases are acquired in Africa. Usually, fewer than 10 deaths from malaria are reported in the United States annually.

Malaria is a major health problem in Africa, Asia, Central America, Oceania, and South America. About 40% of the world's population lives in areas where malaria is common.[1] Approximately 300-500 million cases of malaria occur every year, and 1-2 million deaths occur, most of them in young children.

People of all races are affected by malaria, with some exceptions. People of West African origin who do not have the Duffy blood group are not susceptible to P vivax malaria.

Children of all ages living in nonmalarious areas are equally susceptible to malaria. In endemic areas, children younger than age 5 years have repeated and often serious attacks of malaria. The survivors develop partial immunity. Thus, older children and adults often have asymptomatic parasitemia (ie, the presence of plasmodia in the bloodstream without the clinical manifestations of malaria). Most deaths resulting from malaria occur in children younger than age 5 years.

A study found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. The study also reported that interventions have averted 663 million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor to the reduction in malaria related deaths.[2, 3]

Uncomplicated malaria due to P vivax,P malariae, and P ovale has an excellent prognosis. Most patients have a full recovery with no sequelae. Malaria due to P falciparum is dangerous; if it is not treated quickly and completely, complicated and severe malaria can result, which carries a grave prognosis.

Malaria in children younger than age 5 years carries the worst prognosis in endemic areas. In a nonimmune population, malaria is equally deadly at all ages. Repeated attacks of malaria can lead to chronic anemia, malnutrition, and stunted growth.

Acidosis, seizures, impaired consciousness, renal impairment, and pre-existing chronic diseases are associated with poor outcomes in children with severe malaria. Other markers of poor outcomes are hyperparasitemia, respiratory distress, young age, severe anemia, and hypoglycemia.[4]

Cerebral malaria, caused by P falciparum, has a mortality rate of 25%, even with the best treatment. Most of the mortality from malaria is due to this complication, an acute illness that is mostly observed in children aged 6 months to 3 years. Early diagnosis and prompt treatment with a drug to which P falciparum is susceptible is important to save the life of the child. Survivors may have sequelae (eg, hemiparesis, cerebellar ataxia, aphasia, spasticity).[5]

P falciparum causes sequestration of erythrocytes in the microvasculature of the brain (and other organs). Seizures and coma are common in a child with malaria, and a prolonged postictal state should raise suspicion of this dangerous entity. Even without cerebral malaria, prolonged, frequent convulsions in a child can lead to prostration and death.

A nonimmune child with heavy parasitemia sometimes develops generalized bleeding. Such bleeding is usually due to disseminated intravascular coagulation and is sometimes associated with a bacterial infection.

Some degree of hemolysis is part of malaria, but some children have excessive hemolysis, putting them at risk for renal failure. This hemolysis may be related to glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency or an antibody-mediated destruction of erythrocytes.

Anemia is so common in malaria that it is considered almost a part of the disease. Some children have anemia far exceeding that attributable to erythrocyte destruction by the malarial parasite. Other mechanisms of anemia are dyserythropoiesis, hypersplenism, shortened erythrocyte survival, and bone marrow suppression. Malarial anemia can be quite severe, sometimes causing death.

The malarial parasites consume glucose voraciously. Heavy parasitemia can result in hypoglycemia, which may be compounded by quinine and quinidine therapy. Hypoglycemia can be difficult to differentiate from cerebral malaria.

Blackwater fever is a condition of hemolysis and acute renal failure. It is rarely observed now, being more common when quinine was used for prophylaxis.

Other complications of malaria include the following:

• Pulmonary edema

• Hyperpyrexia

• Circulatory collapse (algid malaria)

• Jaundice

Advise persons visiting a malarious area regarding chemoprophylaxis and the need to continue the regimen for some weeks after leaving the area. Motivate travelers regarding chemoprophylaxis. Fewer than 20% of people diagnosed with imported malaria in the United States have taken recommended prophylaxis; more than 50% have taken no chemoprophylaxis at all.

Recommend mosquito bite avoidance measures (ie, mosquito nets with insecticides, mosquito coils, and appropriate clothing). In addition, advise persons visiting a malarious area regarding treatment of malaria and provide them doses of appropriate medicines to be started if attendance at a hospital is not immediately possible.

For patient education information, see Malaria.

Elicit any history of travel through, or immigration from, a malarious area. Even a few hours at an airport in an endemic area is significant. Obtain history of blood transfusion, organ transplantation, and (for newborns) malaria in the mother.

Young children manifest this disease in many different ways, but the classic picture of malaria, with periodic fever, shivering, and sweating, is not observed. Malaria can mimic any febrile illness and should be suspected in any febrile child who has recently been in a malarious area. Older children may manifest the classic periodicity of fever with chills and shivering.

After the mosquito bite, children are asymptomatic while the parasites complete the liver cycle and 1 erythrocytic cycle, which takes 8-18 days, depending on the species. Children then become restless, drowsy, apathetic, and anorexic. Older children may report aching body, headache, and nausea.

Fever is usually continuous and may be very high (40°C) from the first day. Many children have only flulike respiratory symptoms at presentation, with mild cough and cold. These symptoms abate in 1-2 days, with or without treatment.

Vomiting is very common in children with malaria and may make oral therapy ineffective. Mild diarrhea is often observed, with dark green mucoid stools. Occasionally, profuse diarrhea with dehydration and circulatory failure is observed.

Seizures are common and may occur at the onset of the disease, even before high fever has set in. Differentiating postictal impairment of consciousness from cerebral malaria is often difficult.

Parasitemia in neonates within 7 days of birth implies transplacental transmission. This congenital malaria is usually associated with placental parasitemia, which sometimes persists even after adequate treatment with antimalarial drugs. Babies have fever, are irritable, refuse feeds, and often develop anemia, jaundice, and hepatosplenomegaly.

Children living in an area where malaria is endemic have frequent infections and develop and maintain partial immunity. These children often develop only a low-grade fever, anemia, poor appetite, and malaise. Tiredness, restlessness, cough, and diarrhea are other symptoms that may occur.

Depending on the species of Plasmodium involved, relapses and recrudescences vary in their effects. P vivax and P ovale both give rise to hypnozoites in the liver. P vivax malaria may relapse for up to 3 years and P ovale for 1-1.5 years. P falciparum and P malariae do not form hypnozoites, so they do not have true relapses. However, the disease recrudesces because of surviving erythrocytic forms.

Although P falciparum can recrudesce for up to 1 year, P malariae may continue to cause clinical malarial attacks even 20 years after the original infection. Only the sporozoites (introduced by the mosquitoes themselves) can penetrate the liver cells. Thus, if malaria is acquired by blood transfusion or transplacentally, no infection of the liver occurs and relapses do not occur.

Fever can be very high from the first day. Temperatures of 40°C and higher are often observed. Fever is usually continuous or irregular. Classic periodicity may be established after some days. High fever, poor oral intake, and vomiting all contribute to dehydration.

The liver may be slightly tender. Splenomegaly takes many days, especially in the first attack in nonimmune children. In children from an endemic area, severe splenomegaly sometimes occurs.

Prolonged malaria can cause anemia. Also, with heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria.

Demonstration of the parasite in a smear of the blood definitely establishes the presence of malaria. A negative finding on examination does not rule out malaria. Only 50% of children with malaria have positive smear findings, even on repeated examination.

Asymptomatic parasitemia is common in children from an endemic area who have partial immunity to the disease. A positive smear for malaria parasite does not always confirm a diagnosis of malaria in these children. More importantly, a positive smear should not stop the diagnostic effort in a febrile illness.

Lumbar puncture is indicated to rule out meningitis in cerebral malaria and febrile seizures with malaria. Severe P falciparum malaria is often associated with hypoglycemia. Lower blood glucose levels are associated with higher mortality rates.

Serologic tests provide confirmation of past malaria in patients and are valuable for epidemiologic studies. These tests are also useful for screening donated blood and diagnosing hyperactive malarial splenomegaly. Among the tests used are:

• Indirect fluorescent antibody test (IFAT)

• Indirect hemagglutination antibody (IHA) test

• Enzyme-linked immunosorbent assay (ELISA)

• Immuno-chromatographic test (ICT) for filariasis

All of these tests produce positive results several days after malarial parasites appear in the blood and so do not help in the diagnosis of the acute infection for treatment purposes.

Dipstick tests based on the detection of P falciparum histidine-rich protein-2 (PfHRP-2) antigen are specific for P falciparum infections and do not detect the other 3 species. Dipstick tests based on the detection of parasite lactate dehydrogenase are now available; these tests can detect P falciparum and P vivax. These tests have high sensitivity and specificity, require no special equipment or training, and produce results rapidly. They offer an advantage where the disease is uncommon and blood smear examination expertise is not readily available. However, they remain positive for a week or more after the treatment and cure and, in this situation, can yield false-positive results.

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) probes and polymerase chain reaction (PCR) assays have good sensitivity and specificity but require sophisticated expensive equipment.

Both thick and thin films are essential. If the parasitemia is light, a thin film examination may miss the diagnosis. Thick films save time in diagnosis of scanty infections but make species identification of the parasite difficult. At least 100-200 fields of a thick film should be scrutinized before a slide is reported as negative for malaria. In doubtful cases, the examination can be repeated after 4 hours.

Obtaining thick and thin blood films at the bedside is important. These films may have to be taken repeatedly for diagnosis. Earlobe or finger prick is used for older children; the great toe is used in infants.

Take a large drop of blood on one end of a clean slide, spread uniformly, and air-dry. A smaller drop should be spread thinly so that the end of the smear does not reach the end of the slide. Giemsa staining is suitable for identifying malarial parasites in these films.

Various techniques to enhance the diagnostic value of the peripheral blood smear examination are in use. Fluorescent staining and microscopy, centrifugation, selective magnetic separation techniques, and other techniques have been used but have only a moderate effect.

Histologic findings

The appearance of the parasite varies in the thick and thin films. The thick unfixed film shows only leucocytes and parasites; erythrocytes are destroyed in the staining process. The parasites themselves are also altered.

Young trophozoites appear as incomplete rings or spots of blue cytoplasm with discrete red nuclei. In mature trophozoites, the cytoplasm may be fragmented, and the various characteristics of the different species are often indistinct.

Gametocytes and schizonts usually retain their characteristic appearances. Thin film examination is essential for the accurate identification of plasmodial species, which has an important bearing on treatment.

Oral paracetamol (acetaminophen) is safe and effective for fever and should be used in doses of 10 mg/kg. This dose can be repeated 3-6 times a day, as required. If the child has hyperpyrexia, tepid sponging can rapidly bring the temperature down.

Many children with malaria develop anemia. Because the onset is gradual, children withstand a low level of hemoglobin quite well and blood transfusions are rarely needed. Standard hematinic therapy is effective.

Vomiting is common in malaria. An antiemetic such as domperidone can be used, and antimalarials should be continued. Vomiting stops when the malaria is cured. If repeated vomiting has led to dehydration, the child needs appropriate parenteral fluids to correct it. Glucose-containing fluids help to counter the hypoglycemia that sometimes accompanies severe malaria.

Indications for immediate hospitalization include the following:

• Intractable vomiting

• Dehydration

• Seizures

• Altered consciousness or coma

• Repeated convulsions

• Difficulty in breathing or acidotic breathing

• Severe pallor (indicating severe anemia)

• Hypoglycemia (blood glucose < 2.5 mmol/L, or 3 mmol/L in malnourished children)

• Oliguria or anuria, signifying renal affliction

• Shock

• Hyperparasitemia

• Bleeding diathesis

In a child with malaria, impaired consciousness, respiratory distress, hypoglycemia, and jaundice are risk factors for death. Such a child should be treated as an emergency. On the other hand, children with malaria who are fully conscious, who have low to moderate fever, and who are maintaining their nutrition and hydration orally can be treated on an outpatient basis.

Malaria can be severe in pregnancy. This is a major problem because many antimalarial drugs are considered unsafe during pregnancy.

Severe malaria is known to be associated with bacteremia and may be the cause of a sudden deterioration. The coexisting bacterial infection is difficult to diagnose clinically, especially in children, as the clinical features overlap to a significant extent. The World Health Organization (WHO) recommends a low threshold for starting antibiotic treatment in children with severe malaria. Salmonella species are commonly encountered, but other organisms are also frequently isolated; initial empiric therapy should be broad spectrum.[6]

No restrictions are needed in the diet for patients well enough for outpatient management. Indeed, the appetite and activity level are remarkably well preserved for the degree of fever. Advise increased fluid intake. Children should be allowed to decide their own activity levels. If the fever is intermittent, many children feel quite well between paroxysms of fever and come to no harm through activity.

Consult an infectious diseases specialist for patients with malaria. With regard to patient transfer, if appropriate drugs and experience in treating malaria are not available, the patient may need urgent transfer to a referral hospital.

Malaria can be life threatening, and intensive care may be required. Indications for admission to the intensive care unit (ICU) include the following:

• Suspicion of cerebral malaria (ie, seizures, prolonged postictal coma, repeated seizures)

• Complications of malaria (eg, bleeding, renal failure, pulmonary edema)

Admit patients from nonmalarious areas to the ICU if more than 2% of erythrocytes have malaria parasites. Patients from an endemic area can tolerate higher levels, but patients should be admitted to the ICU if more than 5% of erythrocytes are parasitized.

Blood smears should be repeated after 24-48 hours to ensure that the drug is effective. This is especially important with P falciparum. If parasites are not cleared in 48 hours, a change in drug is required.

An exchange transfusion is valuable in a very sick child. It reduces parasite load rapidly, corrects any bleeding diatheses, and corrects anemia. Erythrocytapheresis, the use of cell separation techniques to remove only the erythrocytes, has been used successfully in adults. It removes the parasites and has the added advantage of hemodynamic stability.

Radical cure implies the destruction of the dormant forms in the liver. Primaquine is the only drug active against the hypnozoites in the hepatocytes.

Measures to prevent mosquito bites are very important for people living in or traveling through a malarious area.

Chemoprophylaxis is undermined by poor adherence and parasite resistance to almost all drugs, and is not fully dependable on its own. Therapy should be started a week before entering a malarious area and continued for 4 weeks after leaving it.

Chloroquine is the most commonly used drug, at a dose of 5 mg/kg once a week; however, significant resistance to it is now present. Mefloquine (5 mg/kg once a week) is recommended in areas where chloroquine resistance is common. Mefloquine may cause adverse neuropsychiatric reactions and should not be prescribed for prophylaxis in patients with active or recent history of depression, generalized anxiety disorder, psychosis, or schizophrenia or other major psychiatric disorders.[7] The CDC provides country-specific advice on malaria chemoprophylaxis. Infants younger than 6 weeks should not be administered chemoprophylaxis.

In July 2018, the FDA approved tafenoquine, an antiplasmodial 8-aminoquinoline derivative 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 for acute P vivax infection. The drug is active against all stages of the P vivax life cycle. Tafenoquine is administered as a single oral dose on the first or second day of appropriate antimalarial therapy (eg, chloroquine) for acute P vivax malaria. Approval was based on an international programme of over 4000 participants.

In 1 of the clinical trials, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 89.2% with tafenoquine 300 mg and 91.9% with tafenoquine 600 mg compared with chloroquine alone (37.5%). The results showed a significantly improved treatment difference compared with chloroquine alone of 51.7% (p < 0.0001) with tafenoquine 300 mg and 54.5% (p < 0.0001) with tafenoquine 600 mg.[8]

Because tafenoquine increases risk of hemolytic anemia in patients with G6PD deficiency, patients must be tested before initiating the drug. The drug is contraindicated in patients with G6PD deficiency (or unknown status), during breastfeeding of an infant with G6PD deficiency (or unknown status), and those with known hypersensitivity.[9]

Prevention of mosquito bites is the most effective means of individual malaria protection. Cover the body while outdoors. Wear full-length sleeves and trousers. Clothes can also be treated with an insecticide, such as permethrin, which is safe for this purpose. Diethyl-m-toluamide (DEET) is an effective mosquito repellent when applied to the skin.

Increased precautions are needed during the night, because Anopheles species are nocturnal in habit. Sleeping under insecticide-treated (permethrin 0.2 g/m2 of material every 6 mo) mosquito nets is perhaps the most beneficial antimalarial measure available. Bedrooms should be sprayed with an aerosol insecticide at dusk.

Malaria vaccines

Vaccines against various malarial antigens have been tried for many years, all around the world. In one study, the use of the RTS,S/AS02D vaccine had a promising safety profile and reduced malaria infections.[10] Other vaccines have been tried and abandoned, and several are currently under evaluation. Unfortunately, the immunity provided by candidate malaria vaccines is inadequate and short lived. A safe, effective vaccine that provides reliable, long-lasting protection against malaria has proven elusive and will probably not be available for some years yet.

Interim phase 3 trial results have been reported for the malaria vaccine RTS,S/AS01. The results included 6000 African children aged 5-17 months who received the malaria vaccine or a comparator vaccine and were followed for 12 months. The incidence of malaria was 0.44 case per person-year in the RTS,S/AS01 group, compared with 0.83 case per person-year in the comparator vaccine group. The vaccine efficacy rate was calculated to be 55.8%.[11, 12]

Blood schizonticides are the first-line drugs for the treatment of malaria and must be started as soon as the diagnosis is made, or even suspected, in severe disease. They act on the asexual forms in the erythrocytes and interrupt clinical attacks. Delay in treatment of P falciparum malaria can lead to the development or worsening of severe malaria, which has a poorer prognosis than uncomplicated malaria. Chloroquine, quinine, quinidine, halofantrine, and artemisinin compounds are the rapidly acting drugs that can terminate an acute malaria attack. While chloroquine acts rapidly, resistance is widespread, and an accurate travel history should be obtained before choosing the antimalarial drug.[13]

Malaria imported from Asia or the Americas is mostly P vivax and is chloroquine responsive. Malaria acquired in Africa is mostly P falciparum and is chloroquine resistant; quinine is an effective drug. P falciparum malaria incurred in Southeast Asia may be quinine and mefloquine resistant as well; a combination of artesunate and mefloquine, or artesunate and lumefantrine, is recommended. Time wasted in trials of a drug to which the parasite is resistant can result in a poor outcome, including death.

P vivax and P ovale have dormant stages (hypnozoites) in the liver, and the treatment of an episode of malaria must include eradication of these. The classic treatment is a 3-day course of chloroquine, followed by a 14-day course of primaquine. A shorter course of 5 days of primaquine, started with chloroquine, has been described but is associated with higher relapse rates. However, this is adequate for gametocidal action, which prevents spread of malaria.

Tafenoquine, an antiplasmodial 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 for acute P vivax infection.[8, 9]

Intravenous (IV) artesunate is superior to quinine in the treatment of severe malaria in children and adults. Artesunate IV was officially approved by the US Food and Drug Administration (FDA) in May 2020 (it was previously available from the Centers for Disease Control and Prevention [CDC] through an Investigational New Drug [IND] protocol). It is indicated for the initial treatment of severe malaria in adults and children.

Approval was based the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) and the African Quinine Artesunate Malaria Trial (AQUAMAT). These 2 studies examined a total of 6,886 patients and included adults, children, and pregnant women. Artesunate IV reduced mortality by 34.7% (P=.0002) and 22.5% (P=.002) compared with quinine in the SEAQUAMAT and AQUAMAT studies, respectively.[14, 15]

Class Summary

Blood schizonticides are the first-line drugs for the treatment of malaria.

Chloroquine (Aralen)

This drug is effective against the erythrocytic forms of the parasite and is the drug of choice for P vivax, P malariae, and P ovale malaria, against which it is gametocidal as well. It is not effective against hypnozoites. It is very effective against sensitive strains of P falciparum. However, P falciparum resistance to chloroquine is now widespread in Africa and Asia, and it should not be depended on in severe malaria. Resistance to this drug in P vivax has also been reported, but resistance is currently rare.

Chloroquine can be used as a suppressive prophylactic agent, with the advantage of once-weekly dosing. It is recommended for such use only in regions where drug resistance is not common (parts of Central America, the Caribbean, parts of the Middle East). It is available as tablets that contain 300 mg of the base and injections that contain 40 mg base/mL.

Quinine (Qualaquin)

Quinine is a blood schizonticidal drug and is still the drug of choice for severe and complicated malaria in most parts of the world. It is gametocidal for P vivax and P malariae but not for P falciparum. It is available as tablets containing 260 mg and as injections containing 300 mg/mL. Spreading resistance among P falciparum strains to this drug make quinine less reliable in certain parts of Asia and Africa.

Quinidine

A stereoisomer of quinine and a blood schizonticidal drug, quinidine is as effective as quinine against blood schizonts but has significantly more cardiac toxicity. This agent is used if quinine is not readily available. It is available as tablets of quinidine sulphate containing 200 mg. The injectable preparation is not always available.

Primaquine

Primaquine is the only drug in clinical use that destroys hypnozoites of P vivax and P ovale and so is used for the radical cure of the relapsing malarias. It is also gametocidal against all 4 species of human plasmodia and is used to render patients noninfectious. Primaquine has a very weak effect against erythrocytic forms of P vivax and cannot be used to terminate an acute attack. It has no activity against erythrocytic forms of P falciparum. This drug can be administered to patients on chemoprophylaxis after they have left the endemic area. It is not to be used until erythrocytic forms have been destroyed by another drug.

Primaquine is an effective and fairly safe drug for chemoprophylaxis. Since it acts on the liver forms, it need not be taken before entering a malarious area or for more than 3 days after leaving it. This is an advantage for people making sudden or short trips.

Mefloquine

Mefloquine is useful for the treatment of multidrug-resistant P falciparum infections. It is effective against blood schizonts but has no activity against hypnozoites and gametocytes. Its long half-life makes it suitable for use as a prophylactic drug, and it is the recommended drug in areas where drug resistance is common (chiefly Africa and Asia). Not having a parenteral preparation limits mefloquine's usefulness for severe and complicated malaria. Mefloquine may cause adverse neuropsychiatric reactions, which may be difficult to identify in children; monitor for symptoms, especially in nonverbal children. The drug is available as tablets containing 250 mg.

Artesunate

Artesunate is effective against blood forms of all 4 types of human malaria parasites. Its special usefulness is against multidrug-resistant P falciparum. It has no action against hepatic schizonts, hypnozoites, or gametocytes. This drug is available as 50-mg tablets (outside of the US) and IV injections containing 10 mg/mL.

Artesunate has been found to be the fastest-acting drug against blood forms of the malarial parasite, and so the IV form is especially valuable in the management of severe and complicated malaria.

However, resistance to this drug is spreading, particularly in Southeast Asia. Used alone, artesunate is associated with a high recrudescence rate. It is also feared that solo use will hasten the development of parasite resistance. Combinations of artesunate with mefloquine, lumefantrine, and other drugs have been found to be effective against multidrug-resistant malaria.

It is indicated for initial treatment of severe malaria in adults and children. Once the patient can tolerate oral therapy, a complete treatment course of an appropriate oral antimalarial regimen should always follow artesunate.

Tetracycline

Tetracycline is an antibiotic with action against blood schizonts of all species of malaria. Its action is slow and it is used in combination with another drug, such as quinine, in areas where resistant P falciparum is common. It is available as capsules containing 250 mg and 500 mg.

Clindamycin (Cleocin)

This is an antibiotic that acts against P falciparum. Clindamycin has been found to be very effective in combination with quinine, even against malaria acquired in areas where drug resistance is common. Used in combination, it shortens the duration of fever and improves cure rates. This is an important drug for use in children, because tetracyclines are contraindicated. It is available as capsules containing 75 mg, 150 mg, and 300 mg and as granules that, after reconstitution with water, contain 75 mg/5 mL.

Atovaquone and proguanil (Malarone)

Atovaquone was recently approved in the United States for the treatment and prophylaxis of malaria. It has significant parasiticidal activity. Proguanil and atovaquone have high failure rates when used alone but are very successful in combination. Combining them also reduces the selection of resistant mutants.

Malarone is available for oral use only and so can be used only for uncomplicated malaria, against which it is very effective, even when used to fight resistant strains. It is also a useful drug for chemoprophylaxis. It is available in adult (250 mg atovaquone and 100 mg proguanil hydrochloride per tablet) and pediatric (62.5 mg atovaquone and 25 mg proguanil hydrochloride per tablet) formulations.

Artemether and lumefantrine (Coartem)

This combination is indicated for the treatment of acute, uncomplicated P falciparum malaria, the most dangerous form of malaria. It contains a fixed ratio of 20 mg of artemether and 120 mg of lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartemisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta hematin. Artemether and lumefantrine have been shown to be effective in geographic regions where resistance to chloroquine has been reported.

Tafenoquine (Krintafel)

Tafenoquine is an 8-aminoquinoline derivative 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 for acute P vivax infection. The drug is active against all stages of the P vivax life cycle, including hypnozoites.