AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

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.

In the 1950s, the World Health Organization launched an ambitious plan to control or eradicate malaria. After initial successes, the plan foundered; today malaria is 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.

Pathophysiology

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 Plasmodium vivax and Plasmodium ovale infection, some sporozoites convert to dormant forms called hypnozoites, which can cause disease after months or years.

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, which causes 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. Plasmodium malariae needs 72 hours for each cycle, leading to the name quartan malaria. The other 3 species each take 48 hours for one 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.

Frequency

United States

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

International

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.

Mortality/Morbidity

• Cerebral malaria: Most of the mortality of malaria is due to this complication of Plasmodium falciparum malaria, 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 the parasite is susceptible is important to save the life of the child.
• Anemia: Anemia is so common in malaria that it is considered almost a part of the disease. The degree of anemia is much greater than can be explained by destruction of parasitized erythrocytes. Malarial anemia can be quite severe, sometimes causing death.
• Repeated frequent seizures: Even without cerebral malaria, a child can experience prolonged, frequent convulsions, which can lead to prostration and death.

Race

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

Sex

Malaria affects females and males equally.

Age

Children of all ages living in nonmalarious areas are equally susceptible to malaria. In endemic areas, children younger than 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, presence of plasmodia in the bloodstream without clinical manifestations of malaria. Most deaths resulting from malaria occur in children younger than 5 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

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.

• Prodrome: After the mosquito bite, children are asymptomatic while the parasites complete the liver cycle and one 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: Fever is usually continuous and may be very high (40°C) from the first day.
• Respiratory symptoms: 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.
• Gastrointestinal symptoms: Vomiting is very common in children with malaria, and it 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.
• Febrile convulsions: 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.
• Congenital malaria: 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.
• Malaria in immune children: Children living in an area where malaria is endemic have repeated 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.
• Relapses and recrudescences: 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.

Physical

• Fever: 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.
• Hepatomegaly: The liver may be slightly tender.
• Splenomegaly: Splenomegaly takes many days, especially in the first attack in nonimmune children. In children from an endemic area, huge splenomegaly sometimes occurs.
• Anemia: Prolonged malaria can cause anemia, and malarial anemia causes significant mortality.
• Jaundice: With heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria.
• Dehydration: High fever, poor oral intake, and vomiting all contribute to dehydration.

Causes

• 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
• Most malaria acquired in Africa is due to P falciparum. P vivax dominates in Asia and the Americas.
• Transmission of malaria
• • 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 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 may transmit malaria.
  • 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.
• Risk factors
• • Residence in, or travel through, a malarious area
  • No previous exposure to malaria (hence no immunity)
  • No chemoprophylaxis or improper chemoprophylaxis

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Ascending cholangitis
Enteric fever
Encephalitis
Heatstroke
Hepatitis
Lobar pneumonia
Pharyngitis
Viral pneumonia
Tonsillitis
Pelvic inflammatory disease

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Examination of blood smear
• • 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.
  • 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.
  • Various techniques to enhance the diagnostic utility 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.
• Serological tests
• • Serological tests provide confirmation of past malaria in patients and are valuable for epidemiological studies. These tests are also useful for screening donated blood and diagnosing hyperactive malarial splenomegaly. Among the tests used are the indirect fluorescent antibody test (IFAT), indirect hemagglutination antibody (IHA) test, enzyme-linked immunosorbent assay (ELISA), and the immuno-chromatographic test (ICT) for filariasis.
  • All these tests produce positive results several days after malaria parasites appear in the blood and so do not help in the diagnosis of the acute infection for treatment purposes.
• Dipstick tests
• • 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 both P falciparum and P vivax.
  • These tests have high sensitivity and specificity, require no special equipment or training, and produce results rapidly. However, they remain positive for a week or more after the treatment and cure, and, in this situation, can yield false-positive results.
• Molecular biological detection tests: DNA and RNA probes and polymerase chain reaction (PCR) have good sensitivity and specificity but require sophisticated expensive equipment.

Imaging Studies

• Imaging studies are not needed in malaria.

Other Tests

• 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.

Procedures

• 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 malaria parasites in these films.

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.

TREATMENT

Section 6 of 11  

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• Follow-up
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• References

Medical Care

• Children 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.
• 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 onset is gradual, the child withstands a low level of hemoglobin quite well, and blood transfusions are rarely needed. Standard hematinic therapy is effective.
• If repeated vomiting has led to dehydration, the child needs appropriate parenteral fluids to correct it. Glucose-containing fluids help counter the hypoglycemia that sometimes accompanies severe malaria. 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.
• 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.

Consultations

Consult an infectious diseases specialist.

Diet

• 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.

Activity

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.

MEDICATION

Section 7 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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. They act on the asexual forms in the erythrocytes and interrupt clinical attacks. Delay in treatment of P falciparum malaria can lead to development of severe malaria, which has a poorer prognosis than uncomplicated malaria. Chloroquine, quinine, quinidine, mefloquine, 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.

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 South East Asia may be quinine and mefloquine resistant as well; a combination of artesunate and mefloquine 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 requires eradication of these forms also. 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.

Treatment guidelines for malaria in the United States were recently updated by the Centers for Disease Control and Prevention (CDC).²

Drug Category: Antimalarials

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

Drug Name	Quinine (Quinamm)
Description	A blood schizonticidal drug and still the DOC 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 tabs containing 260 mg and as injections containing 300 mg/mL. Spreading resistance among P falciparum strains to this drug make the drug less reliable in certain parts of Asia and Africa.
Adult Dose	Treatment: 542 mg as base (650 mg salt) PO q8h for 7 d 10 mg/kg (as base) IV diluted in IV fluid and infused slowly q8h; not to exceed 600 mg; switch to PO therapy when patient can tolerate it to complete 7-d course
Pediatric Dose	Treatment: 8.3 mg as base/kg PO tid for 7 d (equivalent to 10 mg as salt/kg) Do not administer IM except as lifesaving measure in severe malaria while awaiting transport to hospital with requisite facilities 15-20 mg/kg IV diluted in IV infusion fluid to 1 mg/mL; infuse over at least 4 h; followed by 10 mg/kg/dose q8-12h if continuation beyond 48 h is needed; reduce dose to 5 mg/kg q8h; switch to PO therapy as soon as possible
Contraindications	Documented hypersensitivity; myasthenia gravis (possible respiratory distress and dysphagia); G-6-PD deficiency (possible severe hemolysis); tinnitus or optic neuritis
Interactions	Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates the potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other PO anticoagulants by decreasing synthesis of vitamin K–dependent clotting factors; digoxin serum concentrations may increase when digoxin is administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing a decrease in the metabolism of succinylcholine
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	PO use after meals to avoid gastritis; hyperinsulinemia and hypoglycemia; monitor blood glucose; ensure adequate PO intake; if administered parenterally, dilute in dextrose-containing solutions; possible urticaria, angioedema, and asthma even with single dose; possibly fatal orally with large dose, ie, 1 g base in children <5 y; monitor carefully if patient has cardiac dysrhythmia

Drug Name	Quinidine (Quinalan, Quinidex, Quinora)
Description	A stereoisomer of quinine and a blood schizonticidal drug, it 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 tabs of quinidine sulphate containing 200 mg. The injectable preparation is not always available.
Adult Dose	7.5 mg as base/kg/dose IV in IV fluid over 4 h q8h for 7 d (salt equivalent = 12 mg/kg)
Pediatric Dose	25-30 mg as base/kg/d PO in divided doses for 7 d 15 mg/kg diluted in IV infusion fluid over at least 4h followed by 7.5 mg/kg/dose q8-12h; switch to PO therapy as soon as possible, and complete 7-d course
Contraindications	Documented hypersensitivity; myasthenia gravis (possible respiratory distress and dysphagia); G-6-PD deficiency (possible severe hemolysis); AV block or bundle branch block
Interactions	Possible delayed absorption from GIT with coadministration of antacids containing aluminium; possible delayed excretion of digoxin, warfarin, and other anticoagulants; significantly reduced half-life possible with concomitant phenytoin and phenobarbital
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Possible hyperinsulinemia and hypoglycemia; monitor blood glucose; ensure adequate PO intake; if administered parenterally, quinidine should be diluted in dextrose-containing solutions; monitor cardiac activity

Drug Name	Pyrimethamine-sulfadoxine (Fansidar)
Description	Antifolate drug combination that is a slow-acting blood schizonticide, effective in some cases of chloroquine-resistant P falciparum malaria, especially those acquired in Africa. This drug is not effective against P vivax malaria. Being slow acting, this combination cannot be used in potentially severe cases. It has no activity against hypnozoites and gametocytes. It is available as tablets containing 25 mg of pyrimethamine and 500 mg of sulfadoxine.
Adult Dose	3 tab PO (75 mg pyrimethamine and 1500 mg sulfadoxine) as a single dose
Pediatric Dose	<2 months: Contraindicated >2 months: 1.5 mg/kg (based on pyrimethamine component) PO pyrimethamine as a single dose
Contraindications	Documented hypersensitivity; infants <2 mo; nursing mothers (drug passes the placenta, is excreted in milk, and may cause kernicterus); renal impairment; blood dyscrasias; hepatic damage
Interactions	Concurrent use of antifolic acids, such as methotrexate, and pyrimethamine may increase risk of bone marrow suppression; discontinue therapy if signs of folate deficiency develop; mild hepatotoxicity may occur with concomitant administration of lorazepam and pyrimethamine
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Possible severe, even fatal, cutaneous reactions (1 patient in 5000-8000), including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or epidermal necrolysis; reported fatalities with sulfonamide because of fulminant hepatic necrosis, agranulocytosis, and aplastic anemia; hepatitis and megaloblastic anemia can occur, especially with overdosage; not presently used for prophylaxis because of serious adverse effects

Drug Name	Primaquine
Description	The only drug in clinical use that destroys hypnozoites of both 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. Not to be used until erythrocytic forms have been destroyed by another drug. Primaquine is also 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, nor for more than 3 days after leaving it. This is an advantage for people making sudden or short trips.
Adult Dose	For radical cure of P vivax and P ovale malarias: 15 mg as base PO bid for 14 d To render patient noninfectious: 15 mg/d PO for 5 d for P falciparum infection As chemoprophylaxis, 0.5 mg as base/kg daily, starting on the day of entry to a malarious area
Pediatric Dose	For radical cure of P vivax and P ovale malarias: 0.3 mg/kg/d PO primaquine base for 14 d To render patient noninfectious: 0.3 mg/kg/d PO primaquine base for 5 d for P falciparum infection
Contraindications	Documented hypersensitivity; G-6-PD deficiency (significant hemolysis in these patients)
Interactions	Coadministration with quinacrine may increase toxicity, usually not of clinical significance
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Possible severe hemolysis with G-6-PD deficiency, anemia, and renal failure; bone marrow suppression; not to be used with other drugs having a marrow suppressing effect (eg, chloramphenicol); not used parenterally because of severe hypotension

Drug Name	Halofantrine (Halfan)
Description	A rapid-acting drug against erythrocytic forms of malaria. Primarily used for treatment of acute attacks of malaria caused by multidrug-resistant P falciparum. It is not active against hypnozoites and gametocytes. Because it is a slow acting drug and does not have a parenteral preparation available, the drug is not of use for severe and complicated malaria.
Adult Dose	500 mg PO q6h for 3 doses; repeat after 1 wk Administer on an empty stomach at least 1 h ac or 2 h pc
Pediatric Dose	<40 kg: 8 mg/kg PO q6h for 3 doses; not to exceed 500 mg/dose; repeat after 1 wk >40 kg: Administer as in adults Administer on empty stomach at least 1 h ac or 2 h pc
Contraindications	Documented hypersensitivity; heart block; QT prolongation; electrolyte disorders; AV conduction disorders; syncope; thiamine deficiency; ventricular dysrhythmias
Interactions	Mefloquine may interact with halofantrine, leading to potentially fatal prolongation of QTc interval
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	PO absorption unpredictable; possible poor absorption and efficacy with recommended doses; conversely, possible toxicity if absorption (and blood levels) are high; halofantrine prolongs QT interval, with possible ventricular arrhythmias and even death

Drug Name	Mefloquine (Lariam)
Description	It 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 its usefulness for severe and complicated malaria. It is available as tabs containing 250 mg.
Adult Dose	15-25 mg as salt/kg PO as single dose; not to exceed 1500 mg
Pediatric Dose	15-25 mg as salt/kg PO as single dose
Contraindications	Documented hypersensitivity; seizure disorders; neuropsychiatric disorders; cardiac conduction disorders
Interactions	Mefloquine administered with beta-blockers, quinine, quinidine, antiarrhythmics, tricyclic antidepressants, or astemizole may potentially cause ECG abnormalities or cardiac arrest; mefloquine and chloroquine administered concomitantly may increase risk of convulsions; concomitant administration with halofantrine may cause potentially fatal prolongation of the QTc interval; valproic acid administered with mefloquine can increase risk for seizures by reducing valproic acid blood levels
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Possible giddiness and disturbed balance; possibly hazardous to drive or operate machinery; monitor psychiatric symptoms with prolonged use; stop chemoprophylaxis if confusion, depression, anxiety, or restlessness occur; not to be used for >1 y (prophylaxis)

Drug Name	Artemether (Artenam)
Description	Effective against erythrocytic forms of all 4 human plasmodia but is used for multidrug-resistant P falciparum malaria. It has no action on hepatic forms or gametocytes. Very short elimination half-life, requiring follow-up treatment with mefloquine or treatment for at least 7 d.
Adult Dose	200 mg PO on day 1, followed by 100 mg qd for 5 d 3.2 mg/kg IM loading dose, followed by 1.6 mg/kg qd for 5 d, or until patient is able to take PO therapy
Pediatric Dose	4 mg/kg/d PO divided bid IM: Administer as in adults
Contraindications	Documented hypersensitivity; heart block; low leukocyte count
Interactions	Aurothioglucose mat increase the risk of blood dyscrasias
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Possible rash and fever

Drug Name	Artesunate (Lotio Artesan)
Description	Effective against blood forms of all 4 types of human malaria parasites. Special usefulness is its action against multidrug-resistant P falciparum. It has no action against hepatic schizonts, hypnozoites, or gametocytes. This drug is available as 50-mg tabs and IV injections containing 10 mg/mL. It has been found to be the fastest acting drug against blood forms of the malaria parasite, and so the IV form is especially valuable in the management of severe and complicated malaria. Resistance to this drug is also spreading, particularly in Southeast Asia. Combinations of artesunate with mefloquine, lumefantrine, and other drugs have been found to be effective against multidrug-resistant malaria.
Adult Dose	100 mg PO initial dose, followed by 50 mg q12h for 5 d Alternatively, 2.4 mg/kg IV loading dose, followed by 1.2 mg/kg after 12 h, then 1.2 mg/kg qd for 5 d, or until patient is able to take PO therapy
Pediatric Dose	4 mg/kg PO on day 1, followed by 2 mg/kg/d for 3-5 d Alternatively, 3.2 mg/kg IV on day 1; may be divided bid; then 1.6 mg/kg IV qd for 4 d (total 9.6 mg/kg)
Contraindications	Documented hypersensitivity; heart block; low leukocyte count
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Possible rash and fever; possible mild GI upset with PO use

Drug Name	Tetracycline (Achromycin V, Sumycin)
Description	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 are common. It is available as capsules containing 250 mg and 500 mg.
Adult Dose	250-500 mg PO q6h for 7 d
Pediatric Dose	<8 years: Do not use >8 years: 25-40 mg/kg/d PO divided qid for 7 d
Contraindications	Documented hypersensitivity; severe hepatic dysfunction; children <8 y
Interactions	Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (<8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Drug Name	Clindamycin (Cleocin)
Description	An antibiotic that acts against P falciparum. It 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 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.
Adult Dose	20 mg as base/kg/d PO divided tid for 7 d
Pediatric Dose	5-10 mg/kg PO q12h for 3-7 d
Contraindications	Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions	Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Drug Name	Atovaquone/proguanil (Malarone)
Description	Recently approved in the United States for the treatment and prophylaxis of malaria. Atovaquone 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 PO use only, and so can be used only for uncomplicated malaria, where it is very effective, even against resistant strains. It is also a useful drug for chemoprophylaxis. It is available as adult (250 mg atovaquone and 100 mg proguanil hydrochloride per tab) and pediatric (62.5 mg atovaquone and 25 mg proguanil hydrochloride per tab) formulations.
Adult Dose	Treatment of malaria: 4 adult Malarone tab PO as a single daily dose for 3 consecutive d Prophylaxis of malaria: 1 adult tab PO qd; start 2 d before traveling to a malarious area and continue for 7 d after leaving it
Pediatric Dose	Treatment of malaria: single daily dose PO for 3 consecutive d using adult strength tab as follows: 5-8 kg: 2 pediatric tab 9-10 kg: 3 pediatric tab 11-20 kg: 1 adult tab 21-30 kg: 2 adult tab 31-40 kg: 3 adult tab >40 kg: Administer as in adults Prophylaxis of malaria: start 2 d before traveling to a malarious area and continue for 7 d after leaving it; dosage is as follows: 11-20 kg: 1 pediatric tab qd 21-30 kg: 2 pediatric tab qd 31-40 kg: 3 pediatric tab qd >40 kg: 1 adult tab qd
Contraindications	Documented hypersensitivity; severe renal impairment; breastfeeding women
Interactions	Aurothioglucose mat increase the risk of blood dyscrasias
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Dose administered at same time every day with food or milk; abdominal pain, anorexia, nausea, vomiting, headache, and coughing; should not be used for treatment of malaria in persons using Malarone prophylaxis

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Malaria can be life threatening, and intensive care may be required. Indications for admission to ICU include the following:
• • Suspicion of cerebral malaria (ie, seizures, prolonged postictal coma, repeated seizures)
  • Complications of malaria (eg, bleeding, renal failure, pulmonary edema)
  • Heavy parasitemia: 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.
• Proof of cure blood smear examination
• • 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.
• Exchange transfusion
• • 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
• • This implies the destruction of the dormant forms in the liver.
  • Primaquine is the only drug active against the hypnozoites in the hepatocytes.

Transfer

• If appropriate drugs and experience in treating malaria are not available, the patient may need urgent transfer to a referral hospital.

Deterrence/Prevention

• Measures to prevent mosquito bites are very important for people living in or traveling through a malarious area.
• Chemoprophylaxis is never fully effective and is undermined by poor adherence and parasite resistance to almost all drugs. 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.
  • The CDC provides country-specific advice on malaria chemoprophylaxis.
  • Infants younger than 6 weeks should not be administered chemoprophylaxis.
• 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 on 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.
  • A vaccine for malaria would be a major medical advance, but it is proving elusive. Vaccines against various malarial antigens have been tried for many years, all around the world. Unfortunately, the immunity provided is inadequate and short lived. A vaccine with a good rate and duration of protection will not be available for some years yet.

Complications

• Cerebral malaria: 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 prolonged postictal state should raise suspicion of this dangerous entity. Cerebral malaria can be rapidly fatal, and trying drugs to which resistance is common is dangerous. Prompt diagnosis and immediate treatment with a drug known to be effective in the area where the malaria was acquired can be lifesaving. The presentation is varied and may suggest other conditions, such as meningitis, encephalitis, or epilepsy. Thus, cerebral malaria should be considered in the differential diagnosis of a febrile neurological illness if a history of residence or travel through a malarious area exists.
• Bleeding tendency: 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.
• Hemolysis: 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: Anemia is a faithful companion of malaria. Some children have anemia far exceeding that attributable to erythrocyte destruction by the malaria parasite. Other mechanisms of anemia are dyserythropoiesis, hypersplenism, shortened erythrocyte survival, and bone marrow suppression.
• Hypoglycemia: 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.
• Acute renal failure: 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.
• Pulmonary edema
• Hyperpyrexia
• Circulatory collapse (algid malaria)
• Jaundice

Prognosis

• 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 not treated quickly and completely, complicated and severe malaria can result, which carries a grave prognosis.
• Malaria in children younger than 5 years carries the worst prognosis in endemic areas. In a nonimmune population, malaria is equally deadly at all ages.
• Cerebral malaria has a mortality rate of 25%, even with the best treatment. Survivors may have sequelae (eg, hemiparesis, cerebellar ataxia, aphasia, spasticity).
• Repeated attacks of malaria can lead to chronic anemia, malnutrition, and stunted growth.

Patient Education

• 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).
• 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 excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Malaria.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Special Concerns

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

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  The various stages of Plasmodium life cycle are shown. Knowledge of the life cycle of the malarial parasite is essential to understanding the chemotherapy of malaria.
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Media type:  Chart

Media file 2:  The various stages of Plasmodium vivax as observed on Giemsa staining of a peripheral blood smear.
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Media type:  Illustration

Media file 3:  The various stages of Plasmodium falciparum as observed on Giemsa staining of a peripheral blood smear are shown. The presence of more than one parasite in an erythrocyte is unique to this species.
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Media type:  Illustration

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. World Health Organization. WHO Fact Sheet on Malaria. Fact Sheet No 94. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/fs094/en/print.html. Accessed June 29, 2007.
2. Griffith KS, Lewis LS, Mali S, Parise ME. Treatment of malaria in the United States: a systematic review. JAMA. May 23 2007;297(20):2264-77. [Medline]. [Full Text].
3. Eliades MJ, Shah S, Nguyen-Dinh P, et al. Malaria surveillance--United States, 2003. MMWR Surveill Summ. Jun 3 2005;54(2):25-40. [Medline]. [Full Text].
4. Emanuel B, Aronson N, Shulman S. Malaria in children in Chicago. Pediatr. 1993;92:83-85. [Medline].
5. Okie S. Betting on a malaria vaccine. N Engl J Med. Nov 3 2005;353(18):1877-81. [Medline]. [Full Text].
6. Thapa BR, Marwaha RK, Walia BN, et al. Falciparum malaria. Indian Pediatr. Mar 1987;24(3):221-5. [Medline].
7. Tracy JW, Webster LT. Malaria. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9^th ed. New York, NY: McGraw Hill; 1996:965-985.
8. Warrell DA. Treatment and prevention of malaria. In: Bruce-Chwatt's Essential Malariology. 3^rd ed. London, England: Edward Arnold; 1993:164-95.
9. Warrell DA. Clinical features of malaria. In: Bruce-Chwatt's essential malariology. 3^rd ed. London, England: Edward Arnold; 1993:35-49.
10. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. Feb 2005;81(952):71-8. [Medline]. [Full Text].

Article Last Updated: Oct 17, 2007