eMedicine Specialties > Infectious Diseases > Parasitic Infections

Malaria

Emilio V Perez-Jorge, MD, FACP, Fellow, Infectious Disease, Wright State University Boonshoft School of Medicine, Veterans Affairs Medical Center
Thomas Herchline, MD, Professor of Medicine, Wright State University Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio

Updated: Apr 29, 2009

Introduction

Background

Malaria, which predominantly occurs in tropical areas, is a potentially life-threatening disease caused by infection with Plasmodium protozoa transmitted by an infective female Anopheles mosquito vector. Individuals with malaria may present with fever and a wide range of symptoms.

The 4 Plasmodium species known to cause malaria include Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. A fifth species, Plasmodium knowlesi, has recently been identified as a clinically significant pathogen in humans.¹ Timely identification of the infecting species is extremely important, as P falciparum infection can be fatal and is often resistant to standard chloroquine treatment. In some cases, individuals with malaria are infected with multiple Plasmodium species. P falciparum and P vivax are responsible for most new infections. Each Plasmodium species has a defined area of endemicity, although geographic overlap is common. Species can usually be distinguished by morphology on a blood smear. P falciparum is distinguished from the rest of plasmodia by its high level of parasitemia and the banana shape of its gametocytes.

Malaria in travelers typically manifests weeks after the individual leaves the endemic area. Presentation more than 4 weeks after returning from the endemic area is unusual. In some individuals, disease manifests months or years later, usually due to the presence of P vivax or P ovale hypnozoites, which can remain dormant in the liver and reactivate years after infection. Relapse with P vivax or P ovale infection is rare more than 5 years after initial infection. Because symptomatic delay is common, history of even a remote exposure to an endemic area should be elicited. Symptoms of malaria are nonspecific, and, because timely diagnosis and treatment are necessary, malaria should be considered in all patients from tropical areas who present with fever.

Pathophysiology

Individuals with malaria typically acquired the infection in an endemic area following a mosquito bite. Cases of airport malaria and infection secondary to transfusion of infected blood are extremely rare. The risk of infection depends on the intensity of malaria transmission and the use of precautions such as bed nets, diethyl-meta-toluamide (DEET), and malaria prophylaxis.

After a mosquito takes a blood meal, the malarial sporozoites enter hepatocytes (liver phase) within minutes and then emerge in the bloodstream after a few weeks. These merozoites rapidly enter erythrocytes and develop into trophozoites and then into schizonts over a period of days inside erythrocytes during the erythrocytic phase of the life cycle. Rupture of infected erythrocytes containing the schizont results in fever and merozoite release. The merozoites enter new red cells, and the process is repeated, resulting in a logarithmic increase in parasite burden.

The outcome of infection depends on host immunity. Individuals with immunity can spontaneously clear the parasites. In those without immunity, the parasites continue to expand the infection. P falciparum infection can result in death. A small percentage of parasites become gametocytes, which undergo sexual reproduction when taken up by the mosquito. These can develop into infective sporozoites, which continue the transmission cycle after a blood meal in a new host.

The mechanisms that underlie immunity remain poorly defined. Additionally, individuals who develop immunity to malaria who then leave the endemic area may lose protection. Travelers who return to an endemic area may request a test to demonstrate immunity; however, no reliable markers of immunity exist, and waning of immunity should be kept in mind when these patients are advised.

Each Plasmodium species has a specific incubation period. Reviews of travelers returning from endemic areas have reported that P falciparum infection typically develops within one month of exposure, thereby establishing the basis for continuing antimalarial prophylaxis for 4 weeks upon return from an endemic area. This should be emphasized to the patient to enhance posttravel compliance.

Rarely, P falciparum causes initial infection up to a year later. P vivax and P ovale may emerge weeks to months after the initial infection. In addition, P vivax and P ovale have a hypnozoite form during which the parasite can linger in the liver for months before emerging and inducing recurrence after the initial infection. In addition to treating the organism in infected blood, treating the hypnozoite form with a second agent (primaquine) is critical to prevent relapse from this latent liver stage. A useful diagram of the different stages of the parasites can be found at the CDC Malaria site.

P falciparum infection typically causes severe malaria. This species is more virulent because it may create high levels of parasitemia and sequestration that contribute to end-organ damage. Sequestration is a specific property of this species. As it develops through the 48-hour life cycle, it demonstrates adherence properties, which result in the sequestration of the parasite in small postcapillary vessels. For this reason, only early forms are observed in the peripheral blood, before the sequestration property develops; this is an important diagnostic clue that the patient is infected with P falciparum.

Sequestration of parasites may contribute to mental-status changes and coma, observed exclusively in P falciparum infection. In addition, cytokines and a high burden of parasites contribute to end-organ disease. End-organ disease may develop rapidly in patients with P falciparum infection, and it specifically involves the central nervous system (CNS), lungs, and kidneys. Other manifestations of P falciparum infection include hypoglycemia, lactic acidosis, severe anemia, and multiorgan dysfunction due to hypoxia. These severe manifestations may occur among travelers without immunity or young children who live in endemic areas.

Frequency

United States

Malaria was endemic in the southern United States until the 19th and early 20th centuries, but it has since been eradicated. Almost all US cases of malaria are imported from patients traveling from endemic areas. In some cases, infections in individuals who have not traveled occur near airports (so-called airport malaria). This is secondary to a local mosquito becoming infected through a blood meal from an infected traveler or a plane with an infected mosquito; this mosquito then takes a blood meal from a local nontraveling resident and transmits the infection.

Each year, 25-30 million people travel to tropical areas, and approximately 10,000-30,000 US and European travelers acquire malaria.

International

Approximately 40% of the world's population live in endemic areas and are at risk for malaria. An estimated 350-500 million malaria cases occur each year, and more than one million people die of the infection.²

Mortality/Morbidity

Malaria is responsible for approximately 1-3 million deaths per year, typically in children in sub-Saharan Africa infected with P falciparum. Populations at an increased risk for mortality due to malaria include primigravida individuals, travelers without immunity, and young children aged 6 months to 3 years who live in endemic areas.

Age

Young children aged 6 months to 3 years who live in endemic areas are at an increased risk of death due to malaria. Travelers without immunity are at an increased mortality risk, regardless of age.

Clinical

History

• In patients with suspected malaria, obtaining a history of recent or remote travel to an endemic area is critical. Asking explicitly if they have traveled to a tropical area anytime in their life may enhance recall.
• Patients with malaria typically become symptomatic a few weeks after infection, although the host's previous exposure or immunity to malaria affects the symptomatology and incubation period. In addition, each Plasmodium species has a typical incubation period. Importantly, virtually all patients with malaria present with headache.
• Notably, infection with P vivax, particularly in temperate areas of India, may cause symptoms up to 6-12 months after the host leaves the endemic area. In addition, patients infected with P vivax or P ovale may relapse after longer periods because of the hypnozoite stage in the liver. The hypnozoite form develops after initial infection and can remain dormant for months to years before entering the blood stream and producing symptoms.
• P malariae does not have a hypnozoite stage, but patients infected with P malariae may have a prolonged, asymptomatic, erythrocytic infection that becomes symptomatic years after leaving the endemic area.
• Tertian and quartan fevers are due to the cyclic lysis of red blood cells that occurs as trophozoites complete their cycle in erythrocytes every 2 or 3 days, respectively. P malariae causes quartan fever, while P vivax and P ovale cause the benign form and P falciparum the malignant form of tertian fever. The cyclic pattern of fever is very rare.

Physical

• The severity of illness is affected by previous exposure to malaria and the patient’s age. In addition, various genetic factors may enhance or limit disease severity. Protective factors include sickle cell disease, hemoglobinopathies, and polymorphisms in the host's TNF (tumor necrosis factor) gene. New genetic polymorphisms that confer protection or susceptibility in the host continue to be defined. These protective mutations may lessen the likelihood of infection or disease severity; none is completely protective.
• The periodicity of fever associated with each species (ie, 48 h for P falciparum, P vivax, and P ovale; 72 h for P malariae) is not apparent during initial infection because of multiple broods emerging in the blood stream. In addition, the periodicity is often not observed in P falciparum infections. Patients with long-standing synchronous infections are more likely to present with classic fever patterns. In general, the occurrence of periodicity of fever is not a reliable clue to the diagnosis of malaria.
• Most patients with malaria have no physical findings, but splenomegaly may be present.
• Symptoms of malarial infection are nonspecific and may manifest as a flulike illness with fever, headache, malaise, fatigue, and muscle aches. Some patients with malaria present with diarrhea and other GI symptoms. Immune individuals may be completely asymptomatic or may present with mild anemia. Nonimmune patients may quickly become very ill. Severe malaria primarily involves P falciparum infection, although death due to splenic rupture has been reported in patients with non– P falciparum malaria.
• Severe malaria manifests as follows:
  • Cerebral malaria: This feature is almost always caused by P falciparum infection. Coma may occur. Coma can usually be distinguished from a postictal state secondary to generalized seizure if the patient does not regain consciousness after 30 minutes. When evaluating patients with coma-complicated malaria, hypoglycemia, and CNS infections should be excluded.
  • Severe anemia: The anemia associated with malaria is multifactorial and is usually associated with P falciparum infection. In nonimmune patients, anemia may be secondary to erythrocyte infection and a loss of infected RBCs. In addition, uninfected RBCs are inappropriately cleared, and bone marrow suppression may be involved.
  • Renal failure: This is a rare complication of malarial infection. Infected erythrocytes adhere to the microvasculature in the renal cortex, often resulting in oliguric renal failure. Renal failure is typically reversible, and supportive dialysis is often needed until kidney function recovers. In rare cases, chronic P malariae infection results in nephrotic syndrome.
  • Respiratory symptoms: Patients with malaria may develop metabolic acidosis and associated respiratory distress. In addition, pulmonary edema can occur. Signs of malarial hyperpneic syndrome include alar flaring, chest retraction (intercostals or subcostal), use of accessory muscles for respiration, or abnormally deep breathing.

Causes

The 4 Plasmodium species known to cause malaria include P falciparum (the most deadly), P vivax, P ovale, and P malariae. A fifth species, P knowlesi, has recently been identified in Southeast Asia as a clinically significant pathogen in humans.¹ Distinguishing among the various species, especially P falciparum, is imperative to ensure proper treatment and to improve the prognosis. Among patients with malaria, 5-7% are infected with more than a single Plasmodium species.

P falciparum and P vivax are responsible for most new infections. Each species has a defined area of endemicity, although geographic overlap is common. Species can be distinguished by morphology on a blood smear. The thick blood smear provides better sensitivity, while the thin blood smear is more specific and allows better identification of the Plasmodium species. In addition, rapid diagnostic tests are also available (eg, OptiMal, ParaSight, Kat-Quick).

Differential Diagnoses

Other Problems to Be Considered

HIV infection
Viral illness
Bacteremia

Workup

Laboratory Studies

A diagnosis of malaria should be supported by the identification of the parasites on a thin or thick blood smear. The only rare exception is P falciparum infection, in which all the parasites during the life cycle can be sequestered out of the peripheral blood in late-stage forms. If no alternative diagnosis is found in an at-risk patient with possible cerebral malaria (ie, unrevealing lumbar puncture findings), initiate therapy for presumptive malaria and continue to obtain additional blood smears to confirm the diagnosis. This is not an occult infection.

Malaria should be suspected in patients with a malarialike illness, including thrombocytopenia, relative lymphopenia, atypical lymphocytes, and an elevated lactate dehydrogenase (LDH) level.

• Thick smears
  • Three thick and thin smears 12-24 hours apart should be obtained. The highest yield of peripheral parasites occurs during or soon after a fever spike; however, smears should not be delayed while awaiting fever spikes.
  • Thick smears are 20 times more sensitive than thin smears, but speciation may be more difficult. The parasitemia can be calculated based on the number of infected RBCs. This is a quantitative test.
• Thin smears
  • Thin smears are less sensitive than thick smears but facilitate speciation. This should be considered a qualitative test.
  • Treatment greatly depends on the identification of the Plasmodium species responsible for the infection.
• Alternative diagnostic methods
  • Alternative diagnostic methods typically are used if the laboratory does not have sufficient expertise in detecting parasites in blood smears.
  • The quantitative buffy coat (QBC) is a technique that is as sensitive as thick smears. Because results cannot be used to speciate Plasmodium, a thin smear must be examined.
  • Monoclonal antibody to histidine-rich protein-2 (ParaSight-F, immunochromatographic test [ICT]) appears to be very sensitive and specific.
  • A rapid dipstick test that detects LDH of the parasite (eg, OptiMal) can also be used to distinguish P falciparum from the other species. This is particularly useful if laboratory expertise in differentiating the species is lacking. Similar to blood smears, these rapid tests may provide false-negative results in patients with very low parasitemia and should be repeated if results are initially negative and the diagnosis remains unknown.
  • In addition to the rapid diagnostic test listed above (eg, QBC, OptiMal), new molecular techniques such as polymerase chain reaction (PCR) and nucleic acid sequence-based amplification (NASBA) are also available for diagnosis. They are more sensitive than thick smears but are expensive and unavailable in most developing countries.³
  • Malaria is a reportable disease. Identification of parasites by any of the above techniques should prompt notification to the local or state health department.
• Blood tests
  • In returning travelers, malaria is suggested by the triad of thrombocytopenia, elevated LDH levels, and atypical lymphocytes. These findings should prompt obtaining malarial smears.
  • In general, blood cultures should be drawn in a febrile patient. Typhoid is often part of the differential diagnoses in patients returning from tropical areas. In addition, patients from tropical areas may have more than one infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.
  • Hypoglycemia may occur in patients with malarial infection and should be ruled out in patients with mental-status changes.
  • Assess hemoglobin (decreased in 25%, often profoundly in young children), platelet counts (thrombocytopenia in 50-68%), and liver function (results abnormal in 50%). Also monitor renal function, electrolytes (especially sodium), and parameters suggestive of hemolysis (haptoglobin, LDH, reticulocyte count).
  • Importantly, fewer than 5% of patients with malaria have an elevated WBC count. If leukocytosis is present, the examiner should entertain a broader list of differential diagnoses.
  • If the patient is to be treated with primaquine, a glucose-6-phosphate dehydrogenase (G-6-PD) level should be obtained because primaquine can result in severe hemolysis in these patients.
  • If the patient has cerebral malaria, obtain a blood glucose level to rule out hypoglycemia as a cause of mental-status changes. Note that intravenous quinine can induce hypoglycemia; therefore, blood glucose should be monitored when intravenous quinine is used.

Procedures

• If the patient exhibits mental-status changes, and even if the peripheral smear demonstrates P falciparum, a lumbar puncture should be performed to rule out bacterial meningitis.

Histologic Findings

Histologic Variations Among Plasmodium Species

Treatment

Medical Care

Speciating the parasite is critical in patients with malaria. Infection with P falciparum may be more severe than infection with other Plasmodium species. In addition, P falciparum is resistant to chloroquine treatment except in Haiti, the Dominican Republic, parts of Central America, and parts of the Middle East. In the United States, patients with P falciparum infection are often treated on an inpatient basis in order to observe for complications attributable to either the illness or its treatment.

Consultations

Consider consulting an infectious disease specialist for assistance with malaria diagnosis, speciation, patient treatment, and disease management. The CDC is an excellent resource if no local resources are available. The CDC Malaria hotline is 770-488-7788; 770-488-7100 is the telephone number to speak with an on-call malaria specialist.

Diet

Patients with malaria should continue intake as tolerated.

Activity

Patients with malaria should continue activity as tolerated.

Medication

Malaria prevention

DEET may be used to prevent transmission of the parasite through mosquitoes. Apply 95% DEET, which lasts up to 10-12 h, or 35% DEET, which lasts 4-6 h. In children, use a concentration of DEET less than 35%; apply sparingly only on exposed skin and remove when no longer exposed. Toxicity that manifests as encephalopathy and seizures has been reported in children exposed to higher concentrations of DEET.

Malaria prophylaxis

Whether a traveler needs malaria prophylaxis is an important question. This decision should be based on the traveler's detailed itinerary and should be based on whether travel is planned to areas where malaria is endemic and possibly drug resistant. Travel to an urban area may not require malaria prophylaxis, while travel to more remote or underdeveloped cities does. Determine the patient's accommodations and time of exposure. Travel during the transmission season, camping, and long-term trips are high-risk activities. Transmission typically does not occur at elevations higher than 2000 m.

Recommendations regarding prophylaxis should be made after reviewing guidelines published by the CDC as they apply to the planned itinerary. An excellent reference for malaria prophylaxis can be found at the CDC's Malaria and Travelers Web site.

Malaria treatment

P falciparum exhibits widespread resistance to chloroquine. Resistance is rare in P vivax infection, and P ovale and P malariae remain sensitive to chloroquine. Primaquine is required in the treatment of P ovale and P vivax infection in order to eliminate the hypnozoites (liver phase).

Artesunate is unavailable in the United States but may be used at 4 mg/kg/d PO for 3 days. Intravenous quinine is also unavailable in the United States. Intravenous quinidine gluconate is used to treat complicated P falciparum malaria.

P falciparum drug resistance is common in endemic areas such as Africa. Standard antimalarials such as chloroquine and antifolates (sulfadoxine-pyrimethamine) are ineffective in many areas. Because of this increasing prevalence of drug resistance and a high likelihood of resistance development to new agents, combination therapy is now becoming the standard of care for treatment of P falciparum infection worldwide. Artemisinins, a new class of antimalarial agent, are often part of these newly recommended regimens. They are not yet available in the United States; however, other combination drugs such as atovaquone and proguanil HCL (Malarone) or quinine in combination remain highly efficacious.

• P falciparum malaria
  • Quinine-based therapy - Quinine (or quinidine) sulfate plus doxycycline or clindamycin or pyrimethamine-sulfadoxine
  • Alternative therapy - Atovaquone-proguanil or mefloquine
• P falciparum malaria with known chloroquine susceptibility (only a few areas in Central America and the Middle East) - Chloroquine
• P vivax, P ovale malaria - Chloroquine plus primaquine
• P malariae malaria - Chloroquine
• P knowlesi malaria – Recommendations same as those for P falciparum malaria

Antimalarials

These agents inhibit growth by concentrating within acid vesicles of parasite, increasing the internal pH of the organism. They also inhibit hemoglobin utilization and parasite metabolism.

Chloroquine phosphate (Aralen)

Effective for P vivax, P ovale, P malariae, and drug-sensitive P falciparum. Can be used for prophylaxis or treatment. This is the prophylactic DOC for sensitive malaria. The doses listed below are appropriate for chloroquine phosphate, chloroquine sulfate, and hydroxychloroquine sulfate; chloroquine dihydrochloride has a slightly different dose and schedule.

Dosing

Adult

Prophylaxis: 300 mg base PO qwk (starting 1-2 wk prior to travel, once qwk in the endemic area, and continuing weekly for 4 wk after returning from endemic area)
Treatment: 600 mg base PO, then 300 mg base PO at 6 h, then repeat 300 mg base PO at 24 h and 48 h
Severe malaria: 10 mg/kg base IV at constant rate over 8 h, followed by 15 mg/kg base over 24 h

Pediatric

Prophylaxis: 5 mg/kg base PO, up to 300 mg weekly (plus 2 wk prior and 4 wk after travel to endemic area)
Treatment: 10 mg/kg base PO (not to exceed 600 mg), then 5 mg/kg base at 6 h, 24 h, and 48 h

Interactions

Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones

Contraindications

Documented hypersensitivity; psoriasis; retinal changes; visual field changes attributable to 4-aminoquinolones

Precautions

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

Nausea, headache, blood dyscrasias, and retinopathy (rare) may occur with daily use; risk of retinopathy may increase with prophylactic cumulative doses >100 g (ie, 5 y), perform regular ophthalmologic examinations after taking drug for prolonged period or after any visual disturbance

Quinine sulfate (Formula Q)

Used for malaria treatment only, has no role in prophylaxis. Use with second agent in drug-resistant P falciparum. For drug-resistant parasites, second agent is doxycycline, tetracycline, pyrimethamine sulfadoxine, or clindamycin. Quinidine gluconate is an IV alternative. Can also be administered by deep IM injection.

Dosing

Adult

Prophylaxis: Not indicated
Treatment: 650 mg PO q8h for 3-7 d with second agent if drug-resistant P falciparum
Severe malaria: Quinine dihydrochloride 20 mg/kg IV over 4 h, followed by 10 mg/kg IV q8-12h; switch to PO antimalarial when patient has improved and can take PO medications, reduce dose by one third if used parenterally for more than 72 h
Maintenance: 10 mg/kg salt infused over 2-8 h at 8- to 12-h intervals

Pediatric

25 mg/kg/d PO divided tid, for 3-7 d with second agent
Prophylaxis: Not indicated
Treatment with quinine sulfate: 10 mg/kg/d PO tid for 3-7 d
Treatment with quinine dihydrochloride: 20 mg/kg IV over 4 h, followed by 10 mg/kg IV q8-12h; switch to PO antimalarial when patient has improved and can take PO medications, reduce dose by one third if used parenterally for more than 72 h

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

Contraindications

Documented hypersensitivity; optic neuritis; tinnitus; G-6-PD deficiency; history of blackwater fever

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and thus can cause cardiac arrhythmias; monitor blood pressure and glucose levels

Doxycycline (Vibramycin, Vibra-Tabs, Doryx)

Used for prophylaxis or treatment of malaria. When used for treatment of P falciparum malaria, this drug must be used as part of combination therapy (eg, typically with quinine).

Dosing

Adult

Prophylaxis: 100 mg/d PO (start 1 d prior to travel; use qd in endemic area and qd for 4 wk after travel to endemic area)
Treatment: 100 mg PO bid for 7 d with second agent

Pediatric

<8 years: Do not administer
>8 years:
Prophylaxis: 2 mg/kg/d PO, up to 100 mg/d (start 1-2 d prior to entering endemic area, continue qd while in endemic area and continue qd for 4 wk after travel to endemic area)
Treatment: 2 mg/kg/d PO divided bid for 7 d with second agent

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of PO contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

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 (ie, last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines

Pyrimethamine-sulfadoxine (Fansidar)

Can be used for treatment of malaria. No longer considered a first-line agent for prophylaxis because of the adverse effect profile.

Dosing

Adult

Prophylaxis: Not indicated
Treatment: 3 tab of 25 mg pyrimethamine and 500 mg sulfadoxine PO once

Pediatric

Prophylaxis: Not indicated
Treatment:
<1 year: 0.25 tab PO once
1-3 years: 0.5 tab PO once
4-8 years: 1 tab PO once
9-14 years: 2 tab PO once
>14 years: Administer as in adults

Interactions

Do not use antifolic drugs (eg, sulfonamides, trimethoprim-sulfamethoxazole combinations) while patient is receiving sulfadoxine and pyrimethamine tab for antimalarial prophylaxis

Contraindications

Documented hypersensitivity; severe renal insufficiency; marked liver parenchymal damage; blood dyscrasias; documented megaloblastic anemia due to folate deficiency; age <2 mo; pregnancy at term and during nursing period

Precautions

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

Fatalities associated with administration of sulfonamides, although rare, have occurred because of severe reactions, including fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias; caution in impaired renal or hepatic function, possible folate deficiency, severe allergy, or bronchial asthma; hemolysis may occur in G-6-PD–deficient individuals; perform a urinalysis with microscopic examination and renal function tests during therapy for patients who have impaired renal function; discontinue if signs of folic acid deficiency develop; folinic acid (leucovorin) may be administered in doses of 5-15 mg IM daily, for >3 d, for depressed platelet or WBC counts in patients with drug-induced folic acid deficiency (when recovery is too slow)

Clindamycin (Cleocin HCl, Cleocin T)

Part of combination therapy for drug-resistant malaria (eg, typically with quinine). Good second agent in pregnant patients.

Dosing

Adult

900 mg PO tid for 5 d with second agent (typically quinine)

Pediatric

20-40 mg/kg/d PO divided tid for 5 d

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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

Mefloquine (Lariam)

Acts as a blood schizonticide. May act by raising intravesicular pH within parasite acid vesicles. Structurally similar to quinine. For prophylaxis or treatment of drug-resistant malaria.

Dosing

Adult

Prophylaxis: 250 mg PO qd for 3 d prior to entering endemic area, continue qwk in endemic area, and continue qwk for 4 wk after returning from endemic area
Treatment: 750-1250 mg PO once (second-line method because of adverse effects at this higher dose)

Pediatric

Prophylaxis: Administer PO qd for 3 d prior to entering endemic area, continue qwk in endemic area, and continue qwk for 4 wk after returning from endemic area
Prophylaxis:
<15 kg: 5 mg/kg PO
15-19 kg: 0.25 tab PO
20-30 kg: 0.5 tab PO
31-45 kg: 0.75 tab PO
>45 kg: 1 tab PO
Treatment: 15 mg/kg PO as single dose (second-line method because of adverse effects at this higher dose)

Interactions

Mefloquine administered with beta-blockers, quinine, quinidine, antiarrhythmics, TCAs, 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

Contraindications

Documented hypersensitivity; epilepsy or seizure disorder; severe psychiatric disorder; diagnosis or treatment for irregular heartbeat

Precautions

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

Use for >1 y not established; perform periodic evaluations including LFTs when using for prolonged periods; mefloquine may have cardiac depressant effects and antifibrillatory activity; may result in marked GI or CNS adverse effects and, therefore, not first-line treatment recommendation; nausea, strange dreams, seizures (rare), and psychosis may occur

Halofantrine (Halfan)

Blood schizonticidal antimalarial agent with no apparent effects on hepatic stages of infection. Exact mechanism of action is unknown. Use for highly resistant malaria. Do not use if patient is using mefloquine for prophylaxis. No role for prophylaxis.

Dosing

Adult

Prophylaxis: Not indicated
Treatment: 500 mg PO q8h for 3 doses, repeat in 1 wk

Pediatric

Prophylaxis: Not indicated
Treatment: 8 mg/kg PO q8h for 3 doses, repeat in 1 wk

Interactions

Mefloquine may interact with halofantrine, leading to potentially fatal prolongation of QTc interval

Contraindications

Documented hypersensitivity; coadministration with drugs or clinical conditions known to prolong QTc interval (eg, mefloquine); known or suspected AV conduction disorders; ventricular dysrhythmias; unexplained syncopal attacks

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Prolongs QTc interval at recommended therapeutic dose; serious ventricular dysrhythmias, sometimes associated with sudden death, have been reported; do not administer concomitantly or subsequent to mefloquine; cough, pruritus, and rash (rare) may occur

Atovaquone (Mepron)

May inhibit metabolic enzymes, which in turn inhibit growth of microorganisms. Must use in combination with proguanil.

Dosing

Adult

Prophylaxis: 250 mg with 100 mg proguanil PO qd; start 1-2 d before entering endemic area, continue qd while in endemic area, and continue for 7 d after exposure has ended (this shortened dosing schedule following travel makes it a good option for patients who are poorly compliant
Treatment: 500 mg PO bid for 3 d

Pediatric

Prophylaxis: Start 1-2 d before entering endemic area, continue qd while in endemic area, and continue for 7 d after exposure has ended
Treatment:
<11 kg: Not established
11-20 kg: 62.5 mg/25 mg PO qd
21-30 kg: 125 mg/50 mg PO qd
31-40 kg: 187.5 mg/75 mg PO qd

Interactions

May increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease atovaquone levels; atovaquone may decrease levels of TMP-SMZ

Contraindications

Documented hypersensitivity; severe renal impairment; weight <11 kg (24 lb)

Precautions

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

Caution in elderly patients and in hepatic and renal impairment; must use in combination with proguanil; adverse effects are rare and include abdominal pain, nausea, vomiting, and headache

Proguanil (Paludrine)

This is marketed in combination with atovaquone in the United States (Malarone). For pediatric patients, this combination should be used for uncomplicated P falciparum; can also be used in combination with chloroquine.

Dosing

Adult

Prophylaxis: 200 mg PO in combination with weekly chloroquine
Prophylaxis with atovaquone/proguanil: 250 mg/100 mg PO qd
Treatment: 200 mg PO bid for 3 d

Pediatric

Prophylaxis:
<8 months: 1/4 tab PO
8 months-3 years: 1/2 tab PO
4-7 years: 3/4 tab PO
8-10 years: 1 tab PO
11-13 years: 1 1/2 tab PO
>14 years: 2 tab PO
Prophylaxis with atovaquone/proguanil:
11-20 kg: 62.5 mg/25 mg PO qd
21-30 kg: 125 mg/50 mg PO qd
31-40 kg: 187.5 mg/75 mg PO qd
11-20 kg: 50 mg PO bid for 3 d
21-30 kg: 100 mg PO bid for 3 d
31-40 kg: 150 mg PO bid for 3 d

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

Precautions

Anorexia, nausea, mouth ulcers, and hematuria (rare) may occur

Atovaquone/proguanil (Malarone)

This drug has been approved in the United States for both prophylaxis and treatment of mild chloroquine-resistant malaria. May be a good prophylactic option for patients who are visiting areas with chloroquine-resistant malaria and who cannot tolerate mefloquine. Each tab combines 250 mg of atovaquone and 100 mg of proguanil hydrochloride. Dosage for children is based on body weight; in children 40 kg (88 lb) or less, a lower-dose pediatric tab (62.5 mg of atovaquone and 25 mg of proguanil hydrochloride) is available.

Dosing

Adult

Prophylaxis: 1 tab PO qd, taken at the same time qd with food or a milky drink; begin 1-2 d before entering a malaria-endemic area, and continue qd during the stay and for 7 d after return
Treatment (P falciparum malaria): 4 tab PO qd as a single dose for 3 consecutive d
Patients with severe malaria are not candidates for PO therapy, and Malarone has not been evaluated for the treatment of severe malaria, including cerebral malaria

Pediatric

Prophylaxis:
11-20 kg (24-45 lb): 1 pediatric tab PO qd
21-30 kg (46-67 lb): 2 pediatric tab qd as single dose
21-30 kg (46-67 lb): 3 pediatric tab qd as single dose
31-40 kg (68-88 lb): 4 pediatric tab qd as single dose
Treatment:
11-20 kg (24-45 lb): 1 adult tab PO qd as single dose for 3 consecutive d
21-30 kg (46-67 lb): 2 adult tab PO qd as single dose for 3 consecutive d
31-40 kg (68-88 lb): 3 adult tab PO qd as single dose for 3 consecutive d
>40 kg (88 lb): 4 adult tab PO qd as single dose for 3 consecutive d
Patients with severe malaria are not candidates for PO therapy, and Malarone has not been evaluated for treatment of severe malaria, including cerebral malaria

Interactions

Administration of rifampin, rifabutin, tetracycline, and metoclopramide are associated with reduced plasma concentrations of atovaquone; therefore, concomitant administration of Malarone and rifampin or rifabutin is not recommended; parasitemia should be closely monitored in patients receiving tetracycline, and metoclopramide should be used only if other antiemetics are not available

Contraindications

Severe renal impairment (CrCl <30 mL/min), do not use for malaria prophylaxis

Precautions

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

The most common adverse events in subjects taking Malarone for prophylaxis of malaria include headache and abdominal pain and occur at rates comparable to placebo; in adults, the most commonly reported adverse events possibly attributable to Malarone prophylaxis versus placebo are headache (5% vs 7%) and abdominal pain (3% vs 5%); in pediatric patients, adverse effects include headache (14% vs 14%), abdominal pain (31% vs 29%), and vomiting (7% vs 6%); the most common adverse events reported in >10% of patients taking Malarone for treatment of malaria are abdominal pain, nausea, vomiting, and headache in adults and vomiting in children

Primaquine phosphate

Not used to treat erythrocytic stage of malaria. Administer for hypnozoite stage of P vivax and P ovale to prevent relapse.

Dosing

Adult

Prophylaxis: 15 mg base (26.3 mg salt) PO qd for 14 d after departure from malaria-risk area
Treatment: Administer as in prophylaxis

Pediatric

Prophylaxis: 0.3 mg/kg base (0.5 mg/kg salt) PO qd for 14 d after departure from malaria-risk area
Treatment: Administer as in prophylaxis

Interactions

Coadministration with quinacrine may increase toxicity

Contraindications

Documented hypersensitivity; drugs that suppress bone marrow

Precautions

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

Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia

Artemether and lumefantrine (Coartem)

Indicated for treatment of acute, uncomplicated P falciparum malaria, the most dangerous form of malaria. Contains fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartenisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta-hematin.

Dosing

Adult

<35 kg bodyweight: Use pediatric dosing
>35 kg bodyweight: One dose is 4 tab; take 6 doses over 3-d period as described below
Day 1: Take 1 dose, followed 8 h later by 1 dose
Day 2: Take 1 dose bid
Day 3: Take 1 dose bid

Pediatric

Number of tab per dose by body weight
<5 kg: Do not administer
5 to <15 kg: 1 tab
15 to <25 kg: 2 tab
25 to <35 kg: 3 tab
>35 kg: Administer as in adults
Take 6 doses over 3-d period as described for adults

Interactions

CYP3A4 inhibitors (including antiretroviral drugs, macrolide antibiotics, antidepressants, and imidazole antifungal agents) or CYP2D6 inhibitors (eg, flecainide, tricyclic antidepressants) may increase toxicity of lumefantrine, increasing QT prolongation; halofantrine may increase toxicity of lumefantrine, increasing QT prolongation (not for concurrent administration; administer 1 mo apart); antimalarials quinine and quinidine may have additive effects on QT interval (use caution); not approved for severe or complicated P falciparum malaria; not approved for prevention of malaria

Contraindications

Documented hypersensitivity

Precautions

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

QT prolongation may occur; avoid use in patients with congenital prolongation of QT interval (family history) and known disturbances of electrolyte imbalance (including hypokalemia or hypomagnesemia); common adverse effects include headache, dizziness, loss of appetite, and fever

Follow-up

Further Inpatient Care

• Patients with hyperparasitemia (>5% of RBCs infected), CNS infection, or otherwise severe symptoms and those with P falciparum infection should be considered for inpatient treatment to ensure that medicines are tolerated.
• Obtain blood smears every day to demonstrate a response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health or cause any symptoms.

Further Outpatient Care

• Patients with non– P falciparum malaria who are well can be treated on an outpatient basis. Obtain blood smears every day to demonstrate response to treatment. The sexual stage of the protozoan, the gametocyte, does not respond to most standard medications (eg, chloroquine, quinine), but gametocytes eventually die and do not pose a threat to the individual's health.
• Occasionally, morphologic features do not permit distinction between P falciparum and other Plasmodium species. In such cases, patients from a P falciparum –endemic area should be presumed to have P falciparum infection and should be treated accordingly.
• In patients from Southeast Asia, consider the possibility of P knowlesi infection. This species frequently causes hyperparasitemia and tends to be more severe than infections with other non– P falciparum plasmodia. It should be treated as P falciparum infection.

Deterrence/Prevention

• Avoid mosquitoes by limiting exposure during times of typical blood meals (ie, dawn, dusk). Wearing long-sleeved clothing and using insect repellants may also prevent infection.
• Adult-dose 95% DEET lasts up to 10-12 hours, and 35% DEET lasts 4-6 hours. In children, use concentrations of less than 35% DEET. Use sparingly and only on exposed skin. Remove DEET when no longer exposed.
• Consider using bed nets that are treated with permethrin.
• Consider chemoprophylaxis with antimalarials in patients traveling to endemic areas.

Patient Education

• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Parasites and Worms Center. Also, see eMedicine's patient education articles Malaria, Foreign Travel, and Insect Bites.

Miscellaneous

Medicolegal Pitfalls

• Failure to consider a diagnosis of malaria
  • Malaria is often overlooked because infected patients typically present with nonspecific symptoms.
  • Patients with malaria may present with localized findings, including gastrointestinal or pulmonary symptoms, among others. All patients who have been exposed to malaria and present with fever should have blood smears sent to a laboratory.
  • In addition, malaria can still develop in patients who are compliant with malaria prophylaxis.
  • Obtaining blood smears is a simple and inexpensive method to determine if patients are infected.
• Failure to treat hypnozoite stage of P vivax and P ovale infections with primaquine to prevent relapse
• Failure to prescribe appropriate malaria prophylaxis in travelers

Special Concerns

• Pregnant patients with malaria are at increased risk of morbidity and mortality.⁴ In addition, nonimmune mothers and immune primigravidas may be at an increased risk of low birth weight, fetal loss, and prematurity. Consult an expert in malaria to determine the safest and most effective prophylaxis or treatment in a pregnant woman.

References

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2. CDC information website for malaria. Available at http://www.cdc.gov/malaria/.

3. Mens P, Spieker N, Omar S, et al. Is molecular biology the best alternative for diagnosis of malaria to microscopy? A comparison between microscopy, antigen dectection and molecular tests in rural Kenya and urban Tanzania. Trop Med Int Health. Feb/2007;2:238-44. [Medline]. [Full Text].

4. Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, et al. Adverse pregnancy outcomes in an area where multidrug-resistant plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis. May 1 2008;46(9):1374-81. [Medline].

5. Ashley EA, White NJ. Artemisinin-based combinations. Curr Opin Infect Dis. Dec 2005;18(6):531-6. [Medline].

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8. Cunha BA. Malaria or typhoid fever: a diagnostic dilemma?. Am J Med. Dec 2005;118(12):1442-3; author reply 1443-4. [Medline].

9. Cunha BA. The diagnosis of imported malaria. Arch Intern Med. Aug 13-27 2001;161(15):1926-8. [Medline].

10. Cunha BA. The Importance of non-specific laboratory tests in suspecting malaria in returning US travelers. Ann Intern Med. 2004;14:e141/7/547.

11. Cunha BA. Triad of non-specific laboratory tests in malaria. Scand J Infect Dis. 2008;40(4):350-1. [Medline].

12. Dorsey G, Gandhi M, Oyugi JH, Rosenthal PJ. Difficulties in the prevention, diagnosis, and treatment of imported malaria. Arch Intern Med. Sep 11 2000;160(16):2505-10. [Medline].

13. 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].

14. Froude JR, Weiss LM, Tanowitz HB, Wittner M. Imported malaria in the Bronx: review of 51 cases recorded from 1986 to 1991. Clin Infect Dis. Nov 1992;15(5):774-80. [Medline].

15. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. Dec 2005;4(12):827-40. [Medline].

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21. Plowe CV. Antimalarial drug resistance in Africa: strategies for monitoring and deterrence. Curr Top Microbiol Immunol. 2005;295:55-79. [Medline].

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Keywords

malaria, blackwater fever, tertian fever, quartan fever, jungle fever, airport malaria, Anopheles mosquito, Plasmodium falciparum, P falciparum, Plasmodium vivax, P vivax, Plasmodium ovale, P ovale, Plasmodium malariae, P malariae, Plasmodium knowlesi, P knowlesi, paludismo

Contributor Information and Disclosures

Author

Emilio V Perez-Jorge, MD, FACP, Fellow, Infectious Disease, Wright State University Boonshoft School of Medicine, Veterans Affairs Medical Center
Emilio V Perez-Jorge, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, Infectious Diseases Society of America, Infectious Diseases Society of Ohio, Ohio State Medical Association, and Society of Hospital Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas Herchline, MD, Professor of Medicine, Wright State University Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio
Thomas Herchline, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Joseph Richard Masci, MD, Chief of Infectious Diseases, Associate Director, Associate Professor, Department of Internal Medicine, Division of Infectious Diseases, Elmhurst Hospital Center, Mount Sinai School of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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