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Malaria

by Richard D. Pearson, MD

Malaria is infection with Plasmodium sp. Symptoms and signs include fever (which may be periodic), chills, sweating, hemolytic anemia, and splenomegaly. Diagnosis is by seeing Plasmodium in a peripheral blood smear. Treatment and prophylaxis depend on the species and drug sensitivity and include the fixed combination of atovaquone and proguanil, artemisinin derivatives, doxycycline, mefloquine, chloroquine, and quinine. Patients infected with P. vivax and P. ovale also receive primaquine to prevent relapse.

Malaria is endemic in Africa, much of South and Southeast Asia, North and South Korea, Mexico, Central America, Haiti, the Dominican Republic, South America (including northern parts of Argentina), the Middle East (including Turkey, Syria, Iran, and Iraq), and Central Asia. The Centers for Disease Control and Prevention (CDC) has an online map application that shows recent data on malaria prevalence throughout the world; also included are type of malaria, resistance patterns, and recommended prophylaxis (see CDC Malaria Map Application ).

There are 300 to 500 million infected people worldwide, with about 655,000 deaths yearly, mostly in children < 5 yr in Africa. Malaria once was endemic in the US. About 1500 cases/yr occur in the US. Nearly all are acquired abroad, but a small number result from blood transfusions or rarely from transmission by local mosquitoes that feed on infected immigrants.

Pathophysiology

The Plasmodium species that infect humans are

  • P. falciparum

  • P. vivax

  • P. ovale

  • P. malariae

  • P. knowlesi

Concurrent infection with more than one Plasmodium species is uncommon.

Also, simian malaria has been reported in humans; P. knowlesi is an emerging pathogen in Southeast Asia. The degree to which P. knowlesi is transmitted from human to human via the mosquito, without the natural intermediate monkey host, is under study.

The basic elements of the life cycle are the same for all Plasmodium sp (see Figure: Plasmodium life cycle.). Transmission begins when a female Anopheles mosquito feeds on a person with malaria and ingests blood containing gametocytes. During the following 1 to 2 wk, gametocytes inside the mosquito reproduce sexually and produce infective sporozoites. When the mosquito feeds on another human, sporozoites are inoculated and quickly reach the liver and infect hepatocytes. The parasites mature into tissue schizonts within hepatocytes. Each schizont produces 10,000 to 30,000 merozoites, which are released into the bloodstream 1 to 3 wk later when the hepatocyte ruptures. Each merozoite can invade an RBC and there transform into a trophozoite. Trophozoites grow and develop into erythrocyte schizonts; schizonts produce further merozoites, which 48 to 72 h later rupture the RBC and are released in plasma. These merozoites then rapidly invade new RBCs, repeating the cycle. Some trophozoites develop into gametocytes, which are ingested by an Anophelesmosquito. They undergo sexual union in the gut of the mosquito, develop into oocysts, and release infective sporozoites, which migrate to the salivary glands.

Plasmodium life cycle.

  • The malaria parasite life cycle involves 2 hosts. During a blood meal, a malaria-infected female Anophelesmosquito inoculates sporozoites into the human host.

  • Sporozoites infect liver cells.

  • There, the sporozoites mature into schizonts.

  • The schizonts rupture and release merozoites. This initial replication in the liver is called the exoerythrocytic cycle.

  • Merozoites infect RBCs. There, the parasite multiplies asexually (called the erythrocytic cycle). The merozoites develop into ring-stage trophozoites. Some then mature into schizonts.

  • The schizonts rupture, releasing merozoites.

  • Some trophozoites differentiate into gametocytes.

  • During a blood meal, an Anopheles mosquito ingests the male (microgametocytes) and female (macrogametocytes) gametocytes, beginning the sporogonic cycle.

  • In the mosquito’s stomach, the microgametes penetrate the macrogametes, producing zygotes.

  • The zygotes become motile and elongated, developing into ookinetes.

  • The ookinetes invade the midgut wall of the mosquito where they develop into oocysts.

  • The oocysts grow, rupture, and release sporozoites, which travel to the mosquito’s salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle.

With P. vivax and P. ovale (but not P. falciparum or P. malariae), tissue schizonts may persist as hypnozoites in the liver for years. Relapse of P. ovale has occurred as late as 6 yr after an episode of symptomatic malaria, and the infection was transmitted by blood transfusion from a person who was exposed 7 yr before donating blood. These dormant forms serve as time-release capsules, which cause relapses and complicate chemotherapy because they are not killed by most antimalarial drugs, which typically act on bloodstream parasites.

The pre-erythrocytic (hepatic) stage of the malarial life cycle is bypassed when infection is transmitted by blood transfusions, by sharing of contaminated needles, or congenitally. Therefore, these modes of transmission do not cause latent disease or delayed recurrences.

Rupture of RBCs during release of merozoites is associated with the clinical symptoms. If severe, hemolysis causes anemia and jaundice, which are worsened by phagocytosis of infected RBCs in the spleen. Anemia may be severe in P. falciparum or chronic P. vivax infection but tends to be mild in P. malariae infection.

Falciparum malaria

Unlike other forms of malaria, P. falciparum causes microvascular obstruction because infected RBCs adhere to vascular endothelial cells. Ischemia develops with resultant tissue hypoxia, particularly in the brain, kidneys, lungs, and GI tract. Hypoglycemia and lactic acidosis are other potential complications.

Resistance to infection

Most West Africans have complete resistance to P. vivax because their RBCs lack the Duffy blood group, which is required for the attachment of P. vivax to RBCs; many African Americans also have such resistance. The development of Plasmodium in RBCs is retarded in patients with hemoglobin S, hemoglobin C, thalassemia, G6PD deficiency, or elliptocytosis.

Previous infections provide partial immunity. Once residents of hyperendemic areas leave, acquired immunity wanes over time (months to years), and symptomatic malaria may develop if they return home and become reinfected.

Symptoms and Signs

The incubation period is usually 12 to 17 days for P. vivax, 9 to 14 days for P. falciparum, 16 to 18 days or longer for P. ovale, and about 1 mo (18 to 40 days) or longer (years) for P. malariae. However, some strains of P. vivax in temperate climates may not cause clinical illness for months to > 1 yr after infection.

Manifestations common to all forms of malaria include

  • Fever and rigor—the malarial paroxysm

  • Anemia

  • Jaundice

  • Splenomegaly

  • Hepatomegaly

The malarial paroxysm coincides with release of merozoites from ruptured RBCs. The classic paroxysm starts with malaise, abrupt chills and fever rising to 39 to 41° C, rapid and thready pulse, polyuria, headache, myalgia, and nausea. After 2 to 6 h, fever falls, and profuse sweating occurs for 2 to 3 h, followed by extreme fatigue. Fever is often hectic at the start of infection. In established infections, malarial paroxysms typically occur every 2 to 3 days depending on the species; intervals are not rigid.

Splenomegaly usually becomes palpable by the end of the first week of clinical disease but may not occur with P. falciparum. The enlarged spleen is soft and prone to traumatic rupture. Splenomegaly may decrease with recurrent attacks of malaria as functional immunity develops. After many bouts, the spleen may become fibrotic and firm or, in some patients, becomes massively enlarged (tropical splenomegaly). Hepatomegaly usually accompanies splenomegaly.

P. falciparum causes the most severe disease because of its microvascular effects. It is the only species likely to cause fatal disease if untreated; nonimmune patients may die within days of their initial symptoms. Patients with cerebral malaria may develop symptoms ranging from irritability to seizures and coma. Acute respiratory distress syndrome (ARDS), diarrhea, icterus, epigastric tenderness, retinal hemorrhages, algid malaria (a shocklike syndrome), and severe thrombocytopenia may also occur. Renal insufficiency may result from volume depletion, vascular obstruction by parasitized erythrocytes, or immune complex deposition. Hemoglobinemia and hemoglobinuria resulting from intravascular hemolysis may progress to blackwater fever (so named based on the dark color of the urine), either spontaneously or after treatment with quinine. Hypoglycemia is common and may be aggravated by quinine treatment and associated hyperinsulinemia. Placental involvement may lead to low birth weight, spontaneous abortion, stillbirth, or congenital infection.

P. vivax, P. ovale, and P. malariae typically do not compromise vital organs. Mortality is rare and is mostly due to splenic rupture or uncontrolled hyperparasitemia in asplenic patients. The clinical course with P. ovale is similar to that of P. vivax. In established infections, temperature spikes occur at 48-h intervals—a tertian pattern. P. malariae infections may cause no acute symptoms, but low-level parasitemia may persist for decades and lead to immune complex–mediated nephritis or nephrosis or tropical splenomegaly; when symptomatic, fever tends to occur at 72-h intervals—a quartan pattern.

In patients who have been taking chemoprophylaxis (see Table: Prevention of Malaria), malaria may be atypical. The incubation period may extend weeks to months after the drug is stopped. Those infected may develop headache, backache, and irregular fever, but parasites may initially be difficult to find in blood samples.

Diagnosis

  • Light microscopy of blood (thin and thick smears)

  • Rapid blood assays that detect Plasmodium antigens or enzymes

Fever and chills in an immigrant or traveler returning from an endemic region should prompt immediate assessment for malaria. Most cases occur within the first 6 mo, but onset may take up to 2 yr or, rarely, longer.

Malaria can be diagnosed by finding parasites on microscopic examination of thick or thin blood smears. The infecting species (which determines therapy and prognosis) is identified by characteristic features on smears (see Table: Diagnostic Features of Plasmodium Species in Blood Smears). Blood smears should be repeated at 4- to 6-h intervals if the initial smear is negative.

Thin blood smears stained with Wright-Giemsa stain allow assessment of parasite morphology within RBCs, often speciation, and determination of percentage parasitemia. Thick smears are more sensitive but more difficult to prepare and interpret as the RBCs are lysed before staining. Sensitivity and accuracy of the results depend on the examiner's experience.

Commercial rapid assays are based on the presence of certain plasmodium antigens or enzymatic activities. Assays may involve detection of a histidine-rich protein 2 (HRP-2) associated with malaria parasites (especially P. falciparum and P. vivax) and detection of plasmodium-associated lactate dehydrogenase (pLDH). The rapid tests are comparable in sensitivity to microscopy in detecting low levels of parasitemia; However, they do not differentiate single infection from concurrent infection with more than one Plasmodium sp or allow speciation except for P. falciparum.

Light microscopy and rapid assays are complementary tests, and both should be done when available. They have similar sensitivity. Negative results in both does not exclude malaria in a patient with low parasitemia.

PCR and species-specific DNA probes can be used but are not widely available. Because serologic tests may reflect prior exposure, they are not useful in the diagnosis of acute malaria.

Diagnostic Features of Plasmodium Species in Blood Smears

Characteristic

Plasmodium Sp*

Vivax

Falciparum

Malariae

Infected RBCs enlarged

Yes

No

No

Schüffner dots

Yes

No

No

Maurer dots or clefts

No

Yes §

No

Multiple infections in RBCs

Rare

Yes

No

Rings with 2 chromatin dots

Rare

Frequent

No

Crescentic gametocytes

No

Yes

No

Bayonet or band trophozoites

No

No

Yes

Schizonts present in peripheral blood

Yes

Rare

Yes

Number of merozoites per schizont (mean [range])

16 (12–24)

12 (8–24)

8 (6–12)

*RBCs infected with P. ovale are fimbriated, oval, and slightly enlarged; the parasites otherwise resemble P. vivax.

P. knowlesi is morphologically similar to P. malaria and has been confused with it.

Schüffner dots are best seen when the blood smear is stained with Giemsa stain.

§ This feature is not always visible.

Schizonts are trapped in viscera and usually are not present in peripheral blood.

Treatment

  • Antimalarial drugs

Antimalarial drugs are chosen based on the clinical manifestations, the infecting Plasmodium sp, known resistance patterns of strains in the area of acquisition, and the efficacy and adverse effects of drugs available.

In some endemic areas, a significant proportion of locally available antimalarial drugs are counterfeit. Thus, some clinicians advise travelers to remote, high-risk areas to take along a full course of an appropriate treatment regimen to be used if medically confirmed malaria is acquired despite prophylaxis; this strategy also avoids depleting limited drug resources in the destination country.

Malaria is particularly dangerous in children < 5 yr (mortality is highest in those <2 yr), pregnant women, and previously unexposed visitors to endemic areas. If P. falciparum is suspected, therapy should be initiated immediately, even if the initial smear is negative. P. falciparum and, more recently, P. vivax have become increasingly resistant to antimalarial drugs. For recommended drugs and doses for treatment and prevention of malaria, see Table: Treatment of Malaria and Prevention of Malaria. Common adverse effects and contraindications are listed in Adverse Reactions and Contraindications of Antimalarial Drugs. See also the CDC web site ( Malaria Diagnosis and Treatment in the United States ), or call their malaria hotline at 770-488-7788 (after hours, weekends, or holidays, call 770-488-7100) for consultation about treatment.

In case of a febrile illness during travel in an endemic region, prompt professional medical evaluation is essential. When prompt evaluation is not possible (eg, because the region is very remote), self-medication with artemether/lumefantrine or atovaquone/proguanil can be considered pending evaluation. If travelers present with fever after returning from an endemic region and no other diagnosis is made, clinicians should consider giving empiric treatment for uncomplicated malaria even when malaria smears and/or rapid diagnostic test are negative.

Treatment of Malaria

Preferences

Drug a

Adult Dosage

Pediatric Dosage b

P. falciparum or unidentified species acquired in all malarious regions except those specified as chloroquine-sensitive—Oral drugs

Drugs of choice

Atovaquone/proguanil c

4 adult tablets once/day for 3 days

< 5 kg: Not indicated

5–8 kg: 2 pediatric tablets once/day for 3 days

9–10 kg: 3 pediatric tablets once/day for 3 days

11–20 kg: 1 adult tablet once/day for 3 days

21–30 kg: 2 adult tablets once/day for 3 days

31–40 kg: 3 adult tablets once/day for 3 days

> 40 kg: 4 adult tablets once/day for 3 days

or

Artemether/lumefantrine d

6 doses (1 dose = 4 tablets) over 3 days (at 0, 8, 24, 36, 48, and 60 h)

6 doses at intervals as for the adults; dose =

5–< 15 kg: 1 tablet

15–< 25 kg: 2 tablets

25–< 35 kg: 3 tablets

35 kg: 4 tablets

or

Quinine sulfate plus one of the following:

650 mg salt tid for 3 or 7 days e

10 mg salt/kg q 8 h for 3 or 7 days e

  • Doxycycline f

100 mg bid for 7 days

2.2 mg/kg bid for 7 days

  • Tetracycline f

250 mg qid for 7 days

6.25 mg/kg qid for 7 days

  • Clindamycin g

7 mg/kg tid for 7 days

7 mg/kg tid for 7 days

Alternative (if other options cannot be used)

Mefloquine h

750 mg salt, then 500 mg salt 6–12 h later

15 mg salt/kg, then 10 mg salt/kg 6–12 h later

P. falciparum and unidentified species acquired in chloroquine-sensitive areas (Central America west of Panama Canal, Haiti, Dominican Republic, most of the Middle East) and P. malariae and P. knowlesi in all regions —Oral drugs

Drugs of choice

Chloroquine phosphate i,j

1 g salt (600 mg base), then 500 mg salt (300 mg base) at 6, 24, and 48 h

10 mg base/kg (up to 600 mg base), then 5 mg base/kg at 6, 24, and 48 h

or

Hydroxychloroquine j

800 mg salt (620 mg base), then 400 mg salt (310 mg base) at 6, 24, and 48 h

10 mg base/kg, then 5 mg/kg at 6, 24, and 48 h

P. vivax (unless from chloroquine-resistant area) or P. ovale—Oral drugs

Drugs of choice

Chloroquine phosphate i,j or hydroxychloroquine j dosed as above

plus

Primaquine k

30 mg base once/day for 14 days

0.5 mg base/kg once/day for 14 days

P. vivax acquired in areas known to harbor chloroquine-resistant P. vivax l (Papua New Guinea, Indonesia)—Oral drugs

Drugs of choice

A. Quinine sulfate plus one of the following:

650 mg salt tid for 3 or 7 days e

10 mg salt/kg tid for 3 or 7 days e

  • Doxycycline f

100 mg bid for 7 days

2.2 mg/kg bid for 7 days

  • Tetracycline f

250 mg qid for 7 days

6.25 mg/kg qid for 7 days

or

B. Atovaquone/proguanil c

4 adult tablets once/day for 3 days

< 5 kg: Not indicated

5–8 kg: 2 pediatric tablets once/day for 3 days

9–10 kg: 3 pediatric tablets once/day for 3 days

11–20 kg: 1 adult tablet once/day for 3 days

21–30 kg: 2 adult tablets once/day for 3 days

31–40 kg: 3 adult tablets once/day for 3 days

> 40 kg: 4 adult tablets once/day for 3 days

or

C. Mefloquine h

750 mg salt, then 500 mg 6–12 h later

15 mg salt/kg, then 10 mg/kg 6–12 h later

Regimen A, B, or C plus

Primaquine k

30 mg base once/day for 14 days

0.5 mg base/kg once/day for 14 days

Severe infection, all Plasmodium —Parenteral drugs

Drugs of choice

Quinidine gluconate m plus one of the following dosed as above:

  • Doxycycline f,n

  • Tetracycline f

  • Clindamycin g,o

10 mg salt/kg loading dose in normal saline over 1 h, then continuous infusion of 0.02 mg salt/kg/min for at least 24 h

or

24 mg salt/kg loading dose over 4 h, then 12 mg salt/kg infused over 4 h q 8 h, starting 8 h after the loading dose

Once parasite density is < 1% and patient can take oral drugs, complete treatment with oral quinine dosed as above

Same as for adults (except doxycycline and tetracycline are not used in children)

or (investigational)

Artesunate p ,q plus one of the following dosed as above:

  • Atovaquone-proguanil c

  • Doxycycline f,n

  • Clindamycin g,o

  • Mefloquine h

As per investigational new drug protocol (contact CDC for drug and dosing information)

Same as for adults (except doxycycline is not used in children)

Prevention of relapses: P. vivax and P. ovale only

Drug of choice

Primaquine

30 mg base po once/day for 14 days after leaving the endemic area

0.5 mg base/kg po once/day for 14 days after leaving the endemic area

a see Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications. If malaria develops during prophylactic drug therapy, that drug should not be used as part of the treatment regimen.

b The pediatric dose should not exceed the adult dose.

c Atovaquone/proguanil is available as a fixed-dose combination tablet: adult tablets (250 mg atovaquone/100 mg proguanil) and pediatric tablets (62.5 mg atovaquone/25 mg proguanil). To enhance absorption, patients should take it with food or whole milk. This combination is contraindicated in patients with creatinine clearance < 30 mL/min. Generally, this combination is not recommended for pregnant women, particularly during the 1st trimester, because safety data are insufficient; it may be used if other options are unavailable or are not tolerated and benefits outweigh risks. Twice/day dosing reduces nausea and vomiting as does taking it with food or milk. If patients vomit within 30 min of taking a dose, the dose should be repeated.

d Artemether/lumefantrine is available as a fixed-dose combination tablet of 20 mg/120 mg. Generally, this combination is not recommended for use in pregnant women, particularly during the 1st trimester, because safety data are insufficient; it may be used if other options are unavailable or are not tolerated and benefits outweigh risks. Patients should take the drug with food or whole milk. If patients vomit within 30 min of taking a dose, the dose should be repeated.

e In the US, quinine sulfate capsules contain 324 mg, so 2 capsules are sufficient for adults. For children, dosing may be more difficult because noncapsule forms of quinine are not available. In Southeast Asia, relative resistance to quinine has increased, and treatment should be continued for 7 days. In other regions, treatment is continued for only 3 days. To reduce risk of GI adverse effects, patients should take quinine with food. Quinine plus doxycycline or tetracycline is generally preferred to quinine plus clindamycin because there is more data on efficacy.

f Use of tetracyclines is contraindicated during pregnancy and in children < 8 yr. In children < 8 yr with chloroquine-resistant P. vivax, mefloquine is recommended. If these drugs are not available or are not tolerated and if the benefits of treatment outweigh the risks, atovaquone/proguanil or artemether/lumefantrine can be used instead.

g Clindamycin is to be used during pregnancy and in children < 8 yr.

h Mefloquine is not recommended unless other options cannot be used because the rate of severe neuropsychiatric reactions is higher with mefloquine than with other options. Mefloquine is also not recommended for infections acquired in Southeast Asia because resistance to mefloquine has been reported in some areas (eg, the Myanmar borders with Thailand, China, and Laos; Thailand-Cambodia border; southern Vietnam).

i To reduce risk of GI effects, patients should take chloroquine phosphate with food.

j Chloroquine or hydroxychloroquine is recommended for chloroquine-sensitive infections; however, regimens used to treat chloroquine-resistant infections may be used if they are more convenient or preferred or if chloroquine is unavailable.

k Primaquine is used to eradicate any hypnozoites that may remain dormant in the liver and thus prevent relapses in P. vivax and P. ovale infections. Because primaquine can cause hemolytic anemia in patients with G6PD deficiency, G6PD screening must occur before starting treatment with primaquine. For patients with borderline G6PD deficiency or as an alternate to the above regimen, primaquine 45 mg po once/wk may be given for 8 wk; clinicians should consult with an expert in infectious disease and/or tropical medicine if this alternative regimen is being considered for G6PD-deficient patients. Primaquine should not be used during pregnancy.

l If patients acquire P. vivax infection in regions not known to harbor chloroquine-resistant P. vivax infection, treatment should start with chloroquine. If they do not respond, treatment should be changed to a chloroquine-resistant P. vivax regimen, and clinicians should notify the Centers for Disease Control and Prevention (CDC) Malaria Hotline (770-488-7788 or, after hours and on weekends and holidays, 770-488-7100).

m The CDC recommends that patients with severe malaria be treated aggressively with parenteral (IV) quinidine started immediately with a loading dose. If patients have received > 40 mg/kg of quinine in the preceding 48 h or mefloquine within 12 h, the quinidine loading dose should be omitted. Consultation with a cardiologist and a physician with expertise in treating severe malaria is advised. BP monitoring for hypotension, cardiac monitoring for widening of the QRS complex or lengthening of the QTc interval, and blood glucose monitoring for hypoglycemia are necessary. Malaria is considered to be severe when patients have ≥ 1 of the following: impaired consciousness, coma or seizure, severe normocyctic anemia, renal failure, pulmonary edema, acute respiratory distress syndrome, shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, or parasitemia > 5%. Severe malaria is most often caused by P. falciparum.

n If patients cannot take oral doxycycline, 100 mg is given IV q 12 h, then switched to oral administration as soon as patients are able. Rapid IV administration should be avoided. Treatment course is 7 days.

o If patients cannot take oral clindamycin, a loading dose of 10 mg base/kg is given IV, followed by 5 mg base/kg q 8 h, then switched to oral administration as soon as patients are able. Rapid IV administration should be avoided. Treatment course is 7 days.

p In the US, artesunate for IV administration is available only as an investigational new drug (obtained through the CDC by calling the CDC Malaria Hotline [770-488-7788]).

q One of the following (using oral treatment doses) should be given with artesunate:

  • In adults: Atovaquone/proguanil, doxycycline, clindamycin (in pregnant women), or mefloquine

  • In children: Atovaquone/proguanil, clindamycin, or mefloquine

G6PD = glucose-6-phosphate dehydrogenase.

Adapted from the Centers for Disease Control and Prevention: Malaria diagnosis & treatment in the United States. Available at http://www.cdc.gov/malaria/diagnosis_treatment/index.html ; last accessed on January 24, 2014.

Adverse Reactions and Contraindications of Antimalarial Drugs

Drug

Some Adverse Reactions

Contraindications

Artemether/lumefantrine

Headache, anorexia, dizziness, asthenia (usually mild)

With lumefantrine, prolonged QT interval

Pregnancy category C (the drug should be used only if potential benefit justifies potential risk to fetus)

Use of mefloquine prophylaxis

Artesunate

As with artemether

As with artemether

Atovaquone/proguanil

GI disturbances, headache, dizziness, rash, pruritus

Pregnancy category C

Hypersensitivity, breastfeeding*, severe renal impairment (creatinine clearance < 30 mL/min)

Chloroquine phosphate

Chloroquine HCl

Hydroxychloroquine sulfate

GI disturbances, headaches, dizziness, blurred vision, rashes or pruritus, exacerbation of psoriasis, blood dyscrasias, alopecia, ECG changes, retinopathy, psychosis (rare)

Hypersensitivity, retinal or visual field changes

Clindamycin

Hypotension, bone marrow toxicity, renal dysfunction, rashes, jaundice, tinnitus, Clostridium difficile infection (pseudomembranous colitis)

Hypersensitivity

Doxycycline

GI upset, photosensitivity, vaginal candidiasis, C. difficile infection (pseudomembranous colitis), erosive esophagitis

Pregnancy, children 8 yr

Halofantrine

Prolongation of PR and QT intervals, cardiac arrhythmia, hypotension, GI disturbances, dizziness, mental changes, seizures, sudden death

Cardiac conduction defects, familial QT prolongation, use of drugs that affect QT interval, hypersensitivity

Pregnancy category C

Mefloquine

Bad dreams, neuropsychiatric symptoms, dizziness, vertigo, confusion, psychosis, seizures, sinus bradycardia, GI disturbances

Hypersensitivity, history of seizures or psychiatric disorders, cardiac conduction disturbances or arrhythmia, coadministration of drugs that may prolong cardiac conduction (eg, β-blockers, Ca channel blockers, quinine, quinidine, halofantrine), occupations that require fine coordination and spatial discrimination and in which vertigo may be life threatening, 1st trimester of pregnancy

Quinine sulfate

Quinine dihydrochloride

GI disturbances, tinnitus, visual disturbances, allergic reactions, mental changes, arrhythmias, cardiotoxicity

Hypersensitivity, G6PD deficiency, optic neuritis, tinnitus, pregnancy (relative contraindication), past adverse quinine reaction (continuous ECG, BP [when drug is given IV], and glucose monitoring recommended)

Quinidine gluconate

Arrhythmias, widened QRS complex, prolonged QTc interval, hypotension, hypoglycemia

Hypersensitivity, thrombocytopenia (continuous ECG, BP, and glucose monitoring recommended)

No loading dose in patients receiving > 40 mg/kg of quinine in the preceding 48 h or a dose of mefloquine in preceding 12 h

Primaquine phosphate

Severe intravascular hemolysis in people with G6PD deficiency, GI disturbances, leukopenia, methemoglobinuria

Concomitant use of quinacrine or potentially hemolytic or bone marrow suppressing agents, G6PD deficiency, pregnancy (because G6PD status of the fetus is unknown)

Pyrimethamine/sulfadoxine

Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal neurolysis, urticaria, exfoliative dermatitis, serum sickness, hepatitis, seizures, mental changes, GI disturbances, stomatitis, pancreatitis, bone marrow toxicity, hemolysis, fever, nephrosis

Hypersensitivity, folate deficiency anemia, infants 2 mo, pregnancy, breastfeeding

*Proguanil is excreted in human milk; whether atovaquone is excreted in human milk is unknown. Safety and effectiveness of these drugs have not been established in children who weigh < 5 kg.

G6PD =glucose-6-phosphate dehydrogenase.

Prevention of relapses of P. vivax or P. ovale malaria

Hypnozoites must be eliminated from the liver with primaquine to prevent relapses of P. vivax or P. ovale. Primaquine may be given simultaneously with chloroquine or afterward. Some P. vivax strains are less sensitive, and relapse may occur, requiring repeated treatment. Primaquine is not necessary for P. falciparum or P. malariae because these species do not have a persistent hepatic phase. If exposure to P. vivax or P. ovale is intense or prolonged or if travelers are asplenic, a 14-day prophylactic course of primaquine phosphate starting when travelers return reduces the risk of recurrence. The main adverse effect is hemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD levels should be determined before primaquine is given.

Primaquine is contraindicated during pregnancy and breastfeeding, unless the infant has been shown not to be G6PD deficient. In pregnant women, chemoprophylaxis with weekly chloroquine can be given for the remainder of pregnancy, and after delivery, women can be given primaquine, provided they are not G6PD deficient.

Prevention

Travelers to endemic regions should be given to chemoprophylaxis (see Table: Prevention of Malaria).

Malaria during pregnancy poses a serious threat to both mother and fetus. Chloroquine can be used during pregnancy in areas where Plasmodium sp are susceptible, but there is no other safe and effective prophylactic regimen, so pregnant women should avoid travel to chloroquine-resistant areas whenever possible. The safety of mefloquine during pregnancy has not been documented, but limited experience suggests that it may be used when the benefits are judged to outweigh the risks. Doxycycline, atovaquone/proguanil, and primaquine should not be used during pregnancy.

Artemisinins have a short half-life and are not useful for prophylaxis.

Prophylactic measures against mosquitoes include

  • Using permethrin- or pyrethrum-containing residual insecticide sprays (which have prolonged duration of action) on clothing or in homes and outbuildings

  • Placing screens on doors and windows

  • Using mosquito netting (preferably impregnated with permethrin or pyrethrum) around beds

  • Applying mosquito repellents such as DEET (diethyltoluamide) 25 to 35% to exposed skin

  • Wearing protective long-sleeved shirts and pants, especially between dusk and dawn, when Anopheles mosquitoes are active

People who plan to use repellents that contain DEET should be instructed to

  • Apply repellents only to exposed skin as directed on the label and use them sparingly around ears (they should not be applied to or sprayed in the eyes or mouth)

  • Wash hands after application

  • Not allow children to handle repellents (adults should apply the repellent to their hands first, then gently spread it on the child's skin)

  • Apply just enough repellent to cover the exposed area

  • Wash the repellant off after returning indoors

  • Wash clothing before wearing again unless indicated otherwise by the product label

Most repellents can be used on infants and children < 2 mo. The Environmental Protection Agency does not recommend additional precautions for using registered repellents on children or on pregnant or breastfeeding women.

Vaccines are under development. A large clinical trial of the RTS,S recombinant vaccine based on the P. falciparum circumsporozoite protein showed moderate efficacy, resulting in 46% fewer cases of clinical malaria in young children living in endemic regions of Africa. The results are encouraging, but it is unclear when a vaccine is likely to become available for military personal and international travelers.

Prevention of Malaria

Drug a

Use

Adult Dosage

Pediatric Dosage

Comments

Atovaquone/proguanil b

In all areas

1 adult tablet once/day

5–8 kg: one-half pediatric tablet once/day

> 8–10 kg: three-fourths pediatric tablet once/day

> 10–20 kg: 1 pediatric tablet once/day

> 20–30 kg: 2 pediatric tablets once/day

> 30–40 kg: 3 pediatric tablets once/day

> 40 kg: 1 adult tablet once/day

Begun 1 to 2 days before travel and continued daily during the stay and for 7 days after leaving

Chloroquine phosphate

Only in areas with chloroquine-sensitive Plasmodium

500 mg salt (300 mg base) po once/wk

8.3 mg salt/ kg (5 mg base/kg), up to maximum 500 mg salt (300 mg base) po once/wk

Begun 1–2 wk before travel and continued weekly during the stay and for 4 wk after leaving

Doxycycline c

In all areas

100 mg po once/day

> 8 yr: 2.2 mg/kg (up to 100 mg) po once/day

Begun 1–2 days before travel and continued during the stay and for 4 wk after leaving

Hydroxychloroquine d

An alternative to chloroquine in areas with chloroquine-sensitive Plasmodium

400 salt mg (310 mg base) po once/wk

6.5 mg salt/kg (5 mg base/kg), up to 400 mg salt (310 mg base) po once/wk

Begun 1–2 days before travel and continued during the stay and for 4 wk after leaving

Mefloquine e

In areas with mefloquine-sensitive Plasmodium

250 mg salt (228 base) po once/wk

≤ 9 kg: 5 mg salt (4.6 mg/kg base) once/wk

> 9–19 kg: one-fourth tablet once/wk

> 19–30 kg: one-half tablet once/wk

> 30–45 kg: three-fourths tablet once/wk

> 45 kg: 1 tablet once/wk

Begun ≥ 2 wk before travel and continued during the stay and for 4 wk after leaving

Primaquine f

For prophylaxis for brief travel in areas known to harbor mainly P. vivax

30 mg base (52.6 mg salt) po once/day

0.5 mg base/kg (0.8 mg salt /kg) up to adult dose po once/day

Begun 1 to 2 days before travel and continued daily during the stay and for 7 days after departure

For

terminal prophylaxis to prevent relapse of P. vivax or P. ovale infection in people with prolonged exposure or prior infection

Dosed as above

Dosed as above

Given daily for 14 days after departure from endemic area

a see Adverse Reactions and Contraindications of Antimalarial Drugs for adverse reactions and contraindications.

b Atovaquone/proguanil is available as a fixed-dose combination tablet: adult tablets (250 mg atovaquone/100 mg proguanil) and pediatric tablets (62.5 mg atovaquone/25 mg proguanil). To enhance absorption, patients should take the drug with food or a milky drink. Atovaquone/proguanil is contraindicated in patients with a creatinine clearance < 30 mL/min. This combination is not recommended for children weighing < 5 kg or for pregnant or breastfeeding women.

c Use of tetracyclines is contraindicated during pregnancy and in children < 8 yr.

d Hydroxychloroquine is contraindicated during pregnancy and in children < 8 yr.

e Mefloquine has not been approved for use during pregnancy. The drug is contraindicated in patients who have active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, other major psychiatric disorders, or seizures; if patients have psychiatric disturbances or a previous history of depression, the drug should be used cautiously. The drug is not recommended for patients with cardiac conduction abnormalities.

f Primaquine is used as terminal prophylaxis to reduce risk of relapse in people who have taken chloroquine or a drug active against chloroquine-resistant malaria and have had prolonged exposure to P. vivax and/or P. ovale. Primaquine alone can also be used for primary prophylaxis in people at risk of malaria, particularly that due to P. vivax. It is contraindicated in people with G6PD deficiency and in pregnant or breastfeeding women (unless the breastfed infant has a normal G6PD level).

G6PD = glucose-6-phosphate dehydrogenase.

Adapted from the Center for Disease Control and Prevention (CDC): Infectious diseases related to travel. In the Yellow Book. Available at http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/malaria ; last accessed on January 24, 2014.

Key Points

  • There are 300 to 500 million people infected with malaria worldwide; about 660,000 deaths occur yearly, mostly in children < 5 yr in Africa.

  • P. falciparum causes microvascular obstruction and tissue ischemia, particularly in the brain, kidneys, lungs, and GI tract of nonimmune infants and adults; patients may die within days of their initial symptoms.

  • P. vivax, P. ovale, and P. malariae typically do not compromise vital organs; mortality is rare.

  • Manifestations include recurrent fever and rigor, headache, myalgia, and nausea; hemolytic anemia and splenomegaly are common.

  • Diagnose using light microscopy of blood (thin and thick smears) and/or rapid blood assays.

  • Treat with antimalarial drugs based on the species (if known) and drug resistance patterns in the area in which infection was acquired.

  • Give chemoprophylaxis to travelers to endemic areas, and teach them ways to prevent mosquito bites.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • PERIOSTAT, VIBRAMYCIN
  • MEPRON
  • ARALEN
  • QUALAQUIN
  • No US brand name
  • ACHROMYCIN V
  • PLAQUENIL
  • DARAPRIM
  • CLEOCIN
  • ELIMITE, NIX

* This is a professional Version *