Current Trends Recommendations for the Prevention of Malaria in Travelers

Malaria continues to be an important health risk to Americans who travel to malaria-endemic areas of the world. The continued extension of chloroquine resistant Plasmodium falciparum (CRPF) in Africa, Asia, South America, and Oceania has reduced the number of effective drugs for malaria prophylaxis. In addition, some alternative drugs to chloroquine have been found to be associated with serious adverse reactions, and thus their usefulness is limited. Guidelines for prophylaxis must take into account the risk of exposure to malaria, the effectiveness and safety of antimalarial drugs, and the use of personal protective measures. Recommendations for the prevention of malaria should be revised periodically because of geographic changes in the occurrence of drug-resistant P. falciparum malaria, new information on the efficacy or toxicity of drugs used for prophylaxis, and/or the availability of new drugs.

Malaria in humans is caused by one of four protozoan species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. All are transmitted by the bite of an infected female Anopheles mosquito. Occasionally malaria is transmitted by blood transfusion or congenitally from mother to fetus. The disease is characterized by fever and influenza-like symptoms, which may occur at intervals and which include chills, headache, myalgia, and malaise. Malaria may be associated with anemia and jaundice, and P. falciparum infections may cause kidney failure, coma, and death. Deaths due to malaria are preventable.

Risk of Acquiring Malaria

Malaria transmission occurs in large areas of Central and South America, sub- Saharan Africa, the Indian Subcontinent, Southeast Asia,* the Middle East, and Oceania. The estimated risk of acquiring malaria varies markedly from area to area. This variability is a function of the intensity of transmission in both urban and rural areas within the various regions as well as a function of the itineraries of most travelers. For example, during the period 1983-1986, 634 cases of P. falciparum among American civilians were reported to CDC. Of these, 507 (80%) were acquired in sub-Saharan Africa; 44 (7%), in Southeast Asia; and 63 (10%), in the Caribbean and South America. Of the 28 fatal infections, 21 were acquired in sub-Saharan Africa. Thus, most cases of imported malaria among American travelers were acquired in sub-Saharan Africa, despite the fact that only an estimated 90,000 Americans travel to sub-Saharan Africa each year, whereas an estimated 900,000 Americans visit Southeast Asia and South America each year. This disparity in the risk of acquiring malaria stems from the fact that travelers to Africa are at risk in most rural and many urban areas. Moreover, travelers tend to spend considerable amounts of time, including evening and nighttime hours, in rural areas where malaria risk is highest. In contrast, most travelers to Southeast Asia and South America spend most of their time in urban or resort areas where risk of exposure, if any, is limited, and they travel to rural areas only during daytime hours, when risk is limited.

Drug Resistance

Resistance of P. falciparum to chloroquine has been reported from all countries with P. falciparum malaria except the Dominican Republic, Haiti, Central America, the Middle East, and the following countries in West Africa: Chad, Equatorial Guinea, Guinea, Guinea-Bissau, Liberia, Senegal, and Sierra Leone. In addition, resistance to both chloroquine and pyrimethamine/sulfadoxine (Fansidar) is widespread in Thailand, Burma, and Kampuchea.

General Advice for Travelers to Malaria-Endemic Areas

All travelers to malaria-endemic areas are advised to use an appropriate drug regimen and personal protection measures to prevent malaria. However, travelers must be informed that, regardless of methods employed, malaria can still be contracted. Symptoms can develop as early as 8 days after initial exposure in a malaria-endemic area and as late as several months after departure from a malarious area. Travelers should understand that malaria can be treated effectively early in the course of the disease but that delaying appropriate therapy can have serious or even fatal consequences. Individuals who have the symptoms of malaria should seek prompt medical evaluation, including thick and thin malaria smears, as soon as possible.

Personal Protection Measures

Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn. Travelers must be advised of the importance of measures to reduce contact with mosquitoes during those hours. Such measures include remaining in well-screened areas, using mosquito nets, and wearing clothes that cover most of the body. Additionally, travelers should be advised to purchase insect repellent for use on exposed skin before travel. The most effective repellents contain N,N diethylmetatoluamide (DEET), an ingredient in many commercially available insect repellents. The actual concentration of DEET varies among repellents (ranging up to 95%); the higher the concentration, the longer-lasting the repellent effect. Travelers should also be advised to purchase a pyrethrum-containing flying-insect spray to use in living and sleeping areas during evening and nighttime hours.

Chemoprophylaxis

Malaria chemoprophylaxis is the use of drugs to prevent the development of the disease. Preferably, malaria chemoprophylaxis should begin 1-2 weeks prior to travel to malarious areas. In addition to assuring adequate blood levels of the drug, this regimen allows any potential side effects to be evaluated and treated by the traveler's own physician. The exception is doxycycline; because of its short half-life, its use should begin 1-2 days before entering a malarious area. Chemoprophylaxis should continue during travel in malarious areas and for 4 weeks after departure from these areas.

In choosing an appropriate chemoprophylactic regimen prior to travel, several factors should be considered. The travel itinerary should be reviewed in detail and compared with the information on areas of risk within a given country to determine whether the traveler will actually be at risk of acquiring malaria. The risk of acquiring CRPF malaria is another consideration. In addition, any previous allergic or other reaction to the antimalarial drug of choice and the accessibility of medical care during travel must be determined.

Chemoprophylactic Regimens

For travel to areas of risk where CRPF has not been reported or where only low-level or focal chloroquine resistance has been reported, once-weekly use of chloroquine alone is recommended. Chloroquine is usually well tolerated. The few individuals who experience uncomfortable side effects may tolerate the drug better by taking it with meals or in divided, twice-weekly doses. As an alternative, the related compound hydroxychloroquine may be better tolerated. (See Table 1 for recommended dosages for chloroquine and other chemoprophylactic regimens.)

For travel to areas of risk where CRPF is endemic, once-weekly use of chloroquine alone is recommended. In addition, travelers to these areas (except those with histories of sulfonamide intolerance) should be given a treatment dose of Fansidar to be carried during travel and should be advised to take the Fansidar promptly in the event of a febrile illness during their travel when professional medical care is not readily available. It must be emphasized to these travelers that such presumptive self-treatment of a possible malarial infection is only a temporary measure and that prompt medical evaluation is imperative. They should be advised to continue their weekly chloroquine prophylaxis after presumptive treatment with Fansidar. (See Table 1 for recommended dosage.)

Alternative Chemoprophylactic Regimens

Doxycycline alone, taken daily, is an alternative regimen for short-term travel to areas with risk of CRPF. It is particularly appropriate for those individuals with a history of sulfonamide intolerance or for those, such as short-term travelers to forested areas of Thailand, Burma, and Kampuchea, who may be at risk in areas of chloroquine and Fansidar resistance. Travelers who use doxycycline should be cautioned about the possible side effects (see Adverse Reactions, page 282). Doxycycline prophylaxis can begin 1-2 days prior to travel to malarious areas. It should be continued daily during travel in malarious areas and for 4 weeks after departure from these areas.

Fansidar taken once weekly in combination with chloroquine may be considered in exceptional circumstances involving prolonged exposure in areas with intense transmission of CRPF and where medical care is not available. If weekly use of Fansidar is prescribed, the traveler should be cautioned about the possible side effects as described in the section on adverse reactions.

Proguanil (Paludrine) is, like pyrimethamine, a dihydrofolate reductase (DHFR) inhibitor. Resistance of P. falciparum to DHFR inhibitors is present in some endemic regions, but its distribution is not well delineated. Proguanil is not available commercially in the United States. Limited data suggest that it may be effective in Kenya, but not in Thailand and Papua New Guinea. No current data are available on the efficacy of proguanil in other areas of CRPF, especially West Africa. Travelers using proguanil should take a daily 200-mg dose (adult) in combination with a weekly regimen of chloroquine.

Mefloquine (Lariam), a new antimalarial similar in structure to quinine, is highly effective against both chloroquine- and Fansidar-resistant P. falciparum infections. Approval for use in the United States is pending; currently the drug is available in France and Switzerland. Mefloquine may be considered for use by travelers to areas where there is risk of CRPF infection and by travelers to areas where P. falciparum is resistant to both chloroquine and Fansidar. Currently available information suggests the adult prophylactic dose is 250 mg weekly. Mefloquine prophylaxis should begin 1 week before entry into the malarious area and should continue weekly while the traveler is there. Adverse reactions are infrequent at prophylactic dosage but may become more common with the higher doses used in treatment. Minor side effects observed with prophylactic doses, such as gastrointestinal disturbance and dizziness, tend to be transient and self-limited. Because mefloquine has occasionally been associated with asymptomatic sinus bradycardia and a prolonged QT interval, it should not be used by those receiving beta-blockers, calcium channel antagonists, or other drugs that may prolong or alter cardiac conduction.

Primaquine: Prevention of Relapses of P. vivax and P. ovale

Unlike P. falciparum and P. malariae, P. vivax and P. ovale have forms that can persist in the liver and cause relapses for as long as 4 years after routine chemoprophylaxis is discontinued. Travelers to malarious areas should be alerted to this risk; if they develop malaria symptoms after they return home, they should report their travel history and the possibility of malaria to a physician as soon as possible. Primaquine prevents relapses by acting against the liver stages of P. vivax and P. ovale; however, its use is not indicated for all travelers. Primaquine is administered after the traveler leaves an endemic area and usually in conjunction with chloroquine during the last 2 weeks of the 4-week period of prophylaxis after exposure in an endemic area has ended.

Since most malarious areas of the world (except Haiti) have at least one species of relapsing malaria, travelers to these areas have some risk of acquiring either P. vivax or P. ovale. However, this risk is extremely difficult to quantify. Prophylaxis with primaquine is generally indicated for persons who have had prolonged exposure in malaria-endemic areas, e.g., missionaries and Peace Corps volunteers. While the actual risk to the traveler with less intense exposure is difficult to define, with the exception of individuals deficient in glucose-6-phosphate dehydrogenase (G6PD) (see Adverse Reactions, page 282), most individuals can tolerate the standard regimen of primaquine.

Adverse Reactions and Contraindications to Antimalarials

The frequent or serious side effects of recommended antimalarials are discussed below. However, physicians should review the prescribing information in standard pharmaceutical reference texts and in the manufacturers' package inserts.

Chloroquine and hydroxychloroquine rarely have serious adverse reactions when taken at prophylactic doses for malaria. Occasionally, minor side effects such as gastrointestinal disturbance, headache, dizziness, blurred vision, and pruritus occur, but generally these do not require discontinuing the drug. While high doses of chloroquine, such as those used to treat rheumatoid arthritis, have been associated with retinopathy, this serious side effect has not been associated with routine weekly malaria prophylaxis. However, periodic ophthalmologic examinations for persons using chloroquine for extended periods (more than 6 years of cumulative weekly prophylaxis) are recommended. Chloroquine and related compounds may exacerbate psoriasis and may interfere with the antibody response to human diploid cell rabies vaccine.

Amodiaquine, a 4-aminoquinoline similar to chloroquine in structure and activity, has been used as an alternative prophylactic drug in areas where CRPF is endemic. It is not commercially available in the United States. Amodiaquine-associated agranulocytosis has been reported among travelers from the United Kingdom and Switzerland, countries where the drug has been commercially available. Therefore, amodiaquine is not recommended for malaria prophylaxis (1).

Fansidar can cause severe adverse cutaneous reactions. Between 1982 and 1985, 24 cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis were documented among American travelers using Fansidar. Seven of these reactions were fatal. Available data indicate that the incidence of fatal cutaneous reactions associated with the use of Fansidar among American travelers ranges from 1/11,000 to 1/25,000 users. These severe cutaneous reactions were associated with Fansidar when used as once-weekly prophylaxis. Fansidar has also been associated with serum-sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. IF ONCE-WEEKLY USE OF FANSIDAR IS PRESCRIBED, THE TRAVELER SHOULD BE ADVISED TO DISCONTINUE IT IMMEDIATELY IF HE/SHE DEVELOPS A POSSIBLE ILL EFFECT, ESPECIALLY ANY SKIN OR MUCOUS MEMBRANE SIGNS OR SYMPTOMS, SUCH AS ITCHING, REDNESS, RASH, MOUTH OR GENITAL LESIONS, OR SORE THROAT. Use of Fansidar is contraindicated for persons with histories of sulfonamide intolerance and for infants under 2 months of age.

Doxycycline is a tetracycline and may cause side effects associated with this group of drugs. Travelers to tropical climates who use doxycycline should be made aware of the possibility of photosensitivity, usually manifested as an exaggerated sunburn reaction. The risk of such a reaction can be minimized by avoiding prolonged, direct exposure to the sun. In addition, doxycycline use may be associated with an in creased frequency of monilial vaginitis. Doxycycline is contraindicated in pregnancy (see Prophylaxis During Pregnancy, this page) and for children under 8 years of age.

Primaquine may cause severe hemolysis in G6PD-deficient individuals. Before using primaquine, G6PD deficiency should be ruled out by appropriate laboratory testing.

Prophylaxis During Pregnancy

Malaria infection in pregnant women may be more severe than in nonpregnant women. In addition, the risk of adverse pregnancy outcomes, including prematurity, abortion, and stillbirth, may be increased. For these reasons, and because chloroquine has not been found to have any harmful effects on the fetus when used in the recommended doses for malaria prophylaxis, pregnancy is not a contraindication to malaria prophylaxis with chloroquine or hydroxychloroquine. However, because no chemoprophylactic regimen is completely effective in areas with CRPF, women who are pregnant or likely to become so should avoid travel to such areas.

The safety of Fansidar during pregnancy has not been completely established. Experimental data demonstrating the teratogenic effect of pyrimethamine in laboratory animals has resulted in restrictions in the licensing of compounds containing pyrimethamine. However, pyrimethamine, alone and in combination with sulfonamides, has been used for nearly 30 years to treat pregnant women with toxoplas- mosis (another protozoal parasitic infection). While caution must be exercised when extrapolating from accumulated case reports of women treated for this infection, it is difficult to implicate pyrimethamine as a cause of fetal abnormalities. Thus, while the teratogenic effect in animals cannot be ignored, published data do not substantiate the inference that pyrimethamine is a human teratogen.

Sulfadoxine is a sulfonamide antimicrobial that, when administered during the last trimester of pregnancy, theoretically could compete with bilirubin for plasma proteins and exacerbate neonatal jaundice. It is unclear, however, whether this specific sulfa congener poses any risk to the newborn.

Doxycycline, a tetracycline, is generally contraindicated for malaria prophylaxis during pregnancy. Adverse effects of tetracyclines on the fetus include discoloration and severe dysplasia of the teeth and inhibition of bone growth. In pregnancy, therefore, tetracyclines would be indicated only if required to treat life-threatening infections due to multidrug-resistant P. falciparum.

Primaquine should not be used during pregnancy because the drug may be passed transplacentally to a G6PD-deficient fetus and cause life-threatening hemolytic anemia in utero. Whenever radical cure or terminal prophylaxis with primaquine is indicated, chloroquine should be given once a week until delivery, at which time the decision to give primaquine may be made.

Prophylaxis While Breastfeeding

Very small amounts of antimalarial drugs are secreted in the breast milk of lactating women. The amount of drug transferred is not thought to be harmful to the nursing infant; however, more information is needed. Because the quantity of antimalarials transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis should receive the recommended dosages of antimalarials (Table 1).

Chemoprophylaxis for Children

Children of any age can contract malaria. Consequently, the indications for prophylaxis are identical to those described for adults. Doxycycline is contraindicated for children less than 8 years of age, and Fansidar is contraindicated for infants less than 2 months of age.

Chloroquine phosphate, which is manufactured in the United States in tablet form only, tastes quite bitter. Pediatric doses should be calculated carefully according to body weight. Pharmacists can pulverize tablets and prepare gelatin capsules with calculated pediatric doses. Mixing the powder in food or drink may facilitate the weekly administration of chloroquine to children. Alternatively, chloroquine in suspension is widely available overseas.

OVERDOSE OF ANTIMALARIAL DRUGS CAN BE FATAL. THE MEDICATION SHOULD BE STORED IN CHILDPROOF CONTAINERS OUT OF THE REACH OF CHILDREN.

Health Information for International Travel 1988 will soon be published by the Center for Prevention Services, CDC. This document includes the above recommendations for the prevention and presumptive treatment of malaria in travelers. In addition, it includes the chemoprophylactic regimen recommended for each country and the risk of malaria in each country. It will be a useful reference to health professionals, travel agencies, international businesses, and other agencies that advise international travelers concerning malaria and other health risks they may encounter when visiting foreign countries. This publication will be available from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402, telephone (202)783-3238, as DHHS publication no. (CDC)88-8280. Reported by: Malaria Br, Div of Parasitic Diseases, Center for Infectious Diseases; Div of Quarantine, Center for Prevention Svcs, CDC. Reference

1. Centers for Disease Control. Agranulocytosis associated with the use of amodiaquine for malaria prophylaxis. MMWR 1986;35:165-6. *Thailand, Indonesia, Malaysia, People's Republic of China, the Philippines, Burma, Kampuchea, Vietnam, and Laos.

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