Despite 50 years of eradication efforts, malaria remains a major scourge throughout the tropics. The disease is becoming increasingly common, with 300 million to 500 million new infections and 1.5 million to 2.7 million deaths (mostly in children) occurring every year.¹

Efforts to control the spread of malaria have been stymied by increasing drug resistance on the part of the parasite (Plasmodium species) and increasing insecticide resistance on the part of its vector (Anopheles mosquito). The situation has been complicated by political instability in some of the countries where malaria is common. At least 90 countries in Africa, Asia, the Caribbean, and Central and South America are officially considered malarious. In many areas, the disease is spreading through the local population and also to travelers. These travelers may become symptomatic during their stay in these locales or after they return to their home country.²

The increasing popularity of air travel to remote and exotic locales is changing the practice of medicine in the United States. It is possible for an American tourist to return home from East Africa by air and only a few days later present with life-threatening symptoms of a highly contagious exotic disease. Scenarios such as this one have been explored in a number of books and movies addressed to the lay public. Consequently, the general public has become aware of the possibility that a catastrophic epidemic disease could be brought into this country.

The prevention of malaria and other tropical diseases in travelers has become a major concern. Drug-resistant Plasmodium species, particularly Plasmodium falciparum (the most deadly species), have spread throughout tropical countries. None of the present prophylactic regimens provides 100 percent protection against malaria, and research efforts to develop more effective antimalarial agents lag behind work in other fields.³ Only a limited number of antimalarial agents are commercially available in the United States. Few of these agents are suitable for use in children, and others are relatively contraindicated for use in infants and pregnant women.

The potential for serious toxicity with the current antimalarial agents is perhaps the greatest concern and necessitates a careful review of travel plans to assess risk versus benefit. Even minor side effects, however, adversely affect compliance, and many vulnerable travelers never complete their recommended prophylactic regimen.⁴ Of course, the risk of side effects from prophylaxis pales by comparison with the vastly greater risk of morbidity from malaria.

Protection Against Mosquito Bites

The best way to prevent malaria is to avoid exposure to the Anopheles mosquito that carries the disease. This can be difficult in tropical areas because of the pervasiveness of mosquitoes and the inadequate screening of windows. However, the Anopheles mosquito has several distinguishing characteristics that may be helpful in avoiding exposure. Unlike other mosquito types, it flies silently and, at rest, adopts a head-down rather than a horizontal position.² In addition, the Anopheles mosquito feeds from dusk to dawn. Thus, travelers can significantly reduce their risk of malaria by limiting evening exposure to mosquitoes. Travelers who take day trips from a malaria-free city to a malarious countryside are at minimal risk if they return to the city before dusk.

Mosquito bed netting can be useful in reducing nighttime exposure to mosquitoes, especially if the netting is sprayed with permethrin. Wearing long-sleeved, light-colored clothing is also helpful, but the best protection comes from using an insect repellent that contains no more than 35 percent N,N-diethyl-metatoluamide (deet). Insect repellents with higher percentages of deet carry a small risk of neurotoxicity, particularly if they are used repeatedly on small children.⁵

Prophylactic Agents

CHLOROQUINE

Chloroquine (Aralen) is a 4-aminoquinoline that inhibits heme polymerase, thus preventing the conversion of heme, a toxic byproduct of hemoglobin digestion by the parasite, into nontoxic malarial pigment.⁶ The erythrocytic or blood-feeding phase of the parasite life cycle is therefore interrupted but without affecting the hepatic phase.

For many years, chloroquine was the standard prophylactic agent against malaria, as well as a convenient treatment for acute attacks of the disease. Chloroquine is inexpensive, fast acting and fairly nontoxic at usual dosages. Furthermore, it can be used safely in pregnant women and women who are breast-feeding.

Because of the emergence of drug-resistant P. falciparum strains, however, chloroquine has become ineffective in most parts of the world. With a few exceptions, chloroquine is now used as malaria prophylaxis only in the Middle East, Central America and Hispaniola (the island nations of Haiti and the Dominican Republic). The antimalarial dosage for a traveler to these areas is one 500-mg tablet (300-mg base) per week beginning one week before departure, one 500-mg tablet per week during exposure and one tablet per week for four weeks after the traveler returns home.²

Side effects of chloroquine include mild nausea, blurred vision, headache and psoriasis flare-ups. In addition, itching may occur in dark-skinned (black) persons. In dosages higher than 500 mg per week, chloroquine has been associated with retinal degenerative disorders and therefore probably should not be used in persons with such disorders. In the typical prophylactic dosage, however, the drug is not harmful to the retina. Very rare reactions to chloroquine include agranulocytosis, photosensitivity and neuropsychiatric effects.⁵

Because of the bitter taste of chloroquine, pediatric dosing is very difficult. Chloroquine syrups are not commercially available in the United States. However, weekly doses of powdered chloroquine can be prepared in advance by a pharmacist and administered in food to disguise the taste. Child-proof containers are very important because chloroquine is extremely toxic in accidental overdose and has provoked fatal arrhythmias in small children.⁷

MEFLOQUINE

Mefloquine (Lariam), a quinolone methanol derivative, has supplanted chloroquine as the standard prophylactic agent against malaria. The Centers for Disease Control and Prevention (CDC) now recommends the prophylactic use of mefloquine in travelers to most malarious regions. Although mefloquine provides the best current protection against chloroquine-resistant P. falciparum malaria, resistant strains have developed in Cambodia and along Thailand's borders with Cambodia and Myanmar (the former Burma).

Because mefloquine has a long half-life (21 days), the dosing regimen is similar to that for chloroquine. The traveler begins by taking a 250-mg tablet once a week for one to two weeks before departure, then takes a 250-mg dose once a week during travel and takes a 250-mg tablet once a week for four weeks after returning home.² Mefloquine tablets are scored to facilitate pediatric dosing.

Despite its effectiveness, mefloquine prophylaxis has some serious drawbacks. The drug is expensive, and there are relative contraindications to its use in pregnant women (at least in the first trimester), small children (those weighing less than 15 kg [33 lb]) and airline pilots (because the drug may possibly decrease spatial discrimination ability).⁵ Some exceptions to these relative contraindications are made because of increasing evidence that the risk of malaria far outweighs the risk of prophylaxis in persons traveling to destinations such as Africa. For example, pilots at high risk for malaria may be candidates for malaria prophylaxis using mefloquine, but only if they successfully adapt to prophylactic doses before flying. In special high-risk circumstances, use of this agent may also be warranted in pregnant women and children weighing 10 to 15 kg (22 to 33 lb).⁸

Mefloquine should be used with caution in patients with seizure disorders, cardiac conduction defects or a history of psychosis.² Therapy with beta blockers or calcium channel blockers is no longer considered a contraindication to the use of mefloquine unless a traveler has an underlying cardiac conduction problem or arrhythmia.

The neuropsychiatric side effects of mefloquine have led to a public controversy about this drug, particularly in Europe. Numerous anecdotal reports have been made of insomnia, nightmares, paranoid delusions, hallucinations, depression and even frank psychoses occurring in persons who received mefloquine, even in those without a significant psychiatric history. An estimated 70 percent of such problems occur within receipt of the first three doses.⁸ This may justify the use of a longer trial of mefloquine before travelers leave their home country. Most psychiatric problems have resolved on cessation of therapy. It is reasonable to caution patients about the possibility of psychiatric reactions to mefloquine and to provide an alternative therapy if they are unable to take the drug.

The mefloquine drug scare has received attention in the U.S. lay press.^9,10 Consequently, some travelers have become reluctant to take mefloquine, even when no good alternatives are available. The fact remains, however, that most travelers tolerate the weekly dosage of mefloquine quite well. If anything, they have only a few mild gastrointestinal side effects, some slight dizziness and an occasional vivid dream. In multiple clinical trials, rates of serious neuropsychiatric problems have not been found to be significantly higher with prophylactic dosages of mefloquine than with alternative agents.¹¹ Thus, despite some problems, mefloquine remains more convenient and effective than other available therapies suitable for use in areas where Plasmodium species are resistant to chloroquine.

PROGUANIL

Proguanil, or chloroguanide hydrochloride, is an effective antimalarial agent that is manufactured in Great Britain, where its brand name is Paludrine. This drug inhibits dihydrofolate reductase, thereby disrupting the ability of Plasmodium parasites to synthesize nucleic acids in the preerythrocytic phase. Proguanil best serves as a less effective alternative to mefloquine in sub-Saharan Africa, but it must be taken daily (200 mg after food) in conjunction with the weekly chloroquine regimen. The traveler should start taking proguanil several days before departure and continue taking the drug (in addition to the weekly chloroquine dose) for four weeks after returning to the home country.²

Proguanil is usually well tolerated, although it may cause gastrointestinal distress and aphthous ulcers. The dosage must be reduced in patients with renal insufficiency. The combined regimen of proguanil and chloroquine is safe in pregnant women and infants. If this regimen is used with folate supplementation, it is a reasonable prophylactic option in pregnant women who travel to Africa.⁵

Proguanil is not commercially available in the United States, but it may be readily obtained in Canada and overseas. Widespread resistance to proguanil limits its use to Africa. Even in Africa, however, the proguanilchloroquine regimen is significantly less effective than a mefloquine or doxycycline regimen. Therefore, most U.S. physicians consider proguanil the third choice for malaria prophylaxis in travelers.

DOXYCYCLINE

Doxycycline (Vibramycin) attacks both the preerythrocytic phase (occurring in the liver) and the erythrocytic phase of the Plasmodium life cycle through ribosomal inhibition. As an antibiotic, doxycycline has also been used to prevent or treat traveler's diarrhea, although it has become less useful for either purpose because of bacterial resistance.

Fortunately, doxycycline remains an effective option for the multidrug-resistant P. falciparum malaria occurring in areas along Thailand's borders. It is often the best alternative when mefloquine is contraindicated. The drug is taken in a dosage of 100 mg per day during exposure and continued for four weeks after the traveler returns home.

Side effects of doxycycline therapy include photosensitivity (which necessitates the wearing of hats and sunscreen preparations), nausea, esophagitis and monilial vaginitis. With care, most of these side effects can be minimized. Consequently, the daily doxycycline regimen, although cumbersome, is still feasible. Doxycycline therapy is contraindicated in pregnant women and children less than nine years old.^2,5

PRIMAQUINE

Travelers exposed to malaria may use primaquine, in a dosage of one 26.3-mg tablet per day for 14 days, as terminal prophylaxis or for the elimination of Plasmodium vivax or Plasmodium ovale hypnozoites from the liver. Malaria prophylaxis using primaquine is reserved for use in persons who travel for relatively long periods (more than two months) in areas in which the probability of contracting malaria is high even with the use of reasonable prophylaxis.⁵ Before primaquine therapy is initiated, the possibility of glucose-6-phosphate dehydrogenase deficiency must be excluded. If present, this deficiency can result in severe hemolytic anemia in persons taking primaquine (Table 1).

Other Therapeutic Options

SELF-TREATMENT REGIMENS

As drug resistance spreads or more travelers decide not to take mefloquine, self-treatment regimens may become a substitute for standard prophylaxis. Pyrimethamine-sulfadoxine (Fansidar) is a combination drug now used chiefly for emergency self-treatment of malaria in travelers who are unable to take routine antimalarial agents or who are observing a prophylactic regimen but are unable to obtain medical care within 24 hours. A traveler who has symptoms of presumptive malaria (i.e., shaking chills and a high fever) should take three pyrimethamine-sulfadoxine tablets immediately, continue the weekly prophylactic drug and seek medical care as soon as possible.

Pyrimethamine-sulfadoxine was once recommended for routine malaria prophylaxis, but it proved too toxic to be used for that purpose. This combination drug should not be used by pregnant women. It should not be taken by persons who are allergic to sulfa, because it may cause severe rash, hepatitis and Stevens-Johnson syndrome.

Resistance to pyrimethamine-sulfadoxine is widespread, especially in Asia. Therefore, treatment failures can occur. The use of pyrimethamine-sulfadoxine is reserved for those making trips to remote, medically underserved areas or for bolstering an inadequate regimen (usually chloroquine-only) in an area of known chloroquine resistance. Overseas, pyrimethamine is available in combination with dapsone for use as weekly malaria prophylaxis, but this regimen has been associated with fatal agranulocytosis.⁵

FUTURE OPTIONS

Current prophylactic options leave much to be desired. Therefore, several new agents are under investigation. Azithromycin (Zithromax) is being evaluated as a potential suppressive agent with low toxicity.¹² Some of the most interesting new antimalarial agents are derived from sweet wormwood (Artemisia annua), known in China as “qinghaosu.” Artemisinin (the plant's active component) and its synthetic derivatives have proved to be very effective treatments in persons infected with otherwise resistant Plasmodium strains, and they may have additional potential as prophylactic agents.⁵ Their chief disadvantage is a short half-life, which necessitates frequent dosing.

VACCINES

Many travel-related diseases can be prevented by vaccines. Unfortunately, a malaria vaccine is unlikely to be available in the near future. Although immunity to malaria does occur, it is often incomplete and short-lived, and frequent rechallenging with malarial antigen is required. Residents of malarious areas eventually develop some immunity, but they appear to lose this immunity after they spend several years in a nonmalarious area.

One of the most promising vaccines was Spf66. This vaccine was developed by Dr. Manuel Patarroyo of Colombia, who subsequently donated it to the World Health Organization. Initial trials showed that the vaccine was capable of producing 30 percent or greater immunity; however, the results of more recent trials of Spf66 have been disappointing.¹³ Several other experimental vaccines are currently undergoing field trials in Africa. A successful vaccine will probably need to contain sporozoite, merozoite and gametocyte antigens.

Risk Assessment

In counseling travelers about malaria prophylaxis, physicians can make two main errors: they can overprescribe and a patient may have side effects from unnecessary drugs, or they can underprescribe and a patient may contract malaria. Assessing malarial risk requires a detailed knowledge of a patient's travel itinerary and accommodations. Regularly updated maps identifying risk areas are available from several sources and can be invaluable tools in counseling patients (Table 2).² Malaria exposure often depends on where a patient travels within a country. Thus, many tourists can be safely exempted from malaria prophylaxis.

Travelers to the Caribbean (except Hispaniola, especially Haiti) are not at risk of contracting malaria. Travelers are at risk for malaria exposure in some areas of Central America. The risk of malaria is intermediate in the Amazon and other tropical locales in South America. Many popular tourist destinations, such as Rio de Janeiro, are free of malaria.

In contrast, travelers to sub-Saharan Africa are at very high risk of malaria exposure, and failure to prescribe adequate prophylaxis (usually mefloquine) frequently results in illness. More than 82 percent of imported P. falciparum infections in U.S. citizens were contracted in Africa.²

The risk of malaria exposure is also very high throughout New Guinea, except at elevations above 1,600 m (5,249 ft). The risk of contracting malaria is moderate in the Indian subcontinent. In Asia and the Pacific, many cities and the more developed regions (Hong Kong, Singapore, Bali and Taiwan) are free of malaria, but risk may persist in the more rural countryside. Often, the traveler's nocturnal accommodations determine the actual malarial exposure.

Health Information for International Travel, a CDC publication, is an invaluable resource that identifies areas of malaria risk and specifies the appropriate prophylaxis for each country. In more complicated situations, especially those involving pregnant women, small children or travelers with multiple medical contraindications to usual prophylaxis, consultation with a travel clinic is recommended. The International Society of Travel Medicine publishes a directory of travel clinics for this purpose. These and other resources available to travelers and physicians are summarized in Table 2.²