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Revised Recommendations for Preventing Malaria in Travelers to Areas with Chloroquine-Resistant Plasmodium falciparum

Since 1982, CDC has recommended the combined use of chloroquine and Fansidar (pyrimethamine-sulfadoxine) as the primary chemoprophylactic regimen for travelers to areas with transmission of chloroquine-resistant Plasmodium falciparum (CRPF). Based on preliminary reports of serious adverse cutaneous reactions associated with the use of Fansidar, in January 1985, CDC issued interim guidelines that limited areas for which the prophylactic use of the drug was recommended (1). Since then, additional information that has been used to formulate revised recommendations for travelers to specific areas with CRPF (Table 1) has become available. These recommendations, presented below, differ significantly from those previously issued (2,3).

Since Fansidar became available in the United States in 1982, 20 cases of severe cutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis) have been documented among American travelers using Fansidar; 19 of these reactions occurred among persons simultaneously using chloroquine. Six of these reactions were fatal. Based on IMS America Ltd* data, the U.S. Food and Drug Administration (FDA) estimates that, for the United States, between 109,000 and 156,000 persons have been exposed to the drug since 1982. These data indicate that the incidence of fatal cutaneous reactions associated with the prophylactic use of Fansidar among American travelers ranges from 1/18,000 to 1/26,000 users.

These reactions have been associated only with multiple (two to five) doses of Fansidar when used as weekly prophylaxis, and none of these serious reactions have been associated with single-dose Fansidar therapy as used in treating malaria. In addition to these cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, other adverse reactions associated with Fansidar use have also been reported to CDC and FDA. These include serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis.

Because of the risk of these adverse reactions, it is no longer recommended that all travelers to areas with CRPF use Fansidar combined with chloroquine for chemoprophylaxis. The following recommendations have been formulated with the assistance of an ad hoc panel of expert consultants convened at CDC in February 1985. They are based on the estimated risk of acquiring a P. falciparum infection in various geographic areas and on CDC malaria surveillance data and travel industry data on the number of Americans who travel to these areas each year. Of necessity, these revised recommendations place increased emphasis on individualized recommendations for travelers and increased responsibility on individual travelers and their physicians. GENERAL ADVICE FOR TRAVELERS TO MALARIA-ENDEMIC AREAS

Travelers must be informed that, regardless of the malaria prophylactic regimen employed, it is still possible to contract malaria. The symptoms of malaria, such as fever with chills and headache, demand medical attention as soon as possible and should not be presumptively ascribed by either the physician or traveler to a "flu-like" illness. Malaria symptoms can develop as early as 8 days after initial exposure in a malaria-endemic area and can appear months after departure from a malarious area, even after chemoprophylaxis is discontinued. It is important for travelers to understand that malaria can be effectively treated early in the course of the disease but that delays before the institution of appropriate therapy can have serious or even fatal consequences. 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 before travel to use on any exposed areas of skin. The most effective repellent is N,N diethylmetatoluamide (deet), an ingredient in many commercially available insect repellents. Travelers may also be advised to purchase a pyrethrum-containing flying insect spray to use in living and sleeping areas during evening and nighttime hours. RATIONALE FOR USING CHLOROQUINE IN AREAS WITH CRPF

Because of its record of safety and efficacy, chloroquine remains the primary prophylactic drug of choice for travelers to all malarious areas, including areas with CRPF. In all areas with CRPF, there is malaria caused by one or more other species of Plasmodium (P. vivax, P. ovale, P. malariae) that remain sensitive to chloroquine. In addition, chloroquine-sensitive P. falciparum may coexist with chloroquine-resistant parasites within a geographic area. TRAVELERS TO AREAS IN AFRICA WITH CRPF

In general, travelers to malaria-endemic Africa are at considerable risk of exposure to Plasmodium because of the high level of malaria transmission in many areas. Of 358 reports to CDC of P. falciparum infections imported into the United States by American civilian travelers during 1982-1984, 256 (72%) were acquired in Africa. Nine of these were fatal (three fatal cases were acquired in areas of east Africa with CRPF). An estimated 90,000 Americans travel to sub-Saharan Africa each year. Except for the city of Nairobi, where the level of malaria transmission is very low, there is considerable risk of acquiring CRPF in areas in east Africa frequented by tourists.

Short-Term Travel. For short-term travelers (3 weeks or less) to areas of Africa with CRPF, the weekly use of chloroquine alone is recommended. In addition, these travelers (except those with histories of sulfonamide or pyrimethamine intolerance) should be given a single treatment dose of Fansidar (Table 2) to be kept in their possession during travel and should be advised to take the Fansidar promptly in the event of a febrile illness during or after their travel when professional medical care is not readily available. It must be emphasized to travelers that such presumptive self-treatment of a possible malarial infection is only a temporary measure and that professional medical follow-up care as soon as possible is imperative. They should also be advised to continue weekly chloroquine prophylaxis after presumptive treatment with Fansidar.

Longer-Term Travel. Because persons with prolonged exposure in areas of CRPF transmission are at higher risk of acquiring malaria, the use of combined weekly prophylaxis with chloroquine and Fansidar (Table 2) can be considered. Physicians who advise such travelers and expatriate residents must take into consideration individual living conditions while in Africa, the availability of local medical care, and when possible, local malaria transmission patterns. The suitability of the regimen described above for short-term travelers, and alternatives discussed below, should also be assessed. The potential benefit of the routine prophylactic use of Fansidar for these travelers must be weighed against the risk of a possible serious or fatal adverse reaction. If weekly use of Fansidar is prescribed, the traveler should be advised to discontinue it immediately in the event of a possible ill effect, especially if any mucocutaneous signs or symptoms, such as pruritus, erythema, rash, orogenital lesions, or pharyngitis, develop.

Alternatives. Alternatives to these regimens have shortcomings either because of less than conclusive efficacy data and/or unavailability in the United States. Amodiaquine (Camoquin, Flavoquine), a 4-aminoquinoline compound related to chloroquine, has been shown to be more effective than chloroquine in treating CRPF infections and may afford more protection than chloroquine when used as weekly prophylaxis (4). Amodiaquine, like chloroquine, is generally well tolerated. Although licensed, this drug is not marketed in the United States but is widely available in Africa. Its use, therefore, is probably more practicable in long-term visitors and persons who will reside in areas of Africa with CRPF (Table 2). If amodiaquine is prescribed for such travelers, they should also have in their possession a treatment dose of Fansidar to be taken under the same conditions described previously for the short-term traveler.

Another alternative for travelers to areas of Africa with CRPF is the use of daily doxycycline alone (Table 2). This drug could be considered for use in short-term travelers, such as those with previous histories of sulfonamide intolerance. Limited studies conducted in the early 1970s indicated that tetracyclines, when used alone, were effective against P. falciparum (5,6). Tetracyclines are contraindicated in pregnancy and in children under 8 years of age. Persons who use doxycycline as prophylaxis must be made aware of the possible side effects associated with tetracyclines; of particular concern in travelers to tropical climates is 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.

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