Problems Encountered with Using Fansidar as Prophylaxis for Malaria

The drug combination Fansidar* (sulfadoxine-pyrimethamine) has recently become commercially available in the United States. Since the drug was licensed, CDC has received numerous inquiries seeking clarification about the use of Fansidar as prophylaxis for malaria. The case histories of the 2 patients discussed below illustrate some important points that need clarification.

Patient 1: On August 4, 1981, a 38-year-old male geologist was seen in a clinic in Toronto, Canada, with a history of recurrent fever and chills since July 15, 1981. The patient had traveled through the savannah and rain-forest areas of Peru and parts of the Bolivian altiplano in the period April 7-May 15, 1981. He had then returned to Canada for several weeks, but spent an additional week between June 8 and 15 in a tropical rain-forest region of Brazil. He had no other history of foreign travel. The patient had begun taking Fansidar 2 weeks before his initial trip to South America, and had continued to take 1 tablet/week until his first clinic visit 6 weeks after he returned from Brazil. He denied having missed any doses.

At the time of his clinic visit, a peripheral blood smear contained Plasmodium vivax parasites. He was given a therapeutic course of chloroquine and primaquine, rapidly became asymptomatic, and continued to be asymptomatic when examined 2 months after the therapy.

Patient 2: A 28-year-old male geologist returned to Canada on November 24, 1981, after a 2-month stay in southwestern Brazil. He had begun taking chloroquine phosphate (500 mg) and 1 tablet of Fansidar/week beginning 1 week before he left for Brazil. He continued to take both drugs once a week without interruption. One week before returning to Canada, he began having episodes of fever and sweating that recurred every 48 hours. He was admitted to a hospital in Toronto on November 28, 1981.

The only notable finding on physical examination was splenomegaly. Blood smears contained P. falciparum ring forms, with 1% of red blood cells infected. Malaria indirect fluorescent antibody titers obtained 1 month after diagnosis were 1,024 and 16 for P. falciparum and P. vivax, respectively. These results were compatible with a recent falciparum infection. A serum sulfonamide level obtained at the time of diagnosis was consistent with the prophylaxis history.

The patient was then treated with quinine sulfate, 600 mg every 8 hours for 3 days, and tetracycline, 500 mg every 6 hours for 10 days. His parasitemia and fever resolved within 48 hours after this therapy began. Reported by JS Keystone, MD, J Yang, PhD, L McIntyre, MD, SL Chee, RT, Tropical Disease Unit, Toronto General Hospital, AS Macpherson, MD, Office of Health, City of Toronto, Canada; Malaria Br, Div of Parasitic Diseases, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: CDC concurs with the recently published recommendations of the World Health Organization stating that the sole indication for the use of Fansidar is the prophylaxis or treatment of chloroquine-resistant P. falciparum malaria (1). Some information contained in the package insert distributed with the drug in the United States is inconsistent with published data on the use and efficacy of Fansidar. The cases described above illustrate several of these discrepancies.

Although patient 1 took Fansidar as malaria prophylaxis, he still developed P. vivax infection. The package insert states that the drug is indicated for the treatment or prophylaxis of "susceptible strains of Plasmodia." In fact, while Fansidar has been efficacious in the treatment or prophylaxis of chloroquine-resistant P. falciparum, it cannot be recommended as the sole prophylactic drug for the other 3 species of human malaria. Specifically, there is now considerable evidence that Fansidar is not the most effective drug for treatment or prophylaxis of P. vivax infections (2,3). This inefficacy of Fansidar is related to the widespread resistance of P. vivax to pyrimethamine. The effectiveness of Fansidar against P. ovale and P. malariae has not been adequately evaluated. Chloroquine remains the drug of choice for the prophylaxis of malaria in areas with transmission of any malaria species other than P. falciparum. CDC recommends that travelers who will be exposed both to chloroquine-resistant P. falciparum and to other species of malaria take chloroquine plus Fansidar as prophylaxis.

The infection acquired by the second patient raises the question of Fansidar resistance. Drug resistance of the parasite is generally implied when malaria parasitemia develops in a patient taking prophylaxis or when parasitemia fails to be eradicated following drug therapy. However, it has been demonstrated that drug combinations such as Fansidar may not suppress or cure infections (with sensitive strains of malaria) due to a host-drug interaction that impairs the drug action on the parasite (4). The exact mechanism of "host-failure" in the case of Fansidar-like drugs is not yet known, but is not correlated with serum drug levels (5-6).

The ineffectiveness of Fansidar in treating malaria has been reported to be highly prevalant along the Thai-Kampuchean border (7). As-yet-unpublished data documenting Fansidar treatment failures in Brazil are being accumulated. There is currently no in vitro method to test for Fansidar resistance. Therefore, the distinction between parasite drug resistance and host failure can only be inferred epidemiologically. Whether patient 2 was infected with a truly resistant strain of parasite or whether host failure occurred cannot be determined. This case history does, however, illustrate the fact that P. falciparum from widely dispersed geographic areas can be resistant to multiple drugs including Fansidar, and that a febrile illness experienced by a traveler may well be malaria, despite a history of appropriate prophylaxis.

The 2 patients discussed above were effectively treated following the failure of their prophylaxis regimens. The first patient was appropriately treated with primaquine in order to prevent a relapse of the P. vivax infection. Indeed, patients with documented P. vivax or P. ovale infection are candidates for primaquine therapy. In contrast to this therapeutic use of primaquine, the Fansidar package insert states that prophylaxis with Fansidar should be followed by a "regimen of primaquine." Since the only demonstrated indication for using Fansidar prophylaxis is for suppression of infections with P. falciparum (a non-relapsing species of malaria), there is little basis for the routine prophylactic use of primaquine following Fansidar. When primaquine is considered for terminal prophylaxis, an assessment of the intensity and duration of exposure to relapsing malaria should be made, as well as the potential risk of primaquine toxicity, especially when treating persons who may be deficient in glucose-6-phosphate dehydrogenase (G6PD). Indeed, patients with documented P. vivax or P. ovale infection are candidates for primaquine.

In order to clarify these and other current issues regarding malaria proplylaxis and treatment, the CDC Malaria Branch has prepared an MMWR supplement entitled Prevention of Malaria in Travelers, 1982. This document is designed for use by medical and public health personnel who have responsibility for advising travelers. It will not be distributed automatically to all MMWR subscribers; however, copies can be obtained by writing to Chief, Malaria Branch, Division of Parasitic Diseases, Center for Infectious Diseases, CDC, Atlanta, Georgia 30333.

References

Noeypatimanondh S. Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone. Trans Soc Trop Med Hyg 1979;73:15-7. 3. Darlow B, Vrbova H, Gibney S, Jolley D, Stace J, Alpers M.

Sulfadoxine- pyrimethamine for the treatment of acute malaria in children in Papua New Guinea. II. Plasmodium vivax. Am J Trop Med Hyg 1982;31:10-3. 4. Chin W, Contacos PG, Coatney GR, King HK. The evaluation of

sulfonamides, alone or in combination with pyrimethamine, in the treatment of multi-resistant falciparum malaria. Am J Trop Med Hyg 1966;15:823-9. 5. Williams RL, Trenholme GM, Carson PE, Frischer H, Rieckmann KH.

Acetylator phenotype and response of individuals infected with a chloroquine-resistant strain of Plasmodium falciparum to sulfalene and pyrimethamine. Am J Trop Med Hyg 1975;24:734-9. 6. Trenholme GM, Williams RL, Frischer H, Carson PE, Rieckmann, KH.

Host failure in treatment of malaria with sulfalene and pyrimethamine. Ann Intern Med 1975;82:219-23. 7. Hurwitz ES, Johnson D, Campbell CC. Resistance of Plasmodium

falciparum malaria to sulfadoxine-pyrimethamine (Fansidar) in a refugee camp in Thailand. Lancet 1981;1:1068-70. *Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

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