Fansidar resistant falciparum malaria acquired in South East Asia

715 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, VOL. 75, No. 5,198l

Fansidar resistant falciparum

malaria

acquired

in South

East Asia

F. BLACKI, I. BYGBJERG~,P. EFFERS~E~,GRETHE GOMME~, S. JEPSEN~ AND G. AXELGAARD JENSEN~ IRigshospitalet, Dept. of Communicable and Tropical Diseases, Copenhagen, Denmark; 2Statens Seruminstitut, Dept. of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark; 3Statens Seruminstitut, Dept. of Treponematoses, Copenhagen, Denmark; 4County Hospital, Depts of Medicine and Paediatrics, Kolding, Denmark

Summary A caseof Plasmodium falciparum

malaria resistant to Fansidar (sulphadoxine plus pyrimethamine) at a level corresponding to R III and resistant to chloroquine is reported. The infection was most certainly acquired in Malaysia, but diagnosed and treated in a non-malarious area. Normal resorption and elimination rates of the Fansidar components excludes cure failure due to abnormal drug fate in the host. P. falciparum parasites from the patient have been maintained in in vitro cultures. The patient was permanently cured with mefloquine. Introduction The combination of sulphadoxine and pyrimethamine (Fansidar, Roche Laboratories) has in recent years been one of the most commonly used antimalarials in areas with chloroquine-resistant Plasmodium falciparum malaria. We renort here the first case of P. falci~arum malaria resistant to the combination suiphadoxine plus pyrimethamine at a level corresponding to R III (WHO, 1973) where the resorption and elimination rates of the drug components have been investigated. Case Report A 30-year-old Vietnamese female from Saigon, who claimed never to have had malaria, fled by boat on June 6th, 1979, and arrived on June 16th in Malaysia. She spent two weeks in an apparently malaria-free refugee camp (Kota Tinggi) and was then transferred to the abundantly malarious Mersing camp around June 30th. On July 21st she left Malaysia by boat and landed on an uninhabited island in Indonesia ten days later. On August 2nd she developed fever and, later, oedema of the lower limbs. The symptoms were still present two to three weeks later when the patient was transferred to the Teluk Dalan refugee camp on the Indonesian island of Bintan. She was there treated with chloroquine with some clinical response (dose unknown). On September 25th, the patient went by air via Singapore to Copenhagen, Denmark, and on 27th September was admitted with fever, anaemia and oedema to the Department of Communicable and Tropical Diseases. P. falciparum trophozoites (3 x 103/mm3 blood) were found in blood smears. The patient was

given 25 mg of chloroquine base per kg bodyweight orally over three days, and recovered clinically. In view of possible chloroquine resistance two tablets of Fansidar (1000 mg sulphadoxine and 50 mg pyrimethamine) were given on 4th October. Apnroximatelv ten days later the fever reapneared. Trophozoites of P. falciparum were again f&nd in the blood and on October 25th. two tablets of Fansidar were given for the second time. The asexual parasitaemia persisted but, as the patient remained well, no additional treatment was given until November 6th when the temperature rose to 40”, and the parasite count increased to 5 to 10 x 103/mm3 blood. Three tablets of Fansidar were given (32 mg of sulphadoxine and 1.6 mg of pyrimethamine per kg body-weight). Daily examinations showed, however, an increase in asexual parasitaemia to 50 x 103/mm3 blood on November 13th. The same evening the patient was given mefloquine, six tablets (l-5 g) and, from the next morning, remained afebrile. Parasite clearing time after mefloquine was 72 hours. The blood has remained negative for P. falciparum for six months. A P. falciparum isolate from the patient has been maintained in in vitro cultures by one of us (S.J.). In January 1980 the patient suffered from an attack of P. vivax malaria and was treated with chloroquine and primaquine with good clinical response; she has had no relapses. Resorption and elimination

Resorption of the sulphonamide component of Fansidar was determined during treatment of the recrudescence in November 1979. The olasma concentrations were measured by an agar dikusion test and found to be within the range of values for healthy controls. In January 1980, after the patient was cured of falciparum and vivax malaria, two tablets of Fansidar (1000 mg of sulphadoxine and 50 mg of pyrimethamine) were given, and the plasma concentrations were determined after 4, 24, 48, 72, 168, 216 and 336 hours. A microbiological test was used (aaar diffusion against sensitive bacteria) and only ‘b?ologically act&e sulphadoxine and’ not acetylated sulphonamide was measured. The plasma concentrations of both components were found to be within the range of values for eight healthy Correspondence to: P. Effersee, M 772212460, Rigshospitalet, Tagensvej 18, DK-2200 Copenhagen N, Denmark.

716

FANSIDAR RESISTANT P. fdCi&WUm

controls. The terminal half-life for sulphadoxine was 178 hours (healthy controls: 176 f 41 hours) and for pyrimethamine 144 hours (healthy controls : 112 & 33 hours). Discussion In areas with chloroquine-resistant malaria Fansidar is considered the most effective commercially available single dose antimalarial drug (DOBERSTYNet al., 1979). Reports on Fansidar resistance have been published recently (CHONG SUl?HAJAISIDDHI et al., 1979; RUMANSet al., 1979; HOLLER et al., 1980), but re-infection could not always be excluded and in no case was the possibility of cure failure due to abnormal host metabolism of the components investigated. The actual P. falciparum strain was resistant to chloroquine at least at the R I level since asexual parasitaemia recrudesced three weeks after the patient’s chloroquine treatment in Denmark. As to the level of resistance to Fansidar, the clinical and parasitological findings classify the degree as R III. when annlving the WHO criteria fo;evaluation ofchloroq&ere&tance (DOBERSTYN et al., 1979). It can be concluded that the cure failure was due to actual parasite resistance, as resorption and elimination tests for both pyrimethamine and sulphadoxine were normal. The patient had spent her life in Saigon, which is considered malaria-free (BRUCE-CHWATT,1980), and denied having had malaria in Vietnam. Most probably she had acquired her malaria in the abundantly malarious Mersing camp in Malaysia. In accordance with others (HALL et aZ., 1975; DOBERSTYN et al., 1976), we cannot recommend that pyrimethamine and sulphadoxine be administered alone to patients with P. falciparum malaria acquired in South East Asia. Acknowledgement We thank Dr. Weidekamm and Dr. Laimer from F. Hoffmann-La Roche & Co. (Basle), for the

IN SEASIA

supplies of Fansidar and mefloquine, and also for the determination of plasma concentrations of sulphadoxine and pyrimethamme. References Bruce-Chwatt, L. J. (1980). Essential Malariology. London: William Heinemann Medical Books Ltd. Chongsuphajaisiddhi, T., Subchareon, A., Puangpartk, S. & Harinasuta, T. (1979). Treatment of falciparum malaria in Thai children. South East AsianJournal of Medicine and Public Health, 10, 132-137. Doberstyn, E. B., Hall, A. P., Vetvutanapibul, K. & Sonkom, P. (1976). Single-dose therapy of falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine. American Journal of Tropical Medicine and Hygiene, 25, 1419. Doberstyn, E. B., Phintuyothin, P., Noeypatimanondh, S. & Teerakiartkamjorn, C. (1979). Single-dose therapy of’ falciparum malaria with mefloquine or pyrimethamine-sulfadoxine. Bulletin of the World Health Organization, 279.

57, 275-

Hall, A. P., Doberstyn, E. B., Mettaprakong, V. & Sonkom, P. (1975). Falciparum malaria cured by quinine followed by sulfadoxine-pyrimethamine. British Medical Yournal. ii. 15-17. Holzer, B., Kelle;, H., Erossard, E. & Sttirchler, D. (1980). 1st Plasmodium falciparum, der Erreger der Malaria tropica, jetzt such gegen Fans&r resistent? Schweizerische Medizinische Wochenschrift, 110, 324328. Rumans, L. W., Dermis, D. T. & Atmosoedjono, S. (1979). Fansidar resistant falciparum malaria in Indonesia. Lancet, iii 580-581. World Health Organization (1973). Chemotherapy of Malaria

and Resistance

to Antimalarials.

Technical Report Series 529, Geneva: World Health Organization, 121 pp.

Accepted

for

publication 16th February, 1981.