- Email: [email protected]
Two cases of mefloquine resistant malaria in Thailand
152 T~~NSAC~ONS OPTUB Routi Socran OFTROPICALMEDIUNHAND HYGIENE(1989)83, 152-153
Two cases of mefloquine malaria in Thailand
resistant
Jerome J. Kanvacki, H. Kyle Webster, Nipon Limsomwong and G. Dennis Shanks Department of Medicine and Department of Immunology & Biochemistry, U.S. Army Medical Component, AFRIMS, Rajvithi Road, Bangkok 10400, Thailand
Mefloquine resistance has been reported from Africa and other areasof south-east Asia (Philippines, Indonesia and Kampuchea). Our laboratory has previously described clinical mefloquine resistancein south-eastern Thailand (BOUDREAU et al., 1982) and has documented in vitro resistance along the eastern and western Thai borders (WEBSTER et al., 1985; CHILDS et al., 1987). We now report 2 treatment failures on Thailand’s western border at the site described by PANG et al. (1987). Case 1. A 7 year old (21.5 kg) male with Plasmodium vivax malaria began a standard course of chloroquine (4 dosesover 3 d) plus primaquine 5 mg for 14 d. On the fifth day, his malaria smear was negative. On day 12, he was diagnosed with P. fizkiparum malaria and treated with 2 tablets of mefloquine 250 mg + sulfadoxine 500 mg + pyrimethamine 25 mg (MSP, Hoffman-La Roche). Upon completion of the primaquine regimen, he had a low level P. fakiparum gametocytaemia which persisted for another week. On day 20 following the MSP, he had 440 P. fakipawm parasites per 100 leucocytes. Parasites were harvested for in vitro analysis and he was treated with a 7 d course of quinine and tetracycline. P. falciparum gametocytes were present on days 10 and 23 following this last diagnosis. By day 33, P. falciparum trophozoites were
again seen and, after cryopreservation of a blood sample, a second 7 d course of quinine and tetracycline was administered. Subsequent smears were negative. The subject remained asymptomatic throughout this entire period. Case 2. A 10 year old (19 kg) male, also with P. vivax, was started on a course of chloroquine (4 doses over 3 d) and primaquine (5 ‘rng for 14 d). On day 5 of treatment, P. falciparum trophozoites were seen and he was given MSP (1.5 tablets). 13 d after completing the primaquine, P. fakiparum trophozoites were again seen at a level of 15/100 leucocytes, which increased to 1701100leucocytes before a 7 d course of quinine and tetracycline was begun and parasites were preserved for later assay. He had 2 negative blood smearsover the next 2 weeks followed by a smear with P. fakiparum on the twentieth day. After parasites were harvested, he received a second 7 d course of quinine and tetracycline. For 3 weeks he demonstrated a mild P. fakiparum gametocytaemia which terminated after a single dose of primaquine (15 mg). He, too, remained asymptomatic. In the previous year, neither of these individuals had had a P. fakiparum infection detectable by almost weekly screening, although both had had multiple P. vivax infections; each infection had been treated with chloroquine (4 doses over 3 d) plus primaquine (5 mg for 14 d). Red blood cells were cryopreserved from all 4 recurrent episodes. The second isolate from the first subject was unsuitable for in vitro assay; the Table shows the results for the remaining isolates. All 3 had 50% inhibitory dose (ID& values associated with clinical resistance to chloroquine (>19 nmol/litre) and mefloquine (>24 nmohlitre) (WEBSTER et al., 1985). Although precise values denoting resistance have not been established for pyrimethamine, enpirolene and halofantrine, the IDscs for these compounds were also high when compared to the mean values of other isolates from western Thailand. Whether or not the high IDsos observed in vitro for
Table. The 50% inhibitory dose in vitro, in nmol/litre, of isolates of Pfasmodkm fdciparum collected at the time of recurrence of infection
Dmg Chloroquine Quinine Pyrimethamine Mefloquine Enpiroline Halofantrine
Case la First isolate 299
Case 2 First isolate
Second isolate
Regional isolatesb
:zi 51466
229 1033 49366
219+70 300+ 176 13500+6510 9*9+5*8 6*6+3*6 1.1+0.87
43;: >80 40 zz ;z 8 9 6 aSecond isolate from this case was unsuitable for in vitro assay. bIsolates from the same region (n=18); values are means + standard deviations. The opinionsexpressedin this article arethe opinionsof
the authors and are not to be construed as being policy of the U.S. Department of Defense. Correspondence to: Dr Jerome J. Karwacki, U.S. Army Medical Component, AFRIMS, Ai’C 1San I-_ Francisco 96346, U.S.A. -
the structurally related amino-alcohols imply crossresistance will have to await more clinical data. Mefloquine, enpiroline and halofantrine are products of the U.S. Army Malaria Drug Development Program. Of these, only mefloquine has been marketed for the treatment of malaria. It is particularly
153
published data to suggest that the addition of these drugs has delayed the onset of clinical resistance to mefloquine. Perhaps it is time to consider other drug combinations or new approachesin an attempt to prolong the useful lifetime of these antimalarials.
Thailand. Lancer, ii, 1335. Childs, G. E., Pang, L., Wimomvattrawatee, T., Pooyindee, N., Nauakom, A., Limchitee, S. & Webster, H. K. (1987). In uirro mefkrquine resistance of Plurmudium f&l&mm isolated from the Burmese border re ‘on of .. Thailand. SoutheastAsian Journal of Tropical hPedtcme and Public Health, 18, 438-443. Pang, L. W., Limsomwong, N:, Boudreau, E. F. & Siugharaj, P. (1987). Doxycyclme prophylaxis for falcipartmt malaria. Lancet, i, 1161-1164. Webster, H. K., Thaithong, S., Pavauaud, K., Yongvauitchit, K., Piuswasd$ C. & Boudreau, E. F. (1985). Cloning and characterization of mefloquiue-resistant Nasmodiumfakipanon from Thailaud. AmericanJournal of Tropical Medicine and Hygiene, 34, 1022-1027. White, N. J. (1987). Combination treatment for falciparum prophylaxis. Lancet, i, 680-681.
References Boudreau, E. L., Webster, H. K., Pavauaud, K. & Thosingha, L. (1982). Type II meflocluiue resistance in
Received 21 June 1988; accepted for publication August 1988
worrying that the clinical resistance to mefloquine of these parasites might extend to the related amino-
alcohols, which are not yet in general use.
WHITE (1987) has recently questioned the basic rationale for the MSP combination. Given the ineffec-
tiveness and additional risks of the long-acting sulphonamide, the continued use of sulfadoxinepyrimethamine seems unwarranted in those areas where parasites are highly resistant. There are no
1 Announcement
11
1
Maternity Care in Developing Countries A two-day meeting will be held at tbe Royal College of Obstetricians and Gynaecologists in London on 30 June & 1 July 1989.
For further information please contact the Postgraduate Education Secretary, Royal College of and Gynecologists, 27 Sussex Place, 1kgent’s Park, London, NW1 4RG, UK.
Obstetricians
Corrections U Thet Naing et al.: The combined use of artemether, sulfadoxine and pyrimethamine in the treatment of uncomplicated falciparum malaria. Transactions (1988), volume 82, pp. 530-531. In line 5 of the Abstract the dosage of oral pyrimethamine should read 75 mg, not 750 mg.
N. A. El Masry, S. Bassily and Z. Farid: A comparison of the efficacy and side effects of various regimens of praxiquantel for the treatment of schistosomiasis.Transactions (1988), volume 82, pp. 719-720. Dosesgiven in the Table on p. 719 should alI be mg per kg body weight.
I
Two cases of mefloquine malaria in Thailand
resistant
Jerome J. Kanvacki, H. Kyle Webster, Nipon Limsomwong and G. Dennis Shanks Department of Medicine and Department of Immunology & Biochemistry, U.S. Army Medical Component, AFRIMS, Rajvithi Road, Bangkok 10400, Thailand
Mefloquine resistance has been reported from Africa and other areasof south-east Asia (Philippines, Indonesia and Kampuchea). Our laboratory has previously described clinical mefloquine resistancein south-eastern Thailand (BOUDREAU et al., 1982) and has documented in vitro resistance along the eastern and western Thai borders (WEBSTER et al., 1985; CHILDS et al., 1987). We now report 2 treatment failures on Thailand’s western border at the site described by PANG et al. (1987). Case 1. A 7 year old (21.5 kg) male with Plasmodium vivax malaria began a standard course of chloroquine (4 dosesover 3 d) plus primaquine 5 mg for 14 d. On the fifth day, his malaria smear was negative. On day 12, he was diagnosed with P. fizkiparum malaria and treated with 2 tablets of mefloquine 250 mg + sulfadoxine 500 mg + pyrimethamine 25 mg (MSP, Hoffman-La Roche). Upon completion of the primaquine regimen, he had a low level P. fakiparum gametocytaemia which persisted for another week. On day 20 following the MSP, he had 440 P. fakipawm parasites per 100 leucocytes. Parasites were harvested for in vitro analysis and he was treated with a 7 d course of quinine and tetracycline. P. falciparum gametocytes were present on days 10 and 23 following this last diagnosis. By day 33, P. falciparum trophozoites were
again seen and, after cryopreservation of a blood sample, a second 7 d course of quinine and tetracycline was administered. Subsequent smears were negative. The subject remained asymptomatic throughout this entire period. Case 2. A 10 year old (19 kg) male, also with P. vivax, was started on a course of chloroquine (4 doses over 3 d) and primaquine (5 ‘rng for 14 d). On day 5 of treatment, P. falciparum trophozoites were seen and he was given MSP (1.5 tablets). 13 d after completing the primaquine, P. fakiparum trophozoites were again seen at a level of 15/100 leucocytes, which increased to 1701100leucocytes before a 7 d course of quinine and tetracycline was begun and parasites were preserved for later assay. He had 2 negative blood smearsover the next 2 weeks followed by a smear with P. fakiparum on the twentieth day. After parasites were harvested, he received a second 7 d course of quinine and tetracycline. For 3 weeks he demonstrated a mild P. fakiparum gametocytaemia which terminated after a single dose of primaquine (15 mg). He, too, remained asymptomatic. In the previous year, neither of these individuals had had a P. fakiparum infection detectable by almost weekly screening, although both had had multiple P. vivax infections; each infection had been treated with chloroquine (4 doses over 3 d) plus primaquine (5 mg for 14 d). Red blood cells were cryopreserved from all 4 recurrent episodes. The second isolate from the first subject was unsuitable for in vitro assay; the Table shows the results for the remaining isolates. All 3 had 50% inhibitory dose (ID& values associated with clinical resistance to chloroquine (>19 nmol/litre) and mefloquine (>24 nmohlitre) (WEBSTER et al., 1985). Although precise values denoting resistance have not been established for pyrimethamine, enpirolene and halofantrine, the IDscs for these compounds were also high when compared to the mean values of other isolates from western Thailand. Whether or not the high IDsos observed in vitro for
Table. The 50% inhibitory dose in vitro, in nmol/litre, of isolates of Pfasmodkm fdciparum collected at the time of recurrence of infection
Dmg Chloroquine Quinine Pyrimethamine Mefloquine Enpiroline Halofantrine
Case la First isolate 299
Case 2 First isolate
Second isolate
Regional isolatesb
:zi 51466
229 1033 49366
219+70 300+ 176 13500+6510 9*9+5*8 6*6+3*6 1.1+0.87
43;: >80 40 zz ;z 8 9 6 aSecond isolate from this case was unsuitable for in vitro assay. bIsolates from the same region (n=18); values are means + standard deviations. The opinionsexpressedin this article arethe opinionsof
the authors and are not to be construed as being policy of the U.S. Department of Defense. Correspondence to: Dr Jerome J. Karwacki, U.S. Army Medical Component, AFRIMS, Ai’C 1San I-_ Francisco 96346, U.S.A. -
the structurally related amino-alcohols imply crossresistance will have to await more clinical data. Mefloquine, enpiroline and halofantrine are products of the U.S. Army Malaria Drug Development Program. Of these, only mefloquine has been marketed for the treatment of malaria. It is particularly
153
published data to suggest that the addition of these drugs has delayed the onset of clinical resistance to mefloquine. Perhaps it is time to consider other drug combinations or new approachesin an attempt to prolong the useful lifetime of these antimalarials.
Thailand. Lancer, ii, 1335. Childs, G. E., Pang, L., Wimomvattrawatee, T., Pooyindee, N., Nauakom, A., Limchitee, S. & Webster, H. K. (1987). In uirro mefkrquine resistance of Plurmudium f&l&mm isolated from the Burmese border re ‘on of .. Thailand. SoutheastAsian Journal of Tropical hPedtcme and Public Health, 18, 438-443. Pang, L. W., Limsomwong, N:, Boudreau, E. F. & Siugharaj, P. (1987). Doxycyclme prophylaxis for falcipartmt malaria. Lancet, i, 1161-1164. Webster, H. K., Thaithong, S., Pavauaud, K., Yongvauitchit, K., Piuswasd$ C. & Boudreau, E. F. (1985). Cloning and characterization of mefloquiue-resistant Nasmodiumfakipanon from Thailaud. AmericanJournal of Tropical Medicine and Hygiene, 34, 1022-1027. White, N. J. (1987). Combination treatment for falciparum prophylaxis. Lancet, i, 680-681.
References Boudreau, E. L., Webster, H. K., Pavauaud, K. & Thosingha, L. (1982). Type II meflocluiue resistance in
Received 21 June 1988; accepted for publication August 1988
worrying that the clinical resistance to mefloquine of these parasites might extend to the related amino-
alcohols, which are not yet in general use.
WHITE (1987) has recently questioned the basic rationale for the MSP combination. Given the ineffec-
tiveness and additional risks of the long-acting sulphonamide, the continued use of sulfadoxinepyrimethamine seems unwarranted in those areas where parasites are highly resistant. There are no
1 Announcement
11
1
Maternity Care in Developing Countries A two-day meeting will be held at tbe Royal College of Obstetricians and Gynaecologists in London on 30 June & 1 July 1989.
For further information please contact the Postgraduate Education Secretary, Royal College of and Gynecologists, 27 Sussex Place, 1kgent’s Park, London, NW1 4RG, UK.
Obstetricians
Corrections U Thet Naing et al.: The combined use of artemether, sulfadoxine and pyrimethamine in the treatment of uncomplicated falciparum malaria. Transactions (1988), volume 82, pp. 530-531. In line 5 of the Abstract the dosage of oral pyrimethamine should read 75 mg, not 750 mg.
N. A. El Masry, S. Bassily and Z. Farid: A comparison of the efficacy and side effects of various regimens of praxiquantel for the treatment of schistosomiasis.Transactions (1988), volume 82, pp. 719-720. Dosesgiven in the Table on p. 719 should alI be mg per kg body weight.
I