TRANSACTIONS OF THE ROYAL SOCIETYOF TROPICAL.MEDICINEAND HYGIENE(1992) 86, 121-122
Chloroquine-resistant Gerrit J. Schuurkamp’,
Plasmodium
121
vivax in Papua New Guinea
Paul E. Spice*‘, Richard K. Kereu’, Peter K. Bulungol’
and Karl H. Rieckmann2
‘Ok Tedi
Mining Limited, Medical Department, P.O. Box 1, Tabubil, Western Province, Papua New Guinea; 2Army Malaria Research Unit, University of Sydney,Ingleburn, Sydney, NSW 2174, Australia Abstract
An Australian expatriate on regular weekly antimalarial prophylaxis with chloroquine baseand Maloprimm developedsymptomatic Plasmodium vivax infection which failed to respond adequatelyto 600 mg of chloroquine base.More ominously, a resident of the Highlands region of PapuaNew Guinea contracted vivax malaria which failed to be cleared by 2400 mg chloroquine base administered over 4 d. Both patients had achievedappropriate blood and plasmaconcentrationsof chloroquine after treatment. Chloroquine-resistant P. vivax is now a clinical fact in PapuaNew Guinea. Introduction
Patient no. 2
The first indication that Plasmodium vivax might be developing resistanceto chloroquine in PapuaNew Guinea was the failure of an 8 months old infant to respond adequately to treatment with chloroquine (SCHUUR~AMP et al.. 1989). This was corroborated bv the inabilitv of chlorbquine to suppress vivax malaria”in 2 Australian soldiers after their return from Papua New Guinea, despite blood plasma concentrationsof the drug that should have inhibited parasitaemiacompletely (RIECKMANN et al., 1989).Subsequentreports have provided further documentation of and Malo‘prim@(12.5 mg pyrimethamine and 100 mg dapsone) up to the time of presenting at the hospital. Since Tabubil township, where the patient spent most of his working and home life, is well protected against malaria transmission (SCHUURKAMP et al., 1987’1.it is likelv that he acquired his infection in Lae’and &at the infiction was partly suppressedby chloroquine until a definitive diagnosiswas establishedon 10 December. The patient was treated with a single dose of 600 mg chloroquine base and, 48 h later, the parasite density had decreasedto llO/yl. However, parasites were still present 72 h after treatment (531~1).Chloroquine concentrations in plasma and whole blood at this time were 66 and 330 ygilitre, respectively; desethylchloroquine concentrations were 36 and 146 w.a/litre respectively. The patient was then treated with.330 mg qiinine s& nhate 3 times a dav for 3 d followed bv 4 Fansidar@tablets (pvrimethamine+sulfadoxine). F&r days later he comm&ced a 14 d course of primaquine- (22.5 mg dailvl. The natient has remained well sincehis treatment abo;i 8 moiths ago.
Discussion
The failure of weekly dosesof chloroquine and Maloprim@ to suppressP. vivax infection in patient no. 1, and the failure of 600 mg chloroquine to clear parasitaemia confirm the findings of RIECKMANN et al. (1989). This provides further documentation of the presenceof strains of P. vivax that have a reduced sensitivity to chloroquine and cannot be adequately suppressed by prophylaxis. Preliminary monitoring of the chloroquine sensitivity of P. vivax at Ok Tedi suggeststhat such strains are not rare (G. J. Schuurkamp, personal observations). So far, 7.5% (231308)of infected persons have continued to show parasites 1 week after treatment with 10 mg/kg of chloroquine (similar to the RI-RI1 type responsenoted with resistant P. falciparum treated with a standard dose of at least 25 mgikg). This is in marked contrast to the rapid and sustained-ilearanceof parasites observed with most vivax infections treated at Ok Tedi and elsewhere.Consideringthat patient no. 1 had a bodyweight of 80 kg, the prophylactic and 600 mg single treatment dose may be considered suboptimal, but 600 mg of chloroquine base cleared P. vivax Darasitaemias LIPto 42 000&d within 48 h in 8 of 10 adilts investieated at Ok Tedi who weighed between 75 and 100 ke: &ey were still negative on”day 7. One of the resista$
122 adults had no detectableparasitaemiaat 48 h but parasitaemia recrudescedon day 7; the other was patient no. 1 who was the only one on regular weekly prophylaxis and is discussedin this paper. Clearly, chloroquine prophylaxis and treatment can no longer be expected to suppress vivax malaria in an increasing number of residents of, and travellers to, Papua New Guinea. An increased prophylactic doseof chloroquine may be appropriate for non-immune individuals under suchconditions. The poor response observed in patient no. 2 after treatment with a 4 d regimen of chloroquine is particularly disturbing. Parasitesstill persisted in the presence of blood and plasma levels of chloroquine which were more than ten-fold higher than those needed to inhibit ‘normal’ strains of P. vivax (PETERS, 1987). The spread of parasiteswith such a severedegreeof chloroquine resistancewould seriously hamper the control and treatment of malaria. In the Western Pacific region, where short-relapsing strains of P. vivax predominate, one would have to contend with several ‘resistant bombshells’ released from the liver during the course of a single infection. This would present major problems for the individual afflicted with such an infection and, from a public health standpoint, would increasethe likelihood of rapid spread of such chloroquine-resistant strains. Radical cure of the liver stagesof P. vivax is not easybecauseof poor compliancewith the 14 d (22.5 mg daily) or 8 week (45 mg weekly) primaquine regimens. Furthermore, in the south-west Pacific region, these cumbersome regimens are becoming even less effective in view of the proliferation of Chesson-like strains which are refractory to primaquine treatment (K. H. Rieckmann, personal observations). The 8 week regimen of primaquine (45 mg) and 300 mg chloroquine base has failed to clear exoerythrocytic stagesat Ok Tedi, relapses occurring within 8 weeksof ceasingtreatment. Chloroquine-resistant P. vivax is upon us and has only begun to surface. The time has arrived for health personnel to be made aware of this serious development
and for national and international authorities to start taking appropriate measuresto deal with the situation. Acknowledgements
The supportof the Ok Tedi Mining Limited Medical Department staff is greatly appreciated in helping to direct patients with unusual drug responsesto our attention. In particular we thank Sr Kulis Pa&a and H. E. 0. JoshiaBola for the extremely important highlands case,hospital pathology staff Roberto Vergara and Philip Mayarom, and Sgt Tom Travers of the Army Malaria Research Unit’s Pharmacology Department for the chloroquine determinations. References
Alvan, G., Ekman, L. & Lindstorm, B. (1982). Determination of chloroquine and its desethyl metabolize in plasma, red blood cells and urine by liquid chromatography. Journal of Chromatoma6hv. 229.241-247.
Peters,W. (1987). Chemotherapy and Drug Resistancein Malaria, 2nd edition. London: Academic Press. Rieckmann, K. H., Davis, D. R. & Hutton, D. C. 11989).Plasmodium &vax r&istance to chloroquink? Lanck, ii,’ 11831184. Schuurkamp, G. J., Matango, M., Napil, J. & Vergara, R. V. (1987). Malaria control and the development of the Ok Tedi Mining Project in the Star Mountains of Papua New Guinea: the initial construction phase. Papua New Guinea Medical Journal, 30,27-38.
Schuurkamp, G. J,., Spicer, I’. E., Kereu, R. K. & Bulungol, P. K. (1989). A mixed infection of vivax and falciparum malaria auoarentlv resistant to 4-aminoauinoline: a casereoort. Transa%ons of-the Royal Society of Tropical Medicine a;d Hygiene, 83.607-608. Schwartz, I. K., Lackritz, E. M. & Patchen, M. S. (1991). Chloroquine-resistantPlasmodium vivax from Indonesia. New --I-~
~--
EnglandJournal of Medicine, 324,927.
Whitby, M., Wood! G., Veenendaal, J. R. & Rieckmann, K. !;5$9). Chloroqmne-resistant Plasmodium viva%. Lancet, ii, Received 18 June 1991; revised 22 August 1991; accepted for publication 22 August 1991
Announcement XIIIth
International Congress for Tropical Medicine and Malaria ‘Appropriate Technology for Better Health’ 29 November-4 December 1992 Pattaya, Thailand
Last date for registration at reduced rate: 30 June 1992 (late registrations can be accepted on arrival). Further information can be obtained from Professor Thanongsak Bunnag, CongressSecretariat Office, The XIIIth International Congressfor Tropical Medicine and Malaria, c/o Faculty of Tropical Medicine, Mahidol University, 42016 Rajvithi Road, Bangkok 10400, Thailand.
Chloroquine-resistant Gerrit J. Schuurkamp’,
Plasmodium
121
vivax in Papua New Guinea
Paul E. Spice*‘, Richard K. Kereu’, Peter K. Bulungol’
and Karl H. Rieckmann2
‘Ok Tedi
Mining Limited, Medical Department, P.O. Box 1, Tabubil, Western Province, Papua New Guinea; 2Army Malaria Research Unit, University of Sydney,Ingleburn, Sydney, NSW 2174, Australia Abstract
An Australian expatriate on regular weekly antimalarial prophylaxis with chloroquine baseand Maloprimm developedsymptomatic Plasmodium vivax infection which failed to respond adequatelyto 600 mg of chloroquine base.More ominously, a resident of the Highlands region of PapuaNew Guinea contracted vivax malaria which failed to be cleared by 2400 mg chloroquine base administered over 4 d. Both patients had achievedappropriate blood and plasmaconcentrationsof chloroquine after treatment. Chloroquine-resistant P. vivax is now a clinical fact in PapuaNew Guinea. Introduction
Patient no. 2
The first indication that Plasmodium vivax might be developing resistanceto chloroquine in PapuaNew Guinea was the failure of an 8 months old infant to respond adequately to treatment with chloroquine (SCHUUR~AMP et al.. 1989). This was corroborated bv the inabilitv of chlorbquine to suppress vivax malaria”in 2 Australian soldiers after their return from Papua New Guinea, despite blood plasma concentrationsof the drug that should have inhibited parasitaemiacompletely (RIECKMANN et al., 1989).Subsequentreports have provided further documentation of and Malo‘prim@(12.5 mg pyrimethamine and 100 mg dapsone) up to the time of presenting at the hospital. Since Tabubil township, where the patient spent most of his working and home life, is well protected against malaria transmission (SCHUURKAMP et al., 1987’1.it is likelv that he acquired his infection in Lae’and &at the infiction was partly suppressedby chloroquine until a definitive diagnosiswas establishedon 10 December. The patient was treated with a single dose of 600 mg chloroquine base and, 48 h later, the parasite density had decreasedto llO/yl. However, parasites were still present 72 h after treatment (531~1).Chloroquine concentrations in plasma and whole blood at this time were 66 and 330 ygilitre, respectively; desethylchloroquine concentrations were 36 and 146 w.a/litre respectively. The patient was then treated with.330 mg qiinine s& nhate 3 times a dav for 3 d followed bv 4 Fansidar@tablets (pvrimethamine+sulfadoxine). F&r days later he comm&ced a 14 d course of primaquine- (22.5 mg dailvl. The natient has remained well sincehis treatment abo;i 8 moiths ago.
Discussion
The failure of weekly dosesof chloroquine and Maloprim@ to suppressP. vivax infection in patient no. 1, and the failure of 600 mg chloroquine to clear parasitaemia confirm the findings of RIECKMANN et al. (1989). This provides further documentation of the presenceof strains of P. vivax that have a reduced sensitivity to chloroquine and cannot be adequately suppressed by prophylaxis. Preliminary monitoring of the chloroquine sensitivity of P. vivax at Ok Tedi suggeststhat such strains are not rare (G. J. Schuurkamp, personal observations). So far, 7.5% (231308)of infected persons have continued to show parasites 1 week after treatment with 10 mg/kg of chloroquine (similar to the RI-RI1 type responsenoted with resistant P. falciparum treated with a standard dose of at least 25 mgikg). This is in marked contrast to the rapid and sustained-ilearanceof parasites observed with most vivax infections treated at Ok Tedi and elsewhere.Consideringthat patient no. 1 had a bodyweight of 80 kg, the prophylactic and 600 mg single treatment dose may be considered suboptimal, but 600 mg of chloroquine base cleared P. vivax Darasitaemias LIPto 42 000&d within 48 h in 8 of 10 adilts investieated at Ok Tedi who weighed between 75 and 100 ke: &ey were still negative on”day 7. One of the resista$
122 adults had no detectableparasitaemiaat 48 h but parasitaemia recrudescedon day 7; the other was patient no. 1 who was the only one on regular weekly prophylaxis and is discussedin this paper. Clearly, chloroquine prophylaxis and treatment can no longer be expected to suppress vivax malaria in an increasing number of residents of, and travellers to, Papua New Guinea. An increased prophylactic doseof chloroquine may be appropriate for non-immune individuals under suchconditions. The poor response observed in patient no. 2 after treatment with a 4 d regimen of chloroquine is particularly disturbing. Parasitesstill persisted in the presence of blood and plasma levels of chloroquine which were more than ten-fold higher than those needed to inhibit ‘normal’ strains of P. vivax (PETERS, 1987). The spread of parasiteswith such a severedegreeof chloroquine resistancewould seriously hamper the control and treatment of malaria. In the Western Pacific region, where short-relapsing strains of P. vivax predominate, one would have to contend with several ‘resistant bombshells’ released from the liver during the course of a single infection. This would present major problems for the individual afflicted with such an infection and, from a public health standpoint, would increasethe likelihood of rapid spread of such chloroquine-resistant strains. Radical cure of the liver stagesof P. vivax is not easybecauseof poor compliancewith the 14 d (22.5 mg daily) or 8 week (45 mg weekly) primaquine regimens. Furthermore, in the south-west Pacific region, these cumbersome regimens are becoming even less effective in view of the proliferation of Chesson-like strains which are refractory to primaquine treatment (K. H. Rieckmann, personal observations). The 8 week regimen of primaquine (45 mg) and 300 mg chloroquine base has failed to clear exoerythrocytic stagesat Ok Tedi, relapses occurring within 8 weeksof ceasingtreatment. Chloroquine-resistant P. vivax is upon us and has only begun to surface. The time has arrived for health personnel to be made aware of this serious development
and for national and international authorities to start taking appropriate measuresto deal with the situation. Acknowledgements
The supportof the Ok Tedi Mining Limited Medical Department staff is greatly appreciated in helping to direct patients with unusual drug responsesto our attention. In particular we thank Sr Kulis Pa&a and H. E. 0. JoshiaBola for the extremely important highlands case,hospital pathology staff Roberto Vergara and Philip Mayarom, and Sgt Tom Travers of the Army Malaria Research Unit’s Pharmacology Department for the chloroquine determinations. References
Alvan, G., Ekman, L. & Lindstorm, B. (1982). Determination of chloroquine and its desethyl metabolize in plasma, red blood cells and urine by liquid chromatography. Journal of Chromatoma6hv. 229.241-247.
Peters,W. (1987). Chemotherapy and Drug Resistancein Malaria, 2nd edition. London: Academic Press. Rieckmann, K. H., Davis, D. R. & Hutton, D. C. 11989).Plasmodium &vax r&istance to chloroquink? Lanck, ii,’ 11831184. Schuurkamp, G. J., Matango, M., Napil, J. & Vergara, R. V. (1987). Malaria control and the development of the Ok Tedi Mining Project in the Star Mountains of Papua New Guinea: the initial construction phase. Papua New Guinea Medical Journal, 30,27-38.
Schuurkamp, G. J,., Spicer, I’. E., Kereu, R. K. & Bulungol, P. K. (1989). A mixed infection of vivax and falciparum malaria auoarentlv resistant to 4-aminoauinoline: a casereoort. Transa%ons of-the Royal Society of Tropical Medicine a;d Hygiene, 83.607-608. Schwartz, I. K., Lackritz, E. M. & Patchen, M. S. (1991). Chloroquine-resistantPlasmodium vivax from Indonesia. New --I-~
~--
EnglandJournal of Medicine, 324,927.
Whitby, M., Wood! G., Veenendaal, J. R. & Rieckmann, K. !;5$9). Chloroqmne-resistant Plasmodium viva%. Lancet, ii, Received 18 June 1991; revised 22 August 1991; accepted for publication 22 August 1991
Announcement XIIIth
International Congress for Tropical Medicine and Malaria ‘Appropriate Technology for Better Health’ 29 November-4 December 1992 Pattaya, Thailand
Last date for registration at reduced rate: 30 June 1992 (late registrations can be accepted on arrival). Further information can be obtained from Professor Thanongsak Bunnag, CongressSecretariat Office, The XIIIth International Congressfor Tropical Medicine and Malaria, c/o Faculty of Tropical Medicine, Mahidol University, 42016 Rajvithi Road, Bangkok 10400, Thailand.
