Drug Resistant Falciparum Malaria in Thailand
September 1, 2000 7 minutes read
Drug Resistant Falciparum Malaria in Thailand
Special Feature
By Lin Chen, MD
Drug resistant falciparum malaria in thai- land is a well-established medical problem. Nevertheless, both the treatment and chemoprophylaxis of malaria for travelers to Thailand have been confusing due to the epidemiology of antimalarial drug resistance, the use of antimalarials not generally available in the United States, and the evolving drug policy established by the Thai Ministry of Health. One of my goals during a recent visit to Thailand was to extract some useful information out of this apparent quagmire.
Historical Background1-3
Chloroquine came into wide use in Thailand during the 1950s for individual presumptive and radical treatment, mass radical treatment, as well as self-medication and prophylaxis. It was often used haphazardly in areas of high malaria transmission, resulting in selection pressures favoring the emergence of resistance. Hence, resistance to chloroquine emerged near the Thai-Cambodia border in 1957 and spread rapidly. By 1973, chloroquine was no longer useful for the treatment of falciparum malaria, but it was still used for other species as well as for presumptive therapy. Instead the combination agent, sulfadoxine/pyrimetha-mine (Fansidar®), was used to treat falciparum malaria from 1973 on, but by 1975 the dosage used in Thailand had to be increased.
By 1982, resistance to sulfadoxine/pyrimethamine had been demonstrated throughout Thailand. Although the combination continued to be used for presumptive treatment, confirmed infections with Plasmodium falciparum were treated with the combination of quinine for three days plus tetracycline, which was continued for seven days total therapy. The sensitivity of P. falciparum decreased rapidly and dictated an increase in the duration of quinine therapy to five days in 1984 with a further increase to seven days in 1990.
The longer courses of quinine plus tetracycline met poor compliance in field trials. Consequently, the combination of mefloquine/sulfadoxine/pyrimethamine (MSP) in a single dose was recommended as treatment for all cases of microscopically confirmed falciparum malaria in 1985. After a comparison of mefloquine and MSP found them to be equally effective and, given that MSP led to more frequent gastrointestinal side effects, the recommendation was changed to mefloquine therapy alone in 1990-1991.
Unfortunately, mefloquine resistance had already been observed in 1982. Furthermore, an outbreak of mefloquine-resistant falciparum malaria emerged in Bo Rai, Trat Province, on the Thai-Cambodia border in 1989. In 1991, the Thai Ministry of Health recommended seven days of quinine and tetracycline to treat falciparum malaria, and disseminated public information on mefloquine resistance.2 In addition, primaquine therapy was strongly recommended for all P. falciparum cases to eliminate human carriage of gametocytes and decrease their transmission to mosquitoes.2,3
Since 1994, artesunate and artemether regimens, either alone or in combination with mefloquine, have been added to the treatment options useful against P. falciparum in Thailand. Currently, the combination of artesunate plus mefloquine is considered the treatment of choice for multidrug-resistant falciparum malaria acquired in Thailand.
Causes of Antimalarial Drug Resistance1-3
"Population migration" and "drug pressure" are felt to be two major factors contributing to the development and spread of drug-resistant malaria in Thailand. Speculation is that spontaneous mutations probably first emerged in Trat Province, at the Thai-Cambodia border, where malaria transmission was intense. Gem miners, who were generally not immune, moved in and out of this region. Mass suppressive, rather than curative, antimalarial therapy was used, and drug levels were often subtherapeutic. Under these conditions, parasite adaptation occurred, and resistant strains were selected. The migration of gem miners back to their homes allowed dissemination of these resistant strains to other areas. Similar population movements occurred in the Tak Province, at the Thai-Myanmar border, also resulting in the spread of resistant strains.
Recent Sensitivity Patterns in Thailand
The rapid emergence and spread of resistance to antimalarial drugs resulted in a call for judicious use of all currently effective drugs. P. falciparum infections were found to be resistant to chloroquine in more than 90% of cases by 1973.1 Resistance to sulfadoxine/pyrimeth-amine occurred in 70-90% of P. falciparum cases by the early 1980s.2 The combination of quinine and tetracycline for seven days was curative in more than 80% of patients with falciparum malaria as of 1990.4,6 Resistance to high-dose (25 mg/kg) mefloquine, when used alone, was nearly 50% by the early 1990s.4,5
Drug Policy in the Control of Resistance2,3
The Thai Ministry of Health has restricted the distribution of drugs such as mefloquine so they would be available only through government and some private hospitals or malaria clinics in the hope of minimizing further evolution and spread of drug resistance. In general, the Thai Ministry of Health advocates for radical treatment of proven malaria at malaria clinics and hospitals. Its current drug policy discourages chemoprophylaxis and presumptive treatment of malaria. Mefloquine, for example, is used only for microscopically confirmed P. falciparum infections.
The Ministry of Health discontinued mass drug administration and selective drug administration in 1984-1985 because of the risk of encouraging resistance. However, in 1991 mass treatment with primaquine was started for gem miners at the Thai-Cambodian border who were returning home. Primaquine is equally effective at treating the gametocytes of both drug-resistant and drug sensitive P. falciparum; hence mass treatment was aimed at preventing the spread of mefloquine resistance by gametocyte carriers.
Current Treatment Options4-9
Since 1994, the treatment of choice in Thailand for uncomplicated falciparum malaria has been oral artesunate, 12 mg/kg over three days, plus a single dose of mefloquine 25 mg/kg. However, artesunate is not available in the United States. Artemether, a parenteral artemisinin derivative, has also been shown to be effective both alone and in combination for treatment of falciparum malaria in Thailand. Another treatment option in Thailand has been quinine plus tetracycline for seven days. (The equivalent regimen in the U.S. would be quinine plus doxycycline.) Atovaquone/proguanil (250 mg/100 mg) in the fixed dose preparation, Malarone®, (4 tablets daily for 3 days) has also been shown to be effective in Thailand, although it has not yet been registered in that country.
Since neither artesunate nor artemether are available in the United States, our treatment of P. falciparum infections acquired in Thailand would be limited to the combination of quinine plus tetracycline (or doxycycline) or the newly available atovaquone/proguanil combination.
Current Options for Chemoprophylaxis
The Thai Ministry of Health has established a drug policy that both discourages the use of malaria chemoprophylaxis, and restricts the distribution of mefloquine and newer antimalarials. The travel clinics in Bangkok, for example, do not prescribe malaria chemoprophylaxis as a general policy. Our travelers could receive contradictory recommendations from health providers in the United States vs. those in Thailand. It is important for travel medicine consultants to be aware of the current antimalarial drug policies of the Thai Ministry of Health, and discuss the rationale for various prophylaxis and treatment recommendations with each traveler.
For most tourist travel destinations such as Bangkok, Chiang Mai, and Phuket, the risk of acquiring malaria is not significant, and chemoprophylaxis is not necessary. However, some specific groups of travelers may be at increased risk while in Thailand. These include backpackers traveling overland throughout the country, adventure travelers, and persons working in rural areas—especially those along the Thai-Cambodian border and the Thai-Myanmar border.
What are the most reasonable antimalarial chemoprophylaxis regimens for use in Thailand? P. falciparum sensitivity to mefloquine may still be acceptable in the northern and southern regions of the country, although the emergence of mefloquine-resistant strains is unpredictable. On the other hand, multidrug resistance is high along borders in the Trat Province as well as the Tak Province. Mefloquine is not routinely considered as malaria chemoprophylaxis for travelers in Thailand, even when prophylaxis is planned. As recommended by the U.S. Centers for Disease Control, doxycycline (100 mg daily starting 1-2 days before going to malarious areas and continued through 4 weeks after departing the malarious areas) has been the drug of choice for malaria prevention in travelers to Thailand. Atovaquone/proguanil is now available in the United States and provides a long-awaited option for travelers at risk. Malarone should not be used with tetracyclines for any reason, particularly malaria prophylaxis. Concomitant treatment with tetracycline has been associated with a 40% reduction in plasma concentrations of atovaquone. The combination of artemether-benflumetol (20 mg and 120 mg in each tablet, respectively) continues to be evaluated in Thailand for the treatment of multidrug-resistant falciparum malaria. A four-dose schedule (4 tablets at 0, 8, 24, 48 hours) has been shown to have a 28-day cure rate of only 69% in a comparison with mefloquine. A six-dose regimen given over three or five days appears to have an improved 28-day cure rate of 96-99%.10-11 Whether the 8-aminoquinolines, primaquine, and the new longer-acting agent, tafenoquine, will have a role in prophylaxis against P. falciparum in Thailand remains to be determined. Could they represent yet another option for prophylaxis? Regardless, each of these chemoprophylactic agents must be used judiciously to avoid further development and spread of drug resistance. (Dr. Chen is Clinical Instructor, Harvard Medical School and Travel/Tropical Medicine Clinic, Lahey Clinic Medical Center, Cambridge, Mass.)
References
1. Rooney W. Southeast Asian J Trop Med Public Health 1992;23(suppl 4):131-137.
2. Thimasarn K. Southeast Asian J Trop Med Public Health 1992;23(suppl 4):139-142.
3. Looareesuwan S, et al. Southeast Asian J Trop Med Public Health 1992;23(4):621-634.
4. Price R, et al. Am J Trop Med Hyg 1998;59(6): 883-888.
5. Price R, et al. Trans R Soc Trop Med Hyg 1995;89: 523-527.
6. Looareesuwan S, et al. Lancet 1992;339:369.
7. Price R, et al. Am J Trop Med Hyg 1999;60(4):547-555.
8. Looareesuwan S, et al. Southeast Asian J Trop Med Public Health 1998;29(2):344-354.
9. Looareesuwan S, et al. Am J Trop Med Hyg 1999;60(4):526-532.
10. Looareesuwan S, et al. Am J Trop Med Hyg 1999; 60(2):238-243.
11. Van Vugt M, et al. Am J Trop Med Hyg 1999;60(6): 930-942.
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