Pyrimethamine/Sulfadoxine

Plasmodium (P.) falciparum, responsible for the most dangerous form of malaria, is particularly prone to develop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine/ sulfadoxine. 

Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial selftreatment. 

Malaria (doxycycline only) Prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. 

In areas where chloroquine-resistant P. falciparum is common, a combination of a rapidly acting blood schi-zonticide and pyrimethamine-sulfadoxine may be the treatment of choice. An acute attack of malaria caused... 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Pyrimethamine-sulfadoxine Oral second-line malaria treatment... 

Chloroquine-resistant Quinine Artemisinin derivatives Atovaquone-proguanil Mefloquine Pyrimethamine-sulfadoxine Antibacterials (e.g., clindamycin, doxycycline, sulfamethoxazole, or tetracycline] ... 

Sibley CH, Hyde JE, Sims PF, et al. Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum what next Trends Parasitol. 2001 17 582-588. 

In Irian Jay a, a randomized, controlled trial (n = 105 88 children) of oral artesunate (4 mg/kg od for 3 days) with pyrimethamine (1.25 mg/kg) + sulfadoxine or pyrimethamine + sulfadoxine alone (same dose) showed reduced gametocyte carriage and reduced treatment failure rates (RR = 0.3 95% Cl = 0.1, 1.3) in the combination group (16). Self-limiting adverse events of combination treatment were mild diarrhea (2.1%), rashes (4.3%), and itching (2.1%). 

In a double-blind, randomized, placebo-controlled trial in Gambian children with uncomplicated falciparum malaria treated with pyrimethamine + sulfadoxine (25/ 500 mg n — 600) or pyrimethamine + sulfadoxine combined with two regimens of oral artesunate (4 mg/kg, n — 200 or 4 mg/kg od for 3 days, n — 200), there were mild adverse events, such as headache, anorexia, nausea, vomiting, abdominal pain, and diarrhea, in a high proportion of children (56%) (17). Combination treatment with... 

Single-dose pyrimethamine + sulfadoxine (25 mg/kg n = 54) has been compared with mefloquine (15 mg/kg n = 48) in the treatment of uncomplicated P. falciparum malaria in an unblinded, randomized study in 102 Malawi children (10). Immediate vomiting was more common in those who took mefloquine (eight cases) than in those who took pyrimethamine + sulfadoxine (one case), with comparable parasite failure rates at 14 days (20 and 22% respectively). 

A review of the use of mefloquine in pregnancy (47) did not suggest that mefloquine has a worse effect in pregnancy than other antimalarial drugs, such as chloroquine and pyrimethamine + sulfadoxine. 

The chemotherapeutic response of Plasmodium berghei to various combinations of mefloquine with other drugs (sulfadoxine + pyrimethamine, primaquine, floxacrine) have shown that the desired effects are purely additive (SEDA-13, 809), so the adverse effects too are probably only those of the individual compounds. Adverse reactions occurred in 46% of 400 patients treated with Fanimef (mefloquine + pyrimethamine + sulfadoxine) (SEDA-12, 693). Of note were dizziness (29%), nausea (9.5%), vomiting (7.3%), weakness/lassitude (5.8%), abdominal discomfort or pain (5.5%), diarrhea (3.8%), pruritus (3.0%), insomnia (2.0%), and headache (2.0%). 

In Britain, the retrospective reported rate for serious reactions with Maloprim was one in 9100, the incidence of blood dyscrasias being one in 20 000. These figures are lower than those reported with Fansidar (pyrimethamine + sulfadoxine) (SEDA-16, 309). 

In a placebo-controlled study of chemoprophylaxis for malaria, 701 Tanzanian infants were assigned to intermittent pyrimethamine + sulfadoxine (under 5 kg, a quarter of a tablet 5-10 kg, half a tablet over 10 kg, one tablet each tablet contained pyrimethamine 25 mg plus sulfadoxine 500 mg) alongside routine childhood immunizations and iron supplementation at 2, 3, and 9 months of age (4). The combination was well tolerated, with no reported adverse events. Episodes of clinical malaria fell by 59% (95% Cl = 41, 72) and the incidence of severe anemia by 50% (95% Cl = 8, 73%) in the first year of life. Contrary to previous studies involving continuous prophylaxis in infants, there was no increase in the frequency of rebound episodes of malaria up to 18 months of age, suggesting that the development of malaria-specific immunity was unimpaired. Responses to vaccines were unaffected. 

Intermittent iron supplementation with pyrimethamine + sulfadoxine has been investigated in 328 anemic but symptom-free Kenyan children, who were randomly given either iron (ferrous fumarate suspension 6.25 g/1 twice a week) or placebo and pyrimethamine + sulfadoxine (25 mg and 1.25 mg/kg once every 4 weeks) or placebo (82 in each group) (6). After 12 weeks, those who took iron and pyrimethamine + sulfadoxine, iron alone, or pyrimethamine + sulfadoxine alone had higher hemoglobin concentrations than those who took the double placebo. No adverse effects were reported. 

Liver function abnormalities with Fansidar (pyrimethamine + sulfadoxine) vary from raised serum transaminase activities to more marked disturbances, with jaundice and granulomatous hepatitis. An occasional case of fatal hepatic failure has been reported this was the case in a young white American woman who had taken three doses of Fansidar with chloroquine (SEDA-12,242). Hepatic symptoms may be part of a vasculitis sjmdrome or can be seen in association with skin reactions (SEDA-13, 241). 

Severe skin reactions have been reported with the combination of pyrimethamine + sulfadoxine (Fansidar) from various countries. These include erythema exudativum multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous vasculitis, lichen planus, a single case of ectodermosis pluriorificialis, and some cases of photosensitivity. 

Sulfonamide and/or pyrimethamine sensitivity, pregnancy, and G6PD deficiency are contraindications. Use in young infants is considered inadvisable the history of an 8-month-old infant with P. falciparum malaria who developed high fever, tachycardia, hypotension, chills, jaundice, and splenomegaly 48 hours after a single parenteral dose of Fansidar (pyrimethamine + sulfadoxine) (SEDA-16, 309) seems to confirm the wisdom of this advice. It has been advocated that Fansidar should not be used prophylactically if exposure to malaria will last less then 3 weeks, in view of the incidence of severe skin reactions during the first month. 

Schurmann D, Bergmann F, Albrecht H, Padberg J, Wunsche T, Grunewald T, Schurmann M, Grobusch M, Vallee M, Ruf B, Suttorp N. Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Eur J CUn Microbiol Infect Dis 2002 21(5) 353-61. 

In children with acute uncomplicated Plasmodium falciparum malaria, pyrimethamine + sulfadoxine (25 mg + 500 mg) and artesunate (4 mg/kg) were well tolerated, and no adverse reactions attributable to treatment were recorded (7). 

In an open prospective study in 95 HIV-infected patients with successfully treated Pneumocystis proved pneumonia, pyrimethamine + sulfadoxine (25/500 mg) was given twice weekly to prevent relapse (159). There were allergic skin reactions in 16 patients, resulting in permanent withdrawal in six. Two patients developed serious adverse reactions (Stevens-Johnson syndrome), both of whom had continued to take prophylaxis despite progressive hypersensitivity reactions. 

Miller KD, Lobel HO, Satriale RF, Kuritsky JN, Stern R, Campbell CC. Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986 35(3) 451-8. 

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