The only useful combinations of antifolate drugs for the treatment of malaria are synergistic mixtures that act against the parasite-specific enzymes, dihydropteroate synthetase and dihydrofolate reductase. Available combinations include the sulfa drug-pyrimethamine combinations sulfadoxine-pyrimethamine and sulfalene-pyrimethamine, the former being more widely available.

Cotrimoxazole, the co-formulated combination of sulfamethoxazole and trimethoprim, has weak antimalarial properties because trimethoprim has a much lower affinity than pyrimetha-mine for the parasite dihydrofolate reductase enzyme (129). Cotrimoxazole should not be used for the treatment of malaria.

The use of sulfa drug-pyrimethamine combinations for chemoprophylaxis is no longer recommended because of the risk of severe skin reactions.

Formulations

Sulfadoxine-pyrimethamine:
• Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine.
• Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 ml of injectable solution.
  
  Sulfalene-pyrimethamine:
• Tablets containing 500 mg of sulfalene and 25 mg of pyrimethamine.

Efficacy

Sulfa drug-pyrimethamine combinations are highly active blood schizonticides against P. falciparum but are less effective against other Plasmodium species. There is no cross-resistance with the 4-aminoquinolines, mefloquine, quinine, halofantrine or the artemisinin derivatives. The combinations do not have game-tocytocidal activity but have been shown to be sporontocidal in animal models.

The long half-life of sulfa drug-pyrimethamine combinations provides a potent selective pressure for parasite resistance in areas of high transmission. In Africa since the late 1980s, P. falciparum sensitivity has decreased, particularly in East Africa where sulfadoxine-pyrimethamine has been used on a large scale (130-132), and resistance is demonstrable in parts of West Africa (133). At present parasitological failure rates on day 7 range from an average of 13% in Malawi, where sulfadoxine-pyrimethamine has been the first-line drug for the treatment of P. falciparum since 1993 (134), to around 50% at one site in the United Republic of Tanzania, where pyrimethamine was formerly used for chemoprophylaxis. The corresponding clinical failure rates for sulfadoxine- pyrimethamine are < 5% in Malawi and 6.4-34% (mean 9.5%) in the United Republic of Tanzania (135). The efficacy of sulfadoxine-pyrimethamine treatment is being monitored regularly in Kenya, Uganda and United Republic of Tanzania at eight sentinel sites in each country using the WHO therapeutic efficacy test protocol (29). The ACR for sulfadoxine-pyrimethamine treatment throughout the subregion varies from 66% to 100% (East African Network for Monitoring Antimalarial Treatments, unpublished data, 2000).

In the Amazon Basin of South America and most areas of South East Asia, P. falciparum resistance to sulfadoxine-pyrimethamine combinations has rapidly followed their introduction (within 5 years) and now precludes their use in almost all of these areas. These combinations remain effective along the Pacific coast of South America. Sulfa drug-pyrimethamine combinations have low efficacy against P. vivax (136). The combination of sulfa drug-pyrimethamine plus chloroquine can therefore be used, not because of a hypothetical effect on the development of resistance, but because it offers an inexpensive and effective option for treatment in areas where chloroquine-resistant, sulfa drug-pyrimethamine-sensitive P. falciparum and chloroquine-sensitive P. vivax coexist. For example, Ethiopia (137) and Papua New Guinea, countries where these two Plasmodium species are found together, have recently chosen sulfadoxine-pyrimethamine plus chloroquine as first-line treatment for clinically diagnosed malaria. Such combinations may, however, increase the risk of adverse skin reactions (109).

Use

Sulfa drug-pyrimethamine combinations have been successfully used in areas with highly developed P. falciparum resistance to chloroquine and during malaria epidemics. Compliance is high since they offer single-dose therapy. Sulfadoxine-pyrimethamine is the most widely used formulation, sulfalene- pyrimethamine has been largely used in the Indian subcontinent. It is generally assumed that these two formulations are equipotent although there are no comparative data to support this assumption.

There is evidence that folic acid, even in physiological doses, administered concurrently with sulfadoxine-pyrimethamine, can antagonize the action of sulfadoxine (138). It has been suggested that folic acid supplements should be delayed for one week after sulfa drug-pyrimethamine treatment to avoid an inhibitory effect on antimalarial efficacy. However, there are as yet no clinical data to substantiate this.

Recommended treatment

Sulfadoxine-pyrimethamine and sulfalene-pyrimethamine are recommended as single adult doses of 1500 mg of sulfa drug plus 75 mg pyrimethamine (25 mg of the sulfa component per kg as a single dose). This comprises 3 tablets. Details of the dosage schedules for all age groups are given in Table 10.

Sulfadoxine-pyrimethamine dosage should be based on the weight of the patient. In situations where weight cannot be obtained, dosage should at least be based on age.

The following table has been drawn up as the result of a joint effort between field experts and WHO. A weight-for-age data set from WHO containing weight relative to age from children and adults in developing countries only was used. Prior to analysis, the weight-for-age data set was standardized by age and sex to represent the age distribution of a typical population of a developing country. Several combinations of age cut-offs were compared using the proportion that would receive an adequate dose, less than the minimum dose and more than the maximum dose as the primary end-point. The data were weighted for "malaria risk", with young children contributing relatively more to the analysis than adults (16; F. Ter Kuile, personal communication, 2000)

Chemoprophylaxis

Sulfa drug-pyrimethamine combinations are no longer recommended for chemoprophylaxis in travellers because of the risk of severe adverse reactions (see below).

Use in pregnancy

Studies in Kenya and Malawi have shown that administration of a full adult treatment dose of sulfadoxine-pyrimethamine given at the first attendance at an antenatal clinic during the second trimester of pregnancy and repeated once at the beginning of the third trimester is effective in clearing or preventing placental infection and peripheral parasitaemia with P. falciparum and reducing the risk of low birth weight (51, 53, 139, 140). Several national malaria control programmes in Africa have adopted this intermittent regimen for the prevention of malaria during pregnancy.

There is no clinical evidence that the use of sulfa drug-pyrimethamine combinations for malaria treatment in pregnant women has any effect on the fetus (109). Although there is a theoretical risk of jaundice among premature babies born to mothers given sulfa drugs late in the third trimester, there does not appear to be an increased risk of kernicterus (141, 142).

Both pyrimethamine and sulfadoxine are excreted in small amounts in breast milk. Pyrimethamine is considered safe during breastfeeding. Diarrhoea and rash have been reported in nursing infants exposed to sulphonamides through breast milk; however, these reports are rare, amd more serious adverse reaction have not been documented. Thus, sulphonamide excretion in breast milk does not appear to pose a significant risk for risk for most infants.

Drug disposition

Sulfadoxine, sulfalene and pyrimethamine are highly bound to protein with relatively long mean elimination half-lives of around 180 h, 65 h and 95 h, respectively (143, 144). Pyrimethamine is extensively metabolized whereas only a small proportion of sulfadoxine is metabolized to acetyl and glucuronide derivatives. Excretion is mainly in the urine. All three drugs cross the placental barrier and are also detected in breast milk.

The mean elimination half-life of pyrimethamine has been reported to be as short as 23 h in patients with acquired immunodeficiency syndrome (AIDS) (83).

Adverse effects

Sulfa drug-pyrimethamine combinations are generally well tolerated when used at the recommended doses for malaria therapy. The most serious events are associated with hypersensitivity to the sulfa component, involving the skin and mucous membranes and normally occurring after repeated administration. Serious cutaneous reactions following single-dose treatment with sulfadoxine- pyrimethamine are rare. Of 12 cases of cutaneous events reported to the manufacturer following therapeutic use of the combination, none had received the recommended single dose (Hoffmann-La Roche, personal communication, 1995). However, such events, including life-threatening erythema multiforme (Stevens-Johnson syndrome) and toxic epidermal necrolysis, have been reported in 1 in 5 000 to 1 in 8 000 people taking the drug for weekly chemoprophylaxis (145). The combination is therefore no longer recommended for prophylactic use. Data on the incidence of serious cutaneous events following sulfalene- pyrimethamine use are lacking.

Cutaneous drug reactions are more common in patients who are HIV positive (83). There is therefore concern that the high prevalence of HIV infection in parts of Africa may result in an increased frequency of sulfa drug-associated toxicity in HIV-positive people treated with sulfa drug-pyrimethamine combinations for a concomitant malaria infection.

There have been isolated reports of a transient increase in liver enzymes as well as hepatitis occurring after administration of sulfadoxine-pyrimethamine. Haematological changes including thrombocytopenia, megaloblastic anaemia and leukopenia have also been observed. These conditions have usually been asymptomatic but, in very rare cases, agranulocytosis and purpura have occurred. As a rule, these changes regress after withdrawal of the drug.

Concomitant or consecutive administration of sulfa drug-pyrimethamine combinations with trimethoprim or sulfa drug-trimethoprim combinations such as cotrimoxazole may intensify the impairment of folic acid metabolism and related haematological adverse reactions, as well as increasing the risk of severe adverse skin reactions. It should, therefore, be avoided.

Contraindications

The use of sulfadoxine- or sulfalene-pyrimethamine combinations is contraindicated:

• in persons with known hypersensitivity to sulfa drugs or pyrimethamine,
• for chemoprophylaxis,
• in persons with severe hepatic or renal dysfunction (except when benefits exceed the risks involved),
• in infants in the first two months of life.

Overdosage

High doses of the combinations are potentially fatal. Symptoms include headache, anorexia, nausea, vomiting, excitation and possibly convulsions and haematological changes. In cases of acute intoxication, induction of emesis or gastric lavage is useful if undertaken within a few hours of ingestion. Convulsions can be controlled with diazepam and blood dyscrasias treated with intramuscular folinic acid.