Sulfadoxine and pyrimethamine Fansidar

Sulfadoxine and Pyrimethamine. The combination of sulfadoxine and pyrimethamine (Fansidar) (Fig. 9-S) uses a drug from the sulfonamide antibacterial group and a pyri-... 

In addition, sulfadoxine and pyrimethamine (Fansidar) are indicated in prophylaxis of malaria in individuals traveling to areas where chloroquine-resistant P. falciparum malaria is endemic. However, resistant strains may be encountered. Regardless of the prophylactic regimen used, it is still possible to contract malaria. Moreover, this combination has been used as a prophylactic agent in the prevention of Pneumocystis carinii pneumonia in patients with AIDS. 

SULFADOXINE AND PYRIMETHAMINE (Fansidar tablets 500 mg sulfadoxine and 25 mg pyrimethamine)... 

FIGURE 107 Patients with a clinical diagnosis of AIDS should undergo long-term therapy with zidovudine (AZT, 1200 mg q. 4 hrs). Acyclovir may potentiate the beneficial effects of AZT. In addition, patients should be treated prophylactically for Pneumocystis carinii pneumonia such regimens include sulfadoxine and pyrimethamine (Fansidar), dapsone, or aerosolized pentamidine. Dextran sulfate is also useful because it blocks the binding of HIV to target cells. 

The sulfones and sulfonamides synergize with the inhibitors of dihydrofolate reductase, and the combinations have been effective in controlling malaria, toxoplasmosis, and coccidiosis. Fansidar, a combination of sulfadoxine and pyrimethamine, has been successful in controlling some strains of chloroquine-resistant Plasmodium falciparum malaria (see Chapter 53 Antiprotozoal Drugs). However, reports of Fansidar resistance have increased in recent years. New inhibitors effective against the sulfonamide-resistant 7,8-dihydropteroate synthase are needed. 

Note Fansidar is sulfadoxine and pyrimethamine (this combination is almost always prescribed)... 

Nebulized pentamidine at the dosage of 300 mg every two weeks should be used in patients with a CD4-I- count less than 100 mm if systemic therapy cannot be tolerated. Sulfadoxine/pyrimethamine (Fansidar), one tablet given once or twice a week, is useful in patients in whom compliance is considered to be a problem. However, it has been associated with hepatotoxicity, Stevens-Johnson syndrome and toxic epidermal necrolysis. 

Sulfadoxine is the only long-acting sulfonamide currently available in the USA and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in treatment for malaria (see Chapter 52). 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

A study in patients with AIDS found that zidovudine 250 mg four times daily did not adversely affeet the prevention of toxoplasma eneephalitis with pyrimethamine/sulfadoxine (Fansidar), one tablet twice weekly for up to 8 months. /w vitro and animal data have shown that the combination of zidovudine and pyrimethamine caused synergistic decreases in lymphocyte and neutrophil numbers. ... 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

Pyrimethamine and sulfadiazine have been used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used (see Chapter 52). 

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. 

In P. falciparum (chloroquine-resistant) infections, a dose of 750 mg mefloquine followed by 500 mg 12 hours later is recommended. The pediatric dose of mefloquine is 15 mg/kg (<45 kg) followed by 10 mg/kg 8 to 12 hours later.Intravenous quinidine gluconate followed by oral quinine should be administered for severe illness, as already indicated.A second drug needs to be administered in chloroquine-resistant P. falciparum, and this second drug should follow the oral quinidine regimen either a single dose of three tablets of pyrimethamine-sulfadoxine (Fansidar) on the last day of intravenous quinidine or clindamycin 900 mg three times daily for 3 to 5 days. An alternative oral treatment for chloroquine-resistant P falciparum infection in adults, especially in those with a history of seizures or psychiatric disorders, is the combination of atovaquone 250 mg and proguanil 100 mg (Malarone) (4 tablets daily... 

Pyrimethamine-sulfadoxine (fansidar). This combination is available for oral use only in tablets containing 25 mg pyrimethamine and 500 mg sulfadoxine. One dose is taken by mouth on the last day of quinine sulfate therapy Adults take 3 tablets children 5-10 kg, 0.5 tablet 11-14 kg, 0.75 tablet 15-20 kg, 1 tablet 21-30 kg, 1.5 tablets 31 0 kg, 2 tablets 41-50 kg, 2.5 tablets over 50 kg, 3 tablets. Owing to extensive drug resistance, pyrimethamine-sulfadoxine should be used as an adjunct treatment primarily in young children or women who are not able to tolerate clindamycin. 

Sulfonamides or sulfones usually account for most toxicity associated with coadministration of these antifolate drugs (see Chapter 43). The combination of pyrimethamine (25 mg) and sulfa-doxine (500 mg) (fansidar) causes severe and even fatal cutaneous reactions in up to 1 in 5000 people. This combination also has been associated with serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated in individuals with previous reactions to sulfonamides, lactating mothers, and infants <2 months of age. Administration of pyrimethamine with dapsone (MALOPRIM, unavailable in the U.S.), occasionally has been associated with agranulocytosis. Higher doses pyrimethamine (75 mg daily) used along... 

Sulfadoxine has a particularly long t (7-9 days). In combination with pyrimethamine (500 mg sulfadoxine plus 25 mg pyrimethamine as fansidar), it is used for prophylaxis and treatment of malaria caused by mefioquine-resistant strains of Plasmodium falciparum (see Chapter 39). Because of severe adverse reactions (e.g., Stevens-Johnson syndrome), the drug should be used for prophylaxis only where the risk of resistant malaria is high. 

Oinical use The antifols are blood schizonticides that act mainly against P falciparum. Pyrimethamine with sulfadoxine in fixed combination (Fansidar) is used in the treatment of chloroquine-resistant forms of this species, although the onset of activity is slow. Many strains of P falciparum are now resistant to antifols, and the drugs are not commonly used for prophylaxis because of their toxicities. 

In a preliminary study in healthy subjects, pyrimethamine/sulfadoxine (Fansidar) raised the AUCq. and peak plasma levels of halofantrine by about 1.6-fold, without changing the overall AUC. This might lead to an increased incidence of arrhythmias, see also (b) above. 

A 19-year-old with a valve replacement and taking warfarin presented with melaena and coughing up blood about a week after self-medicating with Fansidar (sulfadoxine/pyrimethamine). He had not had his anticoagulant control monitored. ... 

---