Toxoplasmosis pyrimethamine

Sulfadiazine achieves therapeutic concentrations in cerebrospinal fluid and in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. Pyrimethamine, an antiprotozoal agent, is a potent inhibitor of dihydrofolate reductase. The combination of sulfadiazine and pyrimethamine is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade (Figure 46-2). The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75 mg loading dose followed by a 25 mg once-daily dose. Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression. 

Pyrimethamine is an inhibitor of dihydrofolate reductase and causes tetrahydrofolate deficiency. It is teratogenic in animals in rats it produces limb defects, cleft palate, and brachygnathia, and in chick embryos micromelia. Fetal death has been seen in rats and hamsters. However, in toxoplasmosis, pyrimethamine, with or without a sulfonamide, has been given to pregnant women without evidence of subsequent abnormalities. Supplementation with folic acid has been advocated to prevent or reduce adverse effects (SEDA-13,812), but it is not known if this could impair efficacy. 

Toxoplasmosis Pyrimethamine + sulfadiazine TMP-SMX is also prophylactic against Pneumocystis carinii in AIDS... 

The sulfas also remain clinically useful in the treatment of chancroid, lymphogranuloma venereum, trachoma, inclusion conjunctivitis, and the fungus-related nocardiosis (7). In combination with pyrimethamine, they are recommended for toxoplasmosis (8) and have been used for chloroquine-resistant falciparium malaria (4,9). There has also been some use of sulfas for the prophylaxis of rheumatic fever. The sulfone, dapsone, remains an accepted treatment for all forms of leprosy (4). 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

Pyrimethamine, a folic acid antagonist, exhibits antimicrobial action against the causative agent of malaria and possesses sporontocidal action. It is also effective with respect to the causative agent of toxoplasmosis. It is used for preventing malaria and treating toxoplasmosis. 

Pyrimethamine in combination with sulfadiazine or trisnlfapyrimidine is the dmg of choice for toxoplasmosis. A synonym of this combined dmg is daraprim. 

Infants (younger than 2 months of age) - Contraindicated, except as adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis. 

Hypersensitivity to sulfonamides or chemically related drugs (eg, sulfonylureas, thiazide and loop diuretics, carbonic anhydrase inhibitors, sunscreens with PABA, local anesthetics) pregnancy at term lactation infants less than 2 months of age (except in congenital toxoplasmosis as adjunct with pyrimethamine) porphyria salicylate hypersensitivity. 

The treatment of choice for toxoplasmosis is pyrimethamine with sulfadiazine a folate supplement is also given to counteract the megaloblastic... 

Sulfadiazine 1-1.5 g orally or i.v. 6-hourly -f Pyrimethamine 50 to 100 mg orally initially, then 25-50 mg daily Sulfadiazine 500 mg orally 6-hourly or 1 g orally 12-hourly -f Pyrimethamine 25 to 50 mg orally daily Prophylaxis for P. carinii with cotrimoxazole is effective prophylaxis for toxoplasmosis... 

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections. 

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. 

It is used in the treatment of severe anaerobic infections caused by bacteroides and other anaerobes. It is also used in combination with aminoglycoside in the treatment of abdomen and GIT wounds, infections of female genital tract, pelvic abscesses, aspiration pneumonia and septic abortion. It is also used for prophylaxis of endocarditis. It is also used along with primaquine in Pneumocystis carinii pneumonia in AIDS patients and with pyrimethamine for toxoplasmosis. 

The combination is indicated in chloro-quine resistant malaria and prophylaxis. Pyrimethamine-sulfadiazine combination is used for treatment of toxoplasmosis. 

Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It is often active against community-acquired strains of methicillin-resistant S aureus, an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut infections originating in the female genital tract, eg, septic abortion and pelvic abscesses and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain. 

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). 

Sulfadiazine Oral first-line therapy for toxoplasmosis when combined with pyrimethamine... 

Pyrimethamine, in combination with sulfadiazine, is first-line therapy in the treatment of toxoplasmosis, including acute infection, congenital infection, and disease in immunocompromised patients. For immunocompromised patients, high-dose therapy is required followed by chronic suppressive therapy. Folinic acid is included to limit myelosuppression. Toxicity from the combination is usually due primarily to sulfadiazine. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen. 

Toxoplasmosis Lymph nodes many organs and tissues Pyrimethamine-sulfadiazine [see antimalarial drugs] other antibacterials [clindamycin] Trimethoprim-sulfamethoxazole another agent [azithromycin, clarithromycin, atovaquone, or dapsone]... 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

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. 

The sulfas, including co-trimoxazole (sulfamethoxazole plus trimethoprim, see p. 293), are bacteriostatic. These drugs are active against selected enterobacteria, chlamydia, Pneumocystis, and nocardia. Typical clinical applications are shown in Figure 29.3. In addition, sulfadiazine [sul fa DYE a zeen] in combination with the dihydrofolate reductase inhibitor pyrimethamine [py ri METH a meen] is the only effective form of chemotherapy for toxoplasmosis (p. 353). 

One of the most common infections in man is caused by the protozoan, Toxoplasma gondii, which is transmitted to humans when they consume raw or inadequately cooked, infected meat. Infected pregnant women can transmit the organism to the fetus. Cats are the only animals that shed oocysts that can infect other animals as well as man. The treatment of choice for this condition is the antifolate drug, pyrimethamine [peer i METH a meen] (see p. 353). A combination of sulfadiazine (see p. 289) and pyrimethamine is also efficacious. Leucovorin is often administered to protect against folate deficiency. Other inhibitors of folate biosynthesis, such as trimethoprim (see p. 293) and sulfamethoxazole (see p. 289) are without therapeutic efficacy in toxoplasmosis. [Note At the first appearance of a rash, pyrimethamine should be discontinued since hypersensitivity to this drug can be severe.]... 

Classic triple therapy for retinal toxoplasmosis consists of pyrimethamine plus sulfediazine, with steroids to reduce inflammation. Pyrimethamine and the sulfonamides act synergistically on T. gondii. Pyrimethamine is... 

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachy-zoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects. 

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