Toxoplasmosis, drugs used

Describe the pharmacodynamic and pharmacokinetic properties of the major amebicides tdilox-anide, emetine, iodoquinol, and metronidazole). List other clinical applications of metronidazole. Identify the drugs useful for prophylaxis and treatment of pneumocystosis and toxoplasmosis and know their toxic effects. 

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. 

Sulfonamides are used for controlling urinary tract infections, acute and chronic lung infections (norcadiosis), protozoan infections of the nervous system (i.e., toxoplasmosis), and a variety of infections in humans and livestock. Their mode of activity is by inhibiting the multiplication of bacteria by competitively inhibiting para-aminobenzioc acid (PABA) in the folic acid metabolism cycle (O Neil et al., 2001). More specifically, they block the synthesis of folic acid in bacteria as the drugs are structurally similar to PABA. Folic acid is essential to the synthesis of amino acids and nucleic acids. In bacteria, folic acid is synthesized from PABA... 

Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprim-sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections. 

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. 

Clinical Use. Atovaquone (Mepron) is used primarily to treat the protozoon that causes toxoplasmosis and the fungus that causes pneumocystis pneumonia in immunocompromised patients.6 This drug is not typically the primary treatment for pneumocystis, but is often reserved for patients who cannot tolerate more traditional treatments using sulfamethoxazole and trimethoprim (see Chapter 34) or pentamidine (see later). Atovaquone can also be used to prevent and treat resistant cases of malaria, and the antimalarial effects of this drug seem especially useful when combined with proguanil.48... 

Pyrimethamine and sulfadiazine have been used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been employed (see Chapter 53 Antiprotozoal Drugs). 

SAFETY PROFILE Poison by ingestion, subcutaneous, and intraperitoneal routes. Experimental teratogenic and reproductive effects. Questionable carcinogen. Human mutation data reported. When heated to decomposition it emits very toxic fumes of CL and NO. Used as an antimalarial drug for humans and to treat toxoplasmosis in hogs. 

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. 

Drug may be used in cases of resistance to usual treatments for toxoplasmosis, such as in immune deficiency. 

With increasing frequency, clindamycin in combination with pyrimethamine is been used as the replacement drug for sulfadiazine in the treatment of cerebral toxoplasmosis. Perhaps this new combination again may send sulfadiazine nephrotoxicity into "oblivion". Nevertheless, until this possibility occurs, primary care physicians should be aware that sulfadiazine can cause renal toxicity and that effective preventive measures are available. 

Pyrimethamine is a folic acid antagonist that for many years has been used as an antimalarial drug [193-195], specially for chloroquine-resistant P. falciparum. Due to its synergistic activity, pyrimethamine also has been used, in combination with sulfadiazine or dapsone for the treatment or prophylaxis of cerebral toxoplasmosis or PCP in patients with AIDS [196]. 

The recommendations for the treatment of EPM using pyrimethamine, trimethoprim and sulfadiazine were originally based on the use of these drugs for the treatment of malaria and toxoplasmosis in humans. Either pyrimethanune or trimethoprim in combination with sulfadiazine or sulfamethoxazole have been used with some success and have gained widespread acceptance as the treatment of choice for EPM. Pyrimethamine and trimethoprim are diaminopyrimidine antimicrobial agents that inhibit dihydrofolate reductase (DHFR see Ch. 2). These agents interfere with... 

AIDS." A primary infection that is treated with the combination is PCP. The sulfonamide-trimethoprim combination can be used fur treatment and prophylaxis. Additionally, cerebral toxoplasmosis con be treated in active infection or prophyluctically. Urinary tract infections and bum therapy" " " round out the list of therapeutic applications. The sulfonamides arc drugs of choice for a few other types of infections, but their u.sc is quite limited in modem antimicrobial chemotherapy." " "... 

Not a macrolide, but has the same mechanisms of action and resistance. Narrow spectrum gram-positive cocci (not MRSA) and anaerobes including B. fragilis (backup drug) has also been used in toxoplasmosis. Its concentration in bone has clinical value in osteomyelitis due to gram-positive cocci. First known drug to cause pseudomembranous colitis. 

The role of spiramycin in the treatment of HIV-associated cryptosporidiosis remains inconclusive and controversial [335, 336]. The drug did hasten clinical recovery and decrease the duration of oocyst excretion in immunocompetent children with cryptosporidial diarrhea [337]. Spiramycin is also used effectively with or without pyrimethamine-sulfadiazine for the treatment of fetal toxoplasmosis [338, 339]. 

Narrow spectrum gram-positive cocci (not MRSA) and anaerobes, including B. fragilis (backup drug) has also been used in toxoplasmosis... 

Trimethoprim-sulfamethoxazole is not effective in the treatment of infections due to viruses, fungi, or mycobacteria. However, the drug combination is active against certain protozoans, including toxoplasma, and can be used for both prevention and treatment of toxoplasmosis in the AIDS patient. The answer is (C). 

With as many as 70% of patients with AIDS developing pneumocystis and, of these, nearly 60% of the patients on cotrimoxazole developing serious side effects to this combination, atovaquone is an important alternative drug (16). Atovaquone also has been reported to be effective for the treatment of toxoplasmosis caused by Toxoplasma gondii, although it has not been approved for this use. 

The manufacturers of pyrimethamine note that the concurrent use of zidovudine may increase the risk of bone marrow depression. They say that if signs of folate deficiency develop, then pyrimethamine should be discontinued and folinie acid given. Note that the prophylactic use of a folate supplement, preferably folinie acid, is recommended for all patients with toxoplasmosis taking high-dose pyrimethamine, to reduce the risk of bone marrow suppression. See also NRTIs Zidovudine + Myelosup-pressive drugs , p.809... 

Established interactions. With the NRTTs that are actively excreted via the kidneys (e.g. lamivudine, stavudine, and zaicitabine), it is unlikely that dosage alterations are necessary unless the patient has renal impairment. However, when both drugs are needed, patients should be closely monitored for signs of toxicity. Moreover, the UK manufacturer of lamivudine recommends that the use of lamivudine with high-dose co-trimoxazole for the treatment of Pneumocystis pneumonia and toxoplasmosis should be avoided. Since renal clearance represents only 20 to 30% of the total clearance of zidovudine, the authors of two of these reports " suggest that this interaction is unlikely to be clinically important for zidovudine unless the glucuronidation by the liver is impaired by liver disease or other drugs. Didanosine also does not appear to interact to a clinically relevant extent. 

An example of sequential blocking is the use of a sulfadiazine with pyrimethamine 9.31) in toxoplasmosis, a protozoal disease (Wettingfeld, Rowe and Eyles, 1956). In this sequence, the sulfonamide blocks the incorporation of / -aminobenzoic acid into dihydrofolic acid, and the pyrimethamine prevents the reduction of this pteridine to tetrahydrofolic acid (Sections 9.3.2 and 9.3.3). In malaria, as early as 1959, Hurly made the observation that pyrimethamine and sulfadiazine potentiated one another to such a degree that the combination could actually cure Pl.falciparum infections. Thus, less than 0.1 m.e.d. (minimal effective dose) of pyrimethamine and 0.25 m.e.d. of sulfadiazine were, together, as effective as 1.0 m.e.d. of either drug separately. In current tropical medicine, Maloprim , a combination of pyrimethamine and dapsone 9.17) (the latter chosen because of its slow rate of excretion which matches that of pyrimethamine), forms an excellent replacement for chloroquine in cases of Pl.falciparum... 

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