Sulfonamides with trimethoprim

Chloroquine-resistant falciparum malaria was first reported in 1960. As of 1996, chloroquine resistance became widespread throughout the world and in many areas there is multidrug resistance. Preventive administration of drugs such as chloroquine, primaquine, and pyrimethamine, as well as the use of various sulfonamide mixtures and combinations of sulfonamides with trimethoprim, has progressively lost its usefulness. Currently, hardly half a century after the therapeutic breakthroughs occurred, quinine is once more one of the most valuable drugs in the treatment of malaria and there is a desperate need for other effective drugs. 

Benzylpyrimidine sulfonamides are based on the combination of a sulfonamide with trimethoprim or tetroxoprim. Chemically, trimethoprim is a 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine and has the following structural formula. 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

Accessory DHPS enzymes confer resistance to sulfonamides. Two different types encoded by the genes sull (located on transposons) and sulll (located on plasmids) have been described. These resistance determinants are often genetically linked to trimethoprim resistance genes. Therefore, the combination of sulfonamide antibiotics with trimethoprim does not prevent resistance selection. 

The answers are 484-k 485-j. (tlardman, pp 1061-1062, 1682-1685.) Sulfonamides can cause acute hemolytic anemia. In some patients it mayr be related to a sensitization phenomenon, and in other patients the hemolysis is due to a glucose-6-phosphate dehydrogenase deficiency Sulfamethoxazole alone or in combination with trimethoprim is used to treat UTls. The sulfonamide sulfasalazine is employed in the treatment of ulcerative colitis. Daps one, a drug that is used in the treatment of leprosy, and primaquine, an anti mala rial agent, can produce hemolysis, particularly in patients with a glucose-6-phosphate dehydrogenase deficiency. 

Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body, but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing folate, more precisely DHF, from precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Intermediate-acting sulfonamides include sulfadiazine and sulfamethoxazole. Sulfamethoxazole is combined with trimethoprim in co-trimoxazole. Sulfadiazine shows good penetration into the cerebrospinal fluid and is effective for cerebral Toxoplasmosis. It has an elimination half-life 10-17 hours which prolonged in renal impairment. 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Because of development of resistance and availability of more advanced antimicrobial agents, the use of sulfonamides is limited. However they are used in combination with trimethoprim. The important therapeutic uses are ... 

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (Figure 46-2). 

Sulfadiazine is a relatively short-acting sulfonamide with an elimination half-life of about 3 h in cattle. The importance of this drug for control of furunculoses in fish is determined by its combined use with the potentiator trimethoprim. 

Apart from the pathophysiological condition of the animal, the mode of drug application may also significantly influence the pharmacokinetic profile of a drug (48, 49). For example, drug residues may persist at the injection site for prolonged periods of time (2). In a study in which various sulfonamides and trimethoprim were injected intramuscularly into swine, detectable residues were found at most sites 6 days after the injection, and with the sulfonamides at 30 days in almost half of the animals (50). Other drugs such as dihydrostreptomycin persist for up to 60 days, while positive residues of chloramphenicol are found at 7 days postinjection. Sodium and procaine penicillin, neomycin, tylosin, and oxytetracycline residues have also been determined at 24 h or more postinjection (51). 

The sulfonamide antibiotics were the first synthetic antibiotics to have general utility in human therapy (B-79MI10806). Of the numerous compounds thus developed, comparatively few are presently used in veterinary practice. They include sulfapyridine (40), sulfamethazine (41) and sulfadimethoxine (42). They are much less potent than the /3-lactams (dose 100-200 mg kg-1), and have a bacteriostatic effect. They are commonly used in combination with trimethoprim (43), when a synergistic effect is observed, i.e. the combination is more potent than either drug alone, and species of bacteria which are unaffected by the drugs individually are susceptible to the combination. 

FIGURE 33-2 Folic acid metabolism in bacterial cells. Certain antibacterial drugs [e.g., sulfonamides and trimethoprim] inhibit the dihydrofolate synthetase and reductase enzymes, thus interfering with DNA biosynthesis. 

Trimethoprim [trye METH oh prim], a potent inhibitor of bacterial dihydrofolate reductase3, exhibits an antibacterial spectrum similar to the sulfonamides. However, trimethoprim is most often compounded with sulfamethoxazole. 

The frequency and severity of the adverse effects of sulfonamides correspond to those seen with other antibacterial agents (2-5%). Dose-related effects, which tend to be more troublesome than serious, include gastrointestinal symptoms, headache, and drowsiness. Crystalluria can occur, but urinary obstruction is rare. Hematological adverse effects due to folic acid antagonism occur primarily in combination with trimethoprim. Hemolytic anemia occurs in patients with enzyme deficiencies and abnormal hemoglobins. Hypersensitivity... 

Neurological disturbances that have been attributed to sulfonamides include polyneuritis, neuritis, and optic neuritis (29,30). Tremor and ataxia have been described with co-trimoxazole (31,32). Aseptic meningitis can be separately caused by sulfonamides and trimethoprim. The occurrence of meningitis has been verified in most patients, with recurrence on re-exposure (33-42). 

Trimethoprim is a 2,4-diamino-5-(3, 4, 5 -trimethoxy-benzyl) pyrimidine that inhibits dihydrofolate reductase, the enzyme in folate synthesis after the step that is blocked by sulfonamides (1). Trimethoprim therefore inhibits the conversion of dihydrofolate to tetrahydrofo-late. It has been combined with sulfonamides, including sulfamethoxazole, sulfametrol, sulfadiazine, sulfamoxole, and sulfadimidine (2,3). 

Severe adverse drug reactions with trimethoprim and co-trimoxazole are rare (12-14). This also applies to children (15). The adverse effects of co-trimoxazole correspond to those expected from a sulfonamide (16). In HIV-infected patients, adverse effects of co-trimox-azole are more frequent and more severe (17-19). Hematological disturbances due to co-trimoxazole include mild anemia, leukopenia, and thrombocytopenia, which may be due to folic acid antagonism. Serious metabolic disturbances that are associated with trimethoprim include hyperkalemia and metabolic acidosis. Trimethoprim can cause hypersensitivity reactions. However, with co-trimoxazole, the sulfonamide is generally believed to be more allergenic (12). Generalized skin reactions predominate. Other effects, such as anaphylactic shock, are extremely rare (20-22). Carcinogenicity due to trimethoprim or co-trimoxazole has not been reported. 

Most hematological adverse effects associated with trimethoprim have been reported with co-trimoxazole. These include macrocytic and megaloblastic anemia, aplastic anemia, neutropenia, hypersegmentation of leukocytes, thrombocytopenia, and pancytopenia (12,61-63,75-79). Sulfonamides alone have not been associated with folate deficiency, but in combination with trimethoprim they can deplete folate stores in patients with preexisting deficiency of folate or vitamin B12 (80). Treatment with co-trimoxazole can impair the function of mobilized autologous peripheral blood stem cells (81). 

The skin reactions observed with co-trimoxazole can be due to trimethoprim or to the sulfonamide. Data collected from five different centers have shown that skin rashes are less frequent with trimethoprim than with co-trimoxazole (9). 

Garg SK, Ghosh SS, Mathur VS. Comparative pharmacokinetic study of four different sulfonamides in combination with trimethoprim in human volunteers. Int J Clin Pharmacol Ther Toxicol 1986 24(l) 23-5. 

Sulfonamides are weak acids. They distribute well but relatively slowly (compared with trimethoprim), and tissue concentrations are lower than plasma concentrations. Some sulfonamides reach significant concentrations in the CSF. The highest drug concentrations are in the liver, kidneys and lungs lower levels are achieved in muscle and bone. Sulfonamides cross the placenta and some may achieve therapeutic concentrations in milk. Some are highly protein bound protein binding varies with both the species and the drug. The Vj values in horses for sulfamethazine, sulfadox-ine and sulfadiazine are 0.63, 0.39 and 0.581/kg, respectively. 

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