SUPRIM 480

Indications

• Urinary tract infections
• Lower respiratory tract infections
• Skin and soft tissue infections
• Gonorrhea

Mechanism of action

Co-trimoxazole inhibits the bacterial synthesis of tetrahydrofolic acid, a vital cofactor for the synthesis of purines, thymidine, glycine, and methionine. Sulfamethoxazole, a sulfonamide, blocks the synthesis of dihydropteroic acid from para-aminobenzoic acid, which is a precursor to dihydrofolic acid. Trimethoprim further inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid by blocking the enzyme dihydrofolate reductase. This dual action leads to an effective blockade of thymidine synthesis, essential for bacterial growth.

Pharmacodynamics

Co-trimoxazole demonstrates bactericidal activity against susceptible bacteria. The combination of sulfamethoxazole and trimethoprim allows for lower doses of each drug compared to their individual use, thereby reducing potential side effects. The drug's efficacy is influenced by the ratio of the two components, which is optimized to be 20:1 (sulfamethoxazole to trimethoprim) for maximal antibacterial effect. Resistance can develop, limiting its effectiveness, particularly against certain bacterial strains.

Pharmacokinetics

Co-trimoxazole is well absorbed after oral administration, with peak plasma concentrations occurring within 1 to 4 hours. It is distributed widely in body tissues and fluids, including the lungs, urine, and bile. The half-life of sulfamethoxazole is approximately 10 hours, while trimethoprim has a half-life of about 8 to 10 hours. Both components are metabolized in the liver and excreted primarily via the kidneys, necessitating dose adjustments in patients with renal impairment.

Contra-indications

• Hypersensitivity to trimethoprim, sulfamethoxazole or any component of the formulation
• Severe liver or kidney impairment
• History of megaloblastic anemia due to folate deficiency
• Pregnancy at term (risk of kernicterus)

Adverse effects

• Nausea
• Vomiting
• Rash
• Allergic reactions
• Bone marrow suppression
• Hyperkalemia
• Hepatic dysfunction

Interactions

• May enhance effects of anticoagulants like warfarin
• Concurrent use with methotrexate may increase toxicity
• May increase levels of phenytoin and other antiepileptics
• Non-steroidal anti-inflammatory drugs may increase risk of renal toxicity

Precautions

• Caution in patients with renal impairment
• Monitor for signs of blood dyscrasias
• Use with caution in patients with a history of asthma or allergies
• Discontinue immediately if a rash or other symptoms of hypersensitivity develop
• Adequate hydration is recommended to prevent crystalluria

Pregnancy

Co-trimoxazole should be avoided during pregnancy, especially during the third trimester due to the risk of kernicterus in the newborn.

Breast-feeding

Trimethoprim and sulfamethoxazole are excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets (400 mg sulfamethoxazole and 80 mg trimethoprim)
• Oral suspension (480 mg co-trimoxazole per 5 ml)
• Intravenous infusion (various dosages)

Mechanism of action

Trimethoprim/sulfamethoxazole ... inhibits sequential steps in the synthesis of tetrahydrofolic acid, an essential metabolic cofactor in the bacterial synthesis of purines, thymidine, glycine, and methionine. Sulfonamides, including sulfamethoxazole, are structural analogues of para-aminobenzoic acid and block the synthesis of dihydropteroic acid, the immediate precursor of dihydrofolic acid, from para-aminobenzoic acid and peridine. Trimethoprim subsequently acts to inhibit the reduction of dihydrofolic acid to the metabolically active tetrahydrofolic acid by the enzyme, dihydrofolate reductase. The most important consequence of this sequential enzymatic inhibition appears to be the interruption of thymidine synthesis. The synergistic interaction between sulfonamide and trimethoprim is thus predictable from their respective mechanisms. There is an optimal ratio of the concentrations of the two agents for synergism, and this is equal to the ratio of the minimal inhibitory concentrations of the drugs acting independently. While this ratio varies for different bacteria, the most effective ratio for the greatest number of microorganisms is 20 parts of sulfamethoxazole to one part of trimethoprim. The combination is formulated to achieve a sulfamethoxazole concentration in vivo 20 times greater than that of trimethoprim. ... The pharmacokinetic properties of the sulfonamide chosen to be in combination with trimethoprim are important, since relative constancy of the concentrations of the two compounds in the body is desired. Trimethoprim/sulfamethoxazole is active in vitro against a variety of gram-negative and gram-postive bacteria. Among aerobic gram-negative enteric bacteria, Escherichia coli, Proteus mirabilis, Salmonella (including Salmonella typhi), Shigella, and Citrobacter are very susceptible. Indole-positive Proteus, Serratia marcescens, Klebsiella pneumoniae, Enterobacter, Providencia stuartii are moderately susceptible. An immunoassay was developed for the detection of sulfamethoxazole reactive IgE antibodies in the sera of patients who experienced life threatening anaphylactic reactions following the ingestion of co-trimoxazole (trimethoprim and sulfamethoxazole). Patients who had significant levels of sulfamethoxazole reactive IgE antibodies in their sera did not have IgE antibodies that reacted with trimethoprim-Sepharose. Inhibition experiments with a number of sulfonamides to determine the fine structural specificities of the sulfamethoxazole reactive IgE antibodies in three patients revealed that sulfamethoxazole and, depending on the serum, sulfamerazine and sulfamethizole, were the most potent inhibitors of IgE binding, whereas the parent sulfonamide, sulfanilamide, was a very poor inhibitor. From a detailed examination of structure-activity relationships, we concluded that the 5-methyl-3-isoxazolyl group on the sulfamethoxazole molecule was the allergenic determinant for all three patients with the 5-methyl group being particularly important for IgE antibody recognition. The assays for the detection of IgE antibodies to sulfamethoxazole and trimethoprim should prove useful for the diagnosis of immediate hypersensitivity to co-trimoxazole and perhaps for monitoring drug therapy in AIDS patients where a high incidence of adverse reactions to co-trimoxazole has been reported.