TRIMOVET

Indications

• Urinary tract infections
• Respiratory infections
• Gastrointestinal infections
• Pneumocystis jirovecii pneumonia
• Toxoplasmosis

Dosage

Adults: Refer to the BNF for specific dosing guidelines

Mechanism of action

Trimethoprim/sulfamethoxazole inhibits sequential steps in the synthesis of tetrahydrofolic acid, which is essential for bacterial synthesis of purines, thymidine, glycine, and methionine. Sulfamethoxazole, a structural analogue of para-aminobenzoic acid, blocks the synthesis of dihydropteroic acid, the precursor to dihydrofolic acid. Trimethoprim inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid by inhibiting dihydrofolate reductase. This combination disrupts thymidine synthesis and maximizes antibacterial activity through a specific concentration ratio of 20:1 of sulfamethoxazole to trimethoprim.

Pharmacodynamics

The combination of trimethoprim and sulfamethoxazole exhibits a synergistic effect that enhances its bactericidal activity. The inhibition of tetrahydrofolate synthesis leads to impaired nucleic acid synthesis and ultimately bacterial cell death. The drug combination is effective against a broad spectrum of gram-positive and gram-negative bacteria, with varying activity depending on the specific organism and its susceptibility.

Pharmacokinetics

Trimethoprim and sulfamethoxazole are well-absorbed orally and distribute widely in body tissues and fluids. They are metabolized in the liver, with trimethoprim having a half-life of approximately 8 to 10 hours and sulfamethoxazole around 10 hours. Both drugs are excreted primarily via the kidneys, with significant amounts appearing in the urine, contributing to their effectiveness in treating urinary tract infections. The pharmacokinetic properties of each component are considered in the formulation to maintain effective concentration levels.

Contra-indications

• Hypersensitivity to trimethoprim, sulfamethoxazole, or any other sulfonamide
• Severe renal impairment
• Porphyria
• Pregnancy at term

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Rash
• Itching
• Bone marrow suppression
• Hyperkalemia
• Hepatotoxicity
• Stevens-Johnson syndrome

Interactions

• Increased effect of anticoagulants
• Reduced efficacy of oral contraceptives
• Increased risk of toxicity with methotrexate
• Increased plasma concentrations of phenytoin
• Potentially increased risk of renal toxicity with cyclosporine

Precautions

• Use with caution in patients with renal or hepatic impairment
• Monitor for signs of hypersensitivity reactions
• Adequate hydration should be maintained to prevent crystalluria
• Consider alternative treatment in patients with glucose-6-phosphate dehydrogenase deficiency

Pregnancy

Trimethoprim/sulfamethoxazole should be avoided during the first trimester and near term due to potential risks to the fetus.

Breast-feeding

Trimethoprim/sulfamethoxazole is excreted in breast milk; caution is advised when administering to breastfeeding mothers.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• Oral tablets
• Oral suspension
• Injectable solution

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.