Indications
Trimethoprim is primarily indicated for use as a monotherapy in the treatment of acute, uncomplicated urinary tract infections (UTIs) caused by susceptible strains of bacteria, including Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Proteus mirabilis, and coagulase-negative Staphylococcus species. Additionally, in combination with sulfamethoxazole, trimethoprim is indicated for a broader range of infections, such as urinary tract infections, acute otitis media in pediatric patients, acute exacerbations of chronic bronchitis in adults, enteritis due to Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and traveler's diarrhea caused by enterotoxigenic Escherichia coli. Furthermore, an ophthalmic solution containing trimethoprim and polymyxin B is available for the treatment of bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria.
Pharmacodynamics
Trimethoprim functions as an antimicrobial agent by inhibiting a crucial step in the bacterial synthesis of nucleic acids and proteins. It demonstrates efficacy against a variety of gram-negative bacteria as well as coagulase-negative Staphylococcus species. However, bacterial resistance to trimethoprim can develop through several mechanisms, such as modifications of the bacterial cell wall, overproduction, or modification of dihydrofolate reductase. Occasionally, the administration of trimethoprim can lead to blood disorders, including thrombocytopenia and leukopenia, possibly preceded by symptoms like sore throat, fever, pallor, or purpura. Consequently, patient monitoring throughout therapy is essential. Given the variability in antimicrobial susceptibility patterns, local antibiograms should be consulted to ensure effective coverage of relevant pathogens prior to treatment initiation.
Absorption
Steady-state concentrations of trimethoprim are achieved approximately three days after repeated administration. Following a single 100 mg oral dose, the average peak serum concentration is about 1 µg/mL and occurs within 1 to 4 hours. Trimethoprim displays first-order pharmacokinetics, evidenced by the doubling of serum concentrations with a 200 mg dose compared to a 100 mg dose. The area under the curve (AUC) for orally administered trimethoprim at steady state is approximately 30 mg/L·h.
Metabolism
Trimethoprim undergoes oxidative metabolism, predominantly forming demethylated metabolites, with the 3'- and 4'-derivatives comprising approximately 65% and 25% of total metabolites, respectively. Minor metabolic products include N-oxide and benzylic metabolites, with the latter present in smaller amounts. The parent drug remains the primary active therapeutic form. The metabolism of trimethoprim involves several cytochrome P450 enzymes, chiefly CYP2C9 and CYP3A4, with a smaller contribution from CYP1A2.
Mechanism of Action
Trimethoprim functions as a reversible inhibitor of dihydrofolate reductase, a crucial enzyme responsible for the conversion of dihydrofolic acid to tetrahydrofolic acid. Tetrahydrofolic acid is essential for the synthesis of bacterial nucleic acids and proteins, which are vital for bacterial survival. By disrupting this pathway, trimethoprim exhibits bactericidal activity. The compound demonstrates a higher affinity for bacterial dihydrofolate reductase compared to its mammalian counterpart, thus selectively targeting bacterial biosynthetic mechanisms. Trimethoprim is frequently administered in conjunction with sulfamethoxazole, which blocks the previous step in bacterial protein synthesis. This combination effectively inhibits two consecutive steps in the biosynthesis pathway, enhancing the antibacterial efficacy. While trimethoprim alone is considered bacteriostatic, its combination with sulfamethoxazole is recognized for its bactericidal properties.
