indication

For the treatment of urinary tract infections, uncomplicated pyelonephritis (with sulfamethoxazole) and mild acute prostatitis. May be used as pericoital (with sulfamethoxazole) or continuous prophylaxis in females with recurrent cystitis. May be used as an alternative to treat asymptomatic bacteriuria during pregnancy (only before the last 6 weeks of pregnancy). Other uses include: alternative agent in respiratory tract infections (otitis, sinusitus, bronchitis and pneumonia), treatment of Pneumocystis jirovecii pneumonia (acute or prophylaxis), Nocardia infections, and traveller's diarrhea.

pharmacology

Trimethoprim is a pyrimidine analogue that disrupts folate synthesis, an essential part of the thymidine synthesis pathway. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication.The drug, therefore, exhibits bactericidal activity.

mechanism of action

Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydrofolate synthetase (aka dihydropteroate synthetase), an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to their synergistic effects. This drug combination also reduces the development of resistance that is seen when either drug is used alone.

toxicity

LD₅₀=4850 (orally in mice)

biotransformation

Hepatic metabolism to oxide and hydroxylated metabolites.

absorption

Readily and almost completely absorbed in the GI tract with peak serum concentrations attained 1-4 hours after oral administration. Widely distributed to tissues and fluids including kidney, lung, seminal fluid, aqueous humour, middle ear fluid, sputum, vaginal secretions, bile, bone and CSF.

half life

8-11 hours in adults with normal renal function

route of elimination

Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim. Trimethoprim also passes the placental barrier and is excreted in human milk.

drug interactions

Capecitabine: The strong CYP2C9 inhibitor, Capecitabine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Capecitabine is initiated, discontinued or dose changed.

Dapsone: Increased toxicity of both products

Delavirdine: The strong CYP2C9 inhibitor, Delavirdine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Delavirdine is initiated, discontinued or dose changed.

Dofetilide: Trimethoprim may significantly reduced the clearance of Dofetilide. Trimethoprim is a cation transport inhibitor and may interfere with renal excretion of Dofetilide. Concomitant use is contraindicated.

Floxuridine: The strong CYP2C9 inhibitor, Floxuridine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Floxuridine is initiated, discontinued or dose changed.

Fluconazole: The strong CYP2C9 inhibitor, Fluconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluconazole is initiated, discontinued or dose changed.

Fluorouracil: The strong CYP2C9 inhibitor, Fluorouracil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Fluorouracil is initiated, discontinued or dose changed.

Flurbiprofen: The strong CYP2C9 inhibitor, Flurbiprofen, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Flurbiprofen is initiated, discontinued or dose changed.

Fosphenytoin: Trimethoprim increases the effect of hydantoin

Gemfibrozil: The strong CYP2C9 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Gemfibrozil is initiated, discontinued or dose changed.

Ibuprofen: The strong CYP2C9 inhibitor, Ibuprofen, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ibuprofen is initiated, discontinued or dose changed.

Indomethacin: The strong CYP2C9 inhibitor, Indomethacine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Indomethacine is initiated, discontinued or dose changed.

Ketoconazole: The strong CYP2C9 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ketoconazole is initiated, discontinued or dose changed.

Leucovorin: The efficacy of Trimethoprim may be reduced by Leucovorin (folinic acid). The antibiotic, Trimethoprim, acts by blocking bacterial folic acid metabolism. Leucovorin may reduce the efficacy of Trimethoprim by providing an alternate source of folic acid. The therapeutic effect of Trimethoprim should be closely monitored.

Mefenamic acid: The strong CYP2C9 inhibitor, Mefenamic acid, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Mefenamic acid is initiated, discontinued or dose changed.

Methotrexate: Trimethoprim may increase the adverse/toxic effects of Methotrexate (e.g. bone marrow suppression). Concomitant use should be avoided or closely monitored for Methotrexate toxicity.

Miconazole: The strong CYP2C9 inhibitor, Miconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Miconazole is initiated, discontinued or dose changed.

Nicardipine: The strong CYP2C9 inhibitor, Nicardipine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Nicardipine is initiated, discontinued or dose changed.

Phenytoin: Trimethoprim increases the effect of hydantoin

Piroxicam: The strong CYP2C9 inhibitor, Piroxicam, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Piroxicam is initiated, discontinued or dose changed.

Procainamide: Trimethoprim may reduce the clearance of Procainamide. Alternative treatments should be considered. If Trimethoprim is initiated or the dose is increased, monitor for increased toxicity of Procainamide (e.g. QTc intervals, EKG, serum drug concentrations). If Trimethoprim is discontinued or the dose decreased, monitor for reduced effects of Procainamide.

Rifampin: Rifampin decreases the effect of trimethoprim

Sitaxentan: The strong CYP2C9 inhibitor, Sitaxsentan, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sitaxsentan is initiated, discontinued or dose changed.

Sulfadiazine: The strong CYP2C9 inhibitor, Sulfadiazine, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sulfadiazine is initiated, discontinued or dose changed.

Sulfisoxazole: The strong CYP2C9 inhibitor, Sulfisoxazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Sulfisoxazole is initiated, discontinued or dose changed.

Tobramycin: Increased risk of nephrotoxicity

Tolbutamide: The strong CYP2C9 inhibitor, Tolbutamide, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Tolbutamide is initiated, discontinued or dose changed.

Trandolapril: Increased risk of hyperkalemia. Monitor serum potassium levels.

Tretinoin: The moderate CYP2C8 inhibitor, Trimethoprim, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Trimethoprim is initiated, discontinued to dose changed.