Action And Clinical Pharmacology: Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the enzyme dihydrofolate reductase. This binding is very much stronger for the bacterial enzyme than for the corresponding mammalian enzyme; thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins by causing a deficiency of endogenously produced thymine. The effect is usually bactericidal in the absence of an adequate external supply of thymine or thymidine.
Trimethoprim is rapidly absorbed following oral administration. Peak blood levels occur 1 to 4 hours after oral administration. The half-life is 8 to 10 hours. Trimethoprim blood levels are dose and time dependent.
A single oral dose of 100 mg produced serum trimethoprim levels ranging from 0.42 to 1.68 µg/mL at 2 hours and 0.32 to 1.55 µg/mL at 4 hours after dosing. Single 200 mg doses of trimethoprim produced serum levels approximately twice as high: ranging from 1.87 to 3.11 µg/mL at 2 hours and 1.57 to 2.58 µg/mL at 4 hours after dosing. Table I gives the mean serum concentrations as a function of time for both of these doses.
Trimethoprim exists in the blood as free, protein bound and metabolized forms. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim is protein bound in the blood.
Excretion is chiefly by the kidneys through glomerular filtration and tubular secretion. Urine concentrations are considerably higher than are concentrations in the blood. Approximately 85% of the excreted drug is in its unmetabolized form.
Urine levels are time and dose related. After a single 100 mg oral dose, urinary trimethoprim levels ranged from 30 to 160 Âµg/mL during the 0 to 4 hour collection period and declined to 18 to 91 Âµg/mL during the 8 to 24 hour collection period. 50% to 60% of trimethoprim was excreted in the urine within 24 hours. Single doses of 200 mg produced urinary trimethoprim levels approximately twice as high. In one study, urinary concentrations ranged from 74 to 394 Âµg/mL for the 0 to 4 hour collection period and in a second study from 71 to 91 Âµg/mL for a 0 to 12 hour collection period. These levels are well above the MIC’s required to be effective against the majority of urinary pathogens.
Concentrations of trimethoprim in prostatic and vaginal secretions are consistently greater than those found in the serum. Oral administration of 5 to 8.1 mg/kg for 1 to 2 days produced trimethoprim levels of 1.9 to 5.6 Âµg/mg in prostatic tissue, and levels of 2.5 to 5.6 µg/mL in prostatic secretions. Administration of 320 mg/day of trimethoprim in combination with sulfamethoxazole for 10 days produced levels of 2.5 to 10 µg/mL in vaginal secretions.
Sufficient trimethoprim is excreted in the feces to eliminate susceptible organisms from the fecal flora. The dominant fecal organisms, Bacteroides and Lactobacillus are not susceptible to trimethoprim; trimethoprim does not cause intestinal upset due to imbalance in the normal colonic flora.
Emergence of resistant strains of fecal bacteria has not been a problem, thus preventing urogenital superinfection by such organisms from the gut.
Trimethoprim should be given with caution to patients with possible folate deficiency. Trimethoprim in vivo and in vitro, in concentrations achieved in plasma by standard dosages, caused no disturbances of folate metabolism in human bone marrow. Folates may be administered concomitantly without interfering with the antibacterial action of trimethoprim except in Enterococci infections.
Indications And Clinical Uses: For treatment of acute, uncomplicated urinary tract infections due to susceptible strains of E. coli and K. pneumoniae. Limited clinical experience suggests the probability of therapeutic response in infections due to susceptible strains of P. mirabilis and Enterobacter.
Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to trimethoprim. Therapy may be initiated prior to obtaining the results of these tests.
For infections associated with urinary tract complications such as obstruction, or where tissue involvement is suspected, the combination of trimethoprim/sulfamethoxazole has been shown to be superior to trimethoprim alone.
Contra-Indications: Hypersensitivity to trimethoprim. Individuals with documented megaloblastic anemia due to folate deficiency.
Pregnancy and Lactation: During pregnancy and during the nursing period.
Manufacturers’ Warnings In Clinical States: Rare incidents of serious hypersensitivity reactions has been reported on trimethoprim therapy. In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
Rare incidents of trimethoprim interfering with hematopoiesis have been reported, especially when administered in large doses and/or for prolonged periods.
The presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice may be early indications of serious blood disorders. Complete blood counts should be obtained if any of these signs are noted in a patient receiving trimethoprim and the drug discontinued if a significant reduction in the count of any formed blood element is found.
Precautions: Trimethoprim should be given with caution to patients with possible folate deficiency. Folates may be administered concomitantly without interfering with the antibacterial action of trimethoprim, except in Enterococci infections.
An increased incidence of skin rashes has been observed when double the recommended dosage was administered.
General: Children: The safety of trimethoprim in infants under 2 months of age has not been demonstrated. The effectiveness of trimethoprim as a single agent has not been established in children under 12 years of age.
Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.
Impaired Renal or Hepatic Function: Trimethoprim should also be given with caution to patients with impaired renal or hepatic function (see Pharmacology and Dosage).
Drug Interactions: Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage increased the phenytoin half-life and decreased the phenytoin metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anemia should cotrimoxazole be prescribed concurrently. The same interaction is likely if trimethoprim be prescribed concurrently.
Trimethoprim may potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism.
Laboratory Test Interactions : Trimethoprim can interfere with a serum methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial dihydrofolate reductase is used as the binding protein. No interference occurs, however, if methotrexate is measured by a radioimmunoassay (RIA).
The presence of trimethoprim may also interfere with the JaffÃ© alkaline picrate reaction assay for creatinine resulting in overestimations of about 10% in the range of normal values.
Adverse Reactions: Hematologic: neutropenia, anemia (megaloblastic, hemolytic, aplastic), leukopenia, thrombocytopenia, methemoglobinemia.
Dermatologic: rash, pruritus and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg once daily each for 10 days, the incidence of rash is 2.9 to 6.7%. In clinical studies which employed high doses of trimethoprim, an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic and generally mild to moderate appearing 7 to 14 days after the initiation of therapy.
Hypersensitivity: Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, Lyell syndrome and anaphylaxis have been reported.
Gastrointestinal: nausea, vomiting, abdominal cramps, glossitis, stomatitis. There have been rare reports of cholestatic jaundice. Elevations of serum transaminase and bilirubin have been noted, but the significance of this finding is unknown.
Metabolic: hyperkalemia, hyponatremia.
Neurologic: Aseptic meningitis has rarely been reported.
Others: headache, joint pain, apathy, fatigue, muscle weakness, nervousness, fever and increases in BUN and serum creatinine levels.
The following adverse reactions have not been reported in patients receiving trimethoprim; however, based upon clinical experience with chemically related drugs, the possibility of these reactions occurring should be recognized.
CNS: convulsions, ataxia, tinnitus and vertigo.
Symptoms And Treatment Of Overdose: Symptoms: Acute: Signs of acute overdosage with trimethoprim may appear following ingestion of 1 g or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronic).
Treatment: Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of trimethoprim. Peritoneal dialysis is not effective and hemodialysis only moderately effective in eliminating the drug.
Chronic: Use of trimethoprim in high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, trimethoprim should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.
Dosage And Administration: Adults: 100 mg every 12 hours or 200 mg every 24 hours, each for 10 days.
The use of trimethoprim in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.
Availability And Storage: 100 mg: Each white, biconvex tablet imprinted with PROLOPRIM 09A on the same side as score mark, contains: trimethoprim 100 mg. Nonmedicinal ingredients: lactose, sodium starch glycolate (potato), cornstarch and magnesium stearate. Bottles of 100 and 500.
200 mg: Each yellow, round, biconvex tablet imprinted with PROLOPRIM R2C on the same side as score mark, contains: trimethoprim 200 mg. Nonmedicinal ingredients: sodium starch glycolate (potato), cornstarch, magnesium stearate and quinoline yellow WS. Bottles of 100.
Store at 15 to 30°C. Protect from light and keep dry.
PROLOPRIM® Glaxo Wellcome Trimethoprim Antibacterial