Professional Information — Trimethoprim

Indications and Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of trimethoprim tablets, USP and other antibacterial drugs, trimethoprim tablets, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.

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.

Dosage and Administration

The usual oral adult dosage is 100 mg of trimethoprim every 12 hours or 200 mg of trimethoprim 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 a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.

Contraindications

Trimethoprim is contraindicated in individuals hypersensitive to trimethoprim and in those with documented megaloblastic anemia due to folate deficiency.

Adverse Reactions

The adverse effects encountered most often with trimethoprim were rash and pruritus.

Dermatologic

Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., 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, toxic epidermal necrolysis (Lyell Syndrome), and anaphylaxis have been received.

Gastrointestinal

Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.

Hematologic

Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.

Metabolic

Hyperkalemia, hyponatremia.

Neurologic

Aseptic meningitis has been rarely reported.

Miscellaneous

Fever, and increases in BUN and serum creatinine levels.

Drug Interactions

Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Overdosage

Acute

Signs of acute overdosage with trimethoprim may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronic subsection).

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 at 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.

Description

Trimethoprim is a synthetic antibacterial available in tablet form for oral administration. Each scored white tablet contains 100 mg trimethoprim.

Trimethoprim is 5-[(3,4,5-trimethoxyphenyl)methyl]-2,4-pyrimidinediamine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.32 and the molecular formula C₁₄H₁₈N₄O₃. The structural formula is:

Inactive Ingredients

Colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, and purified water.

Clinical Pharmacology

Trimethoprim is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound, and metabolized forms. Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free form is considered to be the therapeutically active form. Approximately 44% of trimethoprim is bound to plasma proteins.

Mean peak serum concentrations of approximately 1.0 mcg/mL occur 1 to 4 hours after oral administration of a single 100 mg dose. A single 200 mg dose will result in serum levels approximately twice as high. The half-life of trimethoprim ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim, which requires either dosage regimen adjustment or not using the drug in such patients (see DOSAGE AND ADMINISTRATION). During a 13 week study of trimethoprim administered at a daily dosage of 200 mg (50 mg q.i.d.), the mean minimum steady-state concentration of the drug was 1.1 mcg/mL.

Steady-state concentrations were achieved within 2 to 3 days of chronic administration and were maintained throughout the experimental period.

Excretion of trimethoprim is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim are considerably higher than are the concentrations in the blood. After a single oral dose of 100 mg, urine concentrations of trimethoprim ranged from 30 to 160 mcg/mL during the 0 to 4 hour period and declined to approximately 18 to 91 mcg/mL during the 8 to 24 hour period. A 200 mg single oral dose will result in trimethoprim urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim.

Since normal vaginal and fecal flora are the source of most pathogens causing urinary tract infections, it is relevant to consider the distribution of trimethoprim into these sites. Concentrations of trimethoprim in vaginal secretions are consistently greater than those found simultaneously in the serum, being typically 1.6 times the concentrations of simultaneously obtained serum samples. Sufficient trimethoprim is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.

Trimethoprim also passes the placental barrier and is excreted in human milk.

Microbiology

Mechanism of Action

Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required 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.

Resistance

Resistance to trimethoprim may be conferred by a variety of mechanisms including cell wall impermeability, overproduction of the chromosomal dihydrofolate reductase (DHFR) enzyme, production of a resistant chromosomal DHFR enzyme or production of a plasmid-mediated trimethoprim-resistant DHFR enzyme. Acinetobacter baumannii/Acinetobacter calcoaceticus complex, Burkholderia cepacia complex, Pseudomonas aeruginosa, Stenotrophomonas maltophilia are intrinsically resistant to trimethoprim. Non-Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp. are not susceptible to trimethoprim at the concentrations obtained with the recommended dosage. Enterococcus spp, (E. faecalis, E. faecium, E. gallinarum/E. casseliflavus) may appear active in vitro to trimethoprim but are not effective clinically and should not be reported as susceptible. Moraxella catarrhalis isolates were found consistently resistant to trimethoprim.

Antimicrobial Activity

Trimethoprim has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive bacteria

Staphylococcus species (coagulase-negative strains, including S. saprophyticus)

Aerobic gram-negative bacteria

Enterobacter species

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

How Supplied / Storage and Handling

Trimethoprim tablets, USP, 100 mg:

White, round, convex tablet, debossed "N", bisect, "L" on one side and debossed "330" on the other, in bottles of 100.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required).

Patient Counseling Information

Patients should be counseled that antibacterial drugs including trimethoprim tablets, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When trimethoprim tablets, USP are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by trimethoprim tablets, USP or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with and without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.