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 plasma 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.
Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. This binding is much stronger for the bacterial enzyme than for the corresponding mammalian enzyme. Thus, trimethoprim selectively interferes with bacterial biosynthesis of nucleic acids and proteins.
In vitro serial dilution tests have shown that the spectrum of antibacterial activity of trimethoprim includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa.
The dominant non- Enterobacteriaceae fecal organisms, Bacteroides spp. and Lactobacillus spp., are not susceptible to trimethoprim concentrations obtained with the recommended dosage.
REPRESENTATIVE MINIMUM INHIBITORY CONCENTRATIONS FOR TRIMETHOPRIM-SUSCEPTIBLE ORGANISMS
| Bacteria || Trimethoprim |
| MIC mcg/mL (Range) |
| Escherichia coli ||0.05-1.5|
| Proteus mirabilis ||0.5-1.5|
| Klebsiella pneumoniae ||0.5-5.0|
| Enterobacter species||0.5-5.0|
| Staphylococcus species,||0.15-5.0|
Susceptibility Tests: Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trimethoprim powder. The MIC values should be interpreted according to the following criteria:
| MIC (mcg/mL) || Interpretation |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard trimethoprim powder should provide the following MIC values:
| Microorganism || MIC (mcg/mL) |
| S. aureus ATCC 29213||1-4|
| E. faecalis ATCC 29212||≤1|
| E. coli ATCC 25922||0.5-2|
| P. aeruginosa ATCC 27853||>64|
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5 mcg trimethoprim to test the susceptibility of microorganisms to trimethoprim.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg trimethoprim disk should be interpreted according to the following criteria:
| Zone Diameter (mm) || Interpretation |
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for trimethoprim.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg trimethoprim disk should provide the following zone diameters in these laboratory test quality control strains.
| Microorganism || Zone Diameter (mm) |
| E. coli ATCC 25922||21 - 28 mm|
| S. aureus ATCC 25923||19 - 26 mm|