Trimethoprim

CLINICAL PHARMACOLOGY

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) is rapidly absorbed following oral administration. It exists in the blood as unbound, protein-bound and metabolized forms. Ten to twenty percent of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine. The principal metabolites of trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) is bound to plasma proteins.

Mean peak plasma concentrations of approximately 1 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 (trimethoprim (trimethoprim tablet) tablet) ranges from 8 to 10 hours. However, patients with severely impaired renal function exhibit an increase in the half-life of trimethoprim (trimethoprim (trimethoprim tablet) tablet) , 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 (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) is primarily by the kidneys through glomerular filtration and tubular secretion. Urine concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) are considerably higher than are the concentrations in the blood.

After a single oral dose of 100 mg, urine concentrations of trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) urine levels approximately twice as high. After oral administration, 50% to 60% of trimethoprim (trimethoprim (trimethoprim tablet) tablet) is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim (trimethoprim (trimethoprim tablet) tablet) .

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 (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) is excreted in the feces to markedly reduce or eliminate trimethoprim-susceptible organisms from the fecal flora.

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) also passes the placental barrier and is excreted in human milk.

Microbiology

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 (trimethoprim (trimethoprim tablet) tablet) selectively interferes with bacterial biosynthesis of nucleic acids and proteins.

In vitroserial dilution tests have shown that the spectrum of antibacterial activity of trimethoprim (trimethoprim (trimethoprim tablet) tablet) includes the common urinary tract pathogens with the exception of Pseudomonas aeruginosa.

The dominant non-Entero-bacteriaceae fecal organisms, Bacteroides spp. and Lactobacillusspp., are not susceptible to trimethoprim (trimethoprim (trimethoprim tablet) tablet) concentrations obtained with the recommended dosage.

Trimethoprim (trimethoprim (trimethoprim tablet) tablet) 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 microorganisms

Staphylococcusspecies (coagulase-negative strains, including S. saprophyticus)

Aerobic gram-negative microorganisms

Enterobacter species
Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Susceptibility Testing Methods

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 (trimethoprim (trimethoprim tablet) tablet) powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteri-aceae and Staphylococcus spp.:

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
≥ 16 Resistant (R)

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 (trimethoprim (trimethoprim tablet) tablet) a powder should provide the following MIC values:

Microorganism MIC (mcg/mL)
E. coli ATCC 25922 0.5 - 2.0
S. aureus ATCC 29213 1.0 - 4.0
aVery medium-dependent.

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 (trimethoprim (trimethoprim tablet) tablet) .

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg trimethoprim (trimethoprim (trimethoprim tablet) tablet) disk should be interpreted according to the following criteria:

For testing Enterobacteri-aceae and Staphylococcus spp.:

Zone Diameter (mm) Interpretation
≥ 16 Susceptible (S)
11-15 Intermediate (I)
≤ 10 Resistant (R)

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 (trimethoprim (trimethoprim tablet) tablet) .

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 (trimethoprim (trimethoprim tablet) tablet) diskb should provide the following zone diameters in these laboratory test quality control strains.

Microorganism MIC (mcg/mL)
E. coli ATCC 25922 0.5 - 2.0
Microorganism Zone Diameter (mm)
E. coli ATCC 25922 21 - 28
S. aureus ATCC 25923 19 - 26

bMueller-Hinton agar should be checked for excessive levels of thymidine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with trimethoprim (trimethoprim (trimethoprim tablet) tablet) /sulfamethoxazole disks. A zone of inhibition ≥ 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. 3rd ed.; Approved Standard. NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.

Last reviewed on RxList: 9/18/2008
This monograph has been modified to include the generic and brand name in many instances.

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