Trimethoprim

TRIMETHOPRIM- trimethoprim tablet
Actavis Pharma, Inc.

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 bacteria.

DESCRIPTION

Trimethoprim is a synthetic antibacterial available as 100 mg tablets for oral administration.

Trimethoprim is 5-[(3,4,5-trimethoxyphenyl) methyl]-2,4-pyrimidinediamine. It is a white to cream colored, odorless, bitter compound. The structural formula is represented below:

Trimethoprim Structural Formula

C14 H18 N4 O3       M.W. 290.32

Trimethoprim tablets, USP, 100 mg contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, sodium starch glycolate and stearic acid.

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 3ʹ- and 4ʹ-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 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 DOSAGEAND 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. Steadystate 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

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.

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 microorganisms

Staphylococcus species (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 minimum 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 method1,7 (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:

For testing Enterobacteriaceae 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 trimethoprima powder should provide the following MIC values:

Microorganism

MIC (mcg/mL)

Escherichia coli

ATCC 25922

0.5 to 2

Staphylococcus aureus

ATCC 29213

1 to 4

a Very 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 procedure2,7 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:

For testing Enterobacteriaceae and Staphylococcus spp.:

Zone Diameter
(mm)

Interpretation
MIC
(mcg/mL)
≥16 Susceptible (S) ≤ 4
11 to 15 Intermediate (I) -
≤10 Resistant (R) ≥ 16

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 of trimethoprim.

As with standardized dilution techniques, diffusion methods require the use of the laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5 mcg trimethoprim diskb should provide the following zone diameters in these laboratory test quality control strains:

Microorganism

Zone Diameter (mm)

Escherichia coli

ATCC 25922

21 to 28

Staphylococcus aureus

ATCC 25923

19 to 26

b Mueller-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/ sulfamethoxazole disks. A zone of inhibition ≥ 20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

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