Sulfamethoxazole and Trimethoprim

SULFAMETHOXAZOLE AND TRIMETHOPRIM — sulfamethoxazole and trimethoprim tablet
LUCID PHARMA LLC

To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, sulfamethoxazole and trimethoprim tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Sulfamethoxazole and trimethoprim is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimethoprim for oral administration.Sulfamethoxazole is N 1 -(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C10 H11 N3 O3 S. It is a white to off-white, practically odorless, crystalline powder, tasteless compound with a molecular weight of 253.28 and the following structural formula:

Sulfamethoxazole Chemical Structure
(click image for full-size original)

Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C14 H18 N4 O3 . It is a white or cream-colored crystals or crystalline powder with a molecular weight of 290.3 and the following structural formula:
Trimethoprim Chemical Structure
Inactive Ingredients: Docusate sodium, magnesium stearate, pregelatinized starch (maize), sodium benzoate, and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Sulfamethoxazole and trimethoprim is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4 -acetyl-, N4 -hydroxy-, 5-methylhydroxy-, N4 -acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formulation of N4 -hydroxy metabolite is mediated via CYP2C9.
Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4-hydroxy derivatives.
The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms.

In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.
Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.
Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68 mcg/mL, respectively. These steady-state levels were achieved after three days of drug administration.1 Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N4 -acetylated metabolite.2 When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk.

Geriatric Pharmacokinetics

The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-U.S. approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.3

Microbiology

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.
In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.
Sulfamethoxazole and trimethoprim have 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
Streptococcus pneumoniae
Aerobic gram-negative microorganisms
Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler’s diarrhea)
Klebsiella species
Enterobacter species
Haemophilus influenzae
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Shigella flexneri
Shigella sonnei
Other Organisms

Pneumocystis jiroveci

Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
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 test method (broth or agar)4, 15. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method14, 15. This procedure uses paper disks impregnated with 1.25/23.75 mcg of trimethoprim and sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim and sulfamethoxazole. The disc diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Trimethoprim and Sulfamethoxazole
Bacteria Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
S I R S I R
Enterobacteriaceae ≤ 2/38 - ≥ 4/76 ≥ 16 11 – 15 ≤ 10
Haemophilus influenzae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 16 11 – 15 ≤ 10
Streptococcus pneumoniae ≤ 0.5/9.5 1/19 – 2/38 ≥ 4/76 ≥ 19 16 – 18 ≤ 15

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test4, 14, 15. Standard trimethoprim and sulfamethoxazole powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 1.25/23.75 mcg trimethoprim and sulfamethoxazole disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Susceptibility Testing for Trimethoprim and Sulfamethoxazole
QC Strain Minimal Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
Escherichia coli ATCC 25922 ≤ 0.5/9.5 23–29
Haemophilus influenzae ATCC 49247 0.03/0.59 – 0.25/4.75 24–32
Streptococcus pneumoniae ATCC 49619 0.12/2.4 – 1/19 20–28

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