SULFAMETHOXAZOLE AND TRIMETHOPRIM- sulfamethoxazole and trimethoprim tablet
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.
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 -(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C H N O S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula: N 1 10 11 3 3
Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C H N O . It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula: 14 18 4 3
Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch. Inactive ingredients:
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 N -acetyl-, N -hydroxy-, 5-methylhydroxy-, N -acetyl- 5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formulation of N -hydroxy metabolite is mediated CYP2C9. 4 4 4 4 via
Trimethoprim is metabolized 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. in vitro
The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms.
studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein. In vitro
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 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 µg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achieved after three days of drug administration. 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 N -acetylated metabolite. When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. DOSAGE AND ADMINISTRATION1 4 2
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-US 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
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.
studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. In vitro
Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both and in clinical infections as described in the section. in vitro INDICATIONS AND USAGE
Aerobic gram-positive microorganisms:
(including susceptible enterotoxigenic strains implicated in traveler’s diarrhea) species species
Aerobic gram-negative microorganisms:
Susceptibility Testing Methods
When available, the clinical microbiology laboratory should provide the results of 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. in vitro
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) . The MIC values should be interpreted according to the criteria provided in Table 1. 4,15
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 method . This procedure uses paper disks impregnated with 1.25/23.75 µg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim/sulfamethoxazole. The disc diffusion interpretive criteria are provided in Table 1. 14,15
|Bacteria||Minimal Inhibitory Concentration (mcg/mL)
||Zone Diameter (mm)
|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 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 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 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. Susceptible Intermediate Resistant
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