CLINICAL PHARMACOLOGY
Tablets and Suspensions
Sulfamethoxazole; 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. The metabolism
of sulfamethoxazole occurs predominately by N4-acetylation, although
the glucuronide conjugate has been identified. The principal metabolites
of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy
derivatives. The free forms of sulfamethoxazole; trimethoprim are
considered to be the therapeutically active forms. Approximately
44% of trimethoprim and 70% of sulfamethoxazole 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; 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). Detectable amounts
of sulfamethoxazole; trimethoprim are present in the blood 24 hours
after drug administration. During administration of 160 mg trimethoprim
and 800 mg sulfamethoxazole bid, 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 68.0 mcg/ml,
respectively. These steady-state levels were achieved after 3 days
of drug administration.1
The average percentage of the dose recovered in urine
from 0 to 72 hours after a single oral dose of sulfamethoxazole;
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; trimethoprim, neither sulfamethoxazole
nor trimethoprim affects the urinary excretion pattern of the other.
Tablets, Suspensions, and IV Infusion
Excretion of sulfamethoxazole; trimethoprim is primarily
by the kidneys through both glomerular filtration and tubular secretion.
Urine concentrations of both sulfamethoxazole; trimethoprim are
considerably higher than are the concentrations in the blood.
Both trimethoprim and sulfamethoxazole distribute
to sputum, vaginal fluid and middle ear fluid (for tablets and suspensions
only); trimethoprim also distributes to bronchial secretion, and
both pass the placental barrier and are excreted in breast milk.
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; 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 sulfamethoxazole; trimethoprim than with
either trimethoprim or sulfamethoxazole alone.
In vitro serial dilution tests have shown that the
spectrum of antibacterial activity of sulfamethoxazole; trimethoprim
includes the common urinary tract pathogens with the exception of
Pseudomonas aeruginosa. The following organisms are usually susceptible:
Escherichia coli, Klebsiella species, Enterobacter species, Morganella
morganii, Proteus mirabilis, and indole-positive Proteus species
including Proteus vulgaris. Additional Information for Oral: The
usual spectrum of antimicrobial activity of sulfamethoxazole; trimethoprim
includes the following bacterial pathogens isolated from middle
ear exudate and from bronchial secretions: Haemophilus influenzae,
including ampicillin-resistant strains, and Streptococcus pneumoniae,
and enterotoxigenic strains of Escherichia coli (ETEC) causing bacterial
gastroenteritis. Shigella flexneri and Shigella sonnei are also
usually suceptible.
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