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.
| TABLE
1 Representative Minimum Inhibitory Concentration
Values for Organisms Susceptible to sulfamethoxazole;
trimethoprim (MIC--mcg/ml) |
| |
|
|
TMP/SMX(1:19) |
| Bacteria |
TMP alone |
SMX alone |
TMP |
SMX |
| Escherichia coli |
0.05-1.5 |
1.0-245 |
0.05-0.5 |
0.95-9.5 |
| (Tablets and Pediatric
Suspension Only) Escherichia coli (enterotoxigenic
strains) |
0.015-0.15 |
0.285->950 |
0.005-0.15 |
0.095-2.85 |
| Proteus species (indole
positive) |
0.5-5.0 |
7.35-300 |
0.05-1.5 |
0.95-28.5 |
| Morganella morganii |
0.5-5.0 |
7.35-300 |
0.05-1.5 |
0.95-28.5 |
| Proteus mirabilis |
0.5-1.5 |
7.35-30 |
0.05-0.15 |
0.95-2.85 |
| Klebsiella species |
0.15-5.0 |
2.45-245 |
0.05-1.5 |
0.95-28.5 |
| Enterobacter species |
0.15-5.0 |
2.45-245 |
0.05-1.5 |
0.95-28.5 |
| Haemophilus influenzae |
0.15-1.5 |
2.85-95 |
0.015-0.15 |
0.285-2.85 |
| Streptococcus pneumoniae |
0.15-1.5 |
7.35-24.5 |
0.05-0.15 |
0.95-2.85 |
| Shigella flexneri* |
<0.01-0.04 |
<0.16->320 |
<0.002-0.03 |
0.04-0.625 |
| Shigella sonnei* |
0.02-0.08 |
0.625->320 |
0.004-0.06 |
0.08-1.25 |
| * Rudoy
RC, Nelson JD, Haltalin KC. Antimicrobial Agents
and Chemotherapy 1974; 5:439-443. |
| TMP = trimethoprim |
| SMX=sulfamethoxazole |
Susceptibility Testing
The recommended quantitative disc susceptibility method
may be used for estimating the susceptibility of bacteria
to sulfamethoxazole; trimethoprim.3,4,8 With this procedure,
a report from the laboratory of "Susceptible to sulfamethoxazole;
trimethoprim" indicates that the infection is likely
to respond to therapy with sulfamethoxazole; trimethoprim.
If the infection is confined to the urine, a report of
"Intermediate susceptibility to sulfamethoxazole;
trimethoprim" also indicates that the infection is
likely to respond. A report of "Resistant to sulfamethoxazole;
trimethoprim" indicates that the infection is unlikely
to respond to therapy with sulfamethoxazole; trimethoprim.
IV Infusion
Following a 1-hour intravenous infusion of a single dose
of 160 mg trimethoprim and 800 mg sulfamethoxazole to
11 patients whose weight ranged from 105 lbs to 165 lbs
(mean 143 lbs), the mean peak plasma concentrations of
sulfamethoxazole; trimethoprim were 3.4 ± 0.3 mcg/ml
and 46.3 ± 2.7 mcg/ml, respectively. Following
repeated intravenous administration of the same dose at
8-hour intervals, the mean plasma concentrations just
prior to and immediately after each infusion at steady-state
were 5.6 ± 0.6 mcg/ml and 8.8 ± 0.9 mcg/ml
for trimethoprim and 70.6 ± 7.3 mcg/ml and 105.6
± 10.9 mcg/ml for sulfamethoxazole. The mean plasma
half-life was 11.3 ± 0.7 hours for trimethoprim
and 12.8 ± 1.8 hours for sulfamethoxazole. All
of these 11 patients had normal renal function, and their
ages ranged from 17 to 78 years (median 60 years).6
Pharmacokinetic studies in pediatric patients and adults
suggest an age-dependent half-life of trimethoprim, as
indicated in TABLE 2.8
| TABLE 2 |
| Age (years) |
No. of Patients |
Mean TMP Half-life (hrs) |
| <1 |
2 |
7.67 |
| 1-10 |
9 |
5.59 |
| 10-20 |
5 |
8.19 |
| 20-63 |
6 |
12.82 |
The percent of dose excreted in urine over a 12-hour period
following the intravenous administration of the first dose
of 240 mg of trimethoprim and 1200 mg of sulfamethoxazole
on day 1 ranged from 17% to 42.4 as free trimethoprim; 7%
to 12.7% as free sulfamethoxazole and 36.7% to 56% as total
(free plus the N4-acetylated metabolite) sulfamethoxazole.
When administered together as sulfamethoxazole; trimethoprim,
neither trimethoprim nor sulfamethoxazole affects the urinary
excretion pattern of the other.
It should be noted, however, that there are little clinical
data on the use of sulfamethoxazole; trimethoprim IV infusion
in serious systemic infections due to Haemophilus influenzae
and Streptococcus pneumoniae.
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