SULFAMETHOXAZOLE AND TRIMETHOPRIM suspension

Sulfamethoxazole and Trimethoprim by

Drug Labeling and Warnings

Sulfamethoxazole and Trimethoprim by is a Prescription medication manufactured, distributed, or labeled by Pharmaceutical Associates, Inc., Teva Pharmaceuticals, USA. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

SPL UNCLASSIFIED SECTION

Rx only

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

DESCRIPTION

Sulfamethoxazole and trimethoprim oral suspension USP is a synthetic antibacterial combination product. Sulfamethoxazole is N1-(5-methyl-3-isoxazolyl) sulfanilamide. It is an almost white odorless, tasteless compound. It has the following structural formula:

C10H11N3O3S                   M.W. 253.28

Trimethoprim is a 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine. It is a white to light yellow, odorless, bitter compound. It has the following structural formula:

C14H18N4O3                     M.W. 290.32

Each teaspoonful (5 mL) of the oral suspension contains 200 mg sulfamethoxazole and 40 mg trimethoprim as well as the following inactive ingredients: alcohol 0.04% (v/v), carboxymethylcellulose sodium, cherry flavoring, citric acid, color red FD&C No. 40, glycerin, methylparaben, microcrystalline cellulose, polysorbate 80, purified water, saccharin sodium, sodium benzoate, and sorbitol solution.

CLINICAL PHARMACOLOGY

Sulfamethoxazole and trimethoprim oral suspension 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 and 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 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). Detectable amounts of trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg trimethoprim and 800 mg sulfamethoxazole b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 mcg/mL. The steady-state minimal 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

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 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 metabolite2. When administered together, 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 secretions, 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 an 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 this combination 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 this combination than with either sulfamethoxazole or trimethoprim alone.

In vitro serial dilution tests have shown that the spectrum of antibacterial activity of sulfamethoxazole and 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.

The usual spectrum of antimicrobial activity of sulfamethoxazole and trimethoprim includes 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 susceptible.

Susceptibility Testing

Dilution techniques

Quantitative methods are used to determine antimicrobial minimal 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 method 5,7 (broth or agar) or equivalent with standardized incoulum concentrations and standardized concentrations of sulfamethoxazole/trimethoprim powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Acinetobacter spp., Staphylococcus spp., Burkholderia cepacia, Stenotrophomonas maltophilia, and Vibrio cholerae:

MIC (mcg/mL)	Interpretation
≤ 2/38	Susceptible (S)
≥ 4/76	Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzae:

MIC (mcg/mL)	Interpretation
≤ 0.5/9.5	Susceptible (S)
1/19 to 2/38	Intermediate (I)
≥ 4/76	Resistant (R)

These interpretative standards are applicable only to broth microdilution susceptibility testing using Haemophilus Test Medium5.

For testing Streptococcus pneumoniae:

MIC (mcg/mL)	Interpretation
≤ 0.5/9.5	Susceptible (S)
1/19 to 2/38	Intermediate (I)
≥ 4/76	Resistant (R)

These interpretive standards are applicable only to broth microdilution susceptibility testing using cation-adjusted Mueller-Hinton broth with 2.5 to 5% lysed horse blood 5.

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.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard sulfamethoxazole/trimethoprim powder should provide the following MIC values:

Microorganism	MIC Range (mcg/mL)
Escherichia coli ATCC 25922	≤ 0.5/9.5
Staphylococcus aureus ATCC 29213	≤ 0.5/9.5
Pseudomonas aeruginosa ATCC 27853	8/152 to 32/608
Haemophilus influenzae ATCC 49247	0.03/0.59 to 0.25/4.75
Streptococcus pneumoniae ATCC 49619	0.12/2.4 to 1/19

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 procedure 6,7 requires the use of standard incoculum concentrations. This procedure uses paper disks impregnated with 1.25 mcg/23.75 mcg sulfamethoxazole/trimethoprim to test the susceptibility of microorganism to sulfamethoxazole/trimethoprim.

Reports from the laboratory providing results of the standard disk susceptibility test with a 1.25 mcg/23.75 mcg sulfamethoxazole/trimethoprim disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Acinetobacter spp., Staphylococcus spp., Burkholderia cepacia, Stenotrophomonas maltophilia, and Vibrio cholerae:

Zone Diameter (mm)	Interpretation	MIC (mcg/mL)
≥ 16	Susceptible (S)	≤ 238
11 to 15	Intermediate (I)	-
≤ 10	Resistant (R)	≥ 8/152

For testing Haemophilus influenzae and Haemophilus parainfluenzae:

Zone Diameter (mm)	Interpretation	MIC (mcg/mL)
≥ 16	Susceptible (S)	≤ 0.5/9.5
11 to 15	Intermediate (I)	-
≤ 10	Resistant (R)	≥ 4/76

These zone diameter standards are applicable only to susceptibility testing with Haemophilus species using Haemophilus Test Medium6.

For testing Streptococcus pneumoniae:

Zone Diameter (mm)	Interpretation	MIC (mcg/mL)
≥ 19	Susceptible (S)	≤ 0.5/9.5
16 to 18	Intermediate (I)	-
≤ 15	Resistant (R)	≥ 4/76

These interpretative standards are applicable only to disk diffusion testing using Mueller-Hinton agar adjusted with 5% sheep blood 6.

Quality Control

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 1.25 mcg/23.75 mcg sulfamethoxazole/ trimethoprim disk1 should provide the following zone diameters in these laboratory test quality control strains:

Microorganism	MIC Range (mcg/mL)
Escherichia coli ATCC 25922	23 to 29
Staphylococcus aureus ATCC 25923	24 to 32
Haemophilus influenzae ATCC 49247	24 to 32
Streptococcus pneumoniae ATCC 49619	20 to 28

1 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.