Zotrim

CLINICAL PHARMACOLOGY

Trimethoprim/Sulfamethoxazole: Trimethoprim/sulfamethoxazole 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 the sulfamethoxazole occurs predominately by N4-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are 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% sulfamethoxazole are bound to plasma proteins. The presence of 10% of sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Peak blood concentrations for individual components (trimethoprim and sulfamethoxazole) 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 trimethoprim and sulfamethoxazole are present in the blood 24 hours after drug administration. During administration of 160 mg of trimethoprim and 800 mg of sulfamethoxazole bid, the mean steady-state plasma concentration of trimethoprim was 1.72mg/mL. The steady-state mean plasma concentrations of free and total sulfamethoxazole were 57.4mg/mL and 68.0mg/mL, respectively. These steady-state concentrations were achieved after three days of 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 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. When administered together, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.

Both trimethoprim and sulfamethoxazole 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 breast milk.

Phenazopyridine Hydrochloride: Following oral administration, phenazopyridine is excreted by the kidneys, with as much as 65% of an oral dose being excreted unchanged in the urine.

Trimethoprim/Sulfamethoxazole and Phenazopyridine Hydrochloride: In a prospective two-way crossover drug interaction study between trimethoprim/sulfamethoxazole double strength and phenazopyridine hydrochloride (200 mg) administered first singly for 3 days, then in combination for an additional 3 days to 12 healthy female subjects, it was determined that the coadministration of the two drug products resulted in significantly greater plasma concentrations of trimethoprim, sulfamethoxazole, or phenazopyridine compared to when either drug was administered alone. The median increase in plasma concentrations was 29% for trimethoprim (range: -18% to 132%), 17% for sulfamethoxazole (range: -36% to 110%), and 60% for phenazopyridine (range: -79% to 474%), compared to when either trimethoprim/sulfamethoxazole or phenazopyridine was administered alone. The median (range) plasma concentrations of trimethoprim, sulfamethoxazole, and phenazopyridine at the end of combination treatment were 4.0 (2.3 - 6.9) mg/mL, 100.0 (56.4 - 185) mg/mL, and 26.5 (5.9 -263) ng/mL, respectively.

Microbiology

Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Thus, trimethoprim/sulfamethoxazole 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 trimethoprim and sulfamethoxazole in combination than with either trimethoprim or sulfamethoxazole alone.

Trimethoprim and sulfamethoxazole 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-negative microorganisms

Escherichia coli

Klebsiella species

Enterobacter species

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Susceptibility Testing Methods

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 procedure. Standardized procedures are based on a dilution method1,2 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of trimethoprim/sulfamethoxazole powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae:

MIC (µg/mL)

Interpretation

≤2/38

Susceptible (S)

≥4/76

Resistant (R)

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 trimethoprim/sulfamethoxazole powder should provide the following range of values:

Microorganism

 

MIC (µg/mL)

Escherichia coli

ATCC 25922

≤0.5/9.5

Haemophilus influenzaea

ATCC 49247

0.03/0.59 - 0.25/4.75

Streptococcus pneumoniaeb

ATCC 49619

0.12/2.4 - 1/19

a. This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by broth microdilution procedure using Haemophilus Test Medium (HTM) 1,2.

b. This quality control range is applicable to tests performed by the broth microdilution method only using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood1,2.

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 procedure5,6 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 1.25/23.75 µg of trimethoprim/sulfamethoxazole to test the susceptibility of microorganisms to trimethoprim/sulfamethoxazole.

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

For testing Enterobacteriaceae:

Zone diameter (mm)

Interpretation

≥16

Susceptible

(S)

11-15

Intermediate

(I)

≤10

Resistant

(R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for trimethoprim/sulfamethoxazole.

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 1.25/23.75-µg trimethoprim/sulfamethoxazole disk* should provide the following zone diameters in these laboratory test quality control strains:

Microorganism

 

Zone Diameter Ranges (mm)

Escherichia coli

ATCC 25922

24-32

Haemophilus influenzaec

ATCC 49247

24-32

Streptococcus pneumoniaed

ATCC 49619

20-28

* Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine. 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.

c. This quality control range is applicable only to Haemophilus influenzae ATCC 49247 tested by a disk diffusion procedure using Haemophilus Test Medium (HTM)3,4.

d. This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood when incubated in 5% CO2 3,4.

Last reviewed on RxList: 1/28/2005
This monograph has been modified to include the generic and brand name in many instances.

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