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CLINICAL PHARMACOLOGY

Following oral administration, sulfisoxazole is rapidly and completely absorbed; the small intestine is the major site of absorption, but some of the drug is absorbed from the stomach. Sulfonamides are present in the blood as free, conjugated (acetylated and possibly other forms) and protein-bound forms. The amount present as “free” drug is considered to be the therapeutically active form. Approximately 85% of a dose of sulfisoxazole is bound to plasma proteins, primarily to albumin; 65% to 72% of the unbound portion is in the nonacetylated form.

Maximum plasma concentrations of intact sulfisoxazole following a single 2-gm oral dose of sulfisoxazole to healthy adult volunteers ranged from 127 to 211 mcg/mL (mean, 169 mcg/mL) and the time of peak plasma concentration ranged from 1 to 4 hours (mean, 2.5 hours). The elimination half-life of sulfisoxazole ranged from 4.6 to 7.8 hours after oral administration. The elimination of sulfisoxazole has been shown to be slower in elderly subjects (63 to 75 years) with diminished renal function (creatinine clearance, 37 to 68 mL/min).1 After multiple-dose oral administration of 500 mg qid to healthy volunteers, the average steady-state plasma concentrations of intact sulfisoxazole ranged from 49.9 to 88.8 mcg/mL (mean, 63.4 mcg/mL).2

Wide variation in blood levels may result following identical doses of a sulfonamide. Blood levels should be measured in patients receiving sulfonamides at the higher recommended doses or being treated for serious infections. Free sulfonamide blood levels of 50 to 150 mcg/mL may be considered therapeutically effective for most infections, with blood levels of 120 to 150 mcg/mL being optimal for serious infections. The maximum sulfonamide level should not exceed 200 mcg/mL, since adverse reactions occur more frequently above this concentration.

N1-acetyl sulfisoxazole is metabolized to sulfisoxazole by digestive enzymes in the gastrointestinal tract and is absorbed as sulfisoxazole. This enzymatic splitting is presumed to be responsible for slower absorption and lower peak blood concentrations than are attained following administration of an equal oral dose of sulfisoxazole. With continued administration of acetyl sulfisoxazole, blood concentrations approximate those of sulfisoxazole. Following a single 4-gm dose of acetyl sulfisoxazole to healthy volunteers, maximum plasma concentrations of sulfisoxazole ranged from 122 to 282 mcg/mL (mean, 181 mcg/mL) for the pediatric suspension and occurred between 2 and 6 hours postadministration. The half-life of elimination from plasma ranged from 5.4 to 7.4.

Sulfisoxazole and its acetylated metabolites are excreted primarily by the kidneys through glomerular filtration. Concentrations of sulfisoxazole are considerably higher in the urine than in the blood. The mean urinary excretion recovery following oral administration of sulfisoxazole is 97% within 48 hours, of which 52% is intact drug, with the remaining as the N4-acetylated metabolite. Following administration of acetyl sulfisoxazole pediatric suspension, approximately 58% is excreted in the urine as total drug within 72 hours.

Sulfisoxazole is distributed only in extracellular body fluid. It is excreted in human milk. It readily crosses the placental barrier and enters into fetal circulation and also crosses the blood-brain barrier. In healthy subjects, cerebrospinal fluid concentrations of sulfisoxazole vary; in patients with meningitis, however, concentrations of free drug in cerebrospinal fluid as high as 94 mcg/mL have been reported.

Microbiology

The sulfonamides are bacteriostatic agents and the spectrum of activity is similar for all. Sulfonamides inhibit bacterial synthesis of dihydrofolic acid by preventing the condensation of the pteridine with aminobenzoic acid through competitive inhibition of the enzyme dihydropteroate synthetase. Resistant strains have altered dihydropteroate synthetase with reduced affinity for sulfonamides or produce increased quantities of aminobenzoic acid.

Susceptibility Tests

Diffusion Techniques:Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure3 which has been recommended for use with disks to test susceptibility of organisms to sulfisoxazole uses the 250- or 300-mcg sulfisoxazole disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for sulfisoxazole.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 250- or 300-mcg sulfisoxazole disk should be interpreted according to the following criteria:

Zone Diameter (mm) Interpretation
≥ 17 Susceptible
13-16 Moderately susceptible
≤ 12 Resistant

A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “moderately susceptible” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of “resistant” indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 250- or 300-mcg sulfisoxazole disk should give the following zone diameters:

Organism Zone Diameter (mm)
E. coli ATCC 25922 18-26 mm
S. aureus ATCC 25923 24-34 mm

Dilution Techniques: Use a standardized dilution method4 (broth, agar, microdilution) or equivalent with sulfisoxazole powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL) Interpretation
≤ 256 Susceptible
≥ 512 Resistant

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Dilutions of standard sulfisoxazole powder should provide the following MIC values:

Organism MIC (mcg/mL)
S. aureus ATCC 29213 32-128
E. faecalis ATCC 29212 32-128
E. coli ATCC 25922 8-32

REFERENCES

1. Boisvert A, Barbeau G, Belanger PM. Pharmacokinetics of sulfisoxazole in young and elderly subjects. Gerontology. 1984; 30:125-131.

2. Oie S, Gambertoglio JG, Fleckenstein L. Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing. J Pharmacokinet Biopharm. 1982; 10:157-172.

3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests. 4th ed. Villanova, PA: April 1990. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS.

4. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. 2nd ed. Villanova, PA: April 1990. Approved Standard NCCLS Document M7-A2, Vol. 10, No. 8 NCCLS.

Last reviewed on RxList: 9/16/2008
This monograph has been modified to include the generic and brand name in many instances.

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