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Pediazole (Erythromycin Ethylsuccinate / Sulfisoxazole Acetyl) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Pediazole is a combination of erythromycin ethylsuccinate, USP, and sulfisoxazole acetyl, USP. When reconstituted with water as directed on the label, the granules form a white, strawberry-banana flavor suspension that provides the equivalent of 200 mg erythromycin activity and the equivalent of 600 mg of sulfisoxazole activity per teaspoonful (5 mL).

Erythromycin is produced by a strain of Saccaropolyspora erythraea and belongs to the macrolide group of antibiotics. It is basic and readily forms salts and esters. Erythromycin ethylsuccinate is the 2'-ethylsuccinyl ester of erythromycin. It is essentially a tasteless form of the antibiotic suitable for oral administration, particularly in suspension dosage forms. The chemical name is erythromycin 2'-(ethyl succinate).

Erythromycin ethylsuccinate structural formula:

Sulfisoxazole acetyl or N1-acetyl sulfisoxazole is an ester of sulfisoxazole. Chemically, sulfisoxazole is N-(3,4-Dimethyl-5-isoxazolyl)-N-sulfanilylacetamide.

Sulfisoxazole acetyl structural formula:

Inactive Ingredients: Citric acid, magnesium aluminum silicate, poloxamer, sodium carboxymethylcellulose, sodium citrate, sucrose and artificial flavoring.

CLINICAL PHARMACOLOGY

Orally administered erythromycin ethylsuccinate suspensions are readily and reliably absorbed. Erythromycin ethylsuccinate products have demonstrated rapid and consistent absorption in both fasting and nonfasting conditions. However, higher serum concentrations are obtained when these products are given with food. Bioavailability data are available from Ross Products Division. Erythromycin is largely bound to plasma proteins. After absorption, erythromycin diffuses readily into most body fluids. In the absence of meningeal inflammation, low concentrations are normally achieved in the spinal fluid, but the passage of the drug across the blood-brain barrier increases in meningitis. Erythromycin crosses the placental barrier and is excreted in human milk. Erythromycin is not removed by peritoneal dialysis or hemodialysis.

In the presence of normal hepatic function, erythromycin is concentrated in the liver and is excreted in the bile; the effect of hepatic dysfunction on biliary excretion of erythromycin is not known. After oral administration, less than 5% of the administered dose can be recovered in the active form in the urine.

Wide variation in blood levels may result following identical doses of a sulfonamide. Blood levels should be measured in patients receiving these drugs 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 be 200 mcg/mL, because adverse reactions occur more frequently above this concentration.

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-g 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 q.i.d. 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

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 recovery following oral administration of sulfisoxazole is 97% within 48 hours; 52% of this is intact drug, and the remainder is the N4-acetylated metabolite.

Sulfisoxazole is distributed only in extracellular body fluids. It is excreted in human milk. It readily crosses the placental 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:

Pediazole has been formulated to contain sulfisoxazole for concomitant use with erythromycin.

Erythromycin acts by inhibition of protein synthesis by binding 50 S ribosomal subunits of susceptible organisms. It does not affect nucleic acid synthesis. Antagonism has been demonstrated in vitro between erythromycin and clindamycin, lincomycin, and chloramphenicol.

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 para -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 para -aminobenzoic acid.

SUSCEPTIBILITY TESTING:

Diffusion Techniques:    Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure3 that has been recommended for use with disks to test the susceptibility of microorganisms to the combination erythromycin ethylsuccinate and sulfisoxazole acetyl uses the 15 mcg erythromycin disk and the 250 (300) mcg sulfisoxazole disk. Interpretation involves correlation of the diameter obtained in the disk tests with the respective MIC for erythromycin and sulfisoxazole.

Reports from the laboratory providing results of standard single-disk susceptibility tests should be interpreted according to the following criteria. 3-5

With a 15 mcg erythromycin disk:
Zone Diameter Interpretation
  >/=23 Susceptible (S)
   14-22 Intermediate (I)
   Resistant (R)
With a 250 (or 300) mcg sulfisoxazole disk:
Zone Diameter Interpretation
  >/=17 Susceptible (S)
   13-16 Intermediate (I)
   Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations and other pharmacokinetic properties of this antimicrobial drug product.)

Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 15 mcg erythromycin disk and the 250 (or 300) mcg sulfisoxazole disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism Zone Diameter (mm)
15 mcg Erythromycin Disk:
S. aureus ATCC 25923
22-30
250 (or 300) mcg Sulfisoxazole Disk:
E. coli ATCC 25922
18-26
S. aureus ATCC 25923 24-34

Dilution Techniques:    Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method (broth, agar, or microdilution) or equivalent with erythromycin or sulfisoxazole powder. The MIC values obtained should be intrepreted according to the following criteria:

MIC (mcg/mL) Interpretation
With Erythromycin Powder:
Susceptible (S)
1-4 Intermediate (I)
>/=8 Resistant (R)
With Sulfisoxazole Powder:
Susceptible (S)
>/=512 Resistant (R)

Interpretation should be as stated above for results using diffusion techniques.

As with standard diffusion techniques, dilution methods require the use of laboratory control microorganisms. Standard erythromycin and sulfisoxazole powders should provide the following MIC values:

Microorganism MIC (mcg/mL)
With Erythromycin Powder:
S. aureus ATCC 25923 0.12-0.5
E. faecalis ATCC 29212 1-4
With Sulfisoxazole Powder:
S. aureus ATCC 29213 32-128
E. faecalis ATCC 29212 32-128
E. coli ATCC 25922 8-32

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