ERYTHROMYCIN ETHYLSUCCINATE AND SULFISOXAZOLE ACETYL
Clinical safety rating: safe
Inhibits CYP3A4 increasing levels of many drugs (eg statins carbamazepine) May cause QT prolongation and subsequent arrhythmias.
Erythromycin ethylsuccinate is a macrolide antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit, blocking peptide chain elongation. Sulfisoxazole acetyl is a sulfonamide that inhibits dihydropteroate synthase, blocking folic acid synthesis.
| Metabolism | Erythromycin ethylsuccinate is metabolized by CYP3A4; sulfisoxazole acetyl is metabolized by N-acetylation and glucuronidation. |
| Excretion | Erythromycin ethylsuccinate is primarily excreted in bile (up to 80% as unchanged drug), with about 12-15% eliminated renally. Sulfisoxazole acetyl is renally excreted, with approximately 85% of the dose appearing in urine as acetylated and deacetylated metabolites. Fecal elimination accounts for less than 10% of sulfisoxazole. |
| Half-life | Erythromycin: terminal half-life of 1.4-2.0 hours in adults; prolonged to 4-6 hours in anuria. Sulfisoxazole: half-life 4.5-7 hours in adults; increased in renal impairment. The combination's clinical context warrants dosing interval adjustments in renal dysfunction. |
| Protein binding | Erythromycin: 70-90% bound to albumin. Sulfisoxazole: approximately 85% bound to albumin. Binding is concentration-dependent and may be displaced by other highly bound drugs. |
| Volume of Distribution | Erythromycin: Vd approximately 0.6-0.8 L/kg, indicating extensive tissue distribution. Sulfisoxazole: Vd 0.15-0.3 L/kg, primarily confined to extracellular fluid. Clinical: higher Vd of erythromycin supports its use in intracellular infections. |
| Bioavailability | Erythromycin ethylsuccinate: oral bioavailability is 30-65% due to first-pass metabolism; food may increase absorption. Sulfisoxazole acetyl: well absorbed orally, bioavailability >90%. |
| Onset of Action | Oral administration: clinical effect (e.g., fever reduction, symptom improvement) typically begins within 24-48 hours for susceptible infections; peak serum concentrations achieved by 1-4 hours. |
| Duration of Action | Erythromycin: bacteriostatic levels persist for 6-8 hours after a single dose. Sulfisoxazole: therapeutic levels maintained for 8-12 hours. The combination is usually dosed every 6-8 hours. Note: duration may be shorter for highly susceptible pathogens. |
| Molecular Weight | Erythromycin ethylsuccinate: 862.1 Da; Sulfisoxazole acetyl: 309.3 Da |
Erythromycin ethylsuccinate (400 mg) and sulfisoxazole acetyl (600 mg) per 5 mL suspension: 2-3 teaspoonfuls (10-15 mL) orally every 6 hours for 10-14 days. Maximum daily dose: 6 g sulfisoxazole.
| Dosage form | GRANULE |
| Renal impairment | GFR >50 mL/min: no adjustment. GFR 10-50 mL/min: administer every 8-12 hours. GFR <10 mL/min: administer every 12-24 hours. Avoid in severe renal impairment (CrCl <10 mL/min) due to sulfonamide accumulation. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% or extend interval. Child-Pugh C: avoid use or reduce dose by 75% and monitor for toxicity. |
| Pediatric use | Children 2 months to 12 years: based on sulfisoxazole component: initial dose 75 mg/kg, then 150 mg/kg/day divided every 6 hours (max 6 g/day). Use weight-based dosing: erythromycin ethylsuccinate 50 mg/kg/day and sulfisoxazole acetyl 150 mg/kg/day divided every 6 hours. |
| Geriatric use | Elderly patients are more susceptible to sulfonamide adverse effects (e.g., severe skin reactions, hematologic toxicity). Monitor renal function closely; adjust dose for GFR. Caution with potassium- and magnesium-sparing diuretics (hyperkalemia, sulfonamide potentiation). Standard adult dose may be reduced by 25-50% if GFR <60 mL/min. |
| 1st trimester | Avoid due to known teratogenic effects of sulfonamides (sulfisoxazole) linked to neural tube defects; erythromycin is considered safe but combination not recommended. |
| 2nd trimester | Use with caution; sulfonamides may increase risk of kernicterus if used near term; theoretical risk of jaundice in fetus. |
| 3rd trimester | Contraindicated after 38 weeks due to risk of kernicterus in neonates from sulfisoxazole displacing bilirubin. |
Clinical note
Inhibits CYP3A4 increasing levels of many drugs (eg statins carbamazepine) May cause QT prolongation and subsequent arrhythmias.
| FDA category | Human |
| Placental transfer | Both components cross the placenta extensively; sulfisoxazole achieves fetal serum levels 50-100% of maternal levels. |
■ FDA Black Box Warning
None
| Common Effects | Nausea |
| Serious Effects |
Hypersensitivity to erythromycin, sulfonamides, or any componentPorphyriaInfants <2 months of age (sulfonamides increase risk of kernicterus)Pregnancy at term (38 weeks or later) due to risk of kernicterusConcurrent use with astemizole, terfenadine, ergotamine, dihydroergotamine, cisapride, pimozide (risk of QT prolongation and torsades de pointes)
| Precautions | Hepatic toxicity including jaundice and hepatitis, QT interval prolongation and risk of cardiac arrhythmias (especially with CYP3A4 inhibitors), Clostridioides difficile-associated diarrhea, Severe cutaneous adverse reactions (e.g., Stevens-Johnson syndrome) with sulfonamide component, Hypersensitivity reactions, Hematologic changes (agranulocytosis, aplastic anemia) with sulfonamides |
| Food/Dietary |
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| Breastfeeding |
| Erythromycin and sulfisoxazole are excreted into breast milk in low concentrations. Risk of kernicterus in jaundiced or G6PD-deficient infants; avoid in infants with hyperbilirubinemia or G6PD deficiency. Consider alternative agents with safer profiles. |
| Lactation Rating | L3 (Moderately Safe) - but caution advised due to sulfonamide component. |
| Teratogenic Risk | Pregnancy Category C (original FDA). First trimester: Sulfisoxazole, a sulfonamide, competes with bilirubin for protein binding, increasing risk of kernicterus if used near term. Erythromycin ethylsuccinate not associated with major malformations but limited data. Second and third trimesters: Sulfisoxazole risk of neonatal jaundice and hemolytic anemia in G6PD-deficient infants; avoid after 32 weeks. Overall risk appears low but caution advised. |
| Fetal Monitoring | Monitor maternal liver function, renal function, and CBC with differential due to sulfonamide adverse effects. Monitor infant for jaundice, hemolytic anemia, and kernicterus signs if used near term or during nursing. Assess fetal growth and well-being via ultrasound if prolonged use. Baseline G6PD screening in infant if breastfed. |
| Fertility Effects | No known adverse effects on fertility from erythromycin ethylsuccinate or sulfisoxazole. No human studies indicating impaired fertility. Animal studies limited but no evidence of reproductive toxicity at therapeutic doses. |
| Avoid alcohol as it may increase hepatotoxicity risk with erythromycin. Do not take with pomegranate or grapefruit juice; they increase erythromycin absorption and risk of adverse effects. High-fat meals may delay absorption but reduce GI irritation. |
| Clinical Pearls | Erythromycin ethylsuccinate and sulfisoxazole acetyl is a fixed-dose combination primarily used for otitis media in children due to synergy against Haemophilus influenzae. Erythromycin can prolong QTc interval; avoid with other QT-prolonging drugs. Sulfisoxazole competes for bilirubin binding sites, increasing kernicterus risk in neonates <2 months. Monitor for sulfonamide hypersensitivity reactions (Stevens-Johnson syndrome). Dose adjustment needed in renal impairment. |
| Patient Advice | Take this medication with food to reduce stomach upset. · Complete the full course even if feeling better to prevent resistance. · Do not use if you are allergic to sulfa drugs or erythromycin. · Avoid sun exposure; use sunscreen as this drug may cause photosensitivity. · Inform your doctor if you have liver or kidney disease, or a history of QT prolongation. · Report any rash, severe diarrhea, or signs of liver problems (yellowing skin/eyes). · Shake the suspension well before each use and measure with the provided dosing cup. |