PRINCIPEN W/ PROBENECID
Clinical safety rating
safeIncreases levels of many drugs by inhibiting their renal secretion (eg penicillins methotrexate) Can cause GI upset and nephrotic syndrome.
Ampicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs) and inhibiting transpeptidase activity. Probenecid competitively inhibits renal tubular secretion of ampicillin, increasing its plasma concentration and duration.
| Metabolism | Ampicillin is metabolized by hydrolysis to penicilloic acid; probenecid undergoes hepatic metabolism via glucuronidation and oxidation. |
| Excretion | Renal: ~60-80% of ampicillin excreted unchanged in urine via tubular secretion and glomerular filtration; probenecid reduces this to ~20-30%. Biliary/fecal: minor, <10%. |
| Half-life | Ampicillin: 1-1.8 hours (prolonged to 4-6 hours with probenecid due to reduced renal clearance). Probenecid: 6-12 hours. Clinical context: extended half-life allows less frequent dosing. |
| Protein binding | Ampicillin: 15-25% bound to albumin. Probenecid: 85-95% bound to albumin. |
| Volume of Distribution | Ampicillin: 0.3-0.4 L/kg (distributes well into extracellular fluid, low CNS penetration unless inflamed meninges). |
| Bioavailability | Oral: 30-50% for ampicillin (enhanced by probenecid? probenecid does not significantly alter ampicillin absorption). Probenecid: nearly 100% oral. |
| Onset of Action | Oral: 1-2 hours (peak serum levels). IM: 30-60 minutes. IV: immediate. |
| Duration of Action | 6-8 hours (due to probenecid prolonging ampicillin serum levels). Clinical notes: allows every-6-hour dosing for susceptible infections. |
| Molecular Weight | 590.71 |
1.5-3 g IM q6h (20 mg/kg/day probenecid component).
| Dosage form | CAPSULE |
| Renal impairment | CrCl 30-50 mL/min: 1.5 g IM q8h; CrCl 10-29 mL/min: 1.5 g IM q12h; CrCl <10 mL/min: 1.5 g IM q24h. |
| Liver impairment | No adjustment required for mild to moderate impairment. Severe impairment (Child-Pugh C): consider reducing dose by 25-50%. |
| Pediatric use | Children 2-12 years: 50 mg/kg/day IM in 4 divided doses (probenecid component 25 mg/kg/day). Maximum single dose 2 g. |
| Geriatric use | Reduce dose based on renal function; avoid if CrCl <30 mL/min due to probenecid accumulation. Monitor for CNS toxicity. |
| 1st trimester | Generally avoided unless necessary; ampicillin crosses placenta; probenecid may theoretically affect fetal development but human data limited. |
| 2nd trimester | Use if clearly needed; ampicillin is widely used and considered relatively safe; probenecid safety not well established. |
| 3rd trimester | Use if clearly needed; ampicillin is safe; probenecid may increase risk of neonatal jaundice by displacing bilirubin. |
Clinical note
Increases levels of many drugs by inhibiting their renal secretion (eg penicillins methotrexate) Can cause GI upset and nephrotic syndrome.
| FDA category | Animal |
| Placental transfer | Ampicillin crosses placenta extensively; fetal levels reach 50-100% of maternal. Probenecid crosses placenta to a lesser extent, but data limited. |
| Breastfeeding | Ampicillin excreted in low levels into breast milk, generally considered compatible. Probenecid excreted in minimal amounts, but safety not well studied. Monitor infant for rash or diarrhea. |
| Lactation Rating | L2 (Probably Compatible) |
| Teratogenic Risk | FDA Pregnancy Category B: No evidence of risk in humans. Ampicillin crosses placenta; probenecid crosses placenta but no teratogenicity reported. First trimester: No known teratogenic effects. Second/third trimester: Use caution due to potential for altered fetal gut flora. Peripartum: Risk of kernicterus in neonates if maternal hyperbilirubinemia. |
| Fetal Monitoring | Maternal: Renal function, CBC with differential, liver enzymes, signs of hypersensitivity. Fetal: Ultrasound for growth if prolonged use; neonatal monitoring for jaundice, hypoglycemia, or infection if used near term. |
| Fertility Effects | No known adverse effects on human fertility. Animal studies show no impairment of fertility. Probenecid may affect uric acid excretion but no direct impact on reproductive function. |
■ FDA Black Box Warning
None.
| Common Effects | Hyperuricemia |
| Serious Effects |
Hypersensitivity to ampicillin, penicillins, or probenecidHistory of anaphylactic reaction to penicillinsConcomitant use with methotrexate (increased methotrexate toxicity)
| Precautions | Hypersensitivity reactions including anaphylaxis, Severe cutaneous adverse reactions (SCARs), C. difficile-associated diarrhea, Renal impairment (dose adjustment for ampicillin), Sodium overload with high doses, Allergic cross-reactivity with cephalosporins |
| Food/Dietary | Take with food or milk to reduce gastrointestinal upset. Avoid high-fat meals as they may delay absorption of ampicillin. Probenecid is not affected by food; however, maintain adequate hydration to prevent crystalluria. |
| Clinical Pearls | Principen w/ Probenecid combines ampicillin, a broad-spectrum penicillin, with probenecid to prolong ampicillin serum levels by inhibiting renal tubular secretion. Use in penicillin-allergic patients is contraindicated. Probenecid may reduce excretion of other drugs (e.g., methotrexate, NSAIDs). Monitor renal function; probenecid is contraindicated in patients with uric acid kidney stones or blood dyscrasias. Administer with food if GI upset occurs. Synergistic with aminoglycosides but physically incompatible; do not mix in IV solutions. |
| Patient Advice | Take this medication exactly as prescribed, even if you feel well. · Complete the full course to prevent antibiotic resistance. · May cause diarrhea; contact your doctor if it is severe or contains blood. · Avoid alcohol while taking this medication. · Inform your doctor if you have kidney disease, gout, or a history of penicillin allergy. · Probenecid may increase effects of warfarin; monitor for bleeding. · Drink plenty of fluids to prevent kidney stones while on probenecid. |
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