What is probenecid and why should it be given before cefazolin?

What is Probenecid and Why is it Given Before Cefazolin?

Probenecid is a renal tubular blocking agent that inhibits the kidney's excretion of certain antibiotics like cefazolin, thereby prolonging their blood levels and therapeutic effect. When given with cefazolin, probenecid blocks the renal tubular secretion of the antibiotic, resulting in higher peak serum concentrations, increased area under the curve (AUC), and sustained therapeutic levels with less frequent dosing 1.

Mechanism of Action

• Probenecid competitively inhibits organic acid transport in the renal tubules, preventing the active secretion of drugs like cephalosporins 2
• This blockade impairs renal clearance of cefazolin, leading to increased and prolonged serum concentrations 1
• The drug is extensively bound to plasma proteins (99.9% at therapeutic concentrations) and has a half-life of 4-12 hours, which is dose-dependent 2

Clinical Applications with Cefazolin

The primary reason for combining probenecid with cefazolin is to maintain therapeutic antibiotic levels with less frequent dosing, particularly in outpatient settings where convenience is essential.

Single-Dose Regimens for Sexually Transmitted Infections

• For pelvic inflammatory disease (PID), the CDC recommends cefoxitin 2g IM plus probenecid 1g orally as a single concurrent dose, followed by doxycycline 100mg orally twice daily for 14 days 3
• This combination allows for effective single-dose parenteral therapy in the outpatient setting, with probenecid ensuring sustained cefoxitin levels adequate for initial treatment 3

Extended Dosing Intervals

• Probenecid 500mg orally four times daily effectively maintains therapeutic cefazolin serum concentrations when cefazolin 2000mg is given once daily intravenously, compared to the standard every-8-hour dosing without probenecid 4
• Peak cefazolin concentrations remain similar (146-148 mg/L), while trough levels with once-daily dosing plus probenecid (2-2.67 mg/L) are lower than every-8-hour dosing alone (17-19 mg/L) but still therapeutic 4

Dosing Considerations

Timing and Dose

• Probenecid should be administered concurrently with or immediately before cefazolin administration to achieve the pharmacokinetic interaction 1
• For single-dose therapy: probenecid 1g orally given as a single dose with the cefazolin injection 3
• For extended therapy: probenecid 500mg orally four times daily maintains steady-state cefazolin levels 4
• Larger probenecid doses result in greater changes in cephalosporin pharmacokinetics, making dosage a major determinant of the interaction 1

Route of Administration

• The route of administration (oral versus parenteral) of either probenecid or cefazolin does not significantly influence the characteristics of their interaction 1
• Oral probenecid bioavailability is excellent, with greater than 90% absorption 5

Important Caveats and Safety Considerations

Adverse Effects of Probenecid

• Common side effects include headache, anorexia, nausea, vomiting, and urinary frequency 3
• Serious but rare complications include hypersensitivity reactions, hemolytic anemia, nephrotic syndrome, hepatic necrosis, and precipitation of gout or uric acid stones 3
• Probenecid should be used with caution in children, pregnant women, and persons with sulfa drug allergy 3

When Probenecid is NOT Necessary

• Modern third-generation cephalosporins like ceftriaxone achieve adequate sustained concentrations without probenecid due to their longer half-lives 1
• Ceftriaxone administered alone for gonorrhea treatment is highly effective, making probenecid addition unnecessary 1
• Some cephalosporins (ceforanide, ceftazidime, ceftriaxone) show no significant pharmacokinetic changes with concurrent probenecid administration 1

Clinical Monitoring

• When using probenecid to reduce nephrotoxicity of other drugs (like cidofovir), careful monitoring of renal function is essential 3
• For cidofovir specifically, probenecid must be given with IV hydration: 2g orally 3 hours prior to cidofovir, then 1g at 2 and 8 hours following cidofovir administration 3

Practical Algorithm for Use

For outpatient PID treatment requiring parenteral therapy:

1. Administer cefoxitin 2g IM plus probenecid 1g orally concurrently 3
2. Continue with doxycycline 100mg orally twice daily for 14 days 3
3. Schedule follow-up within 72 hours to assess clinical response 3

For extended cefazolin therapy with reduced dosing frequency:

1. Initiate probenecid 500mg orally four times daily 4
2. Administer cefazolin 2000mg IV once daily instead of every 8 hours 4
3. Monitor for therapeutic response and probenecid-related adverse effects 4