• Penicillins snd others

  • Beta-lactamase inhibitors

    • Pharmacological Properties (ADME)

      • Absorption

        • Among these inhibitors, only clavulanic acid is routinely used orally (as amoxicillin/clavulanate).

        • Clavulanate is moderately well-absorbed orally, with a bioavailability around 60–70% for immediate-release formulations, and is often given with food to improve tolerability.¹ 

        • Sulbactam is not orally absorbed in its active form (it is given parenterally), but an oral prodrug (sultamicillin) exists, which is hydrolyzed after absorption to yield sulbactam plus ampicillin.³ 

        • Tazobactam (i.v. or i.m), avibactam (ceftazidime-avibactam, i.v.)⁴, and relebactam (e.g. Recarbrio™, consisting of imipenem, cilastatin and relebactam) by IV infusion)⁵ are not available orally and are administered parenterally along with their beta-lactam partners.

      • Distribution

        • These inhibitors distribute well into body fluids and tissues, similar to their companion antibiotics.

          • Clavulanic acid and amoxicillin have similar volumes of distribution and short half-lives (~1 hour).^1,6 

          • Sulbactam’s volume of distribution is about 12 liters, indicating it is primarily extracellular; it is ~38% protein bound.¹ 

          • Relebactam’s protein binding is ~22%⁸, and it penetrates into tissues like lung epithelial lining fluid at therapeutically relevant levels.⁷

      • Metabolism

        • Most beta-lactamase inhibitors undergo minimal metabolism.

          • Clavulanic acid is partially metabolized in the liver (a portion of the dose is not recovered unchanged in urine), whereas sulbactam, tazobactam, avibactam, and relebactam are largely excreted unchanged.

          • Sulbactam has <25% hepatic metabolism with minimal biliary excretion⁹, and tazobactam similarly has only minor metabolism (one inactive metabolite).²

          • Avibactam¹⁰ and relebactam⁸ are not significantly metabolized by the liver.

      • Excretion

        • Renal excretion is the primary elimination route for all these agents.

          • They are filtered and secreted by the kidneys, often via active transport mechanisms.

            • Clavulanic acid has a half-life of ~0.8 hours and ~37–57% of an oral dose is excreted unchanged in urine within 6 hours.¹

            • Sulbactam has a half-life ~1 hour, with ~75% of a dose excreted unchanged in urine.¹

            • Tazobactam likewise has ~1 hour half-life; about 57–64% is recovered unchanged in urine over 24 hours.¹

            • Avibactam has a slightly longer half-life (~2 hours); roughly 85–97% of an IV dose is excreted unchanged in the urine, with over half recovered in the first 2 hours.^4,11

            • Relebactam has a half-life of ~1–1.5 hours and >90% is eliminated unchanged by the kidneyss.^12,13 

      • Because renal clearance is so important, doses of these inhibitors (and their partner antibiotics) must be reduced in patients with renal impairment to prevent accumulation.² 

        • Probenecid, which blocks renal tubular secretion, can raise levels of beta-lactamase inhibitors (e.g. it decreases avibactam’s renal clearance by ~56–70%), so concomitant use of probenecid is generally not recommended.

          • Probenecid inhibits avibactam uptake because probenecid is a potent Organic Ion Transporter (OAT) inhibitor.

          • Probenecid in combination with avibactam would potentially reduce avibactam elimination.

            • For example, coadministration of ceftazidime/avibactam with probenecid would not be recommended.¹⁴

August, 2025