• The Aminopenicillins:  Ampicillin and Amoxicillin

  • Pharmacokinetics and Pharmacological Properties¹

    • Absorption

      • Ampicillin and amoxicillin are virtually identical in both their mechanism in antibacterial spectrum.^2,4,5  

        • However, the important differences are pharmacokinetic.

      • Increased use of amoxicillin in oral therapy is the result of its superior pharmacokinetic characteristics.

        • Absorption and bioavailability represent the single most important differentiating factor.^2,3 

      • Amoxicillin

        • This agent exhibits excellent and reliable absorption from the gastrointestinal tract.

          • Its oral bioavailability is approximately 75–90%.

          • Its absorption is not significantly affected by the presence of food³, which allows for more convenient dosing and enhances patient adherence.

      • Ampicillin

        • Oral absorption is incomplete and highly variable, with a bioavailability of only 30–55%.⁶

          • The presence of food markedly decreases both the rate and extent of absorption, necessitating administration on an empty stomach (1 hour before or 2 hours after meals) to maximize efficacy.

            • These dosing requirements represent a significant barrier to compliance.

        • This difference in absorption translates directly into more favorable pharmacodynamics for amoxicillin.

          • An equivalent oral dose of amoxicillin produces a peak serum concentration (C_max) and an area under the concentration-time curve (AUC) that are approximately double those achieved with ampicillin.⁷

          • For a time-dependent class of antibiotics like β-lactams, where efficacy is driven by the duration, drug concentration remaining above the minimum inhibitory concentration (T>MIC) is important.

          • Comparatively superior exposure makes amoxicillin a far more reliable agent for treating systemic infections via the oral route.²

    • Distribution

      • Both ampicillin and amoxicillin are widely distributed into body tissues and fluids.

        • They achieve therapeutic concentrations in many sites such as the lungs, middle ear fluid, bile, and urine.

        • Protein binding is relatively low (~20% for both, which is low compared to anti-staphylococcal penicillins)⁶, meaning a large free fraction of drug is available to act on bacteria.

        • Neither drug penetrates the blood-brain barrier well under normal circumstances; however, in the presence of inflamed meninges (e.g. during meningitis), these agents can attain sufficient levels in cerebrospinal fluid.⁶

          • This property is crucial for treating meningitis caused by susceptible organisms (as discussed below).

        • Both drugs cross the placenta and are excreted in breast milk in small amounts, but they are considered safe in pregnancy and lactation (category B).⁸ 

          • Ampicillin is one of the most used antibiotics in pregnancy and is the drug of choice for Listeria monocytogenes infections in pregnancy, reflecting its safety profile.⁸

            • "Electron micrograph of a flagellated Listeria monocytogenes bacterium"

              "Electron micrograph of a flagellated Listeria monocytogenes bacterium, Magnified 41,250X. Listeria monocytogenes is the infectious agent responsible for the foodborne illness listeriosis. In the United States, an estimated 2500 persons become seriously ill with listeriosis each year. Of these, 500 died. Typical size of Listeria rods: 0.4 by 1 to 1.5um." Attribution Elizabeth White, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Listeria_monocytogenes_PHIL_2287_lores.jpg

          • Pregnancy increases ampicillin clearance by up to 50%, requiring elevated doses in order to reach therapeutic levels.^8,9

    • Metabolism and Excretion

      • Aminopenicillins are not extensively metabolized.^6,8 

        • The majority of an administered dose is excreted unchanged by the kidneys via glomerular filtration and tubular secretion.^6,8

          • Because of this short half-life, dosing is typically frequent (e.g., every 6 hours for ampicillin, every 8–12 hours for amoxicillin) to maintain therapeutic levels.

            • Probenecid, which blocks renal tubular secretion, can prolong the half-life of aminopenicillins by slowing their excretion.¹⁰ 

            • In patients with renal impairment, the elimination is delayed and doses must be adjusted to prevent accumulation.⁶ 

    • Pharmacodynamics

      • These drugs are time-dependent bactericidal agents.

        • Efficacy correlates with the duration that concentrations exceed the MIC of the pathogen, rather than achieving a high peak concentration.

          • Optimized regimens use around-the-clock dosing or continuous infusions for serious infections to minimize troughs in drug level.¹⁰

          • In terms of spectrum, amoxicillin and ampicillin are often described as “extended-spectrum” penicillins relative to penicillin G, given that ampicillin and amoxicillin exhibit enhanced activity against E.coli and other gram-negative enteric bacilli compared with peinicillin G.¹¹ 

          • These aminopenicillins cover most of the penicillin G-sensitive Gram-positives (e.g. streptococci, Enterococcus faecalis, Listeria) and add coverage of some common Gram-negative pathogens (due to the amino side chain).¹¹

September, 2025