Pharmacological properties
Pharmacodynamics. Mechanism of action. Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often called penicillin-binding proteins - PBPs) in the biosynthetic metabolism of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to a weakening of the cell wall, resulting in cell lysis and death.
Amoxicillin is susceptible to cleavage by beta-lactamases produced by resistant bacteria, therefore, the spectrum of activity of amoxicillin in monotherapy does not include organisms that produce these enzymes.
Clavulanic acid is a beta-lactam, structurally related to penicillins. It inactivates some beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid in monotherapy does not produce a clinically useful antibacterial effect.
Pharmacokinetics/pharmacodynamics relationship. Time above the MIC (VMIC) is considered the primary determinant of efficacy for amoxicillin.
Mechanisms of resistance. There are two mechanisms of resistance to amoxicillin/clavulanic acid:
- inactivation by bacterial beta-lactamases that are not themselves markedly reduced by clavulanic acid, including class B, C and D;
- conversion of PSB, which reduces the affinity of the antibacterial drug to the target.
Bacterial impermeability or the reflux pump mechanism can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Breakpoints. The MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are:
| microorganisms | Sensitivity cut-off values, μg/ml |
| sensitive | moderately sensitive | resistant |
| Haemophilus influenzae 1 | ≤1 | - | 1 |
| Moraxella catarrhalis 1 | ≤1 | - | 1 |
| Staphylococcus aureus 2 | ≤2 | - | 2 |
| Coagulase-negative staphylococci 2 | ≤0.25 | | 0.25 |
| Enterococcus 1 | ≤4 | 8 | 8 |
| Streptococcus A, B, C, G 5 | ≤0.25 | - | 0.25 |
| Streptococcus pneumoniae 3 | ≤0.5 | 1-2 | 2 |
| enterobacteria 1.4 | - | - | 8 |
| Gram anaerobic bacteria 1 | ≤4 | 8 | 8 |
| Gram-positive anaerobic bacteria 1 | ≤4 | 8 | 8 |
| Limit values not specific to specific species 1 | ≤2 | 4-8 | 8 |
| 1 Values reported for amoxicillin concentrations. For the purpose of determining susceptibility, the clavulanic acid concentration was set at 2 mg/L. 2 Reported values for oxacillin concentrations. 3 The breakpoints given in the table are calculated from the breakpoints for ampicillin. 4 A resistance breakpoint of R8 mg/L means that all strains with resistance mechanisms are declared resistant. 5 The breakpoints given in the table are calculated from the breakpoints for benzylpenicillin. |
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The prevalence of resistance may vary geographically and over time for individual species, so local susceptibility information is desirable, particularly in severe infections. Expert opinion should be sought if the local prevalence of resistance is such that the benefit of the drug, at least in some types of infections, is questionable.
Pharmacokinetics
Absorption. Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are rapidly and well absorbed after oral administration. The bioavailability of amoxicillin and clavulanic acid is about 70% after oral administration. The plasma profiles of both components are identical, and the time to reach C max in plasma (T max) for each component is approximately 1 hour.
The serum concentrations of amoxicillin and clavulanic acid achieved with amoxicillin/clavulanic acid are identical to those achieved with oral administration of equivalent doses of amoxicillin or clavulanic acid alone.
Distribution: Approximately 25% of the total plasma clavulanic acid and 18% of the total drug in plasma is protein bound. The volume of distribution is approximately 0.3-0.4 l/kg body weight for amoxicillin and approximately 0.2 l/kg for clavulanic acid.
After intravenous administration, amoxicillin and clavulanic acid have been found in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile and pus. Amoxicillin is not distributed sufficiently in the cerebrospinal fluid.
Animal studies have not shown any evidence of significant retention of substances derived from any of the components of the drug in body tissues. Amoxicillin, like most penicillins, can be found in breast milk. Small amounts of clavulanic acid can also be found in breast milk (see Use during pregnancy or lactation).
Biotransformation. Amoxicillin is partially excreted in the urine as inactive penicillic acid in amounts equivalent to 10-25% of the initial dose. Clavulanic acid is extensively metabolized in humans and is excreted in the urine and feces and as d
