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Pharmacology: Pharmacodynamics: Mechanism of Action: Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases and, therefore, the spectrum of activity does not include organisms that produce these enzymes.
Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance.
Thus, Co-amoxiclav possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
In the list, as follows, organisms are categorized according to their in vitro susceptibility to Co-amoxiclav (see table).
Click on icon to see table/diagram/imageIt is generally less effective against chromosomally-mediated type 1 beta-lactamases.
The presence of clavulanic acid in co-amoxiclav formulations protects amoxicillin from degradation by beta-lactamase enzymes and effectively extends the antibacterial spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other penicillins and cephalosporins. Thus, amoxicillin clavulanate possesses the distinctive properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor.
Pharmacokinetics: Absorption: The two components of co-amoxiclav, amoxicillin, and clavulanic acid is fully dissociated in an aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of Co-amoxiclav is optimized when taken at the start of a meal.
Distribution: Following IV administration, therapeutic concentrations of both amoxicillin and clavulanic acid may be detected in the tissues and interstitial fluid. Therapeutic concentrations of both drugs have been found in the gall bladder, abdominal tissue, skin, fat, and muscle tissues; fluids found to have therapeutic levels include synovial and peritoneal fluids, bile, and pus.
Neither amoxicillin nor clavulanic acid is highly protein bound, studies show that about 25% of clavulanic acid and 18% of amoxicillin of total plasma drug content is bound to protein.
From animal studies, there is no evidence to suggest that either component accumulates in any organ. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanate can also be detected in breast milk. With the exception of the risk of sensitization associated with this excretion, there are no known detrimental effects for the breastfeed infant.
Reproduction studies in animals have shown that both amoxicillin and clavulanic acid penetrate the placental barrier. However, no evidence of impaired fertility or harm to the foetus was detected.
Metabolism: Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man to 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-butan-2-one and eliminated in urine and feces as carbon dioxide in expired air.
Elimination: As with other penicillins, the major route of elimination for amoxicillin is via the kidney, whereas for clavulanate it is by both renal and non-renal mechanisms. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250/125 mg or a single 500/125 mg tablet. Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see Interactions).
