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Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of beta-lactamase enzymes commonly found in micro-organisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated beta-lactamases frequently responsible for transferred drug resistance. It 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.
Pharmacodynamic Effects: In the list as follows, organisms are categorised according to their in vitro susceptibility to amoxicillin-clavulanate. (See Table 1).
Click on icon to see table/diagram/imagePharmacokinetics: Augmentin: Absorption: The two components of co-amoxiclav, amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of co-amoxiclav is optimised when taken at the start of a meal.
The pharmacokinetic results for the two separate studies, in which co-amoxiclav 250/125 (375) or 2 x 250/125 and 500/125 (625) mg tablets (in comparison with the two components given separately) were administered in the fasting state to groups of healthy volunteers, are presented in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageAmoxicillin serum concentrations achieved with co-amoxiclav are similar to those produced by the oral administration of equivalent doses of amoxicillin alone.
Distribution: Following i.v. 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% for clavulanic acid and 18% for 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 sensitisation associated with this excretion, there are no known detrimental effects for the breast-fed 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 faeces 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).
Augmentin ES: Pharmacokinetic parameters are given as follows for Co-amoxiclav (Augmentin ES) administered at 45 mg/kg every 12 hours to paediatric patients (see Table 3).
Click on icon to see table/diagram/imageThe pharmacokinetics of the two components of Co-amoxiclav (Augmentin ES) are closely matched. Both clavulanate and amoxicillin have low levels of serum binding; about 70% remains free in the serum.
Toxicology: Pre-clinical Safety Data: No further information of relevance.
