DESCRIPTION
AUGMENTIN is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as:
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)-(2R, 5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:
Inactive Ingredients
Colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide.
Each tablet of AUGMENTIN contains 0.63mEq potassium.
CLINICAL PHARMACOLOGY
Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of AUGMENTIN. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While AUGMENTIN can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when AUGMENTIN was dosed at 30 and 150minutes after the start of a high-fat breakfast. The safety and efficacy of AUGMENTIN have been established in clinical trials where AUGMENTIN was taken without regard to meals.
Meana amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:
|
Doseb and regimen |
AUC0-24 (mcg•hr/mL) |
Cmax (mcg/mL) |
|
amoxicillin/
clavulanate potassium |
amoxicillin (±S.D.) |
clavulanate potassium (±S.D.) |
amoxicillin (±S.D.) |
clavulanate potassium (±S.D.) |
|
250/125mg q8h |
26.7 ± 4.56 |
12.6 ± 3.25 |
3.3 ± 1.12 |
1.5 ± 0.70 |
|
500/125mg q12h |
33.4 ± 6.76 |
8.6 ± 1.95 |
6.5 ± 1.41 |
1.8 ± 0.61 |
|
500/125mg q8h |
53.4 ± 8.87 |
15.7 ± 3.86 |
7.2 ± 2.26 |
2.4 ± 0.83 |
|
875/125mg q12h |
53.5 ± 12.31 |
10.2 ± 3.04 |
11.6 ± 2.78 |
2.2 ± 0.99 |
aMean values of 14 normal volunteers (n=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5hours after the dose.
bAdministered at the start of a light meal.
Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of AUGMENTIN is 1.3 hours and that of clavulanic acid is 1.0hour.
Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6hours after administration of a single 250-mg or 500-mg tablet of AUGMENTIN.
Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.
Neither component in AUGMENTIN is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.
Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.
Microbiology
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 which 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.
The formulation of amoxicillin and clavulanic acid in AUGMENTIN protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibiotics. Thus, AUGMENTIN possesses the properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.
Gram-Positive Aerobes
Staphylococcus aureus (β-lactamase and non−β-lactamase−producing)c
cStaphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.
Gram-Negative Aerobes
Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with AUGMENTIN in urinary tract infections caused by these organisms.)
Escherichia coli (β-lactamase and non−β-lactamase−producing)
Haemophilus influenzae (β-lactamase and non−β-lactamase−producing)
Klebsiella species (All known strains are β-lactamase−producing.)
Moraxella catarrhalis (β-lactamase and non−β
