Mechanism of Action
AUGMENTIN is an antibacterial drug. [see Microbiology 12.4
Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of AUGMENTIN Tablets are shown in Table 3 and following administration of AUGMENTIN Powder for Oral Suspension and Chewable Tablets are shown in Table 4.
Table 3: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b with AUGMENTIN Tablets
|Dose and Regimen
|250/125 mg every 8 hours
||3.3 ± 1.12
||1.5 ± 0.70
||26.7 ± 4.56
||12.6 ± 3.25
|500/125 mg every 12 hours
||6.5 ± 1.41
||1.8 ± 0.61
||33.4 ± 6.76
||8.6 ± 1.95
|500 125 mg every 8 hours
||7.2 ± 2.26
||2.4 ± 0.83
||53.4 ± 8.87
||15.7 ± 3.86
|875/125 mg every 12 hours
||11.6 ± 2.78
||2.2 ± 0.99
||53.5 ± 12.31
||10.2 ± 3.04
a Mean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.
b Amoxicillin/clavulanate potassium administered at the start of a light meal.
Table 4: Mean (±S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parametersa,b with AUGMENTIN Powder for Oral Suspension and Chewable Tablets
|400/57 mg(5 mL of suspension)
||6.94 ± 1.24
||1.10 ± 0.42
||17.29 ± 2.28
||2.34 ± 0.94
|400/57 mg(1 chewable tablet)
||6.67 ± 1.37
||1.03 ± 0.33
||17.24 ± 2.64
||2.17 ± 0.73
a Mean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose.
b Amoxicillin/clavulanate potassium administered at the start of a light meal.
Oral administration of 5 mL of 250 mg/5 mL suspension of AUGMENTIN or the equivalent dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension of AUGMENTIN or equivalent dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN were administered to normal adults. One 250-mg chewable tablet of AUGMENTIN or two 125-mg chewable tablets of AUGMENTIN are equivalent to 5 mL of 250 mg/5 mL suspension of AUGMENTIN and provide similar serum concentrations of amoxicillin and clavulanic acid.
Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of AUGMENTIN in adults and children.
Absorption: 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 one study, the relative bioavailability of clavulanate was reduced when AUGMENTIN was dosed at 30 and 150 minutes after the start of a high‑fat breakfast.
Distribution: Neither component in AUGMENTIN is highly protein‑bound; clavulanic acid is 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.
Two hours after oral administration of a single 35 mg/kg dose of suspension of AUGMENTIN to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.
Metabolism and Excretion: The half‑life of amoxicillin after the oral administration of AUGMENTIN is 1.3 hours and that of clavulanic acid is 1 hour.
Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250‑mg or 500‑mg tablet of AUGMENTIN.
Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms 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.
The formulation of amoxicillin and clavulanic acid in AUGMENTIN protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin.
Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Viridans group Streptococcus
Bacteroidesspecies including Bacteroides fragilis
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 5.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method3,4. This procedure uses paper disks impregnated with 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) to test the susceptibility of bacteria to amoxicillin/clavulanic acid. The disc diffusion interpretive criteria are provided in Table 5.
Table 5:Susceptibility Test Interpretive Criteria for Amoxicillin Clavulanic Acid
|Minimum Inhibitory Concentrations (mcg/mL)
||Disk Diffusion (zone diameters in mm)
Haemophilus influenzae and Staphylococcus aureus
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3,4. Standard amoxicillin/clavulanic acid powder should provide the following range of MIC values noted in Table 6 for the diffusion technique using the 30 mcg amoxicillin/clavulanic acid (20 mcg amoxicillin plus 10 mcg clavulanic acid) disk, the criteria in Table 6 should be achieved.
Table 6: Acceptable Quality Control Ranges for Amoxicillin/Clavulanic Acid
||Minimum Inhibitory Concentration (mcg/mL)
||Disk Diffusion(zone diameter in mm)
Escherichia coli ATCC 25922
||2/1 to 8/4
||18 to 24
Escherichia coli ATCC 35218
||4/2 to 16/8
||17 to 22
Haemophilus influenzae ATCC 49247
||2/1 to 16/8
||15 to 23
Staphylococcus aureus ATCC 29213
||0.12/0.06 to 0.5/0.25
Staphylococcus aureus ATCC 29523
||28 to 36
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long‑term studies in animals have not been performed to evaluate carcinogenic potential.
AUGMENTIN (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. AUGMENTIN was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. AUGMENTIN was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays.
AUGMENTIN (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.