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Mechanism Of Action
AUGMENTIN is an antibacterial drug. [see Microbiology]
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||Cmax (mcg/mL)||AUC0-24(mcg*h/mL)|
|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 ±
|10.2 ± 3.04|
|aMean (± standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the lowdose
regimens). Peak concentrations occurred approximately 1.5 hours after the dose.
bAmoxicillin/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
|6.94 ± 1.24||1.10 ± 0.42||17.29 ±
|2.34 ± 0.94|
|400/57 mg(1 chewable
|6.67 ± 1.37||1.03 ± 0.33||17.24 ±
|2.17 ± 0.73|
|aMean (± standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1
hour after the dose.
bAmoxicillin/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.
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.
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 betalactamases 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 s ignificance 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||4/2||-||8/4||>20||-||≤19|
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
|QC Strain||Minimum Inhibitory
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|
Lower Respiratory Tract And Complicated Urinary Tract Infections
Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg tablets of AUGMENTIN every 12 hours to 500 mg tablets of AUGMENTIN dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg every 12 hours and 500 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg every 12 hours regimen versus 2% for the 500 mg every 8 hours regimen.
In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875 mg tablets of AUGMENTIN every 12 hours (n=308) or 500 mg tablets of AUGMENTIN every 8 hours (n=321).
The number of bacteriologically evaluable patients was comparable between the two dosing regimens. AUGMENTIN produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow up visits (5 to 9 days post therapy) and at a late post therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7.
Table 7: Bacteriologic efficacy rates for AUGMENTIN
|Time Post Therapy||875 mg every 12 hours% (n)||500 mg every 8 hours% (n)|
|2 to 4 days||81% (58)||80% (54)|
|5 to 9 days||58% (41)||52% (52)|
|2 to 4 weeks||52% (101)||55% (104)|
As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.
Acute Bacterial Otitis Media And Diarrhea In Pediatric Patients
One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of AUGMENTIN for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of AUGMENTIN for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., ³ 84%) per treatment group. Otitis media specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2 4 days after the completion of therapy) and at the follow up visit (defined as 22 28 days post completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively.
Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively.
It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/5 mL and 400 mg/5 mL) are sweetened with aspartame.
Last reviewed on RxList: 8/31/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Augmentin Information
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