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Augmentin (Amoxicillin / Clavulanate Potassium) - Description and Clinical Pharmacology

 
 



AUGMENTIN®
(amoxicillin/clavulanate potassium)
Tablets

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To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN (amoxicillin/clavulanate potassium) and other antibacterial drugs, AUGMENTIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

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 (2 S, 5 R, 6 R)-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)-(2 R, 5 R)-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 0.63 mEq 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 150 minutes 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.

Mean* amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:

Dose 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.)

250/125 mg q8h

26.7 ± 4.56

12.6 ± 3.25

3.3 ± 1.12

1.5 ± 0.70

500/125 mg q12h

33.4 ± 6.76

8.6 ± 1.95

6.5 ± 1.41

1.8 ± 0.61

500/125 mg q8h

53.4 ± 8.87

15.7 ± 3.86

7.2 ± 2.26

2.4 ± 0.83

875/125 mg q12h

53.5 ± 12.31

10.2 ± 3.04

11.6 ± 2.78

2.2 ± 0.99

* Mean values of 14 normal volunteers (n = 15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.

Administered 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 1.0 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.

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 ofβ-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)

Staphylococci 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-lactamase−producing)

The following in vitro data are available, but their clinical significance is unknown .

Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less against most (≥90%) strains of Streptococcus pneumoniae §; MICs of 0.06 mcg/mL or less against most (≥90%) strains of Neisseria gonorrhoeae ; MICs of 4 mcg/mL or less against most (≥90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 mcg/mL or less against most (≥90%) strains of other listed organisms. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

§ Because amoxicillin has greater in vitro activity against S. pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin.

Gram-Positive Aerobes

Enterococcus faecalis ||

Staphylococcus epidermidis (β-lactamase and non−β-lactamase−producing)

Staphylococcus saprophyticus (β-lactamase and non−β-lactamase−producing)

Streptococcus pneumoniae || ¶

Streptococcus pyogenes || ¶

viridans group Streptococcus || ¶

Gram-Negative Aerobes

Eikenella corrodens (β-lactamase and non−β-lactamase−producing)

Neisseria gonorrhoeae (β-lactamase and non–β-lactamase–producing)

Proteus mirabilis (β-lactamase and non–β-lactamase–producing)

Anaerobic Bacteria

Bacteroides species, including Bacteroides fragilis (β-lactamase and non–β-lactamase–producing)

Fusobacterium species (β-lactamase and non–β-lactamase–producing)

Peptostreptococcus species

Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.

These are non–β-lactamase−producing organisms, and therefore, are susceptible to amoxicillin alone.

Susceptibility Testing

Dilution Techniques

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Gram-Negative Enteric Aerobes

MIC (mcg/mL)

Interpretation

≤8/4

Susceptible (S)

16/8

Intermediate (I)

≥32/16

Resistant (R)

For Staphylococcus** and Haemophilus species

MIC (mcg/mL)

Interpretation

≤4/2

Susceptible (S)

≥8/4

Resistant (R)

** Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

For S. pneumoniae from non-meningitis sources

Isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used:

MIC (mcg/mL)

Interpretation

≤2/1

Susceptible (S)

4/2

Intermediate (I)

≥8/4

Resistant (R)

NOTE: These interpretive criteria are based on the recommended doses for respiratory tract infections.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values:

Microorganism MIC Range (mcg/mL) ††

Escherichia coli ATCC 25922 2 to 8

Escherichia coli ATCC 35218 4 to 16

Enterococcus faecalis ATCC 29212 0.25 to 1.0

Haemophilus influenzae ATCC 49247 2 to 16

Staphylococcus aureus ATCC 29213 0.12 to 0.5

Streptococcus pneumoniae ATCC 49619 0.03 to 0.12

†† Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin/clavulanic acid.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg amoxicillin/clavulanate acid (20 mcg amoxicillin plus 10 mcg clavulanate potassium) disk should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Staphylococcus ‡‡ species and H. influenzaea

Zone Diameter (mm)

Interpretation

≥20

Susceptible (S)

≤19

Resistant (R)

For Other Organisms Except S. pneumoniae and N. gonorrhoea

Zone Diameter (mm)

Interpretation

≥18

Susceptible (S)

14 to 17

Intermediate (I)

≤13

Resistant (R)

‡‡ Staphylococci which are resistant to methicillin/oxacillin must be considered as resistant to amoxicillin/clavulanic acid.

a A broth microdilution method should be used for testing H. influenzae. Beta-lactamase−negative, ampicillin-resistant strains must be considered resistant to amoxicillin/clavulanic acid.

b Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥20 mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm.

c A broth microdilution method should be used for testing N. gonorrhoeae and interpreted according to penicillin breakpoints.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for amoxicillin/clavulanic acid.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg amoxicillin/clavulanate potassium (20-mcg amoxicillin plus 10-mcg clavulanate potassium) disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism Zone Diameter (mm)

Escherichia coli ATCC 25922 19 to 25

Escherichia coli ATCC 35218 18 to 22

Staphylococcus aureus ATCC 25923 28 to 36

CLINICAL STUDIES

Data from 2 pivotal studies 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 q12h to 500-mg tablets of AUGMENTIN dosed q8h (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the q12h and q8h 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 q12h and 500-mg q8h dosing regimens (14.9% and 14.3%, respectively); however, there was a statistically significant difference (p<0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1.0% for 875-mg q12h dosing versus 2.5% for the 500-mg q8h dosing.

In 1 of these pivotal studies, 629 patients with either pyelonephritis or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication) were randomized to receive either 875-mg tablets of AUGMENTIN q12h or 500-mg tablets of AUGMENTIN q8h in the following distribution:

875 mg q12h 500 mg q8h

Pyelonephritis 173 patients 188 patients

Complicated UTI 135 patients 133 patients

Total patients 308 321

The number of bacteriologically evaluable patients was comparable between the 2 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 1 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 the table below:

875 mg q12h 500 mg q8h

2 to 4 days 81%, n = 58 80%, n = 54

5 to 9 days 58.5%, n = 41 51.9%, n = 52

2 to 4 weeks 52.5%, n = 101 54.8%, n = 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.

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