CLINICAL PHARMACOLOGY

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and clavulanate potassium. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium 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 amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The safety and efficacy of amoxicillin and clavulanate potassium have been established in clinical trials where amoxicillin and clavulanate potassium was taken without regard to meals.

Oral administration of single doses of 400 mg/57 mg chewable tablets of amoxicillin and clavulanate potassium and 400 mg/57 mg per 5 mL suspension to 28 adult volunteers yielded comparable pharmacokinetic data:

Dose*	AUC0–∞ (mcg.hr/mL)	Cmax (mcg/mL)†
(amoxicillin and clavulanate potassium)	amoxicillin (±S.D.)	clavulanate potassium (±S.D.)	amoxicillin (±S.D.)	clavulanate potassium (±S.D.)
Administered at the start of a light meal. † Mean values of 28 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
400 mg/57 mg
(5 mL of suspension)	17.29 ± 2.28	2.34 ± 0.94	6.94 ± 1.24	1.10 ± 0.42
400 mg/57 mg
(1 chewable tablet)	17.24 ± 2.64	2.17 ± 0.73	6.67 ± 1.37	1.03 ± 0.33

Oral administration of 5 mL of Amoxicillin and Clavulanate Potassium for Oral Suspension 250 mg/62.5 mg per 5 mL or the equivalent dose of 10 mL of 125 mg/31.25 mg per 5 mL suspension of amoxicillin and clavulanate potassium 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.hr/mL for amoxicillin and 2.9 mcg.hr/mL for clavulanic acid when 5 mL of Amoxicillin and Clavulanate Potassium for Oral Suspension 250 mg/62.5 mg per 5 mL or equivalent dose of 10 mL of 125 mg/31.25 mg per 5 mL suspension of amoxicillin and clavulanate potassium was administered to adult volunteers. One 250 mg/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31.25 mg chewable tablets of amoxicillin and clavulanate potassium are equivalent to 5 mL of Amoxicillin and Clavulanate Potassium for Oral Suspension 250 mg/62.5 mg per 5 mL and provide similar serum levels of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium 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 amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1 hour. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding q12h and q8h dosing regimens of amoxicillin and clavulanate potassium in adults and children.

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 10 mL of Amoxicillin and Clavulanate Potassium for Oral Suspension 250 mg/62.5 mg per 5 mL.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in amoxicillin and clavulanate potassium 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.

Two hours after oral administration of a single 35 mg/kg dose of suspension of amoxicillin and clavulanate potassium 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.

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 amoxicillin and clavulanate potassium 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, amoxicillin and clavulanate potassium possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.

Amoxicillin and 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)1

Gram-Negative Aerobes:

Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with amoxicillin and clavulanate potassium 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 and clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less against most (≥90%) strains of Streptococcus pneumoniae2; 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; 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 and clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-Positive Aerobes:

Enterococcus faecalis 3
Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing)
Staphylococcus saprophyticus (β-lactamase and non-β-lactamase-producing)
Streptococcus pneumoniae 34
Streptococcus pyogenes 34
viridans group Streptococcus 34

Gram-Negative Aerobes:

Eikenella corrodens (β-lactamase and non-β-lactamase-producing)
Neisseria gonorrhoeae 3 (β-lactamase and non-β-lactamase-producing)
Proteus mirabilis 3 (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 species4

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1

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

2

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.

3

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

4

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 and clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin and 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 AND CLAVULANIC ACID SUSCEPTIBILITY TESTING

Staphylococci which are susceptible to amoxicillin and clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.
For Gram-Negative Enteric Aerobes:
MIC (mcg/mL)	Interpretation
≤8/4	Susceptible	(S)
16/8	Intermediate	(I)
≥32/16	Resistant	(R)
For**Staphylococcus***** andHaemophilus species:**
MIC (mcg/mL)	Interpretation
≤4/2	Susceptible	(S)
≥8/4	Resistant	(R)

ForS. pneumoniae from non-meningitis sources: Isolates should be tested using amoxicillin and 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 that 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 and clavulanate potassium powder should provide the following MIC values:

Microorganism	MIC Range (mcg/mL)*
Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.
E. coli ATCC 25922	2 to 8
E. coli ATCC 35218	4 to 16
E. faecalis ATCC 29212	0.25 to 1
H. influenzae ATCC 49247	2 to 16
S. aureus ATCC 29213	0.12 to 0.5
S. pneumoniae ATCC 49619	0.03 to 0.12

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 and clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin and clavulanic acid.

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

RECOMMENDED RANGES FOR AMOXICILLIN AND CLAVULANIC ACID SUSCEPTIBILITY TESTING

Staphylococci which are resistant to methicillin/oxacillin must be considered as resistant to amoxicillin and clavulanic acid. † A broth microdilution method should be used for testing H. influenzae. Beta-lactamase-negative, ampicillin-resistant strains must be considered resistant to amoxicillin and clavulanic acid. ‡ 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 and clavulanic acid. An amoxicillin and clavulanic acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm. § A broth microdilution method should be used for testing N. gonorrhoeae and interpreted according to penicillin breakpoints.
For**Staphylococcus***** species andH. influenzae†****:**
Zone Diameter (mm)	Interpretation
≥20	Susceptible	(S)
≤19	Resistant	(R)
For Other Organisms ExceptS. pneumoniae‡** andN. gonorrhoeae§****:**
Zone Diameter (mm)	Interpretation
≥18	Susceptible	(S)
14 to 17	Intermediate	(I)
≤13	Resistant	(R)

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 and 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 and 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)
E. coli ATCC 25922	19 to 25 mm
E. coli ATCC 35218	18 to 22 mm
S. aureus ATCC 25923	28 to 36 mm