Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin/clavulanate potassium. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin/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/clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The safety and efficacy of amoxicillin/clavulanate potassium have been established in clinical trials where amoxicillin/clavulanate potassium 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 |
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 amoxicillin/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/clavulanate potassium 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 amoxicillin/clavulanate
potassium.
Concurrent administration of probenecid delays amoxicillin excretion but does
not delay renal excretion of clavulanic acid.
Neither component in amoxicillin/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.
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/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/clavulanate potassium 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.
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
amoxicillin/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/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)†† |
| E. coli ATCC 25922 |
2 to 8 |
| E. coli ATCC 35218 |
4 to 16 |
| E. faecalis ATCC 29212 |
0.25 to 1.0 |
| 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 |
| †† 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 potassium (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. pneumoniaeb and
N. gonorrhoeaec: |
| 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) |
| E. coli ATCC 25922 |
19 to 25 |
| E. coli ATCC 35218 |
18 to 22 |
| S. 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 amoxicillin/clavulanate potassium tablets q12h to 500 mg amoxicillin/clavulanate
potassium tablets 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 amoxicillin/clavulanate potassium tablets
q12h or 500-mg amoxicillin/clavulanate potassium tablets 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. Amoxicillin/clavulanate potassium 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.
REFERENCES
1. National Committee for Clinical Laboratory Standards. Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third
Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. NCCLS, Villanova,
PA, December 1993.
2. National Committee for Clinical Laboratory Standards. Performance Standards
for Antimicrobial Disk Susceptibility Tests - Fifth Edition. Approved Standard
NCCLS Document M2-A5, Vol. 13, No. 24. NCCLS, Villanova, PA, December 1993.
Last updated on RxList: 1/23/2009