CLINICAL
PHARMACOLOGY
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 one 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.
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; clavulanate potassium 250 mg/5 ml
suspension.
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.
Oral Suspension and Chewable Tablets
Oral administration of single
doses of 400 mg amoxicillin; clavulanate potassium chewable
tablets and 400 mg/5 ml suspension to 28 adult volunteers
yielded comparable pharmacokinetic data (see TABLE 1).
| TABLE 1
|
| Dose* |
AUC0-¥
(µg·hr/ml) |
Cmax
(µg/ml)† |
| (amoxicillin; clavulanate
potassium) |
amoxicillin (±S.D.) |
clavulanate potassium
(±S.D.) |
amoxicillin (±S.D.) |
clavulanate potassium
(±S.D.) |
| 400/57 mg (5 ml of suspension) |
17.29 ±2.28 |
2.34 ±0.94 |
6.94 ±1.24 |
1.10 ±0.42 |
| 400/57 mg (one chewable
tablet) |
17.24 ±2.64 |
2.17 ±0.73 |
6.67 ±
1.37 |
1.03 ±0.33 |
| * Administered
at the start of a light meal. |
| † Mean
values of 28 normal volunteers. Peak concentrations
occurred approximately 1 hour after the dose. |
Oral administration of 5 ml
of amoxicillin; clavulanate potassium 250 mg/5 ml suspension
or the equivalent dose of 10 ml amoxicillin; clavulanate
potassium 125 mg/5 ml suspension 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; clavulanate potassium 250
mg/5 ml suspension or equivalent dose of 10 ml of amoxicillin;
clavulanate potassium 125 mg/5 ml suspension was administered
to adult volunteers. One amoxicillin; clavulanate potassium
250 mg chewable tablet or 2 amoxicillin; clavulanate potassium
125 mg chewable tablets are equivalent to 5 ml of amoxicillin;
clavulanate potassium 250 mg/5 ml suspension and provide
similar serum levels of amoxicillin and clavulanic acid.
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. Time above the minimum inhibitory
concentration of 1.0 mcg/ml for amoxicillin has been shown
to be similar after corresponding q12h and q8h dosing regimens
of amoxicillin; clavulanate potassium in adults and children.
Two hours after oral administration of a single 35 mg/kg
dose of amoxicillin; clavulanate potassium suspension to
fasting children, average concentrations of 3.0 mcg/ml of
amoxicillin and 0.5 mcg/ml of clavulanic acid were detected
in middle ear effusions.
Tablets
Mean* amoxicillin; clavulanate
potassium pharmacokinetic parameters are shown in TABLE
2.
| TABLE 2
|
| Dose† and regimen |
AUC0-24
(µg·hr/ml) |
Cmax
(µg/ml) |
| amoxicillin; clavulanate
potassium |
amoxicillin (±
SD) |
clavulanate potassium
(± SD) |
amoxicillin (±
SD) |
clavulanate potassium
(± SD) |
|
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
is 1.3 hours and that of clavulanic acid is 1.0 hour.
Oral Suspension, Chewable Tablets and Tablets
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 b-lactamases and, therefore,
the spectrum of activity does not include organisms which
produce these enzymes. Clavulanic acid is a b-lactam, structurally
related to the penicillins, which possesses the ability
to inactivate a wide range of b-lactamase enzymes commonly
found in microorganisms resistant to penicillins and cephalosporins.
In particular, it has good activity against the clinically
important plasmid mediated b-lactamases frequently responsible
for transferred drug resistance.
The formulation of amoxicillin and clavulanic acid in amoxicillin;
clavulanate potassium protects amoxicillin from degradation
by b-lactamase enzymes and effectively extends the antibiotic
spectrum of amoxicillin to include many bacteria normally
resistant to amoxicillin and other b-lactam antibiotics.
Thus, amoxicillin; clavulanate potassium possesses the distinctive
properties of a broad-spectrum antibiotic and a b-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 (b-lactamase and non-b-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 (b-lactamase and non-b-lactamase producing).
Haemophilus influenzae (b-lactamase and non-b-lactamase
producing).
Klebsiella species (All known strains are b-lactamase producing).
Moraxella catarrhalis (b-lactamase and non-b-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 0.5 mcg/ml or less against most
(³90%) strains of Streptococcus pneumoniae*; MICs of
0.06 mcg/ml or less against most (³90%) strains of
Neisseria gonorrhoeae; MICs of 4 mcg/ml or less against
most (³90%) strains of staphylococci and anaerobic
bacteria; and MICs of 8 mcg/ml or less against most (³90%)
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
Streptococcus 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 (b-lactamase and non-b-lactamase
producing).
Staphylococcus saprophyticus (b-lactamase and non-b-lactamase
producing).
Streptococcus pneumoniae.*†
Streptococcus pyogenes.*†
viridans group Streptococcus.*†
Gram-Negative Aerobes:
Eikenella corrodens (b-lactamase and non-b-lactamase producing).
Neisseria gonorrhoeae* (b-lactamase and non-b-lactamase
producing).
Proteus mirabilis* (b-lactamase and non-b-lactamase producing).
Anaerobic Bacteria:
Bacteroides species, including Bacteroides fragilis
(b-lactamase and non-b-lactamase producing).
Fusobacterium species (b-lactamase and non-b-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-b-lactamase-producing organisms and,
therefore, are susceptible to amoxicillin alone.
Susceptibility Testing
Dilution Techniques
Quantitative methods are used to determine antimicrobial
minimal inhibitory concentrations (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 party clavulanic acid. The MIC values should
be interpreted according to the following criteria found
in TABLE 3.
| TABLE 3
Recommended Ranges for Amoxicillin/Clavulanic Acid
Susceptibility Testing |
| For Gram-Negative
Enteric Aerobes |
| MIC (µg/ml) |
Interpretation |
| £
8/4 |
Susceptible (S) |
| 16/8 |
Intermediate (I) |
| ³32/16 |
Resistant (R) |
| For Staphylococcus*
and Haemophilus Species |
| £4/2 |
Susceptible (S) |
| ³8/4 |
Resistant (R) |
| * Staphylococci
which are susceptible to amoxicillin/clavulanic
acid but resistant to methicillin/oxacillin must
be considered as resistant. |
For Streptococcus pneumoniae Isolates should be tested using
amoxicillin/clavulanic acid and the criteria found in TABLE
4 should be used.
| TABLE 4 |
| MIC (µg/ml) |
Interpretation |
| £
0.5/0.25 |
Susceptible (S) |
| 1/0.5 |
Intermediate (I) |
| ³
2/1 |
Resistant (R) |
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/clavulanate
potassium powder should provide the MIC values found in
TABLE 5.
| TABLE 5
|
| Microorganism |
MIC Range (µg/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 party 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 criteria found
in TABLE 6.
| TABLE 6
Recommended Ranges For Amoxicillin/Clavulanic Acid
Susceptibility Testing |
| For Staphylococcus*
species
and H. influenzae† |
| Zone Diameter (mm) |
Interpretation |
| ³
20 |
Susceptible (S) |
| £
19 |
Resistant (R) |
| For Other
Organisms Except S. Pneumoniae‡ and N. Gonorrhoeae§ |
| ³
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 broth
microdilution method
should be used for testing H. influenzae. Beta-lactamase
negative, ampicillin-resistant strains must be considered
resistant to amoxicillin/clavulanic acid. |
| ‡ Susceptibility
of S. pneumoniae should be determined using a 1
mcg oxacillin
disk. Isolates with oxacillin
zone sizes of ³20
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. |
| §
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 zone diameters found in TABLE 7
in these laboratory quality control strains.
| TABLE 7
|
| Microorganism |
Zone Diameter (mm) |
| Escherichia
coli ATCC 25922 | 19 to 25 mm |
| Escherichia
coli ATCC 35218 | 18 to 22 mm |
| Staphylococcus
aureus ATCC 25923 | 28 to 36 mm |
CLINICAL STUDIES
Oral Suspension and Chewable Tablets
In pediatric patients (aged 2 months to 12 years),
one U.S./Canadian clinical trial was conducted which compared
amoxicillin; clavulanate potassium 45/6.4 mg/kg/day (divided
q12h) for 10 days versus amoxicillin; clavulanate potassium
40/10 mg/kg/day (divided q8h) for 10 days in the treatment
of acute otitis media. Only the suspension formulations
were used in this trial. A total of 575 patients were enrolled,
with an even distribution among the two treatment groups
and a comparable number of patients were evaluable (i.e.,
³84%) per treatment group. Strict 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 to 4 days after the completion of therapy)
and at the follow-up visit (defined as 22 to 28 days post-completion
of therapy) were comparable for the two treatment groups,
with the following cure rates obtained for the evaluable
patients: At end of therapy, 87.2% (n=265) and 82.3% (n=260)
for 45 mg/kg/day q12h and 40 mg/kg/day q8h, respectively.
At follow-up, 67.1% (n=249) and 68.7% (n=243) for 45 mg/kg/day
q12h and 40 mg/kg/day q8h, respectively.
The incidence of diarrhea* was significantly lower in patients
in the q12h treatment group compared to patients who received
the q8h regimen (14.3% and 34.3%, respectively). In addition,
the number of patients with either severe diarrhea or who
were withdrawn with diarrhea was significantly lower in
the q12h treatment group (3.1% and 7.6% for the q12h/10
day and q8h/10 day, respectively). In the q12h treatment
group, three patients (1.0%) were withdrawn with an allergic
reaction, while one patient (0.3%) in the q8h group was
withdrawn for this reason. The number of patients with a
candidal infection of the diaper area was 3.8% and 6.2%
for the q12h and q8h groups, respectively.
It is not known if the finding of a statistically significant
reduction in diarrhea with the oral suspensions dosed q12h,
versus suspensions dosed q8h, can be extrapolated to the
chewable tablets. The presence of mannitol in the chewable
tablets may contribute to a different diarrhea profile.
The q12h oral suspensions are sweetened with aspartame only.
*Diarrhea was defined as either: (a) three or more watery
or four or more loose/watery stools in one day; OR (b) two
watery stools per day or three loose/watery stools per day
for two consecutive days.
Tablets
Data from two pivotal studies in 1191 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 one 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 TABLE 8.
| TABLE 8 |
| |
875 mg q12 h |
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 two 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 the 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 9.
| TABLE 9 |
| |
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.
|
|
