Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal
tract after oral administration of AUGMENTIN XR.
AUGMENTIN XR is an extended-release formulation which provides sustained plasma
concentrations of amoxicillin. Amoxicillin systemic exposure achieved with AUGMENTIN
XR is similar to that produced by the oral administration of equivalent doses
of amoxicillin alone. In a study of healthy adult volunteers, the pharmacokinetics
of AUGMENTIN XR were compared when administered in a fasted state, at the start
of a standardized meal (612 kcal, 89.3 g carb, 24.9 g fat, and 14.0 g protein),
or 30 minutes after a high-fat meal. When the systemic exposure to both amoxicillin
and clavulanate is taken into consideration, AUGMENTIN XR is optimally administered
at the start of a standardized meal. Absorption of amoxicillin is decreased
in the fasted state. AUGMENTIN XR is not recommended to be taken with a high-fat
meal, because clavulanate absorption is decreased. The pharmacokinetics of the
components of AUGMENTIN XR following administration of two AUGMENTIN XR tablets
at the start of a standardized meal are presented below.
Table 1. Mean (SD) Pharmacokinetic Parameters for Amoxicillin
and Clavulanate Following Oral Administration of Two AUGMENTIN XR Tablets (2,000
mg/125 mg) to Healthy Adult Volunteers (n = 55) Fed a Standardized Meal
| Parameter (units) |
Amoxicillin |
Clavulanate |
| AUC(0-inf) (mcg•hr/mL) |
71.6(16.5) |
5.29 (1.55) |
| Cmax (mcg/mL) |
17.0 (4.0) |
2.05 (0.80) |
| Tmax (hours)* |
1.50 (1.00-6.00) |
1.03 (0.75-3.00) |
| T½ (hours) |
1.27 (0.20) |
1.03 (0.17) |
| *Median (range). |
The half-life of amoxicillin after the oral administration of AUGMENTIN XR
is approximately 1.3 hours, and that of clavulanate is approximately 1.0 hour.
Clearance of amoxicillin is predominantly renal, with approximately 60% to
80% of the dose being excreted unchanged in urine, whereas clearance of clavulanate
has both a renal (30% to 50%) and a non-renal component.
Concurrent administration of probenecid delays amoxicillin excretion but does
not delay renal excretion of clavulanate.
In a study of adults, the pharmacokinetics of amoxicillin and clavulanate were
not affected by administration of an antacid (MAALOX®), either simultaneously
with or 2 hours after AUGMENTIN XR.
Neither component in AUGMENTIN XR is highly protein-bound; clavulanate 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,
its spectrum of activity does not include organisms which produce these enzymes.
Clavulanic acid is a β -lactam, structurally related to penicillin, 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 found responsible for transferred drug resistance.
The clavulanic acid component of AUGMENTIN XR 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.
Amoxicillin/clavulanic acid has been shown to be active against most isolates
of the following microorganisms, both in vitro and in clinical infections as
described in the INDICATIONS AND USAGE section.
Aerobic Gram-Positive Microorganisms
Streptococcus pneumoniae (including isolates with penicillin MICs ≤
2 mcg/mL)
Staphylococcus aureus (including β-lactamase–producing isolates)
NOTE: Staphylococci which are resistant to methicillin/oxacillin must
be considered resistant to amoxicillin/clavulanic acid.
Aerobic Gram-Negative Microorganisms
Haemophilus influenzae (including β-lactamase–producing isolates)
Moraxella catarrhalis (including β-lactamase–producing isolates)
Haemophilus parainfluenzae (including β-lactamase–producing isolates)
Klebsiella pneumoniae (all known isolates are β -lactamase–producing)
The following in vitro data are available, but their clinical significance
is unknown. At least 90% of the following microorganisms exhibit in vitro
minimum inhibitory concentrations (MICs) less than or equal to the susceptible
breakpoint for amoxicillin/clavulanic acid.1,2 However, the safety
and efficacy of amoxicillin/clavulanic acid in treating infections due to these
microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms
Streptococcus pyogenes
Anaerobic Microorganisms
Bacteroides fragilis (including β-lactamase–producing isolates)
Fusobacterium nucleatum (including β-lactamase–producing isolates)
Peptostreptococcus magnus
Peptostreptococcus micros
NOTE: S. pyogenes, P. magnus , and P. micros do not produce
β -lactamase, and therefore, are susceptible to amoxicillin alone. Adequate
and well-controlled clinical trials have established the effectiveness of amoxicillin
alone in treating certain clinical infections due to S. pyogenes.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative
results of in vitro susceptibility test results for antimicrobial drugs used
in local hospitals and practice areas 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 the most effective antimicrobial.
Dilution Technique
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
procedure. 1,3 Standardized procedures are based on dilution methods
(broth or agar; broth for S. pneumoniae and H. influenzae)
or equivalent with standardized inoculum concentration 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 criteria provided in Table
2.
Diffusion Technique
Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobials.
One such standardized technique requires the use of a standardized inoculum
concentration. 1,4 This procedure uses paper disks impregnated with
30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate
potassium) to test susceptibility of microorganisms to amoxicillin/clavulanate
potassium. Disk diffusion zone sizes should be interpreted according to criteria
provided in Table 2.
Table 2. Susceptibility Test Result Interpretive Criteria
for Amoxicillin/Clavulanate Potassium
| Pathogen |
Minimum Inhibitory
Concentration (mcg/mL) |
Disk Diffusion
(Zone Diameter in mm) |
| S |
I |
R |
S |
I |
R |
| Haemophilus spp. |
≤ 4/2 |
Not applicable (NA) |
≥ 8/4 |
≥ 20 |
NA |
≤ 19 |
| Klebsiella pneumoniae |
≤ 8/4 |
16/8 |
≥ 32/16 |
≥ 18 |
14 to 17 |
≤ 13 |
| Staphylococcus spp. |
≤ 4/2 |
NA |
≥ 8/4 |
≥ 20 |
NA |
≤ 19 |
| Streptococcus pneumoniae |
≤ 2/1 |
4/2 |
≥ 8/4 |
NA |
NOTE: 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/clavulanate acid. An amoxicillin/clavulanate acid
MIC should be determined on isolates of S. pneumoniae with oxacillin
zone sizes of ≤ 19 mm.
NOTE: β-lactamase–negative, ampicillin-resistant H. influenzae
isolates must be considered resistant to amoxicillin/clavulanic acid.
A report of S (“Susceptible”) indicates that the antimicrobial
is likely to inhibit growth of the pathogen if the antimicrobial compound in
the blood reaches the concentration usually achievable. A report of I (“Intermediate”)
indicates that the result should be considered equivocal, and, if the microorganism
is not fully susceptible to alternative, clinically feasible antimicrobials,
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 doses of antimicrobial 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 R ("Resistant") indicates
that the antimicrobial is not likely to inhibit growth of the pathogen if the
antimicrobial compound in the blood reaches the concentration usually achievable;
other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control
microorganisms to determine the performance of the test procedures.1,3,4
Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges
for the quality control organisms in Table 3. For the disk diffusion technique,
the 30 mcg amoxicillin/clavulanate potassium disk should provide the zone diameter
ranges for the quality control organisms in Table 3.
Table 3. Acceptable Quality Control Ranges for Amoxicillin/Clavulanate
Potassium
| Quality Control Organism |
Minimum Inhibitory Concentration Range
(mcg/mL) |
Disk Diffusion
(Zone Diameter Range in mm) |
| Escherichia coli ATCC®* 35218† (H. influenzae quality
control) |
4/2 to 16/8 |
17 to 22 |
| Escherichia coli ATCC 25922 |
2/1 to 8/4 |
18 to 24 |
| 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 |
Not applicable (NA) |
| Staphylococcus aureus ATCC 25923 |
NA |
28 to 36 |
| Streptococcus pneumoniae ATCC 49619 |
0.03/0.015 to 0.12/0.06 |
NA |
*ATCC is a trademark of the American Type
Culture Collection.
† When using Haemophilus Test Medium (HTM). |
Clinical Studies
Acute Bacterial Sinusitis: Adults with a diagnosis of acute bacterial
sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients
were randomized to receive either AUGMENTIN XR 2,000 mg/125 mg orally every
12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind,
multicenter, prospective trial. These patients were clinically and radiologically
evaluated at the test of cure (day 17-28) visit. The combined clinical and radiological
responses were 83.7% for AUGMENTIN XR and 84.3% for levofloxacin at the test
of cure visit in clinically evaluable patients (95% CI for the treatment difference
= -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and
88.6%, respectively.
The other 2 trials were non-comparative, multicenter studies designed to assess
the bacteriological and clinical efficacy of AUGMENTIN XR (2,000 mg/125 mg orally
q12h for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints
were the same as in the prior study. Patients underwent maxillary sinus puncture
for culture prior to receiving study medication. At test of cure, the clinical
success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1%
(per protocol populations).
Patients with acute bacterial sinusitis due to S. pneumoniae with reduced
susceptibility to penicillin were accrued through enrollment in these 2 open-label
non-comparative clinical trials. Microbiologic eradication rates for key pathogens
in these studies are shown in the following table:
Clinical Outcome for ABS
| Penicillin MICs of S. pneumoniae
Isolates |
Intent-To-Treat |
Clinically Evaluable |
| n/N* |
% |
95% CI † |
n/N* |
% |
95% CI † |
| All S. pneumoniae |
344/370 |
93.0 |
— |
318/326 |
97.5 |
— |
| MIC ≥ 2.0 mcg/mL‡ |
35/36 |
97.2 |
85.5, 99.9 |
30/31 |
95.8 |
83.3, 99.9 |
| MIC = 2.0 mcg/mL |
23/24 |
95.8 |
78.9, 99.9 |
19/20 |
95.0 |
75.1, 99.9 |
| MIC ≥ 4.0 mcg/mL§ |
12/12 |
100 |
73.5, 100 |
11/11 |
100 |
71.5, 100 |
| H. influenzae |
265/305 |
86.9 |
— |
242/259 |
93.4 |
— |
| M. catarrhalis |
94/105 |
89.5 |
— |
86/90 |
95.6 |
— |
*n/N = patients with pathogen eradicated
or presumed eradicated/total number of patients.
†Confidence limits calculated using exact probabilities.
‡S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL
are considered resistant to penicillin.
§Includes one patient each with S. pneumoniae penicillin MICs
of 8 and 16 mcg/mL. |
Community-Acquired Pneumonia
Four randomized, controlled, double-blind clinical studies and one non-comparative
study were conducted in adults with community-acquired pneumonia (CAP). In comparative
studies, 904 patients received AUGMENTIN XR at a dose of 2,000 mg/125 mg orally
every 12 hours for 7 or 10 days. In the non-comparative study to assess both
clinical and bacteriological efficacy, 1,122 patients received AUGMENTIN XR
2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies,
the combined clinical success rate at test of cure ranged from 86.3% to 94.7%
in clinically evaluable patients who received AUGMENTIN XR; in the non-comparative
study, the clinical success rate was 85.6%.
Data on the efficacy of AUGMENTIN XR in the treatment of community-acquired
pneumonia due to S. pneumoniae with reduced susceptibility to penicillin
were accrued from the 4 controlled clinical studies and the 1 non-comparative
study. The majority of these cases were accrued from the non-comparative study.
Clinical Outcome for CAP due to S. pneumoniae
| Penicillin MICs of S. pneumoniae
Isolates |
Intent-To-Treat |
Clinically Evaluable |
| n/N* |
% |
95% CI † |
n/N* |
% |
95% CI † |
| All S. pneumoniae |
318/367 |
86.6 |
— |
275/297 |
92.6 |
— |
| MIC ≥2.0 mcg/mL‡ |
30/35 |
85.7 |
69.7, 95.2 |
24/25 |
96.0 |
79.6, 99.9 |
| MIC = 2.0 mcg/mL |
22/24 |
91.7 |
73.0, 99.0 |
18/18 |
100 |
81.5, 100 |
| MIC ≥ 4.0 mcg/mL§ |
8/11 |
72.7 |
39.0, 94.0 |
6/7 |
85.7 |
42.1, 99.6 |
*n/N = patients with pathogen eradicated
or presumed eradicated/total number of patients.
†Confidence limits calculated using exact probabilities.
‡S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL
are considered resistant to penicillin.
§Includes one patient each with S. pneumoniae penicillin MICs
of 8 and 16 mcg/mL in the Intent-To-Treat group only. |
Safety: In 2 randomized, double-blind, multicenter studies, AUGMENTIN
XR (2,000 mg/125 mg orally q12h, n = 577) was compared to AUGMENTIN (875 mg/125
mg orally q12h, n = 570), administered for 7 days for the treatment of community-acquired
pneumonia. Adverse events, regardless of relationship to test drug, were reported
by 44.4% of patients who received AUGMENTIN XR (versus 46.3% in comparator group).
Treatment-related adverse events were reported in 21.7% of patients who received
AUGMENTIN XR (versus 21.2% in comparator group); most were mild and transient
in nature. Adverse events which led to withdrawal were reported by 2.8% of patients
who received AUGMENTIN XR (versus 5.3% in comparator group). In each group,
the most frequently reported adverse events were diarrhea (14.4% versus 13.0%,
p = 0.47), nausea (3.5 % versus 4.4%), and headache (3.5% versus 3.2%). Only
2 patients (0.3%) who received AUGMENTIN XR and 3 patients (0.5%) in the comparator
group withdrew due to diarrhea. Serious adverse events considered suspected
or probably related to test drug were reported in 0.3% of patients (versus 0.5%
in comparator).
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI) (formerly
the National Committee for Clinical Laboratory Standards). Performance Standards
for Antimicrobial Susceptibility Testing – Fifteenth Informational Supplement.
CSLI Document M100-S15. CLSI, Wayne, PA, 2005.
2. Clinical and Laboratory Standards Institute (CLSI) (formerly
the National Committee for Clinical Laboratory Standards). Methods for Antimicrobial
Susceptibility Testing of Anaerobic Bacteria –Sixth Edition. Approved Standard
CSLI Document M11-A6, Vol. 24, No. 2. CLSI, Wayne, PA, 2004.
3. Clinical and Laboratory Standards Institute (CLSI) (formerly
the National Committee for Clinical Laboratory Standards). Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – Sixth
Edition. Approved Standard CLSI Document M7-A6, Vol. 23, No. 2. CLSI, Wayne,
PA, 2003.
4. Clinical and Laboratory Standards Institute (CLSI) (formerly
the National Committee for Clinical Laboratory Standards). Performance Standards
for Antimicrobial Disk Susceptibility Tests – Eighth Edition. Approved Standard
CLSI Document M2-A8, Vol. 23, No. 1. CLSI, Wayne, PA, 2003.
Last updated on RxList: 2/12/2009