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Augmentin XR

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Augmentin XR

CLINICAL PHARMACOLOGY

Mechanism Of Action

AUGMENTIN XR is an antibacterial drug. [see Microbiology]

Pharmacokinetics

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.

Absorption

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of AUGMENTIN XR.

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 in Table 1.

Table 1: Mean (SD) Pharmacokinetic Parameter 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)a 1.50 (1.00 -6.00) 1.03 (0.75 -3.00)
T½ (hours) 1.27 (0.20) 1.03 (0.17)
aMedian (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.

Distribution

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.

Excretion

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.

Drug Interactions

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanate. [see DRUG INTERACTIONS].

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.

Pediatrics

In a study of pediatric patients with acute bacterial sinusitis, 7 to 15 years of age, and weighing at least 40 kg, the pharmacokinetics of amoxicillin and clavulanate were assessed following administration of AUGMENTIN XR 2000 mg/125 mg (as two 1000 mg/62.5 mg tablets) every 12 hours with food (Table 2).

Table 2: Mean (SD) Pharmacokinetic Parameters for Amoxicillin and Clavulanate Following Oral Administration of Two AUGMENTIN XR Tablets (2,000 mg/125 mg) Every 12 Hours With Food to Pediatric Patients (7 to 15 Years of Age and Weighing ≥ 40kg) With Acute Bacterial Sinusitis

Parameter (units) Amoxicillin
(n=24)
Clavulanate
(n=23)
AUC(0-τ) (mcg•hr/mL) 57.8 (15.6) 3.18 (1.37)
Cmax (mcg/mL) 11.0 (3.34) 1.17 (0.67)
Tmax (hours)a 2.0 (1.0 -5.0) 2.0 (1.0-4.0)
T½(hours) 3.32 (2.21)b 0.94 (0.13)c
a Median (range)
bn=18.
cn=17.

Microbiology

Mechanism of Action

Amoxicillin binds to penicillin-binding proteins within the bacterial cell wall and inhibits bacterial cell wall synthesis. Clavulanic acid is a β-lactam, structurally related to penicillin, that may inactivate certain β-lactamase enzymes.

Mechanism of Resistance

Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibiotic to reach the target site. Amoxicillin alone is susceptible to degradation by β­lactamases, and therefore its spectrum of activity does not include bacteria that produce these enzymes.

Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive Bacteria

Staphylococcus aureus
Streptococcus pneumoniae

Gram-negative Bacteria

Haemophilus influenzae
Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

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

At least 90 percent of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid.1 However, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Streptococcus 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 an antibacterial drug product for treatment.

Dilution Techniques

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 test method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.1,3 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 interpretive criteria should be interpreted according to criteria provided in Table 3.

Table 3: Susceptibility Interpretive Criteria for Amoxicillin/ Clavulanate Potassium

Pathogen Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion Zone Diameter (mm)
S I R S I R
Streptococcus pneumoniae (nonmeningitis isolates) ≤ 2/1 4/2 ≥ 8/4 - - -
Haemophilus spp. ≤ 4/2 - ≥ 8/4 ≥ 20 - ≤ 19
Klebsiella pneumonia ≤ 8/4 16/8 ≥ 32/16 ≥ 18 14 to 17 ≤ 13
S= Susceptible, I=Intermediate, R=Resistant

NOTE: Susceptibility of staphylococci to amoxicillin/clavulanate may be deduced from testing only penicillin and either cefoxitin or oxacillin.

NOTE: Susceptibility of S. pneumoniae by disk diffusion should be determined using a 1mcg oxacillin disk.

NOTE: For nonmeningitis isolates, a penicillin MIC of ≤ 0.06 mcg/ml (or oxacillin zone ≥ 20 mm) can predict susceptibility to amoxicillin/clavulanate.1

NOTE: Beta-lactamase–negative, ampicillin-resistant (BLNAR) H. influenzae isolates should be considered resistant to amoxicillin/clavulanic acid, despite apparent in vitro susceptibility of some BLNAR isolates to these agents.1

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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. 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 antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3 Standard amoxicillin/clavulanate potassium powder should provide the following range of MIC noted in Table 4. For the disk diffusion technique using the 30 mcg amoxicillin/clavulanate potassium disk, the criteria in Table 4 should be achieved.

Table 4: Acceptable Quality Control Ranges for Susceptibility Testing

Quality Control Organism Minimum Inhibitory Concentration Range (mcg/mL) Disk Diffusion Zone Diameters (mm)
Escherichia coli ATCC®abc 35218 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 -
Staphylococcus aureus ATCC 25923 - 28 to 36
Streptococcus pneumoniae ATCC 49619 0.03/0.015 to 0.12/0.06 -
aATCC = American Type Culture Collection.
bQC strain recommended for testing beta-lactam/beta-lactamase inhibitor combinations.
cThis strain may lose its plasmid and develop susceptibility to beta-lactam antimicrobial agents after repeated transfers onto media. Minimize by removing new culture from storage at least monthly, or whenever the strain begins to show increased zone diameters to ampicillin, piperacillin or ticarcillin. 1

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 84% for AUGMENTIN XR and 84% 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% and 89%, 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 every 12 hours 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. 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 Table 5.

Table 5: Clinical Outcome for ABS

Penicillin MICs of S. pneumoniae Isolates Intent-To-Treat Clinically Evaluable
n/Na % 95% CIb n/Na % 95% CIb
All S. pneumonia 344/370 93 318/326 98
MIC ≥ 2.0 mcg/mLc 35/36 97 85.5, 99.9 30/31 96 83.3, 99.9
MIC = 2.0 mcg/mL 23/24 96 78.9, 99.9 19/20 95 75.1, 99.9
MIC ≥ 4.0 mcg/mLd 12/12 100 73.5, 100 11/11 100 71.5, 100
H. influenzae 265/305 87 242/259 93
M. catarrhalis 94/105 90 86/90 96
an/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
bConfidence limits calculated using exact probabilities.
cS. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.
dIncludes 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% to 95% in clinically evaluable patients who received AUGMENTIN XR.

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. Results are shown in Table 6.

Table 6: Clinical Outcome for CAP due to S. pneumonia

Penicillin MICs of S.pneumonia Isolates Intent-To-Treat Clinically Evaluable
n/Na % 95% CIb n/Na % 95% CIb
All S. pneumoniae 318/367 87 275/297 93
MIC ≥ 2.0 mcg/mLc 30/35 86 69.7, 95.2 24/25 96 79.6, 99.9
MIC = 2.0 mcg/mL 22/24 92 73.0, 99.0 18/18 100 81.5, 100
MIC ≥ 4.0 mcg/mLd 8/11 73 39.0, 94.0 6/7 86 42.1, 99.6
an/N = patients with pathogen eradicated or presumed eradicated/total number of patients.
bConfidence limits calculated using exact probabilities.
cS. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.
dIncludes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard -Ninth Edition. CLSI Document M7-A9 Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Eleventh Edition. CLSI Document M2-A11. Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

Last reviewed on RxList: 4/25/2014
This monograph has been modified to include the generic and brand name in many instances.

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