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Augmentin ES

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Augmentin ES

Augmentin ES

CLINICAL PHARMACOLOGY

The pharmacokinetics of amoxicillin and clavulanate were determined in a study of 19 pediatric patients, 8 months to 11 years, given AUGMENTIN ES-600 at an amoxicillin dose of 45 mg/kg every 12 hours with a snack or meal. The mean plasma amoxicillin and clavulanate pharmacokinetic parameter values are listed in the following table.

Table 1: Mean (±SD) Plasma Amoxicillin and Clavulanate Pharmacokinetic Parameter Values Following Administration of 45 mg/kg of AUGMENTIN ES-600 Every 12 Hours to Pediatric Patients

Parametera Amoxicillin Clavulanate
Cmax (mcg/mL) 15.7 ±7.7 1.7 ±0.9
Tmax (hr) 2.0 (1.0 – 4.0) 1.1 (1.0 – 4.0)
AUC0-t (mcg•hr/mL) 59.8 ±20.0 4.0 ±1.9
T½ (hr) 1.4 ±0.3 1.1 ±0.3
CL/F (L/hr/kg) 0.9 ±0.4 1.1 ±1.1
a Arithmetic mean ± standard deviation, except Tmax values which are medians (ranges).

The effect of food on the oral absorption of AUGMENTIN ES-600 has not been studied.

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 250 mg/5 mL suspension of AUGMENTIN.

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

Neither component in AUGMENTIN ES-600 is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Oral administration of a single dose of AUGMENTIN ES-600 at 45 mg/kg (based on the amoxicillin component) to pediatric patients, 9 months to 8 years, yielded the following pharmacokinetic data for amoxicillin in plasma and middle ear fluid (MEF).

Table 2: Amoxicillin Concentrations in Plasma and Middle Ear Fluid Following Administration of 45 mg/kg of AUGMENTIN ES-600 to Pediatric Patients

Timepoint Amoxicillin concentration in plasma (mcg/mL) Amoxicillin concentration in MEF (mcg/mL)
1 hour mean 7.7 3.2
median 9.3 3.5
range 1.5 – 14.0 0.2 – 5.5
(n = 5) (n = 4)
2 hour mean 15.7 3.3
median 13.0 2.4
range 11.0 – 25.0 1.9 – 6
(n = 7) (n = 5)
3 hour mean 13.0 5.8
median 12.0 6.5
range 5.5 – 21.0 3.9 – 7.4
(n = 5) (n = 5)

Dose administered immediately prior to eating.

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 ES-600 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, AUGMENTIN ES-600 possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.

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)

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae (including β-lactamase–producing isolates)
Moraxella catarrhalis
(including β-lactamase–producing isolates)

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. 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

Staphylococcus aureus (including β-lactamase–producing isolates)

NOTE: Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid. Streptococcus pyogenes

NOTE: S. pyogenes 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.1,2 Standardized procedures are based on dilution methods (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 3.

Diffusion Technique: Quantitative methods that require measurement of zone diameters also provides reproducible estimates of the susceptibility of bacteria to antimicrobials. One such standardized technique requires the use of a standardized inoculum concentration.2,3 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 zone sizes should be interpreted according to criteria provided in Table 3.

Table 3: 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
Streptococcus pneumoniae (non­meningitis isolates) ≤ 2/1 4/2 ≥ 8/4   Not applicable (NA)  
Haemophilus influenzae ≤ 4/2 NA ≥ 8/4 ≥ 20 NA ≤ 19

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/clavulanic acid. An amoxicillin/clavulanic 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 Standard amoxicillin/clavulanate potassium powder should provide the MIC ranges for the quality control organisms in Table 4. 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 4.

Table 4: 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®a 35218b (H. influenzae quality control) 4/2 to 16/8 17 to 22
Haemophilus influenzae ATCC 49247 2/1 to 16/8 15 to 23
Streptococcus pneumoniae ATCC 49619 0.03/0.016 to 0.12/0.06 NA
a ATCC is a trademark of the American Type Culture Collection.
b When using Haemophilus Test Medium (HTM).

Description of Clinical Studies

Two clinical studies were conducted in pediatric patients with acute otitis media.

A non-comparative, open-label study assessed the bacteriologic and clinical efficacy of AUGMENTIN ES-600 (90/6.4 mg/kg/day, divided every 12 hours) for 10 days in 521 pediatric patients (3 to 50 months) with acute otitis media. The primary objective was to assess bacteriological response in children with acute otitis media due to S. pneumoniae with amoxicillin/clavulanic acid MICs of 4 mcg/mL. The study sought the enrollment of patients with the following risk factors: Failure of antibiotic therapy for acute otitis media in the previous 3 months, history of recurrent episodes of acute otitis media, ≤ 2 years, or daycare attendance. Prior to receiving AUGMENTIN ES-600, all patients had tympanocentesis to obtain middle ear fluid for bacteriological evaluation. Patients from whom S. pneumoniae (alone or in combination with other bacteria) was isolated had a second tympanocentesis 4 to 6 days after the start of therapy. Clinical assessments were planned for all patients during treatment (4-6 days after starting therapy), as well as 2-4 days post-treatment and 15-18 days post-treatment. Bacteriological success was defined as the absence of the pretreatment pathogen from the on-therapy tympanocentesis specimen. Clinical success was defined as improvement or resolution of signs and symptoms. Clinical failure was defined as lack of improvement or worsening of signs and/or symptoms at any time following at least 72 hours of AUGMENTN ES-600 (amoxicillin/clavulanate potassium); patients who received an additional systemic antibacterial drug for otitis media after 3 days of therapy were considered clinical failures. Bacteriological eradication on therapy (day 4-6 visit) in the per protocol population is summarized in Table 5.

Table 5: Bacteriologic Eradication Rates in the Per Protocol Population

Pathogen Bacteriologic Eradication on Therapy
n/N % 95% CI a
All S. pneumoniae 121/123 98.4 (94.3, 99.8)
S. pneumoniae with penicillin MIC = 2 mcg/mL 19/19 100 (82.4, 100.0)
S. pneumoniae with penicillin MIC = 4 mcg/mL 12/14 85.7 (57.2, 98.2)
H. influenzae 75/81 92.6 (84.6, 97.2)
M. catarrhalis 11/11 100 (71.5, 100.0)
a CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons.

Clinical assessments were made in the per protocol population 2-4 days post-therapy and 15-18 days post-therapy. Patients who responded to therapy 2-4 days post-therapy were followed for 15-18 days post-therapy to assess them for acute otitis media. Nonresponders at 2-4 days post-therapy were considered failures at the latter timepoint.

Table 6: Clinical Assessments in the Per Protocol Population (Includes S. pneumoniae Patients With Penicillin MICs = 2 or 4 mcg/mLa)

Pathogen 2-4 Days Post-Therapy (Primary Endpoint)
n/N % 95% CI b
All S. pneumoniae 122/137 89.1 (82.6, 93.7)
S. pneumoniae with penicillin MIC = 2 mcg/mL 17/20 85.0 (62.1, 96.8)
S. pneumoniae with penicillin MIC = 4 mcg/mL 11/14 78.6 (49.2, 95.3)
H. influenzae 141/162 87.0 (80.9, 91.8)
M. catarrhalis 22/26 84.6 (65.1, 95.6)
  15-18 Days Post-Therapyc (Secondary Endpoint)
Pathogen n/N % 95% CI †
All S. pneumoniae 95/136 69.9 (61.4, 77.4)
S. pneumoniae with penicillin MIC = 2 mcg/mL 11/20 55.0 (31.5, 76.9)
S. pneumoniae with penicillin MIC = 4 mcg/mL 5/14 35.7 (12.8, 64.9)
H. influenzae 106/156 67.9 (60.0, 75.2)
M. catarrhalis 14/25 56.0 (34.9, 75.6)
a S. pneumoniae strains with penicillin MICs of 2 or 4 mcg/mL are considered resistant to penicillin.
b CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons.
c Clinical assessments at 15-18 days post-therapy may have been confounded by viral infections and new episodes of acute otitis media with time elapsed post-treatment.

In the intent-to-treat analysis, overall clinical outcomes at 2-4 days and 15-18 days post-treatment in patients with S. pneumoniae with penicillin MIC = 2 mcg/mL and 4 mcg/mL were 29/41 (71%) and 17/41 (41.5%), respectively.

In the intent-to-treat population of 521 patients, the most frequently reported adverse events were vomiting (6.9%), fever (6.1%), contact dermatitis (i.e., diaper rash) (6.1%), upper respiratory tract infection (4.0%), and diarrhea (3.8%). Protocol-defined diarrhea (i.e., 3 or more watery stools in one day or 2 watery stools per day for 2 consecutive days as recorded on diary cards) occurred in 12.9% of patients.

A double-blind, randomized, clinical study compared AUGMENTIN ES-600 (90/6.4 mg/kg/day, divided every 12 hours) to AUGMENTIN (45/6.4 mg/kg/day, divided every 12 hours) for 10 days in 450 pediatric patients (3 months to 12 years) with acute otitis media. The primary objective of the study was to compare the safety of AUGMENTIN ES-600 to AUGMENTIN. There was no statistically significant difference between treatments in the proportion of patients with 1 or more adverse events. The most frequently reported adverse events for AUGMENTIN ES-600 and the comparator of AUGMENTIN were coughing (11.9% versus 6.8%), vomiting (6.5% versus 7.7%), contact dermatitis (i.e., diaper rash, 6.0% versus 4.8%), fever (5.5% versus 3.9%), and upper respiratory infection (3.0% versus 9.2%), respectively. The frequencies of protocol-defined diarrhea with AUGMENTIN ES-600 (11.1%) and AUGMENTIN (9.4%) were similar (95% confidence interval on difference: -4.2% to 7.7%). Only 2 patients in the group treated with AUGMENTIN ES-600 and 1 patient in the group treated with AUGMENTIN were withdrawn due to diarrhea.

REFERENCES

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing – 21st Informational Supplement. CSLI Document M100-S21. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2011.

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria – Approved Standard 7th ed. CSLI Document M11-A7. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2007.

2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – 8th ed. CLSI Document M07-A8. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2009.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Test; Approved Standard – 10th ed. CLSI Document M02-A10. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2009.

Last reviewed on RxList: 9/15/2011
This monograph has been modified to include the generic and brand name in many instances.

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