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Amoxicillin

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Amoxil

CLINICAL PHARMACOLOGY

Mechanism of Action

Amoxicillin is an antibacterial drug. [see Microbiology].

Pharmacokinetics

Absorption

Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from the tablets and suspension of AMOXIL has been partially investigated; 400-mg and 875-mg formulations have been studied only when administered at the start of a light meal.

Orally administered doses of 250-mg and 500-mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5.0 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively.

Mean amoxicillin pharmacokinetic parameters from an open, two-part, single-dose crossover bioequivalence study in 27 adults comparing 875 mg of AMOXIL with 875 mg of AUGMENTIN® (amoxicillin/clavulanate potassium) showed that the 875-mg tablet of AMOXIL produces an AUC0-∞ of 35.4 ± 8.1 mcg•hr/mL and a Cmax of 13.8 ± 4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast.

Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3.0 mcg/mL and 3.5 mcg/mL to 5.0 mcg/mL, respectively.

Oral administration of single doses of 400-mg chewable tablets and 400 mg/5 mL suspension of AMOXIL to 24 adult volunteers yielded comparable pharmacokinetic data:

Table 3: Mean Pharmacokinetic Parameters of Amoxicillin (400 mg chewable tablets and 400 mg/5 mL suspension) in Healthy Adults

Dose* AUC 0-∞ (mcg•hr/mL) Cmax (mcg/mL)†
Amoxicillin Amoxicillin (±S.D.) Amoxicillin (±S.D.)
400 mg (5 mL of suspension) 17.1 (3.1) 5.92 (1.62)
400 mg (1 chewable tablet) 17.9 (2.4) 5.18 (1.64)
* Administered at the start of a light meal.
† Mean values of 24 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.

Distribution

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. In blood serum, amoxicillin is approximately 20% protein-bound. Following a 1-gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid.

Metabolism and Excretion

The half-life of amoxicillin is 61.3 minutes. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Since most of the amoxicillin is excreted unchanged in the urine, its excretion can be delayed by concurrent administration of probenecid [see DRUG INTERACTIONS].

Microbiology

Mechanism of Action

Amoxicillin is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death of the bacteria.

Method of Resistance

Resistance to amoxicillin is mediated primarily through enzymes called beta-lactamases that cleave the beta-lactam ring of amoxicillin, rendering it inactive.

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

Gram-Positive Bacteria Gram-Negative Bacteria
Enterococcus faecalis
Staphylococcus
spp.
Streptococcus pneumoniae

Alpha and β-hemolytic streptococci.
Escherichia coli
Haemophilus influenzae

Neisseria gonorrhoeae

Proteus mirabilis

Helicobacter pylori

Susceptibility Test Methods

(susceptibility to amoxicillin can be determined using ampicillin powder and a 10 mcg ampicillin disk)

When available, clinical microbiology should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals 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 antimicrobial 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 procedure. Standardized procedures are based on dilution methods (broth or agar)2,3 or equivalent with standardized inoculum concentrations and standardized concentrations of ampicillin powder. The MIC values should be interpreted according to the criteria in Table 4.

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 procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of bacteria to ampicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for amoxicillin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10 mcg ampicillin disk should be interpreted according to the criteria listed in Table 4.

Table 4: Susceptibility Test Interpretive Criteria for Amoxicillin

  Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion (zone diameter in mm)
Susceptible Intermediate Resistant Susceptible Intermediate Resistant
Enterococcus spp. ≤ 8 - ≥ 16 ≥ 17 - ≤ 16
Staphylococcus spp. ≤ 0.25   ≥ 0.5 ≥ 29   ≤ 28
Streptococci, viridians group (alpha-hemolytic streptococci) ≤ 0.25 0.5 to 4 ≥ 8 - - -
β-hemolytic streptococci ≤ 0.25 - - ≥ 24 - -
Streptococcus pneumoniae (non-meningitis isolates)* ≤ 2 4 ≥ 8 - - -
Enterobacteriaceae ≤ 8 16 ≥ 32 ≥ 17 14 to 16 ≤ 13
Haemophilus influenzae ≤ 1 2 ≥ 4 ≥ 22 19 to 21 ≤ 18
Neisseria gonorrhoeae** - - - - - -
*S. pneumoniae should be tested using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20 mm are susceptible to amoxicillin. An amoxicillin MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤ 19 mm.
**A positive beta lactamase test indicates resistance to amoxicillin. Isolates that are resistant to penicillin by MIC testing are also expected to be resistant to amoxicillin.

A report of “Susceptible” indicates the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches concentrations that are usually achievable. A report of “Intermediate” indicates that result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. The intermediate 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. The intermediate category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches concentrations that are usually achievable and other therapy(ies) are likely to be preferred.

Quality Control

Susceptibility techniques require use of laboratory control microorganisms to control the technical aspects of the laboratory standardized procedures.2,3,4 Standard ampicillin powder should provide the MIC values described below. For the diffusion technique using the 10-mcg ampicillin disk, the criteria are provided in Table 5.

Table 5: Acceptable Quality Control Ranges for Amoxicillin

Bacteria ATCC# MIC Range (mcg/mL) Disc Diffusion Zone Range (mm)
Escherichia coli 25922 2 to 8 16 to 22
Enterococcus faecalis 29212 0.5 to 2  
Haemophilus influenzae 49247 2 to 8 13 to 21
Staphylococcus aureus 29213 0.5 to 2  
25923   27 to 35
Streptococcus pneumoniae 49619 0.06 to 0.25  
#ATCC = American Type Culture Collection

Susceptibility Testing for Helicobacter pylori: Amoxicillin in vitro susceptibility testing methods for determining minimum inhibitory concentrations (MICs) and zone sizes have not been standardized, validated, or approved for testing H. pylori . Specimens for H. pylori and clarithromycin susceptibility test results should be obtained on isolates from patients who fail triple therapy. If clarithromycin resistance is found, a non-clarithromycin-containing regimen should be used.

Clinical Studies

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, doubleblind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or in combination with amoxicillin capsules as dual 14-day therapy, for the eradication of H. pylori . Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established: Triple therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily (see Table 6). Dual therapy: Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily (see Table 7). All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment. Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Table 6: H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Triple Therapy Regimen

Study Triple Therapy Triple Therapy
Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients)
Study 1 92 86
[80.0 - 97.7] [73.3 - 93.5]
(n = 48) (n = 55)
Study 2 86 83
[75.7 - 93.6] [72.0 - 90.8]
(n = 66) (n = 70)
a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy.

Table 7: H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Dual Therapy Regimen

Study Dual Therapy Dual Therapy
Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients)
Study 1 77 70
[62.5 - 87.2] [56.8 - 81.2]
(n = 51) (n = 60)
Study 2 66 61
[51.9 - 77.5] [48.5 - 72.9]
a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.
b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy.

REFERENCES

2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 8th ed. CLSI Document M7-A8, Vol. 29, No.2. CLSI, Wayne, PA, Jan. 2009.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard – 10th ed. CLSI Document M2-A10, Vol. 29, No. 1. CLSI, Wayne, PA, 2009.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: 21st Informational Supplement. Approved Standard CLSI Document M100-S21 CLSI, Wayne, PA, January 2011.

Last reviewed on RxList: 12/6/2011
This monograph has been modified to include the generic and brand name in many instances.

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