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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* AUC0-∞ (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.

Mechanism 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

Enterococcus faecalis
Staphylococcus
spp.
Streptococcus pneumoniae

Streptococcus
spp. (alpha and beta-hemolytic)

Gram-Negative Bacteria

Escherichia coli
Haemophilus influenzae

Helicobacter pylori

Proteus mirabilis

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative 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 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 method -(broth or agar)2,4. The MIC values should be interpreted according to the criteria in Table 4.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds3,4. The zone size should be determined using a standardized test method3.

Susceptibility to amoxicillin of Enterococcus spp., Enterobacteriaceae, and H. influenzae, may be inferred by testing ampicillin4. Susceptibility to amoxicillin of Staphylococcus spp., and beta-hemolytic Streptococcus spp., may be inferred by testing penicillin4. The majority of isolates of Enterococcus spp. that are resistant to ampicillin or amoxicillin produce a TEM-type beta-lactamase. A beta-lactamase test can provide a rapid means of determining resistance to ampicillin and amoxicillin4.

Susceptibility to amoxicillin of Streptococcus pneumoniae (non-meningitis isolates) may be inferred by testing penicillin or oxacillin4. The interpretive criteria for S. pneumoniae to amoxicillin are provided in Table 44.

Table 4: Susceptibility Interpretive Criteria for Amoxicillin

  Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion (zone diameter in mm)
Susceptible Intermediate Resistant Susceptible Intermediate Resistant
Streptococcus pneumoniae (non-meningitis isolates)* ≤ 2 4 ≥ 8 - - -
*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 mm4.

A report of “Susceptible” indicates the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches a concentration at the infection site 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 the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected.

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.

Quality Control

Standardized susceptibility test procedures2,3,4 require use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test control. Standard amoxicillin powder should provide the following range of MIC values provided in Table 54. For the diffusion technique the criteria provided in Table 5 should be achieved.

Table 5: Acceptable Quality Control Ranges for Amoxicillina

Quality Control Microorganism Minimum Inhibitory Concentrations (mcg/mL) Disc Diffusion Zone Diameter (mm)
Streptococcus pneumoniae ATCCb 49619 0.03 to 0.12 ----
Klebsiella pneumoniae ATCC 700603 > 128
a QC limits for testing E. coli 35218 when tested on Haemophilus Test Medium (HTM) are ≥ 256 mcg/mL for amoxicillin; testing amoxicillin may help to determine if the isolate has maintained its ability to produce betalactamase4.
bATCC = American Type Culture Collection

Clinical Studies

H. pylori Eradication To Reduce The Risk Of Duodenal Ulcer Recurrence

Randomized, double-blind 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)
aThis 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.
bPatients 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]
(n = 58) (n = 67)
aThis 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.
bPatients 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

1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: 66-67.

2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Last reviewed on RxList: 12/18/2015
This monograph has been modified to include the generic and brand name in many instances.

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