Amoxicillin (Page 5 of 6)

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 procedures^{2 ,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 Amoxicillin *

Quality Control Microorganism	Minimum Inhibitory Concentrations (mcg/mL)	Disc Diffusion Zone Diameter (mm)
* 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 beta- lactamase4. † ATCC = American Type Culture Collection
Streptococcus pneumoniae ATCC † 49619	0.03 to 0.12	—-
Klebsiella pneumoniae ATCC † 700603	>128	—-

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium was nonmutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanate potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and clavulanate potassium was negative in the mouse micronucleus test and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 2 times the 3 g human dose based on body surface area).

14 CLINICAL STUDIES

14.1 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 Analysis * [95% Confidence Interval] (number of patients)	Intent-to-Treat Analysis † [95% Confidence Interval] (number of patients)
* 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. † 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.
Study 1	92 [80.0 — 97.7] (n = 48)	86 [73.3 — 93.5] (n = 55)
Study 2	86 [75.7 — 93.6] (n = 66)	83 [72.0 — 90.8] (n = 70)

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

Study	Dual Therapy	Dual Therapy
	Evaluable Analysis 1 [95% Confidence Interval](number of patients)	Intent-to-Treat Analysis 2 [95% Confidence Interval](number of patients)
Study 1	77 [62.5 — 87.2] (n = 51)	70 [56.8 — 81.2] (n = 60)
Study 2	66 [51.9 — 77.5] (n = 58)	61 [48.5 — 72.9] (n = 67)

• 1.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.
• 2.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.