Amoxicillin

AMOXICILLIN — amoxicillin capsule
Virtus Pharmaceuticals, LLC

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and other antibacterial drugs, amoxicillin is to be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Formulations of amoxicillin capsules, USP contain amoxicillin, a semi-synthetic antibiotic, an analog of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically, it is (2S , 5R , 6R)-6-[(R)-(-)-2-amino-2-(p -hydroxyphenyl) acetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid trihydrate. It may be represented structurally as:

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(click image for full-size original)

The amoxicillin molecular formula is C16 H19 N3 O5 S∙3H2 O, and the molecular weight is 419.45.

Capsules of Amoxicillin are intended for oral administration.

Each capsule contains amoxicillin trihydrate equivalent to 250 mg or 500 mg amoxicillin.

Caramel opaque cap and buff opaque body of the 250 mg capsule are imprinted with AA and 820 respectively. Each 250 mg capsule contains the following inactive ingredients: magnesium stearate, sodium lauryl sulfate, D&C Yellow No. 10, FD&C Yellow No. 6, FD&C Blue No. 1, FD&C Red

No. 3, titanium dioxide and gelatin.

Buff opaque cap and buff opaque body of the 500 mg capsule are imprinted with AA and 825 respectively. Each 500 mg capsule contains the following inactive ingredients: magnesium stearate, sodium lauryl sulfate, D&C Yellow No. 10, FD&C Yellow No. 6, titanium dioxide and gelatin.

CLINICAL PHARMACOLOGY

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 amoxicillin has been partially investigated. The 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal. However, food effect studies have not been performed with the 200 mg and 500 mg formulations. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound.

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 amoxicillin with 875 mg of amoxicillin and clavulanate potassium showed that the 875 mg tablet of amoxicillin produces an AUCo-∞ 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 amoxicillin to 24 adult volunteers yielded comparable pharmacokinetic data:

* Administered at the start of a light meal. Mean values of 24 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
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)

Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. 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. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

Microbiology

Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. Amoxicillin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Positive Microorganisms

Enterococcus faecalis

Staphylococcus spp.* (β-lactamase-negative strains only)

Streptococcus pneumoniae

Streptococcus spp. (α- and β-hemolytic strains only)

*Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.

Aerobic Gram-Negative Microorganisms

Escherichia coli (β-lactamase-negative strains only)

Haemophilus influenzae (β-lactamase-negative strains only)

Neisseria gonorrhoeae (β-lactamase-negative strains only)

Proteus mirabilis (β-lactamase-negative strains only)

Helicobacter

Helicobacter pylori

Susceptibility Tests

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 a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ampicillin powder. Ampicillin is sometimes used to predict susceptibility of S. pneumoniae to amoxicillin; however, some intermediate strains have been shown to be susceptible to amoxicillin. Therefore, S. pneumoniae susceptibility should be tested using amoxicillin powder. The MIC values should be interpreted according to the following criteria:

For Gram-Positive Aerobes

Enterococcus

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
≥ 16 Resistant (R)
Staphylococcus a
MIC (mcg/mL) Interpretation
≤ 0.25 Susceptible (S)
≥ 0.5 Resistant (R)

Streptococcus (except S. pneumoniae)

MIC (mcg/mL) Interpretation
≤ 0.25 Susceptible (S)
0.5 to 4 Intermediate (I)
≥ 8 Resistant (R)

S. pneumoniae b from non-meningitis sources.(Amoxicillin powder should be used to determine susceptibility.)

MIC (mcg/mL) Interpretation
≤ 2 Susceptible (S)
4 Intermediate (I)
≥ 8 Resistant (R)

NOTE: These interpretive criteria are based on the recommended doses for respiratory tract infections.

For Gram-Negative Aerobes

Enterobacteriaceae

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
16 Intermediate (I)
≥ 32 Resistant (R)

H. influenzae c

MIC (mcg/mL) Interpretation
≤ 1 Susceptible (S)
2 Intermediate (I)
≥ 4 Resistant (R)
  1. Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.
  2. These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
  3. These interpretive standards are applicable only to broth microdilution test with H. influenzae using Haemophilus Test Medium (HTM).1

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ampicillin powder should provide the following MIC values:

Microorganism MIC Range (mcg/mL)
E. coli ATCC 25922 2 to 8
E. faecalis ATCC 29212 0.5 to 2
H. influenzae ATCC 49247d 2 to 8
S. aureus ATCC 29213 0.25 to 1

Using amoxicillin to determine susceptibility:

Microorganism MIC Range (mcg/mL)

S. pneumoniae ATCC 49619e 0.03 to 0.12

  1. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.1
  2. This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by the broth microdilution procedure using cation-adjusted Mueller- Hinton broth with 2-5% lysed horse blood.

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 procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of microorganisms, except S. pneumoniae , to amoxicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ampicillin.

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 following criteria:

For Gram-Positive Aerobes

Enterococcus

Zone Diameter (mm) Interpretation
>17 Susceptible (S)
<16 Resistant (R)

Staphylococcus f

Zone Diameter (mm) Interpretation
≥ 29 Susceptible (S)
≤ 28 Resistant (R)

β-hemolytic streptococci

Zone Diameter (mm) Interpretation
≥ 26 Susceptible (S)
19 to 25 Intermediate (I)
≤ 18 Resistant (R)

NOTE: For streptococci (other than β-hemolytic streptococci and S. pneumoniae), an ampicillin MIC should be determined.

S. pneumoniae

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.

For Gram-Negative Aerobes

Enterobacteriaceae

Zone Diameter (mm) Interpretation
≥ 17 Susceptible (S)
14 to 16 Intermediate (I)
≤ 13 Resistant (R)

H. influenzae g

Zone Diameter (mm) Interpretation
≥ 22 Susceptible (S)
19 to 21 Intermediate (I)
≤ 18 Resistant (R)
  1. Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.
  2. These interpretive standards are applicable only to disk diffusion susceptibility tests with H. influenzae using Haemophilus Test Medium (HTM).2

Interpretation should be as stated above for results using dilution techniques.

As with standard dilution techniques, disk diffusion susceptibility test procedures require the use of laboratory control microorganisms. The 10 mcg ampicillin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism Zone diameter (mm)
E. coli ATCC 25922 16 to 22
H. influenzae ATCC 49247h 13 to 21
S. aureus ATCC 25923 27 to 35

Using 1 mcg oxacillin disk:

Microorganism Zone diameter (mm)
S. pneumoniae ATCC 49619i 8 to 12
  1. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM.2
  2. This quality control range is applicable to only S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2 .

Susceptibility Testing for Helicobacter pylori

In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentrations (MICs) and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms.

Culture and susceptibility testing should be obtained in patients who fail triple therapy. If clarithromycin resistance is found, a non-clarithromycin-containing regimen should be used.

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