Amoxicillin

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

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 suspension of amoxicillin has been partially investigated. The 400 mg formulation has been studied only when administered at the start of a light meal. 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 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 mcg/mL and 3.5 mcg/mL to 5 mcg/mL, respectively.
 
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.

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.

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 pylori

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)

a. Staphylococci which are susceptible to amoxicillin but resistant to methicillin/oxacillin should be considered as resistant to amoxicillin.
b. These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
c. 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

d. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.¹
e. 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 to 5% lysed horse blood.

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)

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

h. This quality control range is applicable to only H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM.²
i.  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.

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.

Amoxicillin, in combination with clarithromycin plus lansoprazole as triple therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION .)

Amoxicillin, in combination with lansoprazole delayed-release capsules as dual therapy, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or 1-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected. (See the clarithromycin package insert, MICROBIOLOGY.) Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION .)
 
Indicated surgical procedures should be performed.

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 potassium clavulanate. Amoxicillin and clavulanic acid mixture was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and clavulanic acid mixture 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 clavulanic acid mixture 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 3 times the human dose in mg/m²).

Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

In clinical trials using combination therapy with amoxicillin plus clarithromycin and lansoprazole, and amoxicillin plus lansoprazole, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with amoxicillin, clarithromycin, or lansoprazole.

The most frequently reported adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen.

The most frequently reported adverse events for patients who received amoxicillin three times daily plus lansoprazole three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with amoxicillin three times daily plus lansoprazole three times daily dual therapy than with lansoprazole alone.
 
For more information on adverse reactions with clarithromycin or lansoprazole, refer to their package inserts, ADVERSE REACTIONS.

Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended upper dose of amoxicillin is 30 mg/kg/day divided q12h.

* Dosing for infections caused by less susceptible organisms should follow the recommendations for severe infections. † The children’s dosage is intended for individuals whose weight is less than 40 kg. Children weighing 40 kg or more should be dosed    according to the adult recommendations.
Infection	Severity *	Usual Adult Dose	Usual Dose for Children >3    Months†
Ear/Nose/Throat	Mild/Moderate	500 mg every 12 hours    or 250 mg every 8 hours	25 mg/kg/day in divided    doses every 12 hours
or
20 mg/kg/day in divided    doses every 8 hours
Severe	875 mg every 12 hours    or 500 mg every 8 hours	45 mg/kg/day in divided    doses every 12 hours
or
40 mg/kg/day in divided    doses every 8 hours
Lower Respiratory Tract	Mild/Moderate or Severe	875 mg every 12 hours    or 500 mg every 8 hours	45 mg/kg/day in divided    doses every 12 hours
or
40 mg/kg/day in divided    doses every 8 hours
Skin/Skin Structure	Mild/Moderate	500 mg every 12 hours    or 250 mg every 8 hours	25 mg/kg/day in divided    doses every 12 hours
or
20 mg/kg/day in divided    doses every 8 hours
Severe	875 mg every 12 hours    or 500 mg every 8 hours	45 mg/kg/day in divided    doses every 12 hours
or
40 mg/kg/day in divided    doses every 8 hours
Genitourinary Tract	Mild/Moderate	500 mg every 12 hours    or 250 mg every 8 hours	25 mg/kg/day in divided    doses every 12 hours
or
20 mg/kg/day in divided    doses every 8 hours
Severe	875 mg every 12 hours    or 500 mg every 8 hours	45 mg/kg/day in divided    doses every 12 hours
or
40 mg/kg/day in divided    doses every 8 hours
Gonorrhea Acute,    uncomplicated    ano-genital and    urethral infections    in males and    females		3 grams as single oral    dose	Prepubertal children:   50    mg/kg amoxicillin,    combined with 25 mg/kg    probenecid as a single dose.    NOTE: SINCE    PROBENECID IS    CONTRAINDICATED    IN CHILDREN UNDER    2 YEARS, DO NOT USE        THIS REGIMEN IN    THESE CASES.

After reconstitution, the required amount of suspension should be placed directly on the child’s tongue for swallowing. Alternate means of administration are to add the required amount of suspension to formula, milk, fruit juice, water, ginger ale, or cold drinks. These preparations should then be taken immediately. To be certain the child is receiving full dosage, such preparations should be consumed in entirety.
 
All patients with gonorrhea should be evaluated for syphilis. (See PRECAUTIONS: Laboratory Tests .)
 
Larger doses may be required for stubborn or severe infections.

It should be recognized that in the treatment of chronic urinary tract infections, frequent bacteriological and clinical appraisals are necessary. Smaller doses than those recommended above should not be used. Even higher doses may be needed at times. In stubborn infections, therapy may be required for several weeks. It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy. Except for gonorrhea, treatment should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. It is recommended that there be at least 10 days’ treatment for any infection caused by Streptococcus pyogenes to prevent the occurrence of acute rheumatic fever.

The recommended adult oral dose is 1 gram amoxicillin, 500 mg clarithromycin, and 30 mg lansoprazole, all given twice daily (q12h) for 14 days. (See INDICATIONS AND USAGE .)

The recommended adult oral dose is 1 gram amoxicillin and 30 mg lansoprazole, each given three times daily (q8h) for 14 days. (See INDICATIONS AND USAGE .)
 
Please refer to clarithromycin and lansoprazole full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally impaired patients.

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Patients with a glomerular filtration rate of 10 to 30 mL/min. should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a less than 10 mL/min. glomerular filtration rate should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection.
 
Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

There are currently no dosing recommendations for pediatric patients with impaired renal function.

Prepare suspension at time of dispensing as follows: Tap bottle until all powder flows freely. Add approximately 1/3 of the total amount of water for reconstitution (see table below) and shake vigorously to wet powder. Add remainder of the water and again shake vigorously.

                                             200 mg/5 mL
                                                                                           Amount of Water
   Bottle Size                                                                  Required for Reconstitution
     50 mL                                                                                       35 mL
     75 mL                                                                                       52 mL
   100 mL                                                                                       69 mL

Each teaspoonful (5 mL) will contain 200 mg amoxicillin.
 
                                            400 mg/5 mL

                                                                                          Amount of Water
   Bottle Size                                                                  Required for Reconstitution
     50 mL                                                                                       35 mL
     75 mL                                                                                       52 mL
   100 mL                                                                                       69 mL

Each teaspoonful (5 mL) will contain 400 mg amoxicillin.

NOTE:  SHAKE ORAL SUSPENSION WELL BEFORE USING. Keep bottle tightly closed. Any unused portion of the reconstituted suspension must be discarded after 14 days. Refrigeration preferable, but not required.

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:

Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily.

Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily.
 
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. 

H. pylori Eradication Rates – Triple Therapy (amoxicillin/clarithromycin/lansoprazole) Percent of Patients Cured [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®, (Delta West Ltd., Bentley, Australia), 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. ‡  (p<0.05) versus lansoprazole/amoxicillin and lansoprazole/clarithromycin dual therapy. §  (p<0.05) versus clarithromycin/amoxicillin dual therapy.
Study	Triple Therapy	Triple Therapy
Evaluable Analysis*	Intent-to-Treat Analysis†
Study 1	92‡ [80 - 97.7] (n = 48)	86‡ [73.3 - 93.5] (n = 55)
Study 2	86§ [75.7 - 93.6] (n = 66)	83§ [72 - 90.8] (n = 70)

H. pylori Eradication Rates – Dual Therapy (amoxicillin/lansoprazole) Percent of Patients Cured [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. ‡  (p<0.05) versus lansoprazole alone. §  (p<0.05) versus lansoprazole alone or amoxicillin alone.
Study	Dual Therapy	Dual Therapy
Evaluable Analysis*	Intent-to-Treat Analysis†
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)