Amoxicillin (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Amoxicillin is an antibacterial drug. [ see Microbiology (12.4)].

12.3 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 amoxicillin 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 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 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 mcg/mL and 3.5 mcg/mL to 5 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:

Table 3. Mean Pharmacokinetic Parameters of Amoxicillin (400 mg chewable tablets and 400 mg/5 mL suspension) in Healthy Adults
Dose * AUC0-∞ (mcghr /mL) Cmax (mcg/mL)
*
Administered at the start of a light meal.
Mean values of 24 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.

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)

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 ( 7.1)].

12.4 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 Gram-Negative Bacteria

Enterococcus faecalis

Escherichia coli

Staphylococcus spp.

Haemophilus influenzae

Streptococcus pneumoniae

Helicobacter pylori

Streptococcus spp (alpha and beta-hemolytic)

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 Enterococcu s 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
*
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.

Streptococcus pneumoniae (non-meningitis isolates)*

≤2

4

≥8

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.

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