Chemical formula: C₁₆H₁₉N₃O₅S Molecular mass: 365.404 g/mol PubChem compound: 33613
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bactericidal peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
The main mechanisms of resistance to amoxicillin are:
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
MIC breakpoints for amoxicillin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCASAT) version 5.0.
The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly Susceptible Species:
Gram-positive aerobes:
Enterococcus faecalis
Beta-hemolytic streptococci (Groups A, B, C and G)
Listeria monocytogenes
Species for which acquired resistance may be a problem:
Gram-negative aerobes:
Escherichia coli
Haemophilus influenza
Helicobacter pylori
Proteus mirabilis
Salmonella typhi
Salmonella paratyphi
Pasteurella multocida
Gram-positive aerobes:
Coagulase negative staphylococcus
Staphylococcus aureus£
Streptococcus pneumoniae
Viridans group streptococcus
Gram-positive aerobes:
Clostridium spp.
Gram-negative aerobes:
Fusobactrium spp.
Other:
Borrelia burgdorferi
Inherently resistant organisms†:
Gram-positive aerobes:
Enterococcus faecium†
Gram-negative aerobes:
Acinetobacter spp.
Enterobacter spp.
Klebsiella spp.
Pseudomonas spp.
Gram-negative anaerobes:
Bacteroids spp. (many strains of Bacteroides fragilis are resistant)
Others:
Chlamydia spp.
Mycoplasma spp.
Legionella spp.
† Natural intermediate susceptibility in the absence of acquired mechanism of resistance.
£ Almost all S.aureus are resistant to amoxicillin due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to amoxicillin.
Amoxicillin fully dissociates in aqueous solution at physiological pH. Amoxicillin is stable in the acid gastric secretion and is rapidly absorbed from the gastrointestinal tract after oral administration. Following oral administration, amoxicillin is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.
The pharmacokinetic results for a study, in which an amoxicillin dose of 250 mg three times daily was administered in the fasting state to groups of healthy volunteers are presented below.
| Cmax | Tmax* | AUC | T ½ |
|---|---|---|---|
| (µg/ml) | (h) | (µg.h/ml) | (h) |
| 3.3 ± 1.12 | 1.5 (1.0-2.0) | 26.7 ± 4.56 | 1.36 ± 0.56 |
* Median (range)
In the range 250 to 3000 the bioavailability is linear in proportion to dose (measured as Cmax and AUC). The absorption is not influenced by simultaneous food intake.
Haemodialysis can be used for elimination of amoxicillin.
About 18% of total plasma amoxicillin is bound to protein and the apparent volume of distribution is around 0.3 to 0.41/kg. Following intravenous administration, amoxicillin has been found in gall bladder, abdominal tissue, skin, fat, muscle tissue, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drug-derived material. Amoxicillin, like most penicillins, can be detected in breast milk.
Amoxicillin has been shown to cross the placental barrier.
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose.
The major route of elimination for amoxicillin is via the kidney.
Amoxicillin has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/hour in healthy subjects. Approximately 60 to 70% of an orally administered dose is excreted unchanged in the urine during the first 6 hours after administration of a single 250mg or 500mg dose of amoxicillin. Various studies have found the urinary excretion to be 50-85% for amoxicillin over a 24 hour period.
Concomitant use of probenecid delays amoxicillin excretion.
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. In preterm infants with gestational age 26-33 weeks, the total body clearance after intravenous dosing of amoxicillin, day 3 of life, ranged between 0.75-2 ml/min, very similar to the inuline clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Following oral administration of amoxicillin to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of amoxicillin.
The total serum clearance of amoxicillin decreases proportionately with decreasing renal function.
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
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