Source: Υπουργείο Υγείας (CY) Revision Year: 2021 Publisher: Codal-Synto Ltd, 21 Constantinoupoleos Street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: penicillins with extended spectrum
ATC code: J01CA04
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 bacterial 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 (EUCAST) version 5.0.
| Organism | MIC breakpoint (mg/L) | |
|---|---|---|
| Susceptible ≤ | Resistant > | |
| Enterobacteriaceae | 81 | 8 |
| Staphylococcus spp. | Note2 | Note2 |
| Enterococcus spp.3 | 4 | 8 |
| Streptococcus groups A, B, C and G | Note4 | Note4 |
| Streptococcus pneumoniae | Note5 | Note5 |
| Viridans group steprococci | 0.5 | 2 |
| Haemophilus influenzae | 26 | 26 |
| Moraxella catarrhalis | Note7 | Note7 |
| Neisseria meningitidis | 0.125 | 1 |
| Gram positive anaerobes except Clostridium difficile8 | 4 | 8 |
| Gram negative anaerobes8 | 0.5 | 2 |
| Helicobacter pylori | 0.1259 | 0.1259 |
| Pasteurella multocida | 1 | 1 |
| Non-species related breakpoints10 | 2 | 8 |
1 Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate. When this is the case, use the MIC breakpoint S ≤0.5 mg/L.
2 Most staphylococci are penicillinase producers, which are resistant to amoxicillin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents.
3 Susceptibility to amoxicillin can be inferred from ampicillin.
4 The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility.
5 Breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with amoxicillin. Susceptibility inferred from the MIC of ampicillin.
6 Breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant.
7 Beta lactamase producers should be reported resistant.
8 Susceptibility to amoxicillin can be inferred from benzylpenicillin.
9The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility.
10 The non-species related breakpoints are based on doses of at least 0.5 g x 3 or 4 doses daily (1.5 to 2 g/day).
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.
Gram-positive aerobes:
Enterococcus faecalis
Beta-hemolytic streptococci (Groups A, B, C and G)
Listeria monocytogenes
Gram-negative aerobes:
Escherichia coli
Haemophilus influenzae
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 anaerobes:
Clostridium spp.
Gram-negative anaerobes:
Fusobacterium 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:
Bacteroides 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. It is rapidly and well absorbed by the oral route of 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(0-24h) | T½ |
|---|---|---|---|
| (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 mg 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 0.4 l/kg.
Following intravenous administration, amoxicillin has been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, 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 (see section 4.6).
Amoxicillin has been shown to cross the placental barrier (see section 4.6).
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 the amoxicillin is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg 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 (see section 4.5).
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. 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 (see sections 4.2 and 4.4).
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Carcinogenicity studies have not been conducted with amoxicillin.
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