Source: Υπουργείο Υγείας (CY) Revision Year: 2017 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, P. O. Box 51706, 3056 Limassol, Cyprus
Pharmacotherapeutic Group: Antibacterials for systemic use; Beta-lactam antibacterials, penicillins
ATC Code: J01CR02
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.
Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).
MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).
| Organism | Susceptibility Breakpoints (μg/ml) | ||
|---|---|---|---|
| Susceptible | Intermediate | Resistant | |
| Haemophilus influenza1 | ≤1 | - | >1 |
| Moraxella catarrhalis1 | ≤1 | - | >1 |
| Staphylococcus aureus2 | ≤2 | - | >2 |
| Coagulase-negative staphylococci2 | ≤0.25 | >0.25 | |
| Enterococcus1 | ≤4 | 8 | >8 |
| Streptococcus A, B, C, G5 | ≤0.25 | - | >0.25 |
| Streptococcus pneumonia3 | ≤0.5 | 1-2 | >2 |
| Enterobacteriaceae1,4 | - | - | >8 |
| Gram-negative Anaerobes1 | ≤4 | 8 | >8 |
| Gram-positive Anaerobes1 | ≤4 | 8 | >8 |
| Non-species related breakpoints1 | ≤2 | 4-8 | >8 |
1 The reported values are for Amoxicillin concentrations. For susceptibility testing purposes, the concentration of Clavulanic acid is fixed at 2 mg/l.
2 The reported values are Oxacillin concentrations.
3 Breakpoint values in the table are based on Ampicillin breakpoints.
4 The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance mechanisms are reported resistant.
5 Breakpoint values in the table are based on Benzylpenicillin breakpoints.
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.
Aerobic Gram-positive micro-organisms:
Enterococcus faecalis
Gardnerella vaginalis
Staphylococcus aureus (methicillin-susceptible)
Coagulase-negative staphylococci (methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae1
Streptococcus pyogenes and other beta-hemolytic streptococci
Streptococcus viridans group
Aerobic Gram-negative micro-organisms:
Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae2
Moraxella catarrhalis
Pasteurella multocida
Anaerobic micro-organisms:
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.
Aerobic Gram-positive micro-organisms:
Enterococcus faecium$
Aerobic Gram-negative micro-organisms:
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris
Aerobic Gram-negative micro-organisms:
Acinetobacter sp.
Citrobacter freundii
Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratia sp.
Stenotrophomonas maltophilia
Other micro-organisms:
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetti
Mycoplasma pneumoniae
$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance.
£ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid
1 Streptococcus pneumoniae that is fully susceptible to penicillin may be treated with this presentation of amoxicillin/clavulanic acid. Organisms that show any degree of reduced susceptibility to penicillin should not be treated with this presentation (see sections 4.2 and 4.4).
2 Strains with decreased susceptibility have been reported in some countries in the EU with a frequency higher than 10%.
Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physicological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimized when taken at the start of the meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concetration (Tmax) in each case is approximately one hour.
The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (250 mg/125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below.
| Mean (± SD) pharmacokinetic parameters | |||||
|---|---|---|---|---|---|
| Active substance(s) administered | Dose | Cmax | Tmax* | AUC(0-24h) | T½ |
| (mg) | (μg/ml) | (h) | (μg.h/ml) | (h) | |
| Amoxicillin | |||||
| AMX/CA 500/125 mg | 500 | 7.19 ± 2.26 | 1.5 (1.0-2.5) | 53.5 ± 8.87 | 1.15 ± 0.20 |
| Clavulanic acid | |||||
| AMX/CA 500 mg/125 mg | 125 | 2.40 ± 0.83 | 1.5 (1.0-2.0) | 15.72 ± 3.86 | 0.98 ± 0.12 |
AMX – amoxicillin, CA – clavulanic acid
* Median (range)
Amoxicillin and clavulanic acid serum concentrations achieved with amoxicillin/clavulanic acid are similar to those produced by the oral administration of equivalent doses of amoxicillin or clavulanic acid alone.
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.
Following intravenous administration, both amoxicillin and clavulanic acid have 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 for either component. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk (see section 4.6).
Both amoxicillin and clavulanic acid have 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. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.
The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.
Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Clavomid 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.
Concomitant use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (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/clavulanic acid to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2).
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, genotoxicity and toxicity to reproduction.
Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.
Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid or its components.
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