Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

Mode of action
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.
Pharmacokinetic/pharmacodynamic relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

Mechanisms of resistance
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.
• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints
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                ≤1                   -                      >1 Influenzae 1
Moraxella catarrhalis      ≤1                    -                     >1 1

Staphylococcus             ≤2                    -                     >2 aureus 2
Coagulase-negative         ≤ 0.25                                      > 0.25 staphylococci 2
Enterococcus 1             ≤4                    8                     >8 Streptococcus A, B,        ≤ 0.25                -                     > 0.25 C, G 5
Streptococcus              ≤ 0.5                 1-2                   >2 pneumoniae 3
Enterobacteriaceae         -                     -                     >8 1,4

Gram-negative             ≤4                   8                    >8 Anaerobes 1
Gram-positive             ≤4                   8                    >8 Anaerobes 1
Non-species related       ≤2                   4-8                  >8 Breakpoints 1
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.

Commonly susceptible species
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Gardnerella vaginalis
Staphylococcus aureus (methicillin-susceptible) £
Streptococcus agalactiae
Streptococcus pneumoniae 1
Streptococcus pyogenes and other beta-haemolytic streptococci Streptococcus viridans group
Aerobic Gram-negative micro-organisms
Actinobacillus actinomycetemcomitans
Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae 2
Moraxella catarrhalis
Neisseria gonorrhoeae §
Pasteurella multocida
Anaerobic micro-organisms
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
Enterococcus faecium $
Aerobic Gram-negative micro-organisms
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris
Inherently resistant organisms
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
Chlamydia trachomatis
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.
§ All strains with resistance to amoxicillin that is not mediated by beta- lactamases are resistant to amoxicillin/clavulanic acid
1 This presentation of amoxicillin/clavulanic acid may not be suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin (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%.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
The pharmacokinetic results for studies in which amoxicillin/clavulanic acid was administered to groups of healthy volunteers as either 500 mg/100 mg or 1000 mg/200 mg given as a bolus intravenous injection are presented below.

Mean (±SD) pharmacokinetic parameters
Bolus intravenous injection
Dose             Dose       Mean peak             T 1/2       AUC            Urinary administered                serum conc            (h)         (h.mg/l)       recovery (µg/ml)                                          (%, 0 to
6 h)
Amoxicillin
AMX/CA      1000 mg             105.4           0.9           76.3           77.4 1000 mg/200 mg
Clavulanic acid
AMX/CA         200 mg         28.5               0.9         27.9            63.8 1000 mg/200 mg
Key AMX – amoxicillin, CA – clavulanic acid

Distribution
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).

Biotransformation
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.
Elimination
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 a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. 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).

Age
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.

Renal impairment
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).

Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.