Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Activo Health (Pty) Ltd, Block B, Arena Office Park, 272 West Avenue, Centurion, 0157
Pharmacological Classification: A 20.1.2 Penicillins
Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors
ATC code: J01CR02
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes, that is 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. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
Bactericidal action: the amoxicillin component of ACTIMENTIN 600 BD exerts a bactericidal action against many strains of Gram-positive and Gram-negative organisms. The clavulanic acid component has little bactericidal action. It does however, by inactivation of susceptible β-lactamases, protect amoxicillin from degradation by a large number of β-lactamase enzymes produced by penicillin-resistant strains of organisms.
The time above the minimum inhibitory concentration (T > MIC) is considered to be the major determinant of amoxicillin efficacy.
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.
ACTIMENTIN 600 BD should be used in accordance with local official antibiotic-prescribing guidelines and local susceptibility data. Susceptibility to ACTIMENTIN 600 BD will vary with geography and time. Local susceptibility data should be consulted where available, and microbiological sampling and susceptibility testing performed where necessary.
Aerobic Gram-negative micro-organisms:
Acinetobacter spp.
Citrobacter freundii
Enterobacter spp.
Hafnia alvei
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas spp.
Serratia spp.
Stenotrophomas maltophilia
Yersinia enterolitica
Other micro-organisms:
Chlamydophila pneumoniae
Chlamydophila psittaci
Chlamydia spp.
Coxiella burnetti
Mycoplasma pneumoniae
Amoxicillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption is optimised when taken at the start of a 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 concentration (Tmax) in each case is approximately one hour.
Amoxicillin serum concentrations achieved with the amoxicillin/clavulanic acid combination are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The same applies for clavulanic acid.
Neither amoxicillin nor clavulanic acid is highly protein bound, with approximately 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin 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.
Amoxicillin and clavulanic acid diffuse readily into most body tissues and fluids with the exception of spinal fluid and the brain. 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.
Results from animal studies report that there is no evidence for significant tissue retention of drug-derived material for either component.
Amoxicillin, like most penicillin antibiotics, 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 metabolite (inactive penicilloic acid) in quantities equivalent to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolised in man and eliminated in urine and faeces. It is also eliminated as carbon dioxide in expired air.
The major route of elimination for amoxicillin is via the kidneys, 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 hours after administration. Results from various studies indicate 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 is excreted during the first 2 hours after administration.
Concurrent use of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid (see section 4.5).
Results from pharmacokinetic studies performed in children, comparing three times a day and twice daily formulations, indicate that the elimination pharmacokinetics seen in adults apply to children with mature kidney function.
The mean AUC values for amoxicillin are essentially the same following twice-a-day (b.i.d) dosing or three-times-a-day (t.i.d) dosing, in adults. No differences between the twice daily (bd) and three times a day (tid) dosing regimens are seen when comparing the amoxicillin T1/2, or Cmax after normalisation for the different doses of amoxicillin administered. Similarly, no differences are seen for the clavulanate T1/2, Crnax or AUC values after appropriate dose normalisation.
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 clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route.
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
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