Co-amoxiclav is an antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid).
Pharmacology: Mechanism of Action: Amoxicillin is a semisynthetic antibiotic with a broad-spectrum of bactericidal activity against many gram-positive and -negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases and therefore, the spectrum of activity does not include organisms, which produce these enzymes. Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated β-lactamases frequently responsible for transferred drug resistance.
The formulation of amoxicillin and clavulanic acid protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β-lactam antibiotics. Thus, amoxicillin/clavulanate potassium combination possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.
Pharmacodynamics: Resistance to many antibiotics is caused by bacterial enzymes which destroy the antibiotic before it can act on the pathogen. The clavulanate component in co-amoxiclav anticipates this defense mechanism by blocking the β-lactamase enzymes, thus rendering the organism sensitive to amoxicillin's rapid bactericidal effect at concentrations readily attainable in the body.
Microbiology: CO-AX has been shown to be active against most strains.
Clavulanate by itself has little antibacterial activity; however, in association with amoxicillin, it produces an antibiotic agent of broad-spectrum with wide application in hospital and general practice.
Co-amoxiclav is bactericidal to a wide range of organism, both in vitro and in clinical infections:
Gram-Positive Aerobes: Staphylococcus aureus [Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to co-amoxiclav (β-lactamase and non-β-lactamase producing)], Bacillus anthracis, Listeria monocytogenes.
Gram-Negative Aerobes: Enterobacter sp (although most strains of Enterobacter sp are resistant in vitro, clinical efficacy has been demonstrated with co-amoxiclav combination in urinary tract infections caused by these organisms), Escherichia coli (β-lactamase and non-β-lactamase producing), Haemophilus influenzae (β-lactamase and non-β-lactamase producing), Klebsiella sp (all known strains are β-lactamase producing), Moraxella catarrhalis [Branhamella catarrhalis (β-lactamase and non-β-lactamase producing)], Proteus vulgaris, Shigella sp, Bordetella pertussis, Brucella sp, Neisseria gonorrhoeae, Neisseria meningitidis, Vibrio cholerae, Pasteurella multocida, Salmonella sp (some members of this species of bacteria produce β-lactamase, rendering them insensitive to amoxicillin alone).
The following in vitro data are available, but their clinical significance is unknown.
Co-amoxiclav exhibits in vitro minimal inhibitory concentrations (MICs) of ≤2 mcg/mL against most (≥90%) strains of Streptococcus pneumoniae (because amoxicillin has greater in vitro activity against S. pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin); MICs of ≤0.06 mcg/mL against most (≥90%) strains of Neisseria gonorrhoeae; MICs of ≤4 mcg/mL against most (≥90%) strains of staphylococci and anaerobic bacteria; and MICs of ≤8 mcg/mL against most (≥90%) strains of other listed organism. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of co-amoxiclav in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Because amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin.
Gram-Positive Aerobes: Enterococcus faecalis*, Staphylococcus epidermidis (β-lactamase and non-β-lactamase producing) and other coagulase-negative staphylococci (some members of these species of bacteria produce β-lactamase, rendering them insensitive to amoxicillin alone), Staphylococcus saprophyticus (β-lactamase and non-β-lactamase producing), Streptococcus pneumoniae*+ (these are non-β-lactamase -producing organisms and, therefore, are susceptible to amoxicillin alone), Streptococcus pyogenes*+ (these are non-β-lactamase-producing organisms and, therefore, are susceptible to amoxicillin alone), Viridans-group Streptococcus*+ (these are non-β-lactamase -producing organisms and, therefore, are susceptible to amoxicillin alone), Corynebacterium sp.
Gram-Negative Aerobes: Eikenella corrodens (β-lactamase and non-β-lactamase producing), Neisseria gonorrhoeae* (β-lactamase and non-β-lactamase producing), Proteus mirabilis* (β-lactamase and non-β-lactamase producing).
Anaerobic Bacteria: Bacteroides sp, including Bacteroides fragilis (β-lactamase and non-β-lactamase producing), Fusobacterium sp (β-lactamase and non-β-lactamase producing), Peptostreptococcus sp*+, Clostridium sp, Peptococcus sp.
Note: *Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.
+ Non-β-lactamase producing organisms and therefore, are susceptible to amoxicillin.
Pharmacokinetics: Amoxicillin and clavulanate potassium are well absorbed from the GIT after oral administration of co-amoxiclav. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While co-amoxiclav can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when co-amoxiclav was dosed at 30 and 150 min after the start of a high fat breakfast. The safety and efficacy of co-amoxiclav have been established in clinical trials where co-amoxiclav was taken without regard to meals (see Table).
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Amoxicillin serum concentrations achieved with co-amoxiclav are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The t½ of amoxicillin after the oral administration of co-amoxiclav is 1.3 hrs and that of clavulanic acid is 1 hr.
Approximately 50-70% of the amoxicillin and approximately 25-40% of the clavulanic acid are excreted unchanged in urine during the first 6 hrs after administration of a single 250- or 500-mg tablet of co-amoxiclav.
Concurrent administration of probenecid delays amoxicillin excretion does not delay renal excretion of clavulanic acid.
Neither component in co-amoxiclav is highly protein bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.
Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.