Pharmacotherapeutic group: β-lactam antibacterials, penicillins.
ATCvet code: QJ01CR02
Pharmacodynamic properties
Amoxicillin is an aminobenzylpenicillin from the β-lactam penicillin family which prevents bacterial cell wall formation by interfering with the final step of peptidoglycan synthesis. Clavulanic acid is an irreversible inhibitor of intracellular and extracellular β-lactamases which protects amoxicillin from inactivation by many β-lactamases.
Amoxicillin in combination with clavulanic acid has a wide range of activity which includes β‑lactamase producing strains of both Gram-positive and Gram-negative aerobes, facultative anaerobes and obligate anaerobes, including:
Gram-positives with good susceptibility: Clostridium spp. Corynebacterium spp. Staphylococcus spp. Streptococcus spp.
Gram-negatives with good susceptibility: Pasteurella spp. Bacteroides spp. Proteus mirabilis.
Gram-negatives with variable susceptibility: Escherichia coli.
Susceptibility and resistance patterns can vary with geographical area and bacterial strain, and may change over time.
Amoxicillin/clavulanic acid breakpoints (NCCLS/2012):
Staphylococci: sensitive: MIC ≤ 4/2 μg/ml, resistant: MIC ≥ 8/4 μg/ml
Other organisms: sensitive: MIC ≤ 8/4 μg/ml, resistant: MIC ≥ 32/16 μg/ml
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
- Inactivation by those bacterial β-lactamases that are not themselves inhibited by clavulanic acid, including class B, C and D.
- Alteration of Penicillin-Binding Proteins (PBP), which reduce the affinity of the antibacterial agent for the target (methicillin resistant S. aureus, MRSA and S. pseudintermedius, MRSP).
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria. Resistance genes can be located on chromosomes (mecA, MRSA) or plasmids (LAT, MIR, ACT, FOX, CMY family β-lactamases) and a variety of resistance mechanisms have emerged. Pseudomonas aeruginosa and Enterobacter spp. can be regarded as intrinsically resistant to the combination.
Pharmacokinetic properties
After the oral administration to dogs of the recommended dose of 10 mg amoxicillin/2.5 mg clavulanic acid/kg body weight the following parameters were observed: median Tmax of 1.5 hours for amoxicillin and of 1.0 hours for clavulanic acid.
After the oral administration to cats of the recommended dose of 10 mg amoxicillin/2.5 mg clavulanic acid/kg body weight the following parameters were observed: median Tmax of 2.0 hours for amoxicillin and of 0.75 hours for clavulanic acid.
Amoxicillin is well-absorbed following oral administration. In dogs the systemic bioavailability is 60-70%. Amoxicillin (pKa 2.8) has a relatively small apparent distribution volume, a low plasma protein binding (34% in dogs) and a short terminal half-life due to active tubular excretion via the kidneys. Following absorption the highest concentrations are found in the kidneys (urine) and the bile, and then in liver, lungs, heart and spleen. The distribution of amoxicillin to the cerebrospinal fluid is low unless the meninges are inflamed.
Clavulanic acid (pKa 2.7) is also well-absorbed following oral administration. The penetration to the cerebrospinal fluid is poor. The plasma protein binding is approximately 25% and the elimination half-life is short. Clavulanic acid is mainly eliminated by renal excretion (unchanged in urine).