Pharmacotherapeutic group: antibacterials for systemic use, combinations of penicillins, incl. beta-lactamase inhibitors.
ATC vet code: QJ01CR02.
Pharmacodynamic properties
Amoxicillin is an aminobenzylpenicillin from the beta-lactam penicillin family. It interferes with the synthesis of peptidoglycan, an important component of bacterial cell walls. Therefore, it prevents bacterial cell wall formation. Clavulanic acid binds irreversibly with beta –lactamase and prevents it from inactivating amoxicillin. Therefore, amoxicillin/clavulanic acid combination has a notably broad spectrum of bactericidal activity against bacteria commonly found in cats and dogs. In vitro amoxicillin/clavulanic acid combination is active against a wide range of clinically important aerobic and anaerobic bacteria including: Gram-positive: Staphylococci (including ß-lactamase producing strains); Streptococci. Gram-negative: Escherichia coli (including most ß-lactamase producing strains); Klebsiellae; Pasteurellae.
The Clinical and Laboratory Standards Institute CLSI has set the MIC breakpoints based on disk-diffusion method (CLSI document VET01S, 5th ed, 2020) for amoxicillin-clavulanate against staphylococci and streptococci causing skin and soft tissue infections and urinary tract infections in cats and dogs as ≤0.25 / 0.12 µg/ml susceptible and ≥1 / 0.5 µg/ml resistant. For E. coli causing skin and soft tissue infections in cats and dogs, the susceptible breakpoint is set at ≤0.25 / 0.12 µg/ml and for urinary tract infections as ≤8 / 4 µg/ml. For P. multocida of feline origin, the susceptible breakpoint is set as ≤0.25 / 0.12 µg/ml and the resistant one as ≥1 / 0.5 µg/ml. 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. Issued: June 2021 AN: 00577/2020 Page 6 of 8 - 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 beta-lactamases) and a variety of resistance mechanisms have emerged. Pseudomonas aeruginosa and Enterobacter spp. may be regarded as intrinsically resistant to the combination. Resistance is shown among methicillin-resistant Staphylococcus aureus. A trend in resistance of E. coli is reported, including multidrug-resistant E. coli.
Pharmacokinetic particulars
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.
Following the administration of the product in dogs, a mean Cmax of 7.31 μg/ml was achieved for amoxicillin at approximately 1.37 hours. The mean terminal half-life for amoxicillin was 1.21 hours.
In cats, a mean Cmax of 5.87 µg/ml was achieved for amoxicillin at approximately 1.59 hours. The mean terminal half-life for amoxicillin was 1.18 hours.
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).
Following the administration of the product in dogs, a mean Cmax of 1.33 μg/ml was achieved for clavulanic acid at approximately 1.02 hours. The mean terminal half-life for clavulanic acid was 0.83 hours.
In cats, a mean Cmax of 3.16 μg/ml was achieved for clavulanic acid at approximately 0.70 hours. The mean terminal half-life for clavulanic acid was 0.81 hours.