AMOXICILLIN/CLAVULANATE POTASSIUM & AMOXICILLIN/CLAVULANIC ACID



AMOXICILLIN/CLAVULANATE POTASSIUM
AMOXICILLIN/CLAVULANIC ACID

Chemistry - A beta-lactamase inhibitor, clavulanate potassium occurs as an off-white, crystalline powder that has a pKa of 2.7 (as the acid) and is very soluble in water and slightly soluble in alcohol at room temperatures. Although available in commercially available preparations as the potassium salt, potency is expressed in terms of clavulanic acid.

Synonyms include: clavulanic acid and potassium clavulanate.

Storage/Stability/Compatibility - All commercially available amoxicillin/potassium clavulanate products should be stored at temperatures less than 24oC (75oF) in tight containers. Potassium clavulanate is reportedly very susceptible to moisture and should be protected from excessive humidity. After reconstitution, oral suspensions are stable for 10 days when refrigerated. Unused portions should be discarded after that time.

Pharmacology - Clavulanic acid has only weak antibacterial activity when used alone and presently it is only available in fixed-dose combination with either amoxicillin (oral) or ticarcillin (parenteral). Clavulanic acid acts by competitively and irreversibly binding to beta-lactamases, including types II, III, IV, and V, and penicillinases produced by Staphylococcus. Staphylococci that are resistant to penicillinase-resistant penicillins (e.g., oxacillin) are considered to be resistant to amoxicillin/potassium clavulanate, although susceptibility testing may indicate otherwise. Amoxicillin/potassium clavulanate is usually ineffective against type I cephalosporinases. These plasmid-mediated cephalosporinases are often produced by members of the family Enterobacteriaceae, particularly Pseudomonas aeruginosa. When combined with amoxicillin, there is little if any synergistic activity against organisms already susceptible to amoxicillin, but amoxicillin-resistant strains (due to beta-lactamase inactivation) may be covered. When performing Kirby-Bauer susceptibility testing, the Augmentin¨ (human-product trade name) disk is used. Because the amoxicillin:clavulanic acid ratio of 2:1 in the susceptibility tests may not correspond to in vivo drug levels, susceptibility testing may not always accurately predict efficacy for this combination.

Uses/Indications - Amoxicillin/potassium clavulanate tablets and oral suspension products are approved for use in dogs and cats for the treatment of urinary tract, and skin and soft tissue infections caused by susceptible organisms. It is also indicated for canine periodontal disease due to susceptible strains of bacteria.

Pharmacokinetics (specific) - There is no evidence to suggest that the addition of clavulanic acid alters amoxicillin pharmacokinetics. Clavulanate potassium is relatively stable in the presence of gastric acid and is readily absorbed. In dogs, the absorption half-life is reportedly 0.39 hours with peak levels occurring about 1 hour after dosing. Bioavailability data for dogs or cats was not located. Clavulanic acid has an apparent volume of distribution of 0.32 L/kg in dogs and is distributed (with amoxicillin) into the lungs, pleural fluid and peritoneal fluid. Low concentrations of both drugs are found in the saliva, sputum and CSF (uninflamed meninges). Higher concentrations in the CSF are expected when meninges are inflamed, but it is questionable whether therapeutic levels are attainable. Clavulanic acid is 13% bound to proteins in dog serum. The drug readily crosses the placenta, but is not believed to cause any teratogenic problems. Clavulanic acid and amoxicillin are both found in milk in low concentrations. Clavulanic acid is apparently extensively metabolized in the dog (and rats) primarily to 1-amino-4-hydroxybutan-2-one. It is not known if this compound possess any beta-lactamase inhibiting activity. The drug is also excreted unchanged in the urine via glomerular filtration. In dogs, 34-52% of a dose is excreted in the urine as unchanged drug and metabolites, 25-27% excreted in the feces, and 16-33% into respired air. Urine levels of active drug are considered to be high, but may be only 1/5th of those of amoxicillin.

Doses - All doses are for combined quantities of both drugs (unless noted otherwise).

Dogs:
For susceptible infections:
a) 13.75 mg/kg PO bid; do not exceed 30 days of therapy.
b) 10 - 20 mg/kg (amoxicillin) PO bid
c) 11 - 22 mg/kg PO q8-12h
d) 12.5 - 25 mg/kg PO q8-12h

Cats:
For susceptible infections:
a) 62.5 mg PO bid; do not exceed 30 days of therapy.
b) 62.5 mg PO q8-12h
c) 11 - 22 mg/kg PO q8-12h

Birds:
For susceptible infections:
a) 50 - 100 mg/kg PO q6-8h

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