AMOXICILLIN / CLAVULANATE POTASSIUM, AMOXICILLIN / CLAVULANIC ACID
For general information on the penicillins, including adverse effects, contraindications, overdosage, drug interactions and monitoring parameters, refer to the monograph: Penicillins, General
Information. A separate monograph for amoxicillin is found earlier in this section. Refer to it formore information on amoxicillin chemistry, storage, stability, doses, etc..
Chemistry - A beta-lactamase inhibitor, clavulanate potassium occurs as an off-white, crystallinepowder that has a pKa of 2.7 (as the acid) and is very soluble in water and slightly soluble inalcohol at room temperatures. Although available in commercially available preparations as thepotassium salt, potency is expressed in terms of clavulanic acid. Synonyms include: clavulanic acidand potassium clavulanate.
After reconstitution, oral suspensions are stable for 10 days when refrigerated. Unused portionsshould be discarded after that time.
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 topenicillinase-resistant penicillins (e.g., oxacillin) are considered to be resistant toamoxicillin/potassium clavulanate, although susceptibility testing may indicate otherwise.
Amoxicillin/potassium clavulanate is usually ineffective against type I cephalosporinases. Theseplasmid-mediated cephalosporinases are often produced by members of the family
Enterobacteriaceae, particularly Pseudomonas aeruginosa. When combined with amoxicillin, thereis little if any synergistic activity against organisms already susceptible to amoxicillin, butamoxicillin-resistant strains (due to beta-lactamase inactivation) may be covered.
When performing Kirby-Bauer susceptibility testing, the Augmentin® (human-product tradename) disk is used. Because the amoxicillin:clavulanic acid ratio of 2:1 in the susceptibility testsmay not correspond to in vivo drug levels, susceptibility testing may not always accurately predictefficacy for this combination.
Pharmacokinetics (specific) - The pharmacokinetics of amoxicillin are presented in that drug'smonograph. There is no evidence to suggest that the addition of clavulanic acid alters amoxicillinpharmacokinetics.
Clavulanate potassium is relatively stable in the presence of gastric acid and is readily absorbed. Indogs, the absorption half-life is reportedly 0.39 hours with peak levels occurring about 1 hour afterdosing. 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 bothdrugs are found in the saliva, sputum and CSF (uninflamed meninges). Higher concentrations inthe CSF are expected when meninges are inflamed, but it is questionable whether therapeutic levelsare attainable. Clavulanic acid is 13% bound to proteins in dog serum. The drug readily crosses theplacenta, but is not believed to cause any teratogenic problems. Clavulanic acid and amoxicillin areboth 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 inhibitingactivity. 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 only1/5th of those of amoxicillin.
Information. A separate monograph for amoxicillin is found earlier in this section. Refer to it formore information on amoxicillin chemistry, storage, stability, doses, etc..
Chemistry - A beta-lactamase inhibitor, clavulanate potassium occurs as an off-white, crystallinepowder that has a pKa of 2.7 (as the acid) and is very soluble in water and slightly soluble inalcohol at room temperatures. Although available in commercially available preparations as thepotassium salt, potency is expressed in terms of clavulanic acid. Synonyms include: clavulanic acidand potassium clavulanate.
Storage, Stability, Compatibility
All commercially available amoxicillin/potassium clavulanateproducts should be stored at temperatures less than 24°C (75°F) in tight containers. Potassiumclavulanate is reportedly very susceptible to moisture and should be protected from excessivehumidity.After reconstitution, oral suspensions are stable for 10 days when refrigerated. Unused portionsshould be discarded after that time.
Pharmacology - AMOXICILLIN/CLAVULANATE POTASSIUM, AMOXICILLIN/CLAVULANIC ACID
Clavulanic acid has only weak antibacterial activity when used alone and presentlyit 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 topenicillinase-resistant penicillins (e.g., oxacillin) are considered to be resistant toamoxicillin/potassium clavulanate, although susceptibility testing may indicate otherwise.
Amoxicillin/potassium clavulanate is usually ineffective against type I cephalosporinases. Theseplasmid-mediated cephalosporinases are often produced by members of the family
Enterobacteriaceae, particularly Pseudomonas aeruginosa. When combined with amoxicillin, thereis little if any synergistic activity against organisms already susceptible to amoxicillin, butamoxicillin-resistant strains (due to beta-lactamase inactivation) may be covered.
When performing Kirby-Bauer susceptibility testing, the Augmentin® (human-product tradename) disk is used. Because the amoxicillin:clavulanic acid ratio of 2:1 in the susceptibility testsmay not correspond to in vivo drug levels, susceptibility testing may not always accurately predictefficacy for this combination.
Uses, Indications
Amoxicillin/potassium clavulanate tablets and oral suspension products areapproved 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 tosusceptible strains of bacteria.Pharmacokinetics (specific) - The pharmacokinetics of amoxicillin are presented in that drug'smonograph. There is no evidence to suggest that the addition of clavulanic acid alters amoxicillinpharmacokinetics.
Clavulanate potassium is relatively stable in the presence of gastric acid and is readily absorbed. Indogs, the absorption half-life is reportedly 0.39 hours with peak levels occurring about 1 hour afterdosing. 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 bothdrugs are found in the saliva, sputum and CSF (uninflamed meninges). Higher concentrations inthe CSF are expected when meninges are inflamed, but it is questionable whether therapeutic levelsare attainable. Clavulanic acid is 13% bound to proteins in dog serum. The drug readily crosses theplacenta, but is not believed to cause any teratogenic problems. Clavulanic acid and amoxicillin areboth 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 inhibitingactivity. 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 only1/5th of those of amoxicillin.