Clavulanic Acid

Clavulanic acid, also known by its potassium salt form clavulanate, is FDA approved for clinical use in conjunction with amoxicillin to treat certain bacterial infections. The antibacterial activity of amoxicillin is not improved by clavulanic acid when used against bacteria that do not produce beta-lactamase. Therefore, indications for this drug combination only include patients suspected of infection with beta-lactamase-producing bacteria.[1] This combination has demonstrated efficacy in the treatment of infections such as complicated and uncomplicated urinary tract infections, lower respiratory infections, sinusitis, otitis media, and some skin and soft tissue infections caused by organisms such as H. influenzae, M. catarrhalis, and S. aureus. The amoxicillin/clavulanate combination should be considered before ceftriaxone for urinary tract infections to decrease the risk of re-infection and complications.[2] Some off-label uses for amoxicillin/clavulanate include animal bites, impetigo, chronic obstructive pulmonary disease exacerbations, bronchiectasis, and odontogenic infections.

Clavulanic acid use is always in conjunction with amoxicillin in its salt form clavulanate potassium. Amoxicillin is a beta-lactam antibiotic that disrupts bacterial cell wall synthesis. It binds to penicillin-binding proteins that are present on the inside of the bacterial cell wall, and this inhibits the synthesis of the peptidoglycan layer in the cell wall.[3] This disruption in cell wall synthesis leads to cell lysis and bacterial death. Certain bacterial species produce the enzyme beta-lactamase which can inactivate beta-lactam drugs by hydrolyzing the beta-lactam ring in the antibiotic compound, leading to drug resistance. Clavulanic acid is an inhibitor of beta-lactamase enzymes. Clavulanic acid contains a beta-lactam ring that binds to the beta-lactamase active site and inactivates the enzyme, thereby enhancing the antibacterial effect of beta-lactam antibiotics, such as amoxicillin. Clavulanic acid is classified as a suicide inhibitor of these beta-lactamases because it permanently inactivates the enzyme through chemical reactions at the active site.[1] Clavulanic acid alone has no know antibacterial effect and is always used in combination with amoxicillin.[4]

Clavulanic acid alone has been shown to have no antibacterial effects, and administration must accompany amoxicillin. It is available in both solid and liquid forms. For the solid form, the patient must chew the chewable tablets before swallowing, and there are also immediate and extended-release tablets that must be swallowed whole. The oral liquid suspension should be shaken before administration and is the recommended formulation for children who are unable to chew tablets or swallow whole pills. Administration of all forms of the drug should be done at the start of a light meal to enhance oral absorption and avoid gastrointestinal irritation. Clavulanic acid may increase the absorption of amoxicillin. This drug regimen is to be administered twice to three times daily, depending on dosage, at regular time intervals to maintain constant serum concentrations.[5]

Clavulanic acid, when administered with amoxicillin, can cause some mild gastrointestinal adverse effects. These include vomiting, nausea, loose stools, and discomfort. Antibiotic-associated diarrhea due to amoxicillin-clavulanic acid treatment is the most common adverse effect. There is a higher incidence of diarrhea when clavulanic acid is added to amoxicillin compared to amoxicillin alone. Diarrhea is more common in those who are taking a high dose of the extended-release form of clavulanic acid and amoxicillin.[6] Drug-induced pancreatitis from clavulanic acid and amoxicillin has occurred in a few cases.[7] When used for the treatment of urinary tract infections, this drug combination can cause candida vaginitis.[8] Amoxicillin, in conjunction with clavulanic acid, is the most common cause of idiosyncratic drug-induced injury, specifically cholestatic liver injury, and this can lead to an increase in alkaline phosphatase and bilirubin levels.[9]  Since clavulanic acid administration is always in conjunction with amoxicillin, it is important to consider the adverse effects of amoxicillin alone as well. Hypersensitivity reactions to this drug combination, usually due to amoxicillin, can occur and result in dermatological reactions, but none of these allergic reactions are known to be due to clavulanic acid alone. 

All contraindications for clavulanic acid are considered in conjunction with amoxicillin since clavulanic acid is not administered by itself.  The drug combination is primarily excreted renally, so caution is necessary when a patient has renal impairment or is on hemodialysis.[1] Patients who have renal disease may need to have their dosages adjusted and monitored closely. The liver primarily metabolizes the drug combination and therefore, caution is necessary when given to patients who have liver damage or disease.[1][10] Amoxicillin/clavulanate should never be given to patients who have had an idiosyncratic drug-induced injury from clavulanic acid or amoxicillin, although there is no evidence that clavulanic acid itself is hepatotoxic.[9] Because clavulanic acid is only administered in conjunction with amoxicillin, it is important to consider the adverse effects of amoxicillin, which is penicillin-derived antibiotic so caution is necessary in patients who have a known history of penicillin allergy.