Clavulanic Acid


Article Author:
Leah Uto


Article Editor:
Valerie Gerriets


Editors In Chief:
Dustin Constant
Donald Kushner


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Mark Pellegrini
James Hughes
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Hajira Basit
Phillip Hynes


Updated:
7/28/2019 8:58:27 AM

Indications

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.

Mechanism of Action

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]

Administration

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]

Adverse Effects

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. 

Contraindications

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.

Monitoring

The monitoring and administration of clavulanic acid are only considered in conjunction with amoxicillin. There are reports of hypersensitivity reactions to this drug combination, so monitoring for this at the beginning of an administration is recommended. Monitoring for secondary infection while on this drug regimen is also advisable. Hepatic, hematological, and renal function also require monitoring if the administration lasts for longer than one week. Patients with hepatic and renal impairment require close surveillance while on the drug and after discontinuation of the drug. 

Toxicity

The toxicity of clavulanic acid alone is unknown. However, the toxic effects of amoxicillin/clavulanate have been reported. The most common toxic effect is an idiosyncratic drug-induced hepatic injury which leads to a mixed hepatocellular-cholestatic injury and it is more common in older men.[9] Amoxicillin-clavulanic acid is the most common cause of idiosyncratic drug-induced hepatic injury.[11] Risk factors for hepatic injury include sex, and cytochrome P450 and genetic polymorphisms. These risk factors should be examined before the administration of amoxicillin/clavulanate to reduce the risk of toxic and adverse effects.[12] In addition to early diagnosis and discontinuation of the drug, N-acetylcysteine can be administered to minimize damage.[13] Additionally, steroids can be given to decrease the time it takes to return hepatic enzymes and bilirubin levels to normal.[13] Liver failure is also a rare but possible toxic effect of amoxicillin-clavulanic acid. 

Enhancing Healthcare Team Outcomes

Beta-lactamase inhibitors, such as clavulanic acid, are an essential tool for treating bacterial infections that are beta-lactamase producing. To prevent an increase in antibiotic resistance, it is critical to administer this drug only to patients infected with beta-lactamase-producing bacteria. 

It is also crucial that pharmacists, nurses, and physicians work together to make sure the drug is administered safely and in the appropriate setting to avoid adverse effects or reactions to clavulanic acid and amoxicillin. Physicians are responsible for initial agent selection, but the pharmacist can weigh in after performing medication reconciliation and also verify dosing. Nursing will often be responsible for administration instructions, confirmed by the pharmacist, and can followup to assess compliance as well as the effectiveness of the regimen. Any deviations from expected in the above should be reported to the prescribing/ordering clinician. In this manner, the entire interprofessional team can guide and participate in the antimicrobial regimen to optimize patient results. [Level V]


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Clavulanic Acid - Questions

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A 4-year-old female patient presented to the clinician's office with ear pain after an upper respiratory infection. She was started on amoxicillin for an ear infection, but her mother took her back 6 days later because her symptoms had not improved. The physician decided to add a drug to the patient's treatment regimen that inhibits beta-lactamase. Which of the following is the most likely explanation for the addition of this new drug?



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A 65-year-old man presents to the clinic with inflammation of his nasal cavity and paranasal sinuses. Acute bacterial rhinosinusitis is diagnosed. The patient is started on amoxicillin, but his symptoms fail to improve after a week. Which drug should be administered in conjunction with amoxicillin to resolve the patient's rhinosinusitis?



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A 15-year-old girl presents to the clinic with pain with urination and urinary frequency. A urinary tract infection is diagnosed. The patient is prescribed amoxicillin. What is the most likely mechanism of action of the drug that can be used in conjunction with amoxicillin to enhance its antibacterial action?



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A 2-year-old infant is brought in to the clinic by her parents because she has been tugging at her ear and has a fever and fluid discharge coming out of her right ear. The infant is suspected to have otitis media, and she is prescribed amoxicillin, but her symptoms do not improve after a week of treatment. Why would amoxicillin-clavulanate be more effective in treating the infection rather than amoxicillin alone?



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A 10-year-old boy is brought into the clinic and presents with a runny nose, dry cough, fever, and sore throat, and he is suspected of having a lower respiratory infection. If the patient is infected with a beta-lactamase-producing bacteria, why would clavulanic acid need to be administered in conjunction with amoxicillin for successful treatment of the infection?



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Clavulanic Acid - References

References

Evans J,Wittler M, Amoxicillin Clavulanate 2019 Jan;     [PubMed]
Jacobs MR, Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles. Expert review of anti-infective therapy. 2005 Jun;     [PubMed]
Matho A,Mulqueen M,Tanino M,Quidort A,Cheung J,Pollard J,Rodriguez J,Swamy S,Tayler B,Garrison G,Ata A,Sorum P, High-dose versus standard-dose amoxicillin/clavulanate for clinically-diagnosed acute bacterial sinusitis: A randomized clinical trial. PloS one. 2018;     [PubMed]
Chams S,El Sayegh S,Hamdon M,Kumar S,Tegeltija V, Amoxicillin/clavulanic acid-induced pancreatitis: case report. BMC gastroenterology. 2018 Aug 2;     [PubMed]
Karlović K,Nikolić J,Arapović J, Ceftriaxone treatment of complicated urinary tract infections as a risk factor for enterococcal re-infection and prolonged hospitalization: A 6-year retrospective study. Bosnian journal of basic medical sciences. 2018 Nov 7;     [PubMed]
Iravani A,Richard GA, Treatment of urinary tract infections with a combination of amoxicillin and clavulanic acid. Antimicrobial agents and chemotherapy. 1982 Oct;     [PubMed]
deLemos AS,Ghabril M,Rockey DC,Gu J,Barnhart HX,Fontana RJ,Kleiner DE,Bonkovsky HL, Amoxicillin-Clavulanate-Induced Liver Injury. Digestive diseases and sciences. 2016 Aug;     [PubMed]
Drawz SM,Bonomo RA, Three decades of beta-lactamase inhibitors. Clinical microbiology reviews. 2010 Jan;     [PubMed]
Crass RL,Pai MP, Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors. Pharmacotherapy. 2019 Feb;     [PubMed]
Hussaini SH,Farrington EA, Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert opinion on drug safety. 2014 Jan;     [PubMed]
Sembera S,Lammert C,Talwalkar JA,Sanderson SO,Poterucha JJ,Hay JE,Wiesner RH,Gores GJ,Rosen CB,Heimbach JK,Charlton MR, Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2012 Jul;     [PubMed]
Giordano C,Rivas J,Zervos X, An Update on Treatment of Drug-Induced Liver Injury. Journal of clinical and translational hepatology. 2014 Jun;     [PubMed]
Akhavan BJ,Vijhani P, Amoxicillin 2019 Jan;     [PubMed]

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