Continuing Education Activity

Clavulanic acid is a medication that can be used in conjunction with amoxicillin to manage and treat bacterial infections, specifically bacteria that are beta-lactamase producers. It is in the beta-lactamase inhibitor class of medications. This activity describes the indications, action, and contraindications for clavulanic acid as a valuable agent in the treatment of beta-lactamase-producing bacterial infections when used with amoxicillin and how the interprofessional team can use this agent to drive positive outcomes in fighting infections.

Objectives:

• Identify the mechanism of action of clavulanic acid.
• Describe the potential adverse effects of clavulanic acid.
• Outline the appropriate monitoring for patients receiving clavulanic acid.
• Review interprofessional team strategies for improving care coordination and communication to advance clavulanic acid and improve outcomes.

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. This can be based on the source of the infection, Gram stain, or culture and sensitivity results. 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 treating 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. It is provided in a fixed dosage with 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 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. Still, 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 a penicillin-derived antibiotic so caution is necessary for 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 functions 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, cytochrome P450, and genetic polymorphisms. These risk factors should be examined before administering 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 capable of producing beta-lactamase. 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 as an interprofessional team to make sure the drug is administered safely and in the appropriate setting to avoid adverse effects or reactions to clavulanic acid and amoxicillin. Clinicians are responsible for initial agent selection, but the pharmacist can weigh in after performing medication reconciliation and verifying dosing. Nursing will often be responsible for administration instructions, confirmed by the pharmacist, and can follow up 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 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010 Jan;23(1):160-201. [PMC free article: PMC2806661] [PubMed: 20065329]

2.

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. Bosn J Basic Med Sci. 2018 Nov 07;18(4):361-366. [PMC free article: PMC6252101] [PubMed: 29750894]

3.

Akhavan BJ, Khanna NR, Vijhani P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Nov 17, 2023. Amoxicillin. [PubMed: 29489203]

4.

Evans J, Hanoodi M, Wittler M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 11, 2024. Amoxicillin Clavulanate. [PubMed: 30844191]

5.

Jacobs MR. Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles. Expert Rev Anti Infect Ther. 2005 Jun;3(3):353-60. [PubMed: 15954852]

6.

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;13(5):e0196734. [PMC free article: PMC5940197] [PubMed: 29738561]

7.

Chams S, El Sayegh S, Hamdon M, Kumar S, Tegeltija V. Amoxicillin/clavulanic acid-induced pancreatitis: case report. BMC Gastroenterol. 2018 Aug 02;18(1):122. [PMC free article: PMC6090968] [PubMed: 30071846]

8.

Iravani A, Richard GA. Treatment of urinary tract infections with a combination of amoxicillin and clavulanic acid. Antimicrob Agents Chemother. 1982 Oct;22(4):672-7. [PMC free article: PMC183812] [PubMed: 7181477]

9.

deLemos AS, Ghabril M, Rockey DC, Gu J, Barnhart HX, Fontana RJ, Kleiner DE, Bonkovsky HL., Drug-Induced Liver Injury Network (DILIN). Amoxicillin-Clavulanate-Induced Liver Injury. Dig Dis Sci. 2016 Aug;61(8):2406-2416. [PMC free article: PMC4945382] [PubMed: 27003146]

10.

Crass RL, Pai MP. Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors. Pharmacotherapy. 2019 Feb;39(2):182-195. [PubMed: 30589457]

11.

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 Transpl. 2012 Jul;18(7):803-10. [PMC free article: PMC3396746] [PubMed: 22389256]

12.

Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin Drug Saf. 2014 Jan;13(1):67-81. [PubMed: 24073714]

13.

Giordano C, Rivas J, Zervos X. An Update on Treatment of Drug-Induced Liver Injury. J Clin Transl Hepatol. 2014 Jun;2(2):74-9. [PMC free article: PMC4521262] [PubMed: 26356645]

Disclosure: Leah Uto declares no relevant financial relationships with ineligible companies.

Disclosure: Valerie Gerriets declares no relevant financial relationships with ineligible companies.