Amoxicillin/clavulanic acid

Amoxicillin/clavulanic acid

Combination of
Amoxicillin	Penicillin antibiotic
Clavulanic acid	Beta-lactamase inhibitor
Clinical data
Trade names	Augmentin, Clavulin, Amoclan, others[1]
Other names	Co-amoxiclav; Amox-clav
AHFS/Drugs.com	Monograph
MedlinePlus	a685024
License data	US DailyMed: Amoxicillin clavulanate
Pregnancy category	AU: B1
Routes of administration	By mouth, intravenous[2]
ATC code	J01CR02 (WHO) QJ01CR02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[3] CA: ℞-only[4] UK: POM (Prescription only) US: ℞-only
Identifiers
CAS Number	74469-00-4 74428-36-7
PubChem CID	6435924
ChemSpider	4940608
KEGG	D06485
ChEMBL	ChEMBL1697738
CompTox Dashboard (EPA)	DTXSID40225477
Chemical and physical data
Formula	C24H27KN4O10S
Molar mass	602.66 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CC1(C(N2C(S1)C(C2=O)NC(=O)C(C3=CC=C(C=C3)O)N)C(=O)O)C.C1C2N(C1=O)C(C(=CCO)O2)C(=O)[O-].[K+]
InChI InChI=DWHGNUUWCJZQHO-ZVDZYBSKSA-M Key:1S/C16H19N3O5S.C8H9NO5.K/c1-16(2)11(15(23)24)19-13(22)10(14(19)25-16)18-12(21)9(17)7-3-5-8(20)6-4-7;10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4;/h3-6,9-11,14,20H,17H2,1-2H3,(H,18,21)(H,23,24);1,6-7,10H,2-3H2,(H,12,13);/q;;+1/p-1/b;4-1-;/t9-,10-,11+,14-;6-,7-;/m11./s1
^NY (what is this?)  (verify)

Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections.^[5] It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor.^[5] It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites.^[5] It is taken by mouth or by injection into a vein.^[2]

Common side effects include diarrhea, vomiting, and allergic reactions.^[5] It also increases the risk of yeast infections, headaches, and blood clotting problems.^[2][6] It is not recommended in people with a history of a penicillin allergy.^[2] It is relatively safe for use during pregnancy.^[5]

Amoxicillin/clavulanic acid was approved for medical use in the United States in 1984.^[5] It is on the World Health Organization's List of Essential Medicines.^[7][8] The World Health Organization classifies amoxicillin/clavulanic-acid as critically important for human medicine.^[9] It is available as a generic medication.^[5] In 2022, it was the 96th most commonly prescribed medication in the United States, with more than 6 million prescriptions.^[10][11]

Medical uses

Amoxicillin/clavulanic acid is widely used to treat or prevent many infections caused by susceptible bacteria, such as:

• Urinary tract infections
• Respiratory tract infections
• Skin and soft tissue infections
• Sinus infections
• Tonsillitis
• Cat scratches
• Infections caused by the bacterial flora of the mouth, such as:
  • Dental infections
  • Infected animal bites
  • Infected human bites (including uncomplicated "clenched-fist" or "reverse-bite" injuries)^[12][13]
• Treatment-resistant tuberculosis (see below)

Urinary tract infections

Amoxicillin/clavulanic acid is a second-line therapy in the treatment of uncomplicated urinary tract infections (UTIs).^[14][15] It is active against UTIs caused by Staphylococcus saprophyticus, Enterococci (e.g., Enterococcus faecalis), Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.^[15] It is a definitive treatment against susceptible extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria.^[15] The drug is not effective against Pseudomonas aeruginosa, Morganella morganii, or Providencia stuartii, nor against AmpC β-lactamase- and ESBL-producing Gram-negative bacteria or carbapenem-resistant Enterobacteriaceae (CRE).^[15] It is not recommended in the empiric treatment of acute pyelonephritis or hospital-acquired UTIs.^[15]

As determined by a 2014 literature review of antibiotics for UTIs, respective early clinical cure and early bacterial cure rates were 91% and 91% for trimethoprim/sulfamethoxazole, 92% and 87% for nitrofurantoin, 91% and 83% for fosfomycin, 90% and 91% for fluoroquinolones (ciprofloxacin and norfloxacin), and 86% and 81% for β-lactams (amoxicillin/clavulanic acid and cefpodoxime).^[14] In a large high-quality randomized controlled trial of amoxicillin/clavulanic acid for UTI in 370 women, early and late clinical cure rates were 79% and 58%, respectively.^[14] Amoxicillin/clavulanic acid reaches a relatively low urine concentration, which might be involved in its lower effectiveness than other antibiotics.^[15]

Amoxicillin/clavulanic acid is less effective in the treatment of UTI than first-line therapies used to treat UTIs.^[14][16] A 2012 network meta-analysis of antibiotics for uncomplicated UTIs found that it was less effective than all other assessed agents, including trimethoprim/sulfamethoxazole, nitrofurantoin, fosfomycin, fluoroquinolones (ciprofloxacin, norfloxacin, and gatifloxacin), and pivmecillinam.^[16] However, selection of an empirical antibiotic should be based on local or regional susceptibility data.^[15] Additionally, selection of the most appropriate and narrowest effective antibiotic is recommended to help limit increased antibiotic resistance to broad-spectrum antibiotics.^[15]

Combining amoxicillin/clavulanic acid with aztreonam can further enhance its activity against certain resistant UTI-causing bacteria.^[15]

Tuberculosis

It is also used for tuberculosis that is resistant to other treatments.^[5] The World Health Organization recommends giving amoxicillin-clavulanate along with meropenem as one of the therapeutic options in drug-resistant tuberculosis.^[17] However, across the spectrum of dosage of amoxicillin-clavulanate combination, the dose of clavulanate is constant at 125 mg, whereas the dose of amoxicillin varies at 250 mg, 500 mg and 875 mg. Thus the use of low-dose amoxicillin-clavulanate in combination with meropenem may be used in part of a treatment regimen for drug-resistant TB and this has been demonstrated in a clinical setting also. Its efficacy is attributed not to the amoxicillin component, but to the protective action of clavulanic acid over meropenem against beta-lactamase produced by the mycobacteria. Therefore, the minimum dosage of amoxicillin (250 mg) is recommended.^[18]

Adverse effects

Possible side effects include diarrhea, vomiting, nausea, thrush, and skin rash. These do not usually require medical attention. As with all antimicrobial agents, antibiotic-associated diarrhea due to Clostridioides difficile infection—sometimes leading to pseudomembranous colitis—may occur during or after treatment with amoxicillin/clavulanic acid.^[13]

Rarely, cholestatic jaundice (also referred to as cholestatic hepatitis, a form of liver toxicity) has been associated with amoxicillin/clavulanic acid. The reaction may occur up to several weeks after treatment has stopped and usually takes weeks to resolve. It is more frequent in men, older people, and those who have taken long courses of treatment; the estimated overall incidence is one in 100,000 exposures.^[13] In the United Kingdom, co-amoxiclav carries a warning from the Committee on Safety of Medicines to this effect.^[12]

As all aminopenicillins, amoxicillin has been associated with Stevens–Johnson syndrome / toxic epidermal necrolysis, although these reactions are very rare.^[13][19]

Pharmacology

Amoxicillin is an antibiotic while clavulanic acid is a non-antibiotic β-lactamase inhibitor which prevents metabolism of amoxicillin by certain bacteria.

In addition to its β-lactamase inhibition, clavulanic acid shows central nervous system actions and effects and has been studied in the potential treatment of various psychiatric and neurological disorders.^{[20][21][22][23][24]}

History

British scientists working at Beecham (now part of GlaxoSmithKline), filed for patent protection for the drug combination in 1977, which was granted in 1982.^[25]

It was sold under the brand name Augmentin.^[12][26]

Preparations

Amoxicillin/clavulanic acid is the International Nonproprietary Name (INN) and co-amoxiclav is the British Approved Name (BAN).^{[citation needed]}

Many branded products indicate their strengths as the quantity of amoxicillin. Augmentin 250, for example, contains 250 mg of amoxicillin and 125 mg of clavulanic acid.^[12][27]

An intravenous preparation has been available in the UK since 1985,^[28] but no parenteral preparation is available in the US;^{[citation needed]} the nearest equivalent is ampicillin/sulbactam.^{[citation needed]}

Suspensions of amoxicillin/clavulanic acid are available for use in children. They must be refrigerated to maintain effectiveness.^{[citation needed]}

Veterinary use

Amoxicillin/clavulanic acid is used in numerous animals for a variety of conditions:

• Dogs: Skin and soft tissue infections such as wounds, abscesses, cellulitis, superficial/juvenile and deep pyoderma due to susceptible strains of the following organisms: β-lactamase-producing Staphylococcus aureus, non-β-lactamase-producing Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., and E. coli; and periodontal infections due to susceptible strains of both aerobic and anaerobic bacteria.^[29]

• Cats: Skin and soft tissue infections such as wounds, abscesses, and cellulitis/dermatitis due to susceptible strains of the following organisms: β-lactamase-producing Staphylococcus aureus, non-β-lactamase-producing Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., E. coli, and Pasteurella spp; urinary tract infections (cystitis) due to susceptible strains of E. coli.^[29]

Bacterial resistance

Bacterial antibiotic resistance is a growing problem in veterinary medicine. Amoxicillin/clavulanic acid is reported to be effective against clinical Klebsiella infections, but is not efficacious against Pseudomonas infections.^[30]

References

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2. World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 102. hdl:10665/44053. ISBN 9789241547659.
3. "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 6 July 2023. Retrieved 30 March 2024.
4. "Regulatory Decision Summary - Amoxicillin Sodium And Potassium Clavulanate For Injection". Health Canada. 23 October 2014. Archived from the original on 5 June 2022. Retrieved 4 June 2022.
5. "Amoxicillin and Clavulanate Potassium". The American Society of Health-System Pharmacists. Archived from the original on 29 November 2016. Retrieved 8 December 2016.
6. Gillies M, Ranakusuma A, Hoffmann T, Thorning S, McGuire T, Glasziou P, et al. (January 2015). "Common harms from amoxicillin: a systematic review and meta-analysis of randomized placebo-controlled trials for any indication". CMAJ. 187 (1): E21 – E31. doi:10.1503/cmaj.140848. PMC 4284189. PMID 25404399.
7. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
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17. World Health Organization (2016). WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. World Health Organization. hdl:10665/250125. ISBN 9789241549639.
18. Mishra G, Caminero J (2018). "First Successful Use of Low Dose Amoxicillin-Clavulanic Acid in Management of Drug Resistant Tuberculosis". Journal of Clinical and Diagnostic Research. 12 (10): OD08 – OD10. doi:10.7860/JCDR/2018/37279.12145. Archived from the original on 7 May 2021. Retrieved 7 May 2021.
19. Harr T, French LE (December 2010). "Toxic epidermal necrolysis and Stevens-Johnson syndrome". Orphanet Journal of Rare Diseases. 5: 39. doi:10.1186/1750-1172-5-39. PMC 3018455. PMID 21162721.
20. Balcazar-Ochoa LG, Ventura-Martínez R, Ángeles-López GE, Gómez-Acevedo C, Carrasco OF, Sampieri-Cabrera R, et al. (January 2024). "Clavulanic Acid and its Potential Therapeutic Effects on the Central Nervous System". Arch Med Res. 55 (1): 102916. doi:10.1016/j.arcmed.2023.102916. PMID 38039802.
21. Ochoa-Aguilar A, Ventura-Martinez R, Sotomayor-Sobrino MA, Gómez C, Morales-Espinoza MR (2016). "Review of Antibiotic and Non-Antibiotic Properties of Beta-lactam Molecules". Anti-Inflamm Anti-Allergy Agents Med Chem. 15 (1): 3–14. doi:10.2174/1871523015666160517114027. PMID 27185396.
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30. Federation of Veterinarians in Europe Position Paper: "Antibiotic Resistance & Prudent Use of Antibiotics in Veterinary Medicine"