Amoxicillin/clavulanic acid

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.<ref name=AHFS2016/> It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor.<ref name=AHFS2016/> It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites.<ref name=AHFS2016/> It can be administered orally or intravenously.<ref name=WHO2008>Template:Cite book</ref>

Common side effects include diarrhea, vomiting, and allergic reactions.<ref name=AHFS2016/> It also increases the risk of yeast infections, headaches, and blood clotting problems.<ref name=WHO2008/><ref>Template:Cite journal</ref> It is not recommended in people with a history of a penicillin allergy.<ref name=WHO2008/> It is relatively safe for use during pregnancy.<ref name=AHFS2016/>

Amoxicillin/clavulanic acid was approved for medical use in the United States in 1984.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref><ref name="WHO22nd">Template:Cite book</ref> The World Health Organization classifies amoxicillin/clavulanic-acid as critically important for human medicine.<ref>Template:Cite book</ref> It is available as a generic medication.<ref name=AHFS2016/> In 2022, it was the 96th most commonly prescribed medication in the United States, with more than 6Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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)<ref name="BNF" /><ref name="Kucers">Template:Cite book</ref>
• 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).<ref name="GrigoryanTrautnerGupta2014">Template:Cite journal</ref><ref name="BaderLoebLeto2020">Template:Cite journal</ref> It is active against UTIs caused by Staphylococcus saprophyticus, Enterococci (e.g., Enterococcus faecalis), Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.<ref name="BaderLoebLeto2020" /> It is a definitive treatment against susceptible extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria.<ref name="BaderLoebLeto2020" /> 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).<ref name="BaderLoebLeto2020" /> It is not recommended in the empiric treatment of acute pyelonephritis or hospital-acquired UTIs.<ref name="BaderLoebLeto2020" />

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).<ref name="GrigoryanTrautnerGupta2014" /> In a large high-quality randomized controlled trial of amoxicillin/clavulanic acid for UTI in 370Template:Nbspwomen, early and late clinical cure rates were 79% and 58%, respectively.<ref name="GrigoryanTrautnerGupta2014" /> Amoxicillin/clavulanic acid reaches a relatively low urine concentration, which might be involved in its lower effectiveness than other antibiotics.<ref name="BaderLoebLeto2020" />

Amoxicillin/clavulanic acid is less effective in the treatment of UTI than first-line therapies used to treat UTIs.<ref name="GrigoryanTrautnerGupta2014" /><ref name="KnottnerusGrigoryanGeerlings2012">Template:Cite journal</ref> 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.<ref name="KnottnerusGrigoryanGeerlings2012" /> However, selection of an empirical antibiotic should be based on local or regional susceptibility data.<ref name="BaderLoebLeto2020" /> Additionally, selection of the most appropriate and narrowest effective antibiotic is recommended to help limit increased antibiotic resistance to broad-spectrum antibiotics.<ref name="BaderLoebLeto2020" />

Combining amoxicillin/clavulanic acid with aztreonam can further enhance its activity against certain resistant UTI-causing bacteria.<ref name="BaderLoebLeto2020" />

Tuberculosis

It is also used for tuberculosis that is resistant to other treatments.<ref name=AHFS2016/> The World Health Organization recommends giving amoxicillin-clavulanate along with meropenem as one of the therapeutic options in drug-resistant tuberculosis.<ref>Template:Cite book</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="Kucers" />

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.<ref name="Kucers" /> In the United Kingdom, co-amoxiclav carries a warning from the Committee on Safety of Medicines to this effect.<ref name="BNF" />

As all aminopenicillins, amoxicillin has been associated with Stevens–Johnson syndrome / toxic epidermal necrolysis, although these reactions are very rare.<ref name="Kucers" /><ref>Template:Cite journal</ref>

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.<ref name="Balcazar-OchoaVentura-MartínezÁngeles-López2024">Template:Cite journal</ref><ref name="Ochoa-AguilarVentura-MartinezSotomayor-Sobrino2016">Template:Cite journal</ref><ref name="MilenkovicCampbellRoussel2018">Template:Cite journal</ref><ref name="ConnollyThase2012">Template:Cite journal</ref><ref name="AdisInsight-Clavulanic-Acid">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref>Template:Cite patent</ref>

It was sold under the brand name Augmentin.<ref name="BNF">Template:Cite book</ref><ref name=Bryan2011>Template:Cite journal</ref>

Preparations

Amoxicillin/clavulanic acid is the International Nonproprietary Name (INN) and co-amoxiclav is the British Approved Name (BAN).Template:Cn

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.<ref name="BNF"/><ref name="GSK">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

An intravenous preparation has been available in the UK since 1985,<ref name="pmid3190988">Template:Cite journal</ref> but no parenteral preparation is available in the US;Template:Cn the nearest equivalent is ampicillin/sulbactam.Template:Cn

Suspensions of amoxicillin/clavulanic acid are available for use in children. They must be refrigerated to maintain effectiveness.Template:Cn

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.<ref name="FDA approvals">{{#invoke:citation/CS1|citation

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• 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.<ref name="FDA approvals" />

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.<ref>Federation of Veterinarians in Europe Position Paper: "Antibiotic Resistance & Prudent Use of Antibiotics in Veterinary Medicine"</ref>