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| Pronunciation | /ˌklævjʊˈlænɪk/ |
| Other names | RX-10100; Serdaxin; Zoraxel |
| AHFS/Drugs.com | International Drug Names |
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| Routes of administration | Oral,IV |
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| Pharmacokinetic data | |
| Bioavailability | Oral: 45–64%[1][2] |
| Protein binding | ~25%[2] |
| Metabolism | Unknown[1] |
| Metabolites | Two minor metabolites[2] |
| Onset of action | ≤0.67–2 hours (TmaxTooltip time to peak concentrations)[2] |
| Eliminationhalf-life | 0.8–1.2 hours[1][2] |
| Excretion | Urine: 35–65% (unchanged; within 6 hours)[1][2] |
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| ECHA InfoCard | 100.055.500 |
| Chemical and physical data | |
| Formula | C8H9NO5 |
| Molar mass | 199.162 g·mol−1 |
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Clavulanic acid is aβ-lactam drug that functions as amechanism-basedβ-lactamase inhibitor. While not effective by itself as anantibiotic, when combined withpenicillin-group antibiotics, it can overcomeantibiotic resistance inbacteria that secreteβ-lactamase, which otherwise inactivates most penicillins.
In its most common preparations, potassium clavulanate (clavulanic acid as a salt of potassium) is combined with:
Clavulanic acid was patented in 1974.[3] In addition to its β-lactamase inhibition, clavulanic acid showsoff-target activity in thenervous system by upregulating theglutamate transporter 1 (GLT-1) and has been studied in the potential treatment of a variety ofcentral nervous system disorders.[1][4]
Amoxicillin–clavulanic acid is a first-line treatment for many types of infections, includingsinus infections, andurinary tract infections, includingpyelonephritis. This is, in part, because of its efficacy againstgram-negative bacteria which tend to be more difficult to control thangram-positive bacteria with chemotherapeutic antibiotics.[clarification needed]
The use of clavulanic acid with penicillins has been associated with an increased incidence ofcholestatic jaundice and acutehepatitis during therapy or shortly after. The associated jaundice is usually self-limiting and very rarely fatal.[5][6]
TheUKCommittee on Safety of Medicines (CSM) recommends that treatments such as amoxicillin/clavulanic acid preparations be reserved for bacterial infections likely to be caused by amoxicillin-resistant β-lactamase-producing strains, and that treatment should not normally exceed 14 days.
Allergic reactions have been reported.[7]
The name is derived from strains ofStreptomyces clavuligerus, which produces clavulanic acid.[8][9]
Theβ-lactam like structure of clavulanic acid looks structurally similar topenicillin, but the biosynthesis of this molecule involves a different biochemical pathway. Clavulanic acid is produced by the bacteriumStreptomyces clavuligerus, usingglyceraldehyde-3-phosphate andL-arginine as starting materials.[10][11] Although each of the intermediates of the pathway is known, the exact mechanism for all of the enzymatic reactions is not fully understood. The process mainly involves 3 enzymes:clavaminate synthase, β-lactam synthetase, andN2-(2-carboxyethyl)-L-arginine (CEA)synthase.[10]Clavaminate synthase is a non-heme oxygenase dependent on iron andα-keto-glutarate and is encoded by orf5 of the clavulanic acidgene cluster. The specific mechanism of how this enzyme works is not fully understood, but this enzyme regulates 3 steps in the overall synthesis of clavulanic acid. All 3 steps occur in the same region of the catalytic, iron-containing reaction center, yet do not occur in sequence and affect different areas of the clavulanic acid structure.[12]
β-lactam synthetase is a 54.5 kDa protein that is encoded by orf3 of the clavulanic acid gene cluster, and shows similarity toasparagine synthase – Class B enzymes. The exact mechanism on how this enzyme works to synthesize theβ-lactam is not proven, but is believed to occur in coordination with a CEA synthase andATP.[13]
CEA synthase is a 60.9 kDA protein and is the first gene found in the clavulanic acid biosynthesis gene cluster, encoded by orf2 of the clavulanic acid gene cluster. The specific mechanism of how this enzyme works is still under investigation; however, it is known that this enzyme has the ability to couple togetherglyceraldehyde-3-phosphate withL-arginine in the presence of thiamine diphosphate (TDP orthiamine pyrophosphate), which is the first step of the clavulanic acid biosynthesis.[14]
Clavulanic acid was discovered around 1974-75 by British scientists working at the drug companyBeecham from the bacteriaStreptomyces clavuligerus.[15]After several attempts, Beecham finally filed forUS patent protection for the drug in 1981, and U.S. Patents 4,525,352, 4,529,720, and 4,560,552 were granted in 1985.
Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic ofβ-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzymeβ-lactamase secreted by certain bacteria to confer resistance to β-lactam antibiotics.
Clavulanic acid is asuicide inhibitor, covalently bonding to aserine residue in theactive site of the β-lactamase. This restructures the clavulanic acid molecule, creating a much more reactive species that attacks another amino acid in the active site, permanently inactivating it, and thus inactivating the enzyme.
This inhibition restores the antimicrobial activity of β-lactam antibiotics against lactamase-secreting resistant bacteria. Despite this, some bacterial strains that are resistant even to such combinations have emerged.
In 2005, it was discovered viascreening of 1,040Food and Drug Administration (FDA)-approveddrugs andneutraceuticals that many β-lactams, such asceftriaxone,upregulateastrocyticglutamate transporter 1 (GLT-1)expression.[1][16][17] Subsequently, it was discovered that clavulanic acid, likewise a β-lactam, shares this action.[1][18] The associated effects include enhanced GLT-1 expression in thenucleus accumbens,medial prefrontal cortex, andspinal cord, modulation ofglutamatergic,dopaminergic, andserotonergicneurotransmission, andanti-inflammatory effects via modulation ofcytokinestumor necrosis factor α (TNF-α) andinterleukin-10 (IL-10).[1][19][4] Ceftriaxone lacksoralbioavailability, has poorbrainpermeability, and has concomitant antibiotic activity.[1] These limitations have resulted in more interest in clavulanic acid, which does not share these drawbacks and is morepotent than ceftriaxonein vivo.[1] Themechanism of action underlying the upregulation of GLT-1 expression by β-lactams is unknown.[1][17] However, interactions with theSNAREproteinsMunc18-1 andRab4 may be involved in some of clavulanic acid's effects, such as increased dopamine release.[20][21]
In relation to itscentral nervous system actions, clavulanic acid has been studiedpreclinically inmodels ofanxiety,sexual behavior,addiction,neuropathic pain,inflammatory pain,epilepsy,Parkinson's disease,dementia, andstroke.[1][19][22][20] In animals, including in rodents and/or monkeys, clavulanic acid has shownanxiolytic-like,antidepressant-like,pro-sexual,memory-enhancing,analgesic,antiaddictive,pro-dopaminergic,pro-oxytocinergic, andneuroprotective effects.[1][20][18][23] The drug has been studiedclinically in humans in the treatment oferectile dysfunction,[19]depression,[24][25][26]substance dependence,[27] andpain,[20] with positive or mixed preliminary results for these conditions reported.[4][19][24][26]
Clavulanic acid was under formal development by Revaax Pharmaceuticals (now Ocuphire Pharma) for the treatment of erectile dysfunction,anxiety disorders,major depressive disorder,neurodegenerative disorders, and Parkinson's disease.[4][19][24] However, development for these indications was discontinued by 2014.[4] The developmental code name of clavulanic acid was RX-10100 and its tentative brand names were Serdaxin and Zoraxel.[4] Although its development was discontinued, interest in clavulanic acid for potentialnervous system-related uses has continued as of 2024.[1][27]
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