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street name for lysergic acid diethylamide (同)back breaker, battery-acid, dose, dot, Elvis, loony toons, Lucy in the sky with diamonds, pane, superman, window pane, Zen
any of various water-soluble compounds having a sour taste and capable of turning litmus red and reacting with a base to form a salt
having the characteristics of an acid; "an acid reaction"

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酸性の / 酸味のある,すっぱい(sour) / (言葉・態度などが)厳しい,しんらつな / 酸 / すっぱいもの / 《俗》=LSD

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/05 21:08:17」(JST)

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Clavulanic acid (rINN) /ˌklævjuːˈlænᵻk ˈæsᵻd/ is a β-lactam drug that functions as a mechanism-based β-lactamase inhibitor. While not effective by itself as an antibiotic, when combined with penicillin-group antibiotics, it can overcome antibiotic resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins.

In its most common form, the potassium salt potassium clavulanate is combined with:

amoxicillin (co-amoxiclav, trade names Augmentin, Tyclav (Beximco), Synulox [veterinary], and others) or
ticarcillin (co-ticarclav, trade name Timentin).

Clavulanic acid is an example of a clavam.

Sources

The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.^[1]^[2]

Clavulanic acid is biosynthetically generated from the amino acid arginine and the sugar glyceraldehyde 3-phosphate.

Biosynthesis

The intermediates of the biosynthesis of Clavulanic Acid^[3]

With the β-lactam like structure, clavulanic acid looks structurally similar to penicillin, but the biosynthesis of this molecule involves a different pathway and set of enzymes. Clavulanic acid is biosynthesized by the bacterium Streptomyces clavuligerus, using glyceraldehyde-3-phosphate and L-arginine as the starting materials of the pathway.^[3]^[4] Although all of the intermediates of the pathway are known, the exact mechanism of each enzymatic reaction is not fully understood. The biosynthesis mainly involves 3 enzymes: clavaminate synthase, β-lactam synthetase and N²-(2-carboxyethyl)-L-arginine synthase(CEA).^[3] Clavaminate synthase is a non-heme iron α-keto-glutarate dependent oxygenase that is encoded by orf5 of the clavulanic acid gene 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 center, yet do not occur in-sequence and affect different areas of the clavulanic acid structure.^[5]

β-lactam synthetase is a 54.5 kDa protein that is encoded by orf3 of the clavulanic acid gene cluster, and shows similarity to asparagine synthase – Class B enzymes. The exact mechanism on how this enzyme works to synthesize the β-lactam is not proven, but is believed to occur in coordination with a CEA synthase and ATP.^[6]

Proposed mechanism of beta-lactam synthetase in the biosynthesis of clavulanic acid.^[3]

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 together glyceraldehyde-3-phosphate with L-arginine in the presence of thiamine diphosphate (TDP or thiamine pyrophosphate), which is the first step of the clavulanic acid biosynthesis.^[7]

Proposed mechanism of CEA synthetase in the biosynthesis of clavulanic acid.^[3]

History

Clavulanic acid was discovered around 1974/75 by British scientists working at the drug company Beecham. After several attempts, Beecham finally filed for US 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.

Mechanism of action

Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic of β-lactam antibiotics. However, the similarity in chemical structure allows the molecule to interact with the enzyme β-lactamase secreted by certain bacteria to confer resistance to β-lactam antibiotics.

Clavulanic acid is a suicide inhibitor, covalently bonding to a serine residue in the active site of the β-lactamase. This restructures the clavulanic acid molecule, creating a much more reactive species that is attacked by 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.

Adverse effects

The use of clavulanic acid with penicillins has been associated with an increased incidence of cholestatic jaundice and acute hepatitis during therapy or shortly after. The associated jaundice is usually self-limiting and very rarely fatal.^[8]^[9]

The UK Committee 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.

Allergy has been reported.^[10]

References

^ Arulanantham H, Kershaw NJ, Hewitson KS, Hughes CE, Thirkettle JE, Schofield CJ (January 2006). "ORF17 from the clavulanic acid biosynthesis gene cluster catalyzes the ATP-dependent formation of N-glycyl-clavaminic acid". J. Biol. Chem. 281 (1): 279–87. doi:10.1074/jbc.M507711200. PMID 16251194.
^ Tahlan K, Park HU, Wong A, Beatty PH, Jensen SE (March 2004). "Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus". Antimicrob. Agents Chemother. 48 (3): 930–9. doi:10.1128/AAC.48.3.930-939.2004. PMC 353097. PMID 14982786.
^ ^a ^b ^c ^d ^e Townsend, CA (Oct 2002). "New reactions in clavulanic acid biosynthesis.". Current Opinion in Chemical Biology 6 (5): 583–9. doi:10.1016/S1367-5931(02)00392-7. PMID 12413541.
^ Reading, C.; Cole, M. (1 May 1977). "Clavulanic Acid: a Beta-Lactamase-Inhibiting Beta-Lactam from Streptomyces clavuligerus". Antimicrobial Agents and Chemotherapy 11 (5): 852–857. doi:10.1128/AAC.11.5.852.
^ Busby, RW; Townsend, CA (Jul 1996). "A single monomeric iron center in clavaminate synthase catalyzes three nonsuccessive oxidative transformations.". Bioorganic & Medicinal Chemistry 4 (7): 1059–64. doi:10.1016/0968-0896(96)00088-0. PMID 8831977.
^ Bachmann, BO; Townsend, CA (Sep 19, 2000). "Kinetic mechanism of the beta-lactam synthetase of Streptomyces clavuligerus.". Biochemistry 39 (37): 11187–93. doi:10.1021/bi000709i. PMID 10985764.
^ Khaleeli, Nusrat; Li, Rongfeng; Townsend, Craig A. "Origin of the β-Lactam Carbons in Clavulanic Acid from an Unusual Thiamine Pyrophosphate-Mediated Reaction". Journal of the American Chemical Society 121 (39): 9223–9224. doi:10.1021/ja9923134.
^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
^ "Drug Record - Amoxicillin-Clavulanate". LiverTox - Clinical and Research Information on Drug-Induced Liver Injury. Retrieved April 24, 2013.
^ Tortajada Girbés M, Ferrer Franco A, Gracia Antequera M, Clement Paredes A, García Muñoz E, Tallón Guerola M (2008). "Hypersensitivity to clavulanic acid in children". Allergol Immunopathol (Madr) 36 (5): 308–10. doi:10.1016/S0301-0546(08)75228-5. PMID 19080805.

UpToDate Contents

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1. β-ラクタマーゼ阻害剤、カルバペネム系、およびモノバクタム系抗菌薬の併用 combination beta lactamase inhibitors carbapenems and monobactams
2. β-ラクタム系抗生物質：作用機序、耐性および有害作用 beta lactam antibiotics mechanisms of action and resistance and adverse effects
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4. Surgical management of necrotizing soft tissue infections
5. 小児における急性中耳炎：治療 acute otitis media in children treatment

English Journal

Detection, seroprevalence and antimicrobial resistance of Yersinia enterocolitica and Yersinia pseudotuberculosis in pig tonsils in Northern Italy.

Bonardi S1, Bruini I2, D'Incau M3, Van Damme I4, Carniel E5, Brémont S5, Cavallini P6, Tagliabue S3, Brindani F2.
International journal of food microbiology.Int J Food Microbiol.2016 Oct 17;235:125-32. doi: 10.1016/j.ijfoodmicro.2016.07.033. Epub 2016 Jul 28.
Yersiniosis is the third most common reported zoonoses in Europe, with Y. enterocolitica and Y. pseudotuberculosis responsible for 98.66% and 0.94% of the confirmed human cases in 2013. From June 2013 to October 2014, 201 pigs at slaughter belonging to 67 batches were tested for Y. enterocolitica an
PMID 27500659

Molecular characterization of a clinical Haemophilus parainfluenzae isolate with cefotaxime resistance and decreased susceptibility to fluoroquinolones.

Faccone D1, Lopez-Ruitti P2, Vazquez M3, Guerriero L2, Lucero C2, Gagetti P2, Ceriana P2, Corso A4.
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.Infect Genet Evol.2016 Oct;44:507-9. doi: 10.1016/j.meegid.2016.08.003. Epub 2016 Aug 5.
We report an H. parainfluenzae clinical isolate resistant to cefotaxime and with decreased susceptibility to ciprofloxacin recovered from a patient with cystic fibrosis. The isolate had elevated MICs of ampicillin (256mg/L), amoxicillin-clavulanate (8mg/L), cefuroxime (8mg/L) and cefotaxime (4mg/L),
PMID 27497656

Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

de Velde F1, de Winter BC2, Koch BC3, van Gelder T4, Mouton JW5; COMBACTE-NET consortium.
The Journal of antimicrobial chemotherapy.J Antimicrob Chemother.2016 Oct;71(10):2909-17. doi: 10.1093/jac/dkw226. Epub 2016 Jun 20.
OBJECTIVES: To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens.METHODS: Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg
PMID 27330071

Japanese Journal

Prevalence and antimicrobial resistance of Salmonella isolated from poultry slaughterhouses in Korea

Kidie Dessie Hirut,Bae Dong Hwa,Lee Young Ju
Japanese Journal of Veterinary Research 61(4), 129-136, 2013-11
… High antimicrobial resistance rates against sulfamethoxazole (39.8%) followed by tetracycline (22.7%), nalidixic acid (21.6%), ampicillin and amoxicillin-clavulanic acid (8.0%), and chloramphenicol (4.5%) were observed. …
NAID 120005350102

症例アモキシシリン・クラブラン酸カリウム合剤により皮疹が誘発された伝染性単核球症

清水教子,牧野輝彦,乗杉理 [他]
Journal of environmental dermatology and cutaneous allergology 7(4), 256-260, 2013-10
NAID 40019852643

Efficacy of Fosfomycin on Escherichia coli Isolated from Bitches with Pyometra

INOUE Ikuo,SHIBATA Sanae,FUKATA Tsuneo
Journal of Veterinary Medical Science 75(5), 657-658, 2013
… The antimicrobials used were ampicillin (ABPC), amoxicillin/clavulanic acid, gentamicin, minocycline, cefazolin, levofloxacin (LVFX), trimethoprim-sulfamethoxazole (ST) and fosfomycin (FOM). …
NAID 130002502175

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★リンクテーブル★

リンク元	「クラブラン酸」「clavulanate potassium」「potassium clavulanate」「clavulanate」

「クラブラン酸」

Clavulanic acid
Systematic (IUPAC) name
	(2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy; category	B (USA); B1 (Aust);
Routes of; administration	oral, IV
Legal status
Legal status	Schedule 4 (Au) rx only;
Pharmacokinetic data
Bioavailability	"well absorbed"
Metabolism	hepatic (extensive)
Biological half-life	1 hour
Excretion	renal (30–40%)
Identifiers
CAS Number	58001-44-8
ATC code	J01CR (WHO) (combinations with penicillins)
PubChem	CID 5280980
DrugBank	DB00766
ChemSpider	4444466
UNII	23521W1S24
KEGG	D07711
ChEBI	CHEBI:48947
ChEMBL	CHEMBL777
Chemical data
Formula	C8H9NO5
Molar mass	199.16 g/mol
	SMILES O=C2N1[C@H](C(/O[C@@H]1C2)=C/CO)C(=O)O ;
	InChI InChI=1S/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-/t6-,7-/m1/s1 ; Key:HZZVJAQRINQKSD-PBFISZAISA-N ;
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