β-lactam

Clavulanic acid and ampicillin exhibit synergistic antibacterial activity (against β-lactamase-producing organisms)[2].
Ab11 and Ab51 strains are inhibited by clavulanic acid at MICs of 2–8 μg/mL[3].

An A. baumannii-infected C57BL/6 mouse pneumonia model's lung bacterial load is reduced by clavulanic acid (13 mg/kg, i.p.)[3]. Clavulanic acid (13 mg/kg, i.p.) in the pneumonia model of Ab51-infected C57BL/6 mice exhibits a t1/2 of 6.69 h and an AUC of 4.03 mg·h/L[3].
Rat models of paw edema induced by carrageenan (HY-125474) exhibit anti-inflammatory effects when treated with clavulanic acid (100–300 mg/kg, i.p.)[4].

Pharmacokinetic Study:** Immunocompetent C57BL/6 mice received a single intraperitoneal dose of clavulanic acid (13 mg/kg). Blood was collected from the periorbital plexus of three anesthetized mice per time point at 5, 10, 15, 30, 60, 90, 120, and 240 minutes post-dose. Serum drug concentrations were determined by a bioassay using *Klebsiella pneumoniae* ATCC 29665 as the indicator organism. Pharmacokinetic parameters (Cmax, AUC, t₁/₂, T>MIC) were calculated. [3]
* **Efficacy Study (Pneumonia Model):** C57BL/6 mice were anesthetized and inoculated intratracheally with 50 μL of a bacterial suspension (approximately 8.6 log₁₀ CFU/mL of A. baumannii strain Ab11 or Ab51) mixed 1:1 with 10% porcine mucin. Treatments began 4 hours after inoculation. Mice were randomly allocated to three groups (n=15 per strain per group): untreated control, clavulanic acid (13 mg/kg i.p.), or imipenem (30 mg/kg i.m.). The dosing interval for clavulanic acid was 2.5 hours for Ab11 and 2 hours for Ab51 to maintain T>MIC at 40% of the dosing interval. Animals were observed for 24 hours. Immediately after death or at the end of the experiment, blood and lung samples were collected for quantitative culture. Results were expressed as log₁₀ CFU/g of lung and frequency of sterile blood cultures. [3]
* **Toxicity Control:** A group of 10 uninfected mice were treated with the same dose regimen of clavulanic acid to evaluate its toxicity. No toxicity was observed. [3]

Absorption, Distribution and Excretion
Clavulanic acid is well absorbed in the gastrointestinal tract after oral administration. In a study of four subjects, the minimum absorption rate was 73%, and the mean absolute bioavailability was 64%. In a pharmacokinetic study of eight healthy volunteers, the mean Cmax was 2.098 ± 0.441 μg/mL. The mean Tmax reported in this study was 1.042 ± 0.80 hours. Another pharmacokinetic study reported Tmax ranging from 40 to 120 minutes. Approximately 40% to 65% of clavulanic acid is excreted unchanged in the urine within 6 hours after administration. Metabolites of clavulanic acid are primarily excreted via urine, feces, and carbon dioxide in exhaled air. Clavulanic acid can be eliminated via renal and non-renal routes. Approximately 17% of the dose of radiolabeled clavulanic acid is excreted in exhaled air, and 8% is excreted in feces. A study of four healthy volunteers showed a volume of distribution of 12 liters after administration of radiolabeled clavulanic acid. Clavulanic acid is distributed in various tissues and interstitial fluids. Clinically significant concentrations have been detected in the gallbladder, abdomen, skin, fat, and muscle tissues. Therapeutic concentrations of clavulanic acid have also been detected in bile, pus, synovial fluid, and peritoneal fluid. Animal studies have shown that clavulanic acid can cross the placenta. A pharmacokinetic study in four healthy volunteers showed a clearance of 0.21 L/min after administration of radiolabeled clavulanic acid. Another study showed a mean clearance of 12.20 L/h/70 kg. Dosage adjustments may be necessary for patients with renal failure.

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Metabolism/Metabolites
Clavulanic acid is primarily metabolized to two metabolites: 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy-but-2-one. One pharmacokinetic study found that the first metabolite accounted for 15.6% of the dose, and the second metabolite accounted for 8.8%.

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Biological Half-Life
According to reports, clavulanic acid has a half-life similar to that of amoxicillin, lasting 45-90 minutes. A study of radiolabeled clavulanic acid in four healthy volunteers determined its half-life to be 0.8 hours.

Protein Binding
Amoxicillin has a plasma protein binding rate of approximately 25%.

[1]. Clavulanic acid: a review. Biotechnol Adv. Jul-Aug 2008;26(4):335-51

[2]. Clavulanic acid, a novel inhibitor of beta-lactamases. Antimicrob Agents Chemother. 1978 Nov;14(5):650-5.

[3]. In vitro activity and in vivo efficacy of clavulanic acid against Acinetobacter baumannii. Antimicrob Agents Chemother. 2009 Oct;53(10):4298-304.

[4]. Tannic acid exhibits anti-inflammatory effects on formalin-induced paw edema model of inflammation in rats. Hum Exp Toxicol. 2019 Nov;38(11):1296-1301.

Clavulanic acid is an antibiotic isolated from Streptomyces clavuligerus. It is a suicidal β-lactamase inhibitor that inhibits the activity of bacterial β-lactamases. Clavulanic acid has multiple effects, including antibacterial, anti-anxiety, and EC 3.5.2.6 (β-lactamase) inhibition. It is a conjugate of clavulanic acid. Clavulanic acid is a β-lactamase inhibitor, often used in combination with amoxicillin or ticarcillin. By preventing β-lactamases from degrading the antibiotic, it broadens the antibacterial spectrum against susceptible bacterial infections, thus combating antibiotic resistance. Clavulanic acid is derived from Streptomyces clavuligerus. When used in combination with amoxicillin, clavulanic acid is often called Augmentin, Co-Amoxiclav, or Clavulin. Clavulanic acid is a β-lactamase inhibitor. Clavulanic acid's mechanism of action is as a β-lactamase inhibitor. It has been reported to be present in Streptomyces cattleya and Streptomyces clavuligerus, with supporting data. Clavulanic acid is a semi-synthetic β-lactamase inhibitor isolated from Streptomyces. It contains a β-lactam ring that binds firmly to the active site of β-lactamase or its vicinity, thereby inhibiting enzyme activity. This protects other β-lactam antibiotics from β-lactamase catalysis, thus enhancing their antibacterial activity. This drug is often used in combination with antibiotics sensitive to β-lactamases (such as penicillin and cephalosporins) to treat infections caused by β-lactamase-producing microorganisms. Streptomyces clavuligerus is a β-lactam antibiotic produced by actinomycetes. It is a suicide inhibitor of bacterial β-lactamases. When used alone, it has weak antibacterial activity against most microorganisms, but when used in combination with other β-lactam antibiotics, it can prevent microbial β-lactamases from inactivating the antibiotics.

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Drug Indications
Clavulanic acid, when used in combination with other antibiotics, can prevent the emergence of drug-resistant strains and enhance their antibacterial therapeutic effects.
The following diseases, when the pathogens produce β-lactamases, can be treated with amoxicillin/clavulanic acid or ticarcillin/clavulanic acid in combination: acute otitis media caused by Haemophilus influenzae and Moraxella catarrhalis; sinusitis caused by Haemophilus influenzae and Moraxella catarrhalis; lower respiratory tract infections caused by Haemophilus influenzae, Staphylococcus aureus, Klebsiella spp., and Moraxella catarrhalis; skin and soft tissue infections caused by Staphylococcus aureus, Escherichia coli, and Klebsiella spp.; urinary tract infections caused by Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia marcescens, or Staphylococcus aureus; and gynecological infections caused by various bacteria, including Pseudomonas melanogenans, Enterobacter spp., Escherichia coli, and Klebsiella spp. Septicemia caused by Staphylococcus aureus and Staphylococcus epidermidis; septicemia caused by various bacteria (including Klebsiella spp., Escherichia coli spp., Staphylococcus aureus, or Pseudomonas spp.); bone and joint infections caused by Staphylococcus aureus; intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, or Bacteroides fragilis. Regarding drug susceptibility: It is important to note that this product is only indicated for infections confirmed or highly suspected to be caused by susceptible bacteria. Bacterial culture and drug susceptibility testing should be performed whenever possible, and this should be used as the basis for determining whether to use this antibiotic. Clavulanic acid should not be used if β-lactamase production is not detected in microbiological testing. When these tests are not possible, the local infection pattern and drug susceptibility test results can be used to determine whether clavulanic acid is appropriate. Ticarcillin combined with clavulanate potassium has shown particular efficacy in mixed infections and can be used as empirical treatment before determining the drug susceptibility of the causative bacteria. The ticarcillin-clavulanate potassium combination may be an effective monotherapy for treating infections that usually require multiple drug combinations.

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Mechanism of Action
The structure of potassium clavulanate contains a β-lactam ring, which can irreversibly bind to β-lactamases, thereby preventing β-lactamases from inactivating certain β-lactam antibiotics and effectively treating infections caused by Gram-positive and Gram-negative bacteria that are sensitive to β-lactam antibiotics.

199.048

58001-44-8

Potassium clavulanate cellulose;Clavulanate lithium;61177-44-4;Clavulanate potassium;61177-45-5

5280980

Off-white to light yellow solid powder

1.7±0.1 g/cm3

545.8±50.0 °C at 760 mmHg

117.5-118
117.5 - 118 °C

283.9±30.1 °C

0.0±3.3 mmHg at 25°C

1.644

-1.98

2

5

2

14

324

2

C(=C/1\[C@H](C(=O)O)N2C(=O)C[C@H]2O1)/CO

HZZVJAQRINQKSD-PBFISZAISA-N

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

(2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Clavulanate; Acide clavulanique; Acido clavulanico; Clavulansaeure; Antibiotic MM 14151; acidum clavulanicum;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~13.89 mg/mL (~69.74 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 10% DMSO+90% (20% SBE-β-CD in Saline): ≥ 2.5 mg/mL (12.55 mM)

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Solubility in Formulation 4: 12.5 mg/mL (62.76 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)