Avibactam Sodium

May 06, 2019
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Avibactam sodium and its free acid, avibactam, are diazabicyclooctane (DBO)–based, non-β-lactam β-lactamase inhibitors (BLIs) that are used to treat multi-drug–resistant Gram-negative bacterial pathogens. The compounds were jointly developed by Actavis Generics (now part of Teva Pharmaceutical Industries) and AstraZeneca.  

In 2015, avibactam sodium, in combination with ceftazidime, a cephalosporin antibiotic, was approved by the US Food and Drug Administration. The dual-drug’s target was complex urinary tract and intra-abdominal infections caused by Gram-negative, often hospital-acquired, bacteria.

Last year, in the continuing quest to combat multi-drug–resistant bacteria, Eric M. Gordon, Matthew A. J. Duncton, and Mark A. Gallop at Arixa Pharmaceuticals (Palo Alto, CA) prepared analogues of avibactam that are more orally available than the free acid or its salt. (Currently, avibactam can be administered only intravenously; the only orally available BLI on the market is the less useful clavulanic acid.)

The researchers prepared prodrugs of avibactam in which various moieties form esters of the sulfate group. (Historically, charged sulfate groups on drug molecules were seen as strong obstacles to oral bioavailability.) The derivatives with the highest oral availabilities to laboratory animals had a quaternary carbon atom in the β position of the added sulfate ester and a carboxylate ester as one of the substituents on the quaternary carbon (i.e., –OSO3–CH2–CR1R2–CO2R3).

The authors believe that their avibactam analogues are orally available because of steric hindrance to hydrolysis provided by the sulfate ester and the gem-disubstituent/trimethyl lock effect that brings the carboxylate nucleophile closer to the eventual displacement site. In a simulation of in vivo conditions, they demonstrated that the prodrug can be cleaved under mild conditions to release the unesterified avibactam.

Avibactam sodium hazard information

GHS classification*: skin irritation, category 2
H315—Causes skin irritationChemical Safety Warning
GHS classification: skin sensitization, category 1
H317—May cause an allergic skin reactionChemical Safety Warning
GHS classification: serious eye damage, category 1
H318—Causes serious eye damageChemical Safety Warning
GHS classification: respiratory sensitization, category 1
H334—May cause allergy or asthma symptoms or breathing difficulties if inhaledChemical Safety Warning
GHS classification: specific target organ toxicity, single exposure, respiratory tract irritation, category 3
H335—May cause respiratory irritationChemical Safety Warning
GHS classification: germ cell mutagenicity, category 2
H341—Suspected of causing genetic defectsChemical Safety Warning
GHS classification: reproductive toxicity, category 2
H361—Suspected of damaging fertility or the unborn childChemical Safety Warning
GHS classification: specific target organ toxicity, single exposure, category 1
H370—Causes damage to organsChemical Safety Warning
GHS classification: hazardous to the aquatic environment, long-term hazard, category 4
H413—May cause long-lasting harmful effects to aquatic life

*Globally Harmonized System of Classification and Labeling of Chemicals. Explanation of pictograms.Note: Most safety data sheets list fewer, and in some cases, different, hazard statements.

Avibactam sodium fast facts

CAS Reg. No.1192491-61-4
Empirical formulaC7H10N3NaO6S
Molar mass287.22 g/mol
AppearanceWhite crystalline powder
Melting pointNot reported
Water solubility≈10 g/L

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