In vitro activity of AVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor

J Antimicrob Chemother. 2004 Aug;54(2):410-7. doi: 10.1093/jac/dkh358. Epub 2004 Jul 14.


Objectives: Production of beta-lactamases is the main mechanism of beta-lactam resistance in Gram-negative bacteria. Despite the current use of clavulanic acid, sulbactam and tazobactam, the prevalence of class A and class C enzymes is increasing worldwide, demanding new beta-lactamase inhibitors. Here we report the antimicrobial properties of AVE1330A, a representative of a novel class of bridged bicyclico[3.2.1]diazabicyclo-octanones in combination with ceftazidime.

Materials and methods: IC(50) and kinetic parameters of the hydrolysis reaction were used to characterize beta-lactamase inhibition by AVE1330A. MICs for >600 strains were determined with the combination ceftazidime/AVE1330A at a fixed ratio of 4:1.

Results: IC(50)s of AVE1330A for TEM-1 and P99 enzymes were 0.0023 mg/L (8 nM) and 0.023 mg/L (80 nM), compared with 0.027 mg/L (130 nM) and 205.1 mg/L (1 x 10(6) nM) of clavulanic acid and 0.013 mg/L (40 nM) and 1.6 mg/L (5000 nM) of tazobactam. A highly stable covalent complex led to a low turnover of AVE1330A. MICs of ceftazidime/AVE1330A for Enterobacteriaceae were at least eight-fold lower than those of ceftazidime alone. All of the Escherichia coli, Klebsiella pneumoniae, Citrobacter and Proteus mirabilis strains, including ceftazidime-resistant isolates, were inhibited at 4-8 mg/L. Only 2 mg/L were required to inhibit other Proteeae, Enterobacter, Salmonella and Serratia.

Conclusion: The combination of ceftazidime with AVE1330A exhibited broad-spectrum activity against Ambler class A- and class C-producing Enterobacteriaceae.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / pharmacology*
  • Bacteria / drug effects*
  • Ceftazidime / pharmacology
  • Cephalosporins / pharmacology
  • Clavulanic Acid / pharmacology
  • Dealkylation
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Microbial Sensitivity Tests
  • Penicillanic Acid / analogs & derivatives*
  • Penicillanic Acid / pharmacology
  • Penicillins / pharmacology
  • Piperacillin / pharmacology
  • Staphylococcus aureus / drug effects
  • Sulfuric Acid Esters / pharmacology*
  • Tazobactam
  • beta-Lactamases / pharmacology*


  • AVE 1330A
  • Azepines
  • Cephalosporins
  • Enzyme Inhibitors
  • Penicillins
  • Sulfuric Acid Esters
  • Clavulanic Acid
  • Penicillanic Acid
  • Ceftazidime
  • beta-Lactamases
  • Tazobactam
  • Piperacillin