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JAC Advance Access published online on July 14, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh358
© 2004 by The British Society for Antimicrobial Chemotherapy
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Received December 16, 2003
Revised May 18, 2004
Accepted May 20, 2004

Original article

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

Alain Bonnefoy 1*, Claudine Dupuis-Hamelin 1, Valérie Steier 1, Carole Delachaume 1, Catherine Seys 1, Thérèse Stachyra 1, Monique Fairley 1, Michèle Guitton 1, Maxime Lampilas 2

1 Aventis Pharma, Infectious Disease Group, 102, Route de Noisy, 93235 Romainville Cedex, France
2 Aventis Pharma, Medicinal Chemistry, 102, Route de Noisy, 93235 Romainville Cedex, France

* To whom correspondence should be addressed. E-mail: Alain.Bonnefoy{at}freesbee.fr.


  Abstract

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: IC50 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: IC50s 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 106 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.

Keywords: AmpC; ESBLs; combinations; ceftazidime.
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