Journal Article

<i>In vitro</i> activity of AVE1330A, an innovative broad-spectrum non-β-lactam β-lactamase inhibitor

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

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 54, issue 2, pages 410-417
Published in print August 2004 | ISSN: 0305-7453
Published online August 2004 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkh358
In vitro activity of AVE1330A, an innovative broad-spectrum non-β-lactam β-lactamase inhibitor

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  • Medical Oncology
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Objectives: Production of β-lactamases is the main mechanism of β-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 β-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 β-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 × 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

Journal Article.  3401 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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