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

• Published in: Journal of antimicrobial chemotherapy 2004-08, Vol.54 (2), p.410-417
• Main Authors: Bonnefoy, Alain, Dupuis-Hamelin, Claudine, Steier, Valérie, Delachaume, Carole, Seys, Catherine, Stachyra, Thérèse, Fairley, Monique, Guitton, Michèle, Lampilas, Maxime
• Format: Article
• Language: English
• Subjects: AmpC; Antibiotics. Antiinfectious agents. Antiparasitic agents; Azepines - pharmacology; Bacteria - drug effects; beta-Lactamases - pharmacology; Biological and medical sciences; ceftazidime; Ceftazidime - pharmacology; Cephalosporins - pharmacology; Citrobacter; Clavulanic Acid - pharmacology; combinations; Dealkylation; Enterobacter; Enterobacteriaceae; Enzyme Inhibitors - pharmacology; ESBLs; Escherichia coli; Escherichia coli - drug effects; Klebsiella pneumoniae; Medical sciences; Microbial Sensitivity Tests; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacology; Penicillins - pharmacology; Pharmacology. Drug treatments; Piperacillin - pharmacology; Proteus mirabilis; Staphylococcus aureus - drug effects; Sulfuric Acid Esters - pharmacology
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkh358

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.