Interactions between Avibactam and Ceftazidime-Hydrolyzing Class D β-Lactamases (original) (raw)
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Antimicrobial agents and chemotherapy, 2014
Avibactam, a broad-spectrum β-lactamase inhibitor, was tested with ceftazidime, ceftaroline, or aztreonam against 57 well-characterized Gram-negative strains producing β-lactamases from all molecular classes. Most strains were nonsusceptible to the β-lactams alone. Against AmpC-, ESBL-, and KPC-producing Enterobacteriaceae or Pseudomonas aeruginosa, avibactam lowered ceftazidime, ceftaroline or aztreonam MICs up to 2048-fold, to ≤ 4 μg/ml. Aztreonam-avibactam MICs against a VIM-1 metallo-β-lactamase-producing E. cloacae and a VIM-1/KPC-3-producing E. coli isolate were 0.12 and 8 μg/ml, respectively.
The Journal of antimicrobial chemotherapy, 2015
The objective of this study was to explore the activity of ceftazidime and ceftazidime/avibactam against a collection of isogenic strains of Escherichia coli DH10B possessing SHV and KPC β-lactamases containing single amino acid substitutions in the Ω-loop (residues 164-179). Ceftazidime and ceftazidime/avibactam MICs were determined by the agar dilution method for a panel of isogenic E. coli strains expressing SHV-1 and KPC-2 with amino acid substitutions at positions 164, 167, 169 or 179. Two KPC-2 β-lactamase variants that possessed elevated MICs of ceftazidime/avibactam were selected for further biochemical analyses. Avibactam restored susceptibility to ceftazidime for all Ω-loop variants of SHV-1 with MICs <8 mg/L. In contrast, several of the Arg164 and Asp179 variants of KPC-2 demonstrated MICs of ceftazidime/avibactam >8 mg/L. β-Lactamase kinetics showed that the Asp179Asn variant of KPC-2 demonstrated enhanced kinetic properties against ceftazidime. The Ki app, k2/K an...
Diagnostic Microbiology and Infectious Disease, 2015
Avibactam is a novel β-lactamase inhibitor that restores the activity of otherwise hydrolyzed βlactams against Gram-negative bacteria expressing different classes of serine β-lactamases. In the last decade, β-lactam-avibactam combinations were tested against a variety of clinical isolates expressing multiple commonly encountered β-lactamases. Here, we analyzed isogenic Escherichia coli strains expressing selected single β-lactamase genes that were not previously tested or were not characterized in an isogenic background. The activities of ceftazidime, ceftaroline and aztreonam alone and in combination with 4 mg/L of avibactam, as well as comparator agents, were assessed against an unique collection of isogenic strains of E. coli carrying selected extended-spectrum, inhibitor-resistant, and/or carbapenem-hydrolyzing bla genes. When combined with avibactam, ceftazidime, ceftaroline or aztreonam MICs were reduced for 91.4%, 80.0% and 80.0% of isolates, respectively. The data presented adds to our understanding of the
Interactions of Ceftobiprole with -Lactamases from Molecular Classes A to D
Antimicrobial Agents and Chemotherapy, 2007
The interactions of ceftobiprole with purified β-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent β-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 β-lactamase, the class A TEM-1 β-lactamase, and the class C AmpC β-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum β-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpC-producing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly...
β-Lactamases: A Focus on Current Challenges
Cold Spring Harbor Perspectives in Medicine, 2016
b-Lactamases, the enzymes that hydrolyze b-lactam antibiotics, remain the greatest threat to the usage of these agents. In this review, the mechanism of hydrolysis is discussed for both those enzymes that use serine at the active site and those that require divalent zinc ions for hydrolysis. The b-lactamases now include .2000 unique, naturally occurring amino acid sequences. Some of the clinically most important of these are the class A penicillinases, the extended-spectrum b-lactamases (ESBLs), the AmpC cephalosporinases, and the carbapenem-hydrolyzing enzymes in both the serine and metalloenzyme groups. Because of the versatility of these enzymes to evolve as new b-lactams are used therapeutically, new approaches to antimicrobial therapy may be required.
PubMed, 2002
Beta-lactams represent one of the most important class of antibiotics for the treatment of infectious diseases due to pathogenic bacteria. The selective pressure exerted from the wide spread use of third generation cephalosporins generated mutant beta-lactamases belonging mainly to the TEM or SHV family that are able to extend the activity spectrum of hydrolysis. Moreover, extended spectrum cephalosporins are often a good choice in clinical practice towards Enterobacteriaceae. Here we report a comparative analysis of stability between cefotaxime, desacetyl-cefotaxime and ceftazidime with some common TEM-derivatives extended spectrum beta-lactamases.
Prediction of the Evolution of Ceftazidime Resistance in Extended-Spectrum β-Lactamase CTX-M-9
Antimicrobial Agents and Chemotherapy, 2006
A random mutagenesis technique was used to predict the evolutionary potential of β-lactamase CTX-M-9 toward the acquisition of improved catalytic activity against ceftazidime. Thirty CTX-M mutants were obtained during three rounds of mutagenesis. These mutants conferred 1- to 128-fold-higher MICs of ceftazidime than the parental enzyme CTX-M-9. The CTX-M mutants contained one to six amino acid substitutions. Mutants harbored the substitutions Asp240Gly and Pro167Ser, which were previously observed in clinical CTX-M enzymes. Additional substitutions, notably Arg164His, Asp179Gly, and Arg276Ser, were observed near the active site. The kinetic constants of the three most active mutants revealed two distinct ways of improving catalytic efficiency against ceftazidime. One enzyme had a 17-fold-higher k cat value than CTX-M-9 against ceftazidime. The other two had 75- to 300-fold-lower K m values than CTX-M-9 against ceftazidime. The current emergence of CTX-M β-lactamases with improved ac...
Kinetics of Avibactam Inhibition against Class A, C, and D -Lactamases
Journal of Biological Chemistry, 2013
Background: Avibactam is a -lactamase inhibitor with a broad spectrum of activity. Results: Kinetic parameters of inhibition as well as acyl enzyme stability are reported against six clinically relevant enzymes. Conclusion: Inhibition efficiency is highest against class A, then class C, and then class D. Significance: These base-line inhibition values across enzyme classes provide the foundation for future structural and mechanistic enzymology experiments.