BACKGROUND: The beta-lactamase landscape is changing radically, with CTX-M types now the most prevalent extended-spectrum beta-lactamases (ESBLs) worldwide, except maybe in the USA. In addition, there are growing numbers of Enterobacteriaceae with KPC and metallo-carbapenemases. We examined whether combinations of oxyimino-cephalosporins with NXL104, a novel non-beta-lactam beta-lactamase inhibitor, overcame these resistances. METHODS: NXL104 was tested at 4 mg/L in combination with cefotaxime and ceftazidime versus: (i) Escherichia coli transconjugants and wild-type Enterobacteriaceae with CTX-M ESBLs; (ii) Enterobacteriaceae with ertapenem resistance contingent on combinations of impermeability and ESBLs or AmpC; and (iii) Enterobacteriaceae with KPC, SME, metallo- or OXA-48 carbapenemases. RESULTS: MICs of cefotaxime + NXL104 were < or = 1 mg/L for most Enterobacteriaceae with CTX-M, KPC or OXA-48 enzymes and were < or = 2 mg/L for those that also had ertapenem resistance contingent on combinations of beta-lactamase and impermeability. MICs of the ceftazidime + NXL104 combination were < or = 4 mg/L, except for a single Enterobacter aerogenes with KPC and AmpC enzymes together with porin loss, which required an MIC of 32 mg/L. The major gap was that NXL104 could not potentiate cephalosporins against Enterobacteriaceae with IMP or VIM metallo-enzymes. CONCLUSIONS: Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.
BACKGROUND: The beta-lactamase landscape is changing radically, with CTX-M types now the most prevalent extended-spectrum beta-lactamases (ESBLs) worldwide, except maybe in the USA. In addition, there are growing numbers of Enterobacteriaceae with KPC and metallo-carbapenemases. We examined whether combinations of oxyimino-cephalosporins with NXL104, a novel non-beta-lactam beta-lactamase inhibitor, overcame these resistances. METHODS:NXL104 was tested at 4 mg/L in combination with cefotaxime and ceftazidime versus: (i) Escherichia coli transconjugants and wild-type Enterobacteriaceae with CTX-M ESBLs; (ii) Enterobacteriaceae with ertapenem resistance contingent on combinations of impermeability and ESBLs or AmpC; and (iii) Enterobacteriaceae with KPC, SME, metallo- or OXA-48 carbapenemases. RESULTS: MICs of cefotaxime + NXL104 were < or = 1 mg/L for most Enterobacteriaceae with CTX-M, KPC or OXA-48 enzymes and were < or = 2 mg/L for those that also had ertapenem resistance contingent on combinations of beta-lactamase and impermeability. MICs of the ceftazidime + NXL104 combination were < or = 4 mg/L, except for a single Enterobacter aerogenes with KPC and AmpC enzymes together with porin loss, which required an MIC of 32 mg/L. The major gap was that NXL104 could not potentiate cephalosporins against Enterobacteriaceae with IMP or VIM metallo-enzymes. CONCLUSIONS:Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.
Authors: Dora E Wiskirchen; Jared L Crandon; Guilherme H Furtado; Gregory Williams; David P Nicolau Journal: Antimicrob Agents Chemother Date: 2011-04-25 Impact factor: 5.191
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Authors: David E Ehmann; Haris Jahic; Philip L Ross; Rong-Fang Gu; Jun Hu; Thomas F Durand-Réville; Sushmita Lahiri; Jason Thresher; Stephania Livchak; Ning Gao; Tiffany Palmer; Grant K Walkup; Stewart L Fisher Journal: J Biol Chem Date: 2013-08-02 Impact factor: 5.157
Authors: Andrea Endimiani; Kristine M Hujer; Andrea M Hujer; Mark E Pulse; William J Weiss; Robert A Bonomo Journal: Antimicrob Agents Chemother Date: 2010-11-01 Impact factor: 5.191
Authors: Amira A Bhalodi; Jared L Crandon; Gregory Williams; David P Nicolau Journal: Antimicrob Agents Chemother Date: 2013-09-16 Impact factor: 5.191