NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum β-lactamases and 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 1 NXL104 were <= 1 mg/L for most Enterobacteriaceae with CTX-M, KPC or OXA-48 enzymes and were <= 2 mg/L for those that also had ertapenem resistance contingent on combinations of b-lactamase and impermeability. MICs of the ceftazidime 1 NXL104 combination were <= 4mg/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 1 NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.