NXL104 combinations versus Enterobacteriaceae with CTX-M extended-spectrum -lactamases and carbapenemases

Abstract

The β-lactamase landscape is changing radically, with CTX-M types now the most prevalent extended-spectrum β-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-β-lactam β-lactamase inhibitor, overcame these resistances. 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. MICs of cefotaxime + 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 β-lactamase and impermeability. MICs of the ceftazidime + NXL104 combination were ≤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. Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.