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JAC Advance Access originally published online on August 9, 2008
Journal of Antimicrobial Chemotherapy 2008 62(5):1053-1056; doi:10.1093/jac/dkn320
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

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

David M. Livermore1,*, Shazad Mushtaq1, Marina Warner1, Christine Miossec2 and Neil Woodford1

1 Health Protection Agency Centre for Infections, London, UK 2 Novexel SA, Romainville, France

Received 29 April 2008; returned 12 June 2008; revised 7 July 2008; accepted 14 July 2008

* Correspondence address. Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK. Tel: +44-20-8327-7223; Fax: +44-20-8327-6264; E-mail: david.livermore{at}hpa.org.uk

Background: 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.

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 ≤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.

Conclusions: Oxyimino-cephalosporin + NXL104 combinations have potential against strains with the prevalent ESBLs and non-metallo-carbapenemases.

Keywords: β-lactamase inhibitors , ESBLs , KPC carbapenemase , metallo-β-lactamases


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