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JAC Advance Access published online on June 4, 2009
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkp187
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© The Author 2009. 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

Activity of the anti-MRSA carbapenem razupenem (PTZ601) against Enterobacteriaceae with defined resistance mechanisms

David M. Livermore*, Shazad Mushtaq and Marina Warner

Antibiotic Resistance Monitoring & Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London, NW9 5EQ, UK

Received 5 March 2009; returned 5 April 2009; revised 22 April 2009; accepted 24 April 2009

* Corresponding author. Tel: +44-(0)-208-327-7223; Fax: +44-(0)-208-327-6264; E-mail: david.livermore{at}hpa.org.uk

Background: Razupenem (previously known as PTZ601, PZ-601, SMP-601 or SM-216601) is a novel carbapenem, active against Enterobacteriaceae as well as Gram-positive bacteria including methicillin-resistant staphylococci and enterococci.

Methods: We examined the effect of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases on the activity of razupenem, using the CLSI agar dilution method to measure MICs for mutants, transconjugants and isolates with and without these enzymes.

Results: ESBLs had no effect on the activity of razupenem against Escherichia coli and Klebsiella spp., and only a small effect when coupled with outer membrane impermeability. Inducible or, more especially, derepressed AmpC enzymes gave some protection, with most AmpC-derepressed Enterobacter and Citrobacter spp. requiring MICs of ~8 mg/L. This relative resistance was further increased when porins were lost, restricting drug uptake. Metallo- and class A-carbapenemases conferred resistance, with MICs ≥16 mg/L.

Conclusions: Razupenem has good activity against ESBL producers, but is affected by AmpC enzymes, especially when derepressed and coupled with outer membrane impermeability; its activity is also compromised by carbapenemases.

Key Words: AmpC β-lactamases , extended-spectrum β-lactamases , ESBLs , carbapenemases


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