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Interaction of PZ-601 (SMP-601) and other b-lactams with chromosome- and plasmid-encoded class C b-lactamases

Abstract number: P565

Docquier J.D., Xerri L.

Objectives: The overproduction of chromosome-encoded class C b-lactamases in derepressed mutants of Enterobacteriaceae and Pseudomonas aeruginosa is a known mechanism able to compromise the efficacy of penicillins and cephalosporins for the treatment of infections caused by these organisms. More recently, the emergence of plasmid-encoded class C b-lactamases, currently spreading in Enterobacteriaceae, is of increasing concern. We carried out a comparative study on the interaction of PZ-601 (a novel carbapenem with a spectrum including multidrug resistant Gram-positive pathogens) with several class C enzymes.

Methods: The stability of PZ-601, imipenem and cephalosporins to hydrolysis by P99 AmpC, CMY-2 and FOX-7 b-lactamases was investigated spectrophotometrically, using either direct hydrolysis measurements or the reporter substrate method. Antimicrobial susceptibilities of clinical isolates and transconjugants (or transformants) thereof were measured using the microdilution broth method as recommended by the CLSI.

Results: In enzyme assays, PZ-601 behaved as a poor substrate of these enzymes and, similarly to imipenem (IPM), showed degradation rates slower than those observed with tested oxyimino-cephalosporins cefotaxime (CTX) and ceftazidime (CAZ), and piperacillin (PIP), as reflected by the higher catalytic efficiencies measured with the latter compounds. These data were confirmed by the changes in the antimicrobial susceptibility profiles when a CMY-2-encoding plasmid was transferred into an E. coli laboratory strain (J53). This transformed strain gained resistance to CAZ, CTX and PIP, while it showed only a reduced susceptibility to PZ-601.

The parental clinical isolates all exhibit the lower MIC values with IPM and PZ-601, while a high level of resistance was observed with the other agents. It is likely that for PZ-601, permeability defects in these isolates may act synergistically with a slow b-lactamase degradation, explaining in part the different susceptibility to the latter, as compared to IPM.

Conclusion: PZ-601 was confirmed to have a better stability to class C b-lactamases than tested oxyimino-cephalosporins and penicillins, even though it appeared to be slightly less stable to these enzymes than imipenem.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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