Activity of ertapenem (MK-0826) versus Enterobacteriaceae with potent beta-lactamases

Abstract

Ertapenem (MK-0826; L-749,345), a new carbapenem with a long serum half-life, was tested, in vitro, against beta-lactamase-producing bacteria. The new compound had a MIC at which 90% of the isolates were inhibited of 0.06 microg/ml for extended-spectrum beta-lactamase (ESBL)-producing klebsiellas, compared with 0.5 microg/ml for imipenem, 16 microg/ml for cefepime, and >128 microg/ml for ceftazidime and piperacillin-tazobactam. MICs of ertapenem for AmpC-derepressed mutant Enterobacteriaceae were 0.015 to 0.5 microg/ml, whereas imipenem MICs were 0.25 to 1 microg/ml and those of cefepime were 0.5 to 4 microg/ml, and resistance to ceftazidime and piperacillin-tazobactam was generalized. Despite this good activity, the MICs of ertapenem for ESBL-positive klebsiellas mostly were two- to fourfold above those for ESBL-negative strains, and the MICs for AmpC-hyperproducing Enterobacter cloacae and Citrobacter freundii mutants exceeded those for the corresponding AmpC-basal mutants. These differentials did not increase when the inoculum was raised from 10(4) to 10(6) CFU/spot, contraindicating significant lability. Carbapenemase producers were also tested. The IMP-1 metallo-beta-lactamase conferred substantial ertapenem resistance (MIC, 128 microg/ml) in a porin-deficient Klebsiella pneumoniae strain, whereas a MIC of 6 microg/ml was recorded for its porin-expressing revertant. SME-1 carbapenemase was associated with an ertapenem MIC of 2 microg/ml for Serratia marcescens S6, compared with <0.03 microg/ml for Serratia strains lacking this enzyme. In summary, ertapenem had good activity against strains with potent beta-lactamases, except for those with known carbapenemases.