Ertapenem (MK-0826; L-749,345), a new carbapenem with a long serum half-life, was tested, in vitro, against β-lactamase-producing bacteria. The new compound had a MIC at which 90% of the isolates were inhibited of 0.06 μg/ml for extended-spectrum β-lactamase (ESBL)-producing klebsiellas, compared with 0.5 μg/ml for imipenem, 16 μg/ml for cefepime, and >128 μg/ml for ceftazidime and piperacillin-tazobactam. MICs of ertapenem for AmpC-derepressed mutant Enterobacteriaceae were 0.015 to 0.5 μg/ml, whereas imipenem MICs were 0.25 to 1 μg/ml and those of cefepime were 0.5 to 4 μg/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 104 to 106 CFU/spot, contraindicating significant lability. Carbapenemase producers were also tested. The IMP-1 metallo-β-lactamase conferred substantial ertapenem resistance (MIC, 128 μg/ml) in a porin-deficient Klebsiella pneumoniae strain, whereas a MIC of 6 μg/ml was recorded for its porin-expressing revertant. SME-1 carbapenemase was associated with an ertapenem MIC of 2 μg/ml for Serratia marcescens S6, compared with <0.03 μg/ml for Serratia strains lacking this enzyme. In summary, ertapenem had good activity against strains with potent β-lactamases, except for those with known carbapenemases.