The activity of meropenem, a new carbapenem, was determined against 82 Gram-negative bacteria in agar dilution tests. Many of these isolates were resistant to one or more beta-lactam antibiotics and the mechanisms responsible for the resistance had been characterized. The production of beta-lactamases had little influence on susceptibility to either meropenem or imipenem except in tests with Aeromonas hydrophila and Pseudomonas (Xanthomonas) maltophilia. These species produced metalloenzymes capable of hydrolyzing the carbapenems, and strains expressing high levels of these enzymes were resistant to both meropenem and imipenem. Clinical isolates of P. aeruginosa that had developed resistance to imipenem during therapy with the drug were two- to 32-fold less susceptible to meropenem than the corresponding pretreatment isolates. Alterations in outer membrane proteins were associated with this change in susceptibility to the carbapenems. Meropenem was a less potent inducer of Class I beta-lactamases than imipenem but was still a better inducer than ceftazidime or piperacillin. Overall, meropenem showed excellent activity against bacteria producing a variety of beta-lactamases, but cross-resistance between meropenem and imipenem due to enzymatic and non-enzymatic mechanisms did occur.