Using clinical isolates of Pseudomonas aeruginosa, we studied the ability of imipenem to antagonize the activity of nine other antipseudomonal jP-lactam antimicrobial agents. Imipenem caused truncation of the zones of inhibition in a disk diffusion test for 91 to 100% of the strains, depending on the I-lactam tested. Addition of subinhibitory concentrations of imipenem caused a fourfold or greater increase in MICs for 72 of 74 isolates and in 20 to 87% of the tests, again depending on the antibiotic tested. P-Lactamase assays with both whole-cell suspensions and cell sonicates showed that exposure to subinhibitory concentrations of imipenem resulted in a significant increase in enzyme production. Studies with mutant strains with uninducible and constitutive 1-lactamase production supported the hypothesis that induction of l-lactamase was responsible for antagonism. In hydrolysis studies with a P-lactamase extract, most of the antagonized drugs were either not hydrolyzed or only poorly hydrolyzed. We conclude that imipenem induces significantly elevated levels of ,-lactamase in P. aeruginosa. This increase in P-lactamase is associated with increased resistance of the organism to many other ,-lactam agents.Pseudomonas aeruginosa possesses an inducible 1B-lactamase enzyme which is chromosomally mediated. In addition, Pseudomonas isolates can harbor a wide variety of plasmids which may code for other types of 1-lactamase (15,20). Both chromosome and plasmid-mediated ,B-lactamases have been implicated as factors important in the development of resistance to 1-lactam antibiotics. Consequehtly, many of the newer ,B-lactams are designed to be 1-lactamase resistant to increase their efficacy. However, it has been shown that for many of the Enterobacteriaceae species, the ,B-lactamase-resistant compound cefoxitin can antagonize other 1-lactams in vitro (17, 18) and in vivo (3). There is additional evidence that other newer 1-lactamase-resistant cephalosporins may also be responsible for induction of 13-lactamase, which in turn can result in antagonism against other 13-lactam agents (13, 16).Imipenem (N-formimidoyl thienamycin, imipemide, MK 0787) is a new carbapenem which is both highly active in vitro against P. aeruginosa and relatively stable against 1-lactamase-mediated hydrolysis (8). The compound has also been shown to be a potent inducer of chromosomally mediated ,B-lactamase in Enterobacter cloacae (2, 7).We investigated the ability of imipenem to induce ,3-lactamase production in P. aeruginosa. We also looked at the effect of such induction on the in vitro activity of other antipseudomonal 13-lactams. We found that in 100% of the Pseudomonas isolates 3-lactam antibiotics were subject to imipenem-mediated antagonism in a disk diffusion test. Virtually all strains, excepting two highly resistant isolates, showed at least a fourfold increase in the MICs of one or more antipseudomonal ,B-lactam agents when exposed to subinhibitory concentrations of imipenem (0.0625 ,ug/ml).The amount of ,B-lactamase produced in strai...
