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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...

We studied the ability of clavulanic acid (CA) to induce beta-lactamase in Pseudomonas aeruginosa isolates and what effect this might have on the susceptibilities to beta-lactam agents. We first used a disk approximation method to test 4 laboratory and 16 clinical P. aeruginosa isolates against antipseudomonal beta-lactam agents for truncation by CA and found this to be very common. All antimicrobial compounds except imipenem demonstrated truncation in the vicinity of CA. We also evaluated the extent to which chromosomal beta-lactamase is induced by CA and found this to occur to some degree in most isolates and to be dependent on the concentration of CA. Finally, we performed time kill curves on these isolates to compare bacterial growth in ticarcillin alone with growth in ticarcillin-CA (the CA at 2 or 4 micrograms/ml). We found that CA at this concentration has neither an antagonistic nor a synergistic antibacterial effect in combination with ticarcillin.

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Recent clinical reports have described the emergence of cross-resistance to aminoglycosides during beta-lactam therapy. We therefore studied the effect of imipenem-mediated beta-lactamase induction on the susceptibilities of 92 clinical isolates of Pseudomonas aeruginosa to gentamicin, tobramycin, and amikacin. We performed a disc approximation test to look for truncation by imipenem of the inhibitory zone sizes of the aminoglycosides. We also compared aminoglycoside inhibitory zone sizes of strains grown in the presence and absence of subinhibitory concentrations of imipenem. Finally, we compared aminoglycoside MIC values determined with and without subinhibitory concentrations of imipenem. The results showed that simultaneous emergence of resistance to beta-lactams and aminoglycosides is very rare.