Multifocal outbreaks of metallo-β-lactamase-producing Pseudomonas aeruginosa resistant to broad-spectrum β-lactams, including carbapenems

A total of 3,700 Pseudomonas aeruginosa isolates were collected from 17 general hospitals in Japan from 1992 to 1994. Of these isolates, 132 carbapenem-resistant strains were subjected to DNA hybridization analysis with the metallo-β-lactamase gene (bla(IMP))-specific probe. Fifteen strains carrying the metallo-β-lactamase gene were identified in five hospitals in different geographical areas. Three strains of P. aeruginosa demonstrated high-level imipenem resistance (MIC, ≥128 μg/ml), two strains exhibited low-level imipenem resistance (MIC, ≤4 μg/ml), and the rest of the strains were in between. These results revealed that the acquisition of a metallo- β-lactamase gene alone does not necessarily confer elevated resistance to carbapenems. In several strains, the metallo-β-lactamase gene was carried by large plasmids, and carbapenem resistance was transferred from P. aeruginosa to Escherichia coli by electroporation in association with the acquisition of the large plasmid. Southern hybridization analysis and genomic DNA fingerprinting profiles revealed different genetic backgrounds for these 15 isolates, although considerable similarity was observed for the strains isolated from the same hospital. These findings suggest that the metallo-β- lactamase-producing P. aeruginosa strains are not confined to a unique clonal lineage but proliferated multifocally by plasmid-mediated dissemination of the metallo-β-lactamase gene in strains of different genetic backgrounds. Thus, further proliferation of metalloβ-lactamase-producing strains with resistance to various β-lactams may well be inevitable in the future, which emphasizes the need for early recognition of metallo-β-lactamase-producing strains, rigorous infection control, and restricted clinical use of broad- spectrum β-lactams including carbapenems.