Metallo-beta-lactamases: the quiet before the storm?

Abstract

The ascendancy of metallo-beta-lactamases within the clinical sector, while not ubiquitous, has nonetheless been dramatic; some reports indicate that nearly 30% of imipenem-resistant Pseudomonas aeruginosa strains possess a metallo-beta-lactamase. Acquisition of a metallo-beta-lactamase gene will invariably mediate broad-spectrum beta-lactam resistance in P. aeruginosa, but the level of in vitro resistance in Acinetobacter spp. and Enterobacteriaceae is less dependable. Their clinical significance is further embellished by their ability to hydrolyze all beta-lactams and by the fact that there is currently no clinical inhibitor, nor is there likely to be for the foreseeable future. The genes encoding metallo-beta-lactamases are often procured by class 1 (sometimes class 3) integrons, which, in turn, are embedded in transposons, resulting in a highly transmissible genetic apparatus. Moreover, other gene cassettes within the integrons often confer resistance to aminoglycosides, precluding their use as an alternative treatment. Thus far, the metallo-beta-lactamases encoded on transferable genes include IMP, VIM, SPM, and GIM and have been reported from 28 countries. Their rapid dissemination is worrisome and necessitates the implementation of not just surveillance studies but also metallo-beta-lactamase inhibitor studies securing the longevity of important anti-infectives.

FIG. 1.

Phylogeny of chromosomally encoded MBLs. Represented sequences of various MBLs were obtained from GenBank. IMP-1 and IMP-12 (most divergent from IMP-1) and VIM-1 and VIM-7 (most divergent from VIM-1) were also added for comparison. Signal peptides were removed prior to alignment. Sequences were aligned and phylogeny trees were constructed with Clustal W (PAM250 matrix; DNA Star) using the neighbor joining method.

FIG. 2.

Phylogeny of IMP-type MBLs. Signal peptides were removed prior to alignment. Sequences were aligned and phylogeny trees were constructed with Clustal W (PAM250 matrix; DNA Star) using the neighbor-joining method.

FIG. 3.

Phylogeny of VIM-type MBLs. Signal peptides were removed prior to alignment. Sequences were aligned and phylogeny trees were constructed with Clustal W (PAM250 matrix; DNA Star) using the neighbor-joining method.

FIG. 4.

Etest MBL strip (reprinted with permission from AB BIODISK, Solna, Sweden) and an Acinetobacter sp. expressing a VIM-2 MBL. The intersection of the ellipses at the strip is read from two halves, i.e., at the section with imipenem alone (IP) and imipenem plus EDTA (IPI). A reduction in the MIC of imipenem of ≥3 dilutions in the presence of EDTA is interpreted as a positive test.