Antimicrobial Resistance

Livermore, D M, Livermore, David M.

The carbapenems have the broadest spectra of all beta-lactams but resistance still occurs, caused by target modification, impermeability or beta-lactamase production. Target modification or replacement is important in methicillin-resistant staphylococci, E. faecium and some pneumococci. These organisms present the greatest current threat to carbapenem efficacy. Impermeability to carbapenems arises in P. aeruginosa mutants, where it is contingent on loss of D2 outer membrane protein, a minor porin. This resistance functions only if the Pseudomonas retains its chromosomal group 1 beta-lactamase, and so reflects the interplay of impermeability and hydrolysis rather than impermeability alone; nevertheless porin loss is the critical change that engenders resistance. Resistance based on impermeability coupled to a group 1 beta-lactamase has also been described in E. cloacae, but demands loss of a major porin and is much rarer and less stable than in P. aeruginosa. Although group 1 beta-lactamases contribute to resistance in these organisms, they have only feeble carbapenemase activity. Chromosomal beta-lactamases with potent carbapenemase activity occur in most or all X. maltophilia, A. hydrophila and F. odoratum isolates. These enzymes, which cause carbapenem resistance when expressed copiously, are all zinc-dependent. Zinc carbapenemases also are a concern in B. fragilis, where they are encoded by the chromosomal DNA of c. 3% of isolates, though expressed by only 1%. Carbapenemases are extremely rare outside these species. Nevertheless, a plasmidic zinc carbapenemase was reported from one P. aeruginosa isolate and from several S. marcescens. Further carbapenemases, some not zinc-dependent, are known from a tiny numbers of Serratia, Enterobacter, and Acinetobacter isolates. Despite these various modes of resistance, carbapenems have retained their efficacy far better than have expanded-spectrum cephalosporins. Whether this advantage will be retained indefinitely is uncertain. If resistance does become more prevalent it may be possible to derivatize the carbapenems so as to extend their activity. There is already interest in the design of carbapenems that bind beta-lactam-resistant PBPs and, to an extent, in the development of carbapenemase inhibitors.