Bench-to-bedside review: The role of β-lactamases in antibiotic-resistant Gram-negative infections

Multidrug resistance has been increasing among Gram-negative bacteria and is strongly associated with the production of both chromosomal- and plasmid-encoded β-lactamases, whose number now exceeds 890. Many of the newer enzymes exhibit broad-spectrum hydrolytic activity against most classes of β-lactams. The most important plasmid-encoded β-lactamases include (a) AmpC cephalosporinases produced in high quantities, (b) the expanding families of extended-spectrum β-lactamases such as the CTX-M enzymes that can hydrolyze the advanced-spectrum cephalosporins and monobactams, and (c) carbapenemases from multiple molecular classes that are responsible for resistance to almost all β-lactams, including the carbapenems. Important plasmid-encoded carbapenemases include (a) the KPC β-lactamases originating in Klebsiella pneumoniae isolates and now appearing worldwide in pan-resistant Gram-negative pathogens and (b) metallo-β-lactamases that are produced in organisms with other deleterious β-lactamases, causing resistance to all β-lactams except aztreonam. β-Lactamase genes encoding these enzymes are often carried on plasmids that bear additional resistance determinants for other antibiotic classes. As a result, some infections caused by Gram-negative pathogens can now be treated with only a limited number, if any, antibiotics. Because multidrug resistance in Gram-negative bacteria is observed in both nosocomial and community isolates, eradication of these resistant strains is becoming more difficult.