Inducible β-lactamase-mediated resistance to third-generation cephalosporins

The emergence of multiple resistance to β-lactam antimicrobial agents is a major problem in the treatment of patients infected with Enterobacteriaceae that characteristically produce inducible β-lactamases. Inducible and 'derepressed' AmpC β-lactamases are produced by Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii and Providencia spp. Resistance to broad-spectrum β-lactams has emerged in 16-44% of these strains from infections treated with one of the newer cephalosporins, even in combination with other antimicrobials. Multiply resistant organisms have spread widely both locally, within hospitals, and nationally. This trend has been shown to correlate closely with the extent of usage of some third-generation cephalosporins. These resistant strains, especially Enterobacter spp., are more regularly isolated from seriously ill patients (especially from respiratory sources), or in intensive care units and pose one of the greatest challenges to contemporary chemotherapy of infections in hospitalized patients. Zwitterionic fourth-generation cephalosporins combine the properties of rapid bacterial outer membrane penetration with high stability to AmpC β-lactamase with good affinity for the penicillin-binding proteins to achieve in vitro activity against AmpC-producing organisms, including the majority of strains highly resistant to ceftazidime and other earlier generation cephalosporins. These features have contributed to their clinical success in the therapy of infections caused by Enterobacter spp. with and without resistance to third-generation compounds. Other alternative agents for chemotherapy of infections due to AmpC β-lactamase-producing strains (inducible or derepressed expression) should also be considered e.g. carbapenems, aminoglycosides and fluoroquinolones.