Important and Emerging β-Lactamase-mediated Resistances in Hospital-based Pathogens: The Amp C Enzymes

Abstract

Resistance to third-generation cephalosporins mediated by β-lactamases is an increasing problem for clinical therapeutics. A wide range of Enterobacteriaceae produce these AmpC enzymes (Bush-Jacoby-Medeiros group 1), including Enterobacter spp., Citrobacter freundii, Morganella morganii, Providencia spp., and Serratia marcescens. Resistance via this mechanism has been shown to be statistically correlated with the use of some third-generation cephalosporins, and the infections caused by these stably derepressed enzyme-producing species seem to occur most frequently in the seriously ill. More recently the genes encoding this enzyme have been documented on plasmids capable of transfer into other species such as Klebsiella pneumoniae. Fourth-generation cephalosporins, with stability and low affinity for the Amp C β-lactamases and the ability to penetrate rapidly into the periplasmic space of Gram-negative organisms, offer a viable alternative in the treatment of these infections or as empiric regimens. Furthermore, these compounds (example: cefpirome) possess greater potency against the frequently occurring Gram-positive cocci such as oxacillin-susceptible staphylococci and the streptococci (including some penicillin-resistant strains) as compared to previously used anti-pseudomonal cephalosporias, ceftazidime.

Introduction

Resistance in hospital-based bacterial pathogens to commonly used antimicrobials has been a serious problem since the late 1940s when Gram-positive organisms such as Staphylococcus aureus developed enzyme mechanisms which made them refractory to the newly introduced penicillins. The rapidity with which bacteria produce mutants ensures that commonly used treatments such as the currently popular extended spectrum (third-generation) cephalosporins are, in turn, compromised. Pharmaceutical research has been focused on finding new bacterial targets and novel classes of antimicrobial agents or on chemically manipulating existing classes of antimicrobials to enhance their activities. The fourth-generation cephalosporins are a case in point derived from the basic cephalosporin nucleus, but enhanced by the substitution of a quaternary ammonium group at the C-3′ position (Jones et al. 1991). This substitution has several effects: 1) it enhances the overall potency of these compounds; 2) it provides compounds with a more balanced spectrum of activity against Gram-positive and Gram-negative organisms and; 3) it confers a low affinity and stability to some clinically important β-lactamases (Amp C).