Mechanisms of Resistance to Cephalosporin Antibiotics

Cephalosporins, like other β-lactams, bind to the bacterial penicillin-binding proteins (PBPs). These correspond to the D-ala- D-ala trans-, carboxy- and endo-peptidases responsible for catalysing the cross-linking of newly formed peptidoglycan. Resistance arises when the PBPs — and particularly the transpeptidases — are modified, or when they are protected by β-lactamases or ‘permeability barriers’. Target-mediated cephalosporin resistance can involve either reduced affinity of an existing PBP component, or the acquisition of a supplementary β-lactam-insensitive PBP. β-lactamases are produced widely by bacteria and may be determined by chromosomal or plasmid DNA. The chromosomal β-lactamases are species-specific, but can be classified into a few broad groups. The plasmid-mediated enzymes cross interspecific and intergeneric boundaries. The level of β-lactamase-mediated resistance relates to the amount of enzyme produced with or without induction; to the location of the enzyme (extracellular for Gram-positive organisms and periplasmic in Gram-negative ones); and to the kinetics of the enzyme’s activity.