Mechanisms of resistance to cephalosporin antibiotics

Cephalosporins, like other beta-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 beta-lactamases or 'permeability barriers'. Target-mediated cephalosporin resistance can involve either reduced affinity of an existing PBP component, or the acquisition of a supplementary beta-lactam-insensitive PBP. beta-lactamases are produced widely by bacteria and may be determined by chromosomal or plasmid DNA. The chromosomal beta-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 beta-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. In Gram-positive organisms the PBPs are located on the outer aspect of the cytoplasmic membrane and so shielding by permeability barriers is minimal. In Gram-negative cells, however, the PBPs are protected by the outer membrane, which most beta-lactams cross by diffusion through aqueous pores composed of 'porin' proteins. In enterobacteria, a clear correlation exists between porin quantity and cephalosporin resistance, suggesting that the outer membrane is the sole barrier to drug entry. Such relationships are less clear for Pseudomonas aeruginosa, where the cell may contain additional barriers between the outer membrane and the PBPs. Although elevated cephalosporin resistance often is attributed to a single factor (PBP-modification, beta-lactamase action or impermeability) an organism's response to a drug often reflects the interplay of several factors. Mathematical models can be proposed to describe this interplay.