Resistance to β-lactam antibiotics

β-lactams have a long history in the treatment of infectious diseases, though their use has been and continues to be confounded by the development of resistance in target organisms. β-lactamases, particularly in Gram-negative pathogens, are a major determinant of this resistance, although alterations in the β-lactam targets, the penicillin-binding proteins (PBPs), are also important, especially in Gram-positive pathogens. Mechanisms for the efflux and/or exclusion of these agents also contribute, though often in conjunction these other two. Approaches for overcoming these resistance mechanisms include the development of novel β-lactamase-stable β-lactams, β-lactamase inhibitors to be employed with existing β-lactams, β-lactam compounds that bind strongly to low-affinity PBPs and agents that potentiate the activity of existing β-lactams against low-affinity PBP-producing organisms.