Most enterobacterial species carry a chromosomal ampC beta-lactamase gene. In Escherichia coli and Shigella, expression from ampC is non-inducible and the beta-lactamase is synthesized at low levels. Mutations leading to increased beta-lactamase synthesis occur rather infrequently, making resistance to modern cephalosporins a rare event in these species. In other enterobacteria and Pseudomonas, ampC beta-lactamase synthesis is induced by beta-lactams. In Enterobacter cloacae, Citrobacter freundii and probably also in other species with inducible beta-lactamase expression, ampC is regulated by at least two genes, ampR and ampD. Mutations affecting ampR abolish beta-lactamase inducibility, and mutants devoid of ampR, produce ampC beta-lactamase at low constitutive levels. Mutations in ampD lead to constitutive overproduction of inducible beta-lactamase if an intact ampR protein is present in the cell. The latter type of mutations occur at a high frequency and result in clinical resistance to several third-generation cephalosporins.