Selection of naturally occurring extended-spectrum TEM β-lactamase variants by fluctuating β-lactam pressure

Despite the large number of in vitro mutations that increase resistance to extended-spectrum cephalosporins in TEM-type beta-lactamases, only a small number occur in naturally occurring enzymes, In nature, and particularly in the hospital, bacteria that contain beta-lactamases encounter simultaneous or consecutive selective pressure with different beta-lactam molecules. All variants obtained by submitting an Escherichia coli strain that contains a bla(TEM.1) gene to fluctuating challenge with both ceftazidime and amoxicillin contained only mutations previously detected in naturally occurring beta-lactamases, Nevertheless, some variants obtained by ceftazidime challenge alone contained mutations never detected in naturally occurring TEM beta-lactamases, suggesting that extended-spectrum TEM variants in hospital isolates result from fluctuating selective pressure with several beta-lactams rather than selection with a single antibiotic.