Chapter 13 : β-Lactamase Inhibitors

Abstract:

The most widespread mechanism of bacterial resistance to β-lactams is the biosynthesis of chromosomal or plasmid-mediated β-lactamases. Generally, the term β-lactamase inhibitor is reserved for β-lactams whose spectrum of inhibition covers all the β-lactamases to various degrees. While proposed in a fixed combination with ampicillin, only sulbactam was also available for extemporaneous combination with the most appropriate β-lactam for the β-lactamase-producing bacterial species concerned. It can be seen that for three TEM-3-producing species, the combinations of sulbactam plus cefotaxime, ceftazidime, and aztreonam are more effective than the fixed combinations clavulanic acid-ticarcillin and tazobactam-piperacillin. With 70% bioavailability following oral administration, clavulanic acid has proved to be well absorbed by the intestinal mucosa; as the same applies to amoxicillin, the combination of the two products is suggested for oral administration. The inhibitor and the β-lactam present in the bacterium compete for binding to the active site of the β-lactamase. As the inhibitors generally have a better affinity for the enzyme, the β-lactam may escape the hydrolytic activity of the β-lactamase if the concentration of inhibitor combined with it is sufficient to inactivate all of the β-lactamase molecules. It can thus be seen that the ideal combination is that of the best inhibitor with the β-lactam most resistant to the hydrolytic activity of the β-lactamases. The results obtained therapeutically suggest that clavulanic acid and tazobactam might also be proposed. This would allow the prescription of the most suitable combination of inhibitor and β-lactam for the bacterial species responsible for the infection.