Evolution of beta-lactamase inhibitors

beta-Lactamases present the greatest single challenge to beta-lactam antibiotics, including piperacillin. beta-Lactamase-mediated resistance to supposedly beta-lactamase stable agents such as second- and third-generation cephalosporins is now emerging and inhibitor combinations provide an alternative strategy to overcome this problem. The success of this strategy depends on 1) how efficiently the inhibitor inhibits important beta-lactamases, 2) on how much beta-lactamase the bacteria produce, 3) on the drug that is to be protected, 4) on the permeability and intrinsic susceptibility of the organisms and 5) on the conditions, notably the pH. Tazobactam inhibits most of the clinically important beta-lactamases that give piperacillin resistance, except for the Class I types. Piperacillin itself is a relatively easy drug to protect, particularly against the TEM-type enzymes. The result is that tazobactam greatly extends the activity of piperacillin, notably against enterobacteria, but also against staphylococci and anaerobes. The survey confirmed the very broad spectrum of activity of piperacillin/tazobactam. Resistance occurred in about 17% of the Enterobacter, Citrobacter, Serratia group, where we believe it to have been caused by derepressed Class I enzymes since these strains were cross-resistant to third-generation cephalosporins. Otherwise, resistance was largely confined to such organisms as E. faecium and methicillin-resistant staphylococci, which have piperacillin insensitive penicillin-binding proteins. Finally, some question remains on the antistaphylococcal activity of piperacillin/tazobactam, where MIC tests gave a more favorable impression than disc tests. Nevertheless, early clinical results against staphylococcal infection appear good, with a response rate of nearly 90% [15].