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Inhibitor combinations provide one strategy to overcome β-lactamase-mediated resistance. Their success depends, obviously, on the inhibitor being able to bind and inactivate the β-lactamase molecules. Clavulanate, sulbactam and tazobactam are irreversible inactivators of many β-lactamases, forming covalent complexes which resist hydrolysis. ‘Suicide’ kinetics are seen with some, but not all, enzymes. All three compounds inactivate staphyiococcal peniculinase, the chromosomal β-lactamases of Proteus vulgaris and Bacteroides spp, and the Class IV β-lactamases present in some klebsiellae. Tazobactam, but not the other compounds, has moderate activity against some Class I (AmpC) chromosomal β-lactamases, notably that of Morganella morganii, but not that of Enterobacter cloacae. Both clavulanate and tazobactam are strong inhibitors of the widely distributed TEM and SHV plasmid-mediated β-lactamases; sulbactam is a weaker inhibitor. Other factors, aside from the affinity of the inhibitor for the enzyme, co-determine the success or failure of inhibition. Potentiation is most readily achieved if little enzyme is produced, and if the organism is very permeable to the inhibitor. Thus, resistance to inhibitor combinations is rare in strains of Haemophilia influenzae and Neisseria gonorrhoeae that produce TEM-β-lactamase, but is commoner in enterobacteria that produce this enzyme, since these are less permeable and sometimes manufacture very large amounts of enzyme. The partner β-lactam agent is also important Irrespective of the inhibitor used, piperacillin is easier to protect against TEM β-lactamases and the M. morganii Class I enzyme than are ampicillin, amoxycillin or ticarcillin. This may relate to the lower affinity of piperacillin for these enzymes, or to its greater affinity for the bacterial penicillin-binding proteins. Finally, pH can affect the degree of inhibition achieved with sulphones for some β-lactamases, notably TEM-1. |
