Interactions of tazobactam and clavulanate with inducibly- and constitutively-expressed Class I beta-lactamases

Clavulanate and tazobactam (YTR 830) were tested as inhibitors and inducers of the AmpC-type Class I beta-lactamases of Pseudomonas aeruginosa, Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii and the Ic beta-lactamase of Proteus vulgaris. Both clavulanate and tazobactam inhibited the Pr. vulgaris Class Ic beta-lactamase and potentiated ticarcillin and piperacillin against beta-lactamase derepressed variants of this species. Tazobactam, but not clavulanate, also had some ability to inhibit the AmpC Class I enzymes of M. morganii, C. freundii, Ps. aeruginosa, E. cloacae and S. marcescens. The piperacillin + tazobactam combination, unlike ticarcillin + clavulanate, showed some degree of synergy against most derepressed strains of these species. This behaviour partly depended upon the greater inhibitory activity of tazobactam for the enzymes, but also on piperacillin being easier to potentiate than ticarcillin. The synergy between piperacillin and tazobactam was greatest for M. morganii and C. freundii, least for Ps. aeruginosa and E. cloacae. Unfortunately, it is in the last two species that these enzymes pose the greatest resistance threat. Tazobactam caused little or no antagonism of piperacillin against beta-lactamase inducible species, whereas clavulanate antagonized ticarcillin against beta-lactamase inducible strains of E. cloacae and M. morganii (not other species). The antagonism of ticarcillin was attributable to beta-lactamase induction. The lack of antagonism with the tazobactam+piperacillin combination was related to tazobactam being a weaker inducer than clavulanate, not to piperacillin being less susceptible to antagonism than ticarcillin.