beta-Lactamase production protects Staphylococcus aureus against piperacillin and amoxycillin. Tazobactam and clavulanate inhibit the enzyme, but beta-lactamase producers remained substantially less susceptible than non-producers to piperacillin/tazobactam and co-amoxiclav in disc tests. These observations reflected the fact the inhibition zones for beta-lactamase non-producers expanded with time, as bacterial growth was killed by the diffusing antibiotic, whereas those for enzyme producers maintained a constant diameter after they first became discernible, indicating equilibrium between diffusion and destruction of the antibiotic. The antibiotic destruction required for this equilibrium depended on biomass formation, which was apparent from the luxuriant growth on beta-lactamase-producers around the inhibition zone edges, and on beta-lactamase induction, which was demonstrable when S. aureus cultures were exposed to discs containing tazobactam alone. beta-Lactamase-related effects on the activity of inhibitor combinations were apparent also in MIC tests, but only when these were performed with large inocula. Thus, the MICs of piperacillin or amoxycillin with tazobactam or clavulanate were only two- to four-fold higher for beta-lactamase producers than non-producers at low inocula (10(4) cfu), but this differential increased to 6- to 16-fold at high inocula (10(6) cfu). Inoculum effects were greater for tazobactam combinations than for clavulanate combinations, irrespective of the partner penicillin. These beta-lactamase-related inhibition zone differentials and inoculum effects for the inhibitor combinations resemble previous observations for first-generation cephalosporins, notably cephazolin and cephaloridine. Their significance for the latter compounds has occasioned long debate.
Anti-Bacterial Agents Drug Synergism