Sulbactam and clavulanic acid: enzyme kinetics and synergy with ampicillin and mezlocillin

Abstract

The two β-lactamase inhibitors, sulbactam and clavulanic acid, exhibit high affinity ( K I < 10 −6mol/l) for the β-lactamases of Gram-negative organisms with predominantly penicillinase activity and much less affinity (especially clavulanic acid) for organisms with predominantly cephalosporinase activity. In tests to compare the synergy of these β-lactamase inhibitors with other antibiotics, clavulanic acid and ampicillin or mezlocillin demonstrated greater synergy than sulbactam and ampicillin or mezlocillin, with isolates forming either a plasmid-coded β-lactamase or a chromosomal enzyme with predominantly penicillinase activity. However, neither sulbactam nor clavulanic acid were able to protect ampicillin or mezlocillin adequately against inactivation by β-lactamase overproducing variants of Klebsiella pneumoniae or Klebsiella oxytoca, irrespective of the extent of synergy seen with the corresponding wild strains. It was interesting to note the synergy between mezlocillin and sulbactam with respect to β-lactamase overproducing variants of clinical isolates of Enterobacter cloacae. A statistically significant correlation between the quantities of β-lactamase formed and synergy between the β-lactamase inhibitor and the antibiotic with which it was combined was not retained in studies of clinical isolates in any case. These observations correlate well with the results obtained in routine testing of the combinations of amoxycillin/clavulanic acid and ampicillin/sulbactam.