Combination β-lactam and β-lactamase-inhibitor products: Antimicrobial activity and efficiency of enzyme inhibition

Classification schemes for gram-negative β-lactamases are presented, mechanisms by which β-lactamases inactivate β-lactam antibiotics are reviewed, and methods for assessing the efficiency of β-lactamase inhibitors are evaluated. Beta-lactamases are commonly produced by Staphylococcus species, the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter species, and some anaerobes. Currently available β-lactamase inhibitors are thought to be 'suicide inhibitors' that form stable complexes between the bacterial β-lactamase and the β-lactamase inhibitor in a multistep chemical reaction. Each step can be quantitated; however, the overall process is difficult to measure. Thus, a comparative evaluation of commercially available β-lactamase inhibitors is extremely difficult and must be done under standardized test conditions. In general, sulbactam, clavulanate, and tazobactam are all potent inhibitors of staphylococcal penicillinase; chromosomal β-lactamases produced by Bacteroides species, Proteus vulgaris, Haemophilus influenzae, Neisseria gonorrhoeae; and type IV enzymes of Klebsiella species. Although sulbactam possesses activity against TEM-1 and TEM-2 β-lactamases, it does not have reliable activity against SHV-1 β- lactamases. Clavulanate and tazobactam are potent inhibitors of both TEM and SHV-1 β-lactamases. P. aeruginosa and some Enterobacteriaceae produce an inducible, extremely potent, broad-spectrum enzyme (type 1 β-lactamase). Tazobactam is the only currently available. β-lactamase inhibitor with activity against type Iβ-lactamases; however, some enzymes are not inhibited by tazobactam.