The Cefoperazone–Sulbactam Combination: In Vitro Qualities Including Beta-Lactamase Stability, Antimicrobial Activity, and Interpretive Criteria for Disk Diffusion Tests

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Abstract
Three concentrations of the penicillanic acid sulfone, sulbactam were tested in combination with cefoperazone against 632 recent clinical bacterial isolates. Cefoperazone was effective alone (≤16 μg/mL) against 95% of Enterobacteriaceae and combined with 4 μg/mL sulbactam inhibited 99.5% of strains. This coverage of enteric bacilli was superior to timentin (99.1%), ceftazidime (98.2%), and tobramycin (90.9%). The minimum inhibitory concentrations (MICs) of cefoperazone-susceptible strains also were markedly decreased by sulbactam (overall MIC90s, 8.0 μg/mL for cefoperazone and 1.0 μg/mL for cefoperazone and 4.0 μg/mL for sulbactam). Sulbactam also expanded the spectrum of cefoperazone against Acinetobacter species, some rare Pseudomonas species, and Bacteroides fragilis group species. Sulbactam had direct antimicrobial activity against the acinetobacters and Pseudomonas acidovorans, but the increased activity of cefoperazone–sulbactam against some other Pseudomonas species and anaerobes was attributed to β-lactamase inhibition. The cefoperazone MICs against β-lactamase producing Staphylococcus species also were lowered to the level of enzyme-deficient strains. Cefoperazone bactericidal activity was improved by 4.0 μg/mL sulbactam, and no antagonism was observed. β-lactamase hydrolysis studies confirmed a slow hydrolysis of cefoperazone only by TEM β-lactamases and a high-grade resistance to enzyme breakdown by sulbactam. Differential β-lactamase affinity studies for cefoperazone and sulbactam showed potential efficacy and applications to plasmid-mediated TEM and OXA enzymes and only marginal effective sulbactam inhibition of Pseudomonas and Klebsiella species enzymes. Disk diffusion studies on 556 strains confirmed the applicability of the cefoperazone 75-μg disk to testing routine isolates other than enterococci and methicillin-resistant Staphylococcus aureus. The addition of 4.0 μg sulbactam/mL in a fixed concentration to dilution test systems and 15 μg sulbactam to the 75 μg cefoperazone disk were recommended for in vitro tests. Susceptibility and resistant interpretive criteria for the disk and dilution tests can be applied with confidence. Only 0.4% false-susceptibility errors and a 97.5% absolute interpretive agreement were achieved using the 75 μg cefoperazone/15 μg sulbactam disk.

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