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

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 (less than or equal to 16 micrograms/mL) against 95% of Enterobacteriaceae and combined with 4 micrograms/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 micrograms/mL for cefoperazone and 1.0 microgram/mL for cefoperazone and 4.0 micrograms/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 beta-lactamase inhibition. The cefoperazone MICs against beta-lactamase producing Staphylococcus species also were lowered to the level of enzyme-deficient strains. Cefoperazone bactericidal activity was improved by 4.0 micrograms/mL sulbactam, and no antagonism was observed. beta-lactamase hydrolysis studies confirmed a slow hydrolysis of cefoperazone only by TEM beta-lactamases and a high-grade resistance to enzyme breakdown by sulbactam. Differential beta-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-micrograms disk to testing routine isolates other than enterococci and methicillin-resistant Staphylococcus aureus. The addition of 4.0 micrograms sulbactam/mL in a fixed concentration to dilution test systems and 15 micrograms sulbactam to the 75 micrograms 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 micrograms cefoperazone/15 micrograms sulbactam disk.

In vitro activities of various piperacillin and sulbactam combinations against bacterial pathogens isolated from Intensive Care Units in Taiwan: SMART 2004 programme data

“…Previous in vitro and in vivo studies of a ␤-lactam antibiotic and sulbactam combination on bacteria producing ESBLs showed variable responses [6,7,11,[26][27][28][29][30][31][32][33][34]. In this study, piperacillin/sulbactam at a ratio of 2:1 significantly decreased the rate of ESBL-producing non-susceptible E. coli from 100% to 50% and decreased the MIC 50 from >128 mg/L to 16 mg/L compared with piperacillin alone.…”

Comparison of antimicrobial efficacy of a fixed dose combination of ceftazidime + sulbactam with ceftazidime and sulbactam alone against five bacteria

“…The antibacterial eefect of Cep and a combined action of Cef + Sul individually has already been assessed in vitro and in vivo on bacteria producing ESBLs (Jones et al 1985;Drew et al 1998). The interest in using Sul as a suicide inhibitor lies in the fact that it is available independently of β-lactams.…”

Beta-lactamase inhibitors from laboratory to clinic.

“…In this procedure synergy is defined as a fourfold reduction in MIC for both components (107). Standard procedures for disk diffusion susceptibility testing have been outlined for Augmentin (a combination of 2 parts amoxicillin to 1 part clavulanic acid) (67), Timentin (a combination of 15 parts ticarcillin to 2 parts clavulanic acid) (66,78), cefoperazone-sulbactam (79), and ampicillin-sulbactam (17). However, a cautionary note has been reported, indicating that susceptibility test results may differ according to the medium used.…”