Objective:
Cefoperazone/
sulbactam is a commonly used
antibiotic combination against the extended-spectrum
beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new
cefoperazone/
sulbactam combination (3:1) for
Enterobacteriaceae infection via model-informed
drug development (MIDD) approaches. Methods:
Sulperazon [
cefoperazone/
sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free
drug concentration exceeded the minimum inhibitory concentration (%fT>MIC) was used as the pharmacokinetic/pharmacodynamic
indicator correlated with efficacy. Models were developed to characterize the PK profile of
cefoperazone and
sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of
cefoperazone/
sulbactam (3:1) for the treatment of
infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria. Results: Two 2-compartment models were developed to describe the PK profiles of
cefoperazone and
sulbactam. Simulation results following the single-dose showed that the regimens of
cefoperazone/
sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of
cefoperazone/
sulbactam (4 g, TID, 3 g:1 g) showed slightly better antibacterial effect than
cefoperazone/
sulbactam (6 g, BID, 4 g:2 g) against the Escherichia coli (ESBL-) and Klebsiella pneumoniae (ESBL-). For the other tested bacteria, the above regimens achieved a similar PTA. Conclusions:
Cefoperazone/
sulbactam (3:1) showed similar bactericidal activity to
sulperazon [
cefoperazone/
sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and
cefoperazone-resistant E. coli and K. pneumoniae,
Cefoperazone/
sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.