RESUMEN
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.
RESUMEN
Benapenem is a novel carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of benapenem for the treatment of bacterial infections via PK/PD modeling and simulation. Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of benapenem or ertapenem of 14.6, 58.4, or 233.6 mg/kg of body weight, and the PK/PD profiles were evaluated. The MICs were determined by using a 2-fold agar dilution method. Mathematical models were developed to characterize the pharmacokinetic profile of benapenem in humans and mice. Monte Carlo simulations were employed to determine the cutoff values and the appropriate benapenem dosing regimens for the treatment of infections caused by clinical isolates of Enterobacteriaceae Two 2-compartment models were developed to describe the PK profiles of benapenem in humans and mice. A two-site binding model was applied to fit the protein binding in mouse plasma. Through correlation analysis, the percentage of the time that the free drug concentration remains above the MIC (%fT>MIC) was determined to be the indicator of efficacy. Results from the simulation showed that the probability of target attainment (PTA) against the tested isolates was over 90% with the dosing regimens studied. The PK/PD cutoff value of benapenem was 1 mg/liter at a %fT>MIC of 60% when given at a dose of 1,000 mg/day by i.v. drip for 0.5 h. The established model provides a better understanding of the pharmacological properties of benapenem for the treatment of Enterobacteriaceae infections. The proposed PK/PD cutoff value suggests that benapenem is a promising antibacterial against the Enterobacteriaceae The cutoff value of 1 mg/liter may be a useful guide for the clinical use of benapenem and for surveillance for benapenem resistance.
