The use of Pharmacokinetic and Pharmacodynamics to evaluate The recommended dosing regimens of Cefoperazone-Sulbactam in patients with hospital-Acquired Pneumonia

Abstract

This study used pharmacokinetics/pharmacodynamics to evaluate the recommended cefoperazone/sulbactam regimens for the empirical treatment patients with hospital-acquired pneumonia (HAP). Thirty- two of HAP patients who treated with cefoperazone/sulbactam (500/500mg): 1 g every 12 h (n=8), 2 g every 12 h (n=18), and 2 g every 8 h (n=6), blood samples were collected after the fifth dose and concentrations of cefoperazone and sulbactam were determined by a validated High – Performance Liquid Chromatography assay. The mean pharmacokinetic parameters of cefoperazone and sulbactam: volume of distribution (Vd), eliminination rate of constant (Ke), total clearance of cefoperazone (CL) and elimination half life (T1/2), presented not significantly difference between dosage regimens (p>0.05), but there were significantly differences in area under the concentration-time curve (AUC) (p<0.05). A 5,000-subjects Monte Carlo simulation was used to model the percent time of total drug concentration above the MIC (%T>MIC) for cefoperazone/sulbactam regimens against Acinetobacter baumannii , and Pseudomonas aeruginosa. The cumulative fraction of response (CFR) were determined for bactericidal target at >50% of total cefoperaozone concentration time above MIC. The 90% of cumulative fraction response (CFR) was considered the optimal empirical regimen. For A. baumannii, cefoperazone/sulbactam 2 g q 8 h and 2 g q 12 h displayed highest CFR (72.84, and 72.76%, respectively), while cefoperazone/sulbactam 1 g q 12 h provided a lower CFR (52.58%). For P.aeruginosa, cefoperazone/sulbactam 2 g q 8h and 2 g q 12 h also displayed highest CFR (77.78, and 76.84%, respectively), and cefoperazone/sulbactam 1 g q 12 h provided a lower CFR (63.60%). Although the regimens 2 g q 12 h and 2 g q 8 h of cefoperazon/sulbactam had a high bactericidal CFR, there could not be achieved the target at 90%CFR. Thus the use of combination therapy with cefoperazone/sulbactam to treat these pathogens in the hospital should be justified. Using chi-squares analyses, we found that CFR of the 50%T>MIC and the ages of the patients which were less than 60 years were the significant variables associated to the clinical response of hospital-acquired pneumonia patients treated by cefoperazone/sulbactam (p=0.041 (OR=6.8), and p=0.01 (OR=13.71), respectively)