头孢哌酮钠/三唑巴坦钠不同配比复方制剂的体内、外抗菌活性试验及小鼠毒性研究

In vitro and in vivo synergistic antibacterial activity of cefoperazone/tazobactam

目的 考察及评价头孢哌酮钠 /三唑巴坦钠以 1∶ 1、2∶ 1、4∶ 1、8∶ 1配比的复方制剂对临床分离致病菌的体外抗菌作用 ,及其对金葡球菌、大肠埃希氏菌和铜绿假单胞菌感染小鼠的体内保护作用 ,拟找出头孢哌酮钠与三唑巴坦钠的最佳配比 ,为进一步开发头孢哌酮 /三唑巴坦复方制剂提供依据。方法 采用琼脂二倍稀释法测定了头孢哌酮钠 /三唑巴坦钠复方制剂 (1∶ 1、2∶ 1、4∶ 1、8∶ 1)对临床分离致病菌 (包括产 β-内酰胺酶和产超广谱酶 ESBL s菌株 )的体外抗菌作用及对产酶金葡球菌和大肠埃希氏菌感染小鼠的体内保护作用。采用紫外分光光度法测定头孢哌酮钠 /三唑巴坦钠复方制剂 (1∶ 1、2∶ 1、4∶ 1、8∶ 1)及单用头孢哌酮对 8种标准 β-内酰胺酶的稳定性 ,并与头孢哌酮 /舒巴坦、哌拉西林、哌拉西林 /三唑巴坦等 β-内酰胺抗生素进行比较。比较小鼠一次静脉注射头孢哌酮钠 /三唑巴坦钠 (4∶ 1)的急性毒性。结果 头孢哌酮钠 /三唑巴坦钠以 1∶ 1、2∶ 1、4∶ 1和 8∶ 1配伍均可比单用头孢哌酮对产酶耐药菌株的 MIC50 降低 1/ 2～ 1/ 6 4 ,其中 1∶ 1、2∶ 1、4∶ 1的体外抗菌活力基本相同 ,略强于 8∶ 1。4∶ 1配伍体外活性与头孢哌酮 /舒巴坦相当。头孢哌酮钠/三唑巴坦钠 (4∶ 1)

Objective To evaluate the in vitro synergistic activity of cefoperazone/tazobactam (CPZ) ( 1∶1 ,2∶1,4∶1,8∶1,16∶1) against 351 clinical isolates,the hydrolysis rate of CPZ/TB (4∶1) by β-lactamases and the activity of enzyme inhibitors preventing hydrolysis of ceftoperazone. Methods The minimal inhibitory concentrations (MICs) of CPZ/TB (1∶1,2∶1,4∶1,8∶1) were detected by the agar dilution method,and compared with each other. The in vivo antibacterial activity of CPZ/TB (1∶1,2∶1,4∶1, 8∶1 ) were detected and compared with those of cefoperazone,cefoperazone/sulbactam,in mice with experimental systemic infection caused by S.aureus 991915,E.coli 99115,E.coli 9912 and P.aeruginasa 98220. The hydrolysis rate of CPZ/TB (4∶1) by β-lactamases and the activity of β-lactamase inhibitors were measured by ultra violet spectrophotometry with cephaloridine as reference,and compared with those of cefoperazone/sulbactam (CPZ/SB 1∶1),piperacilin/tazobactam (PIPC/TB 8∶1). Results The antibacterial activity of combination of CPZ and TB was superior to CPZ itself. The ratio of CPZ/TB of 1∶1,2∶1 and 4∶1 showed much better antibacterial activity than the ratio of 8∶1. The MIC_ 50 of CPZ/TB (1∶1,2∶1,4∶1) were lowered by 1/2 to 1/32 of that of cefoperazone alone against β-lactamase producing organisms. The ED_ 50 of CPZ/TB (4∶1) in mice infected by S.aureus 991915,E.coli 99115,E.coli 9912 and P.aeruginasa were 34.85,29.09,41.00 and 62.34mg/kg,respectively. The in vivo activities of CPZ/TB (1∶1,2∶1,4∶1) were twice to three times better than that of CPZ,and superior to cefoperazone/sulbactam. The differentiations among the CPZ/TB 1∶1,2∶1 and 4∶1 were not significant. The hydrolysis rate of CPZ/TB (4∶1) was lower than those of cefoperazone CPZ/SB (1∶1) and PIPC/TB (8∶1). The hydrolysis rate of CPZ/TB (4∶1) by β-lactamases TAM-1,TEM-5,SHV-4,PSE-1 OXA-1,OXA-5 and K1,D31 were 2.2%,2.9%,10.6%,6.2%,3.75%,27.7%,58.2% and 64.6%,respectively. Conclusion CPZ/TB (4∶1) is an effective antibiotic preparation against β-lactamase.