头孢曲松-舒巴坦复方制剂体外药动学/药效学研究

An in vitro study on the pharmacokinetics/pharmacodynamics of ceftriaxone-sulbactam

目的通过体外药动学/药效学(PK/PD)研究,确定头孢曲松-舒巴坦(4∶1)对产超广谱β内酰胺酶(ESBL)肠杆菌科细菌作用特点,评价其组方的合理性。方法建立体外PK/PD模型,模拟人体单剂静脉注射头孢曲松、头孢曲松-舒巴坦(4∶1)(同步与非同步消除)、头孢哌酮、头孢哌酮-舒巴坦(1∶1)药动学过程,比较药物对肺炎克雷伯菌ATCC700603(产SHV-18型酶)、大肠埃希菌EC-1和EC-2(分别产CTX-M-3、TEM-1型酶)的药效学特征。结果头孢曲松、头孢哌酮单药对肺炎克雷伯菌ATCC700603具有缓慢杀菌作用,3种复方模型显示出相似的杀菌活性,杀菌效果在6h最为明显;头孢曲松、头孢哌酮杀菌效果不显著;头孢曲松-舒巴坦复方制剂非同步消除模型杀菌效果不彻底;头孢曲松-舒巴坦同步消除模型杀菌效果最明显;对大肠埃希菌EC-2,5种模型均有明显杀菌活性。结论对产ESBLs肠杆菌,头孢曲松-舒巴坦(4∶1)复方制剂同步消除具有协同抗菌作用,非同步消除协同作用不明显;头孢曲松与舒巴坦复方制剂,可能临床价值有限,不具有发挥协同抗菌效果的基础。

Objective To explore the pharmacokinetic/pharmacodynamic characteristics of ceftriaxone-sulbactam（4∶1） against ESBLs-producing Enterobacteriaceae strains and evaluate the rationality of the formulation in an in vitro pharmacokinetic/pharmacodynamic（PK/PD） model.MethodsThe in vitro PK/PD model was established successfully.The PK profiles in humans following a single dose of intravenous administration of ceftriaxone,ceftriaxone-sulbactam（4∶1）（synchronously or non-synchronously excretion）,cefoperazone and cefoperazone-sulbactam（1∶1） were simulated in the established model.The bactericidal effect against K.pneumoniae ATCC 700603（SHV-18 producer）,E.coli EC-1（CTX-M-3 producer） and EC-2（TEM-1 producer） was compared.ResultsAll the five models showed obvious antibacterial activity against E.coli EC-2.The bactericidal effect of ceftriaxone and cefoperazone against K.pneumoniae ATCC 700603 was weak,but the other three compounds demonstrated remarkable antibacterial activity.The maximal efficacy was achieved at 6h.Ceftriaxone and cefoperazone did not have potent bactericidal effect against E.coli EC-1.The bactericidal curves were similar to that of control.The antibacterial activity of cefoperazone-sulbactam and ceftriaxone-sulbactam in non-synchronous models was weak,but the antibacterial activity of ceftriaxone-sulbactam was significantly powerful than others in synchronous model.The bacterial count decreased from 106 to 101.5 CFU/mL at 6 h after incubation.ConclusionsCeftriaxone-sulbactam（4∶1） showed better antibacterial activity in synchronous excretion model than in the nonsynchronous model.The clinical value of ceftriaxone-sulbactam compound is limited.The combination cannot provide meaningful synergistic bactericidal effect.