Use of pharmacodynamic parameters to predict efficacy of combination therapy by using fractional inhibitory concentration kinetics
Use of pharmacodynamic parameters to predict efficacy of combination therapy by using fractional inhibitory concentration kinetics
复制标题
DOI：
10.1128/aac.42.4.744
复制
发表时间：
1998-04-01
影响因子：
4.9
通讯作者：
Verbrugh, HA
中科院分区：
文献类型：
--
作者：
den Hollander, JG;Mouton, JW;Verbrugh, HA
与抗微生物剂的组合疗法可用于对抗对单一药剂敏感性降低的细菌。我们研究了不同的妥布霉素和头孢他啶给药方案对四个耐药铜绿假单胞菌菌株在体外药代动力学模型，以确定联合治疗的可用性，由于耐药菌株的感染治疗。对于最佳给药方案的选择，有必要确定哪个药效学参数最能预测联合治疗期间的疗效，并找到一种简单的药敏试验方法。评估了一种易于使用、先前描述的E测试方法，作为对联合治疗敏感性的测试。该测试产生MICcombi，其为例如妥布霉素在头孢他啶存在下的MIC。通过将妥布霉素和头孢他啶浓度除以MICcombi，在给药间隔期间的每个时间点，构建部分抑制浓度（FIC）曲线，并从这些曲线计算联合治疗的新药效学参数（即，AUC（combi）、Cmax-combi、T>MIC-combi、T->FICi，其中AUC（combi）、Cmax-combi、T>MIC-combi和T->FICi分别是FICcombi曲线下面积、FICcombi的峰浓度、组合浓度高于MICcombi的时间和高于FIC指数的时间）。多元逐步回归分析表明，T->FICi是妥布霉素和头孢他啶联合用药的最佳疗效预测指标（R-2 = 0.6821; P < 0.01）。我们得出结论，对于妥布霉素和头孢他啶的联合治疗，T->FICi是疗效的最佳预测参数，并且用于联合治疗的药敏试验的E-检验给出了有希望的结果。联合治疗的这些新的药效学参数有望更好地了解联合治疗背后的原理。
Combination therapy with antimicrobial agents can be used against bacteria that have reduced susceptibilities to single agents. We studied various tobramycin and ceftazidime dosing regimens against four resistant Pseudomonas aeruginosa strains in an in vitro pharmacokinetic model to determine the usability of combination therapy for the treatment of infections due to resistant bacterial strains. For the selection of an optimal dosing regimen it is necessary to determine which pharmacodynamic parameter best predicts efficacy during combination therapy and to find a simple method for susceptibility testing. An easy to-use, previously described E-test method was evaluated as a test for susceptibility to combination therapy. That test resulted in a MICcombi, which is the MIC of, for example, tobramycin in the presence of ceftazidime. By dividing the tobramycin and ceftazidime concentration by the MICcombi, at each time point during the dosing interval, fractional inhibitory concentration (FIC) curves were constructed, and from these curves new pharmacodynamic parameters for combination therapy were calculated (i.e., AUC(combi), Cmax-combi, T>MIC-combi, T->FICi, where AUC(combi), Cmax-combi, T>MIC-combi, and T->FICi are the area under the FICcombi curve, the peak concentration of FICcombi the time that the concentration of the combination is above the MICcombi, and the time above the FIC index, respectively). By stepwise multilinear regression analysis, the pharmacodynamic parameter T->FICi proved to be the best predictor of therapeutic efficacy during combination therapy with tobramycin and ceftazidime (R-2 = 0.6821; P < 0.01). We conclude that for combination therapy with tobramycin and ceftazidime the T->FICi is the parameter best predictive of efficacy and that the E-test for susceptibility testing of combination therapy gives promising results. These new pharmacodynamic parameters for combination therapy promise to provide better insight into the rationale behind combination therapy.