Madaras-Kelly K J, Moody J, Larsson A, Baeker Hovde L, Rotschafer J C
St. Paul-Ramsey Medical Center, Minn., USA.
Chemotherapy. 1997 Mar-Apr;43(2):108-17. doi: 10.1159/000239544.
The purposes of this study were to investigate the potential for synergy between ceftazidime, tobramycin, and ofloxacin against two clinical isolates (PSA 9258, and PSA 9263) of Pseudomonas aeruginosa utilizing time-concentration-kill curves. A pharmacodynamic model was used to simulate one-compartment pharmacokinetics for single-, double-, or triple-drug combinations utilizing two different elimination half-lives (T1/2). Each duplicate experiment was conducted for 24 h in cation-supplemented Mueller-Hinton broth. Synergy, indifference, and antagonism were defined as reductions of > or = 2.0, > or = 0 to < or = 2, or < or = 0 in mean log10 CFU/ml (CFU = colony-forming units) in bacterial counts at any time point during the 24-hour experiment, respectively. Time-concentration-kill curve studies simulating a peak concentration (CP) = 6 micrograms/ml and T1/2 = 5.5 h for ofloxacin combined with ceftazidime (CP = 80 micrograms/ml; T1/2 = 2 h) resulted in 2.18 and 1.81 log CFU/ml mean decreases in bacterial counts for PSA 9258 and 9263, respectively. Simulated ofloxacin pharmacokinetic parameters (CP = 6 micrograms/ml); T1/2 = 5.5 h) combined with tobramycin (CP = 8 micrograms/ml; T1/2 = 2 h) produced 2.26 and 0.6 log CFU/ml mean reductions in bacterial counts for PSA 9258 and 9263, respectively. Time-concentration-kill curve results were inconsistent with checkerboard synergy experiments which indicated antagonism for ofloxacin/tobramycin combinations (fractional inhibitory concentrations = 2.0/2.5) and indifference for ofloxacin/ceftazidime combinations (fractional inhibitory concentrations = 1.0/1.0). In secondary experiments, tobramycin (T1/2 = 2 h) and ceftazidime (T1/2 = 2 h) at concentrations of one fourth and equal to the minimum inhibitory concentration were combined with ofloxacin (CP = 6 micrograms/ml; T1/2 = 5.5 h). When ofloxacin was combined with tobramycin equivalent to the minimum inhibitory concentration, mean reductions in bacterial counts were 3.74 and 5.59 CFU/ml. These results suggest that an enhanced antipseudomonal activity may result by the combination of clinically achievable concentrations of ofloxacin with minimum inhibitory concentration equivalent concentrations of tobramycin.
本研究的目的是利用时间-浓度-杀菌曲线，研究头孢他啶、妥布霉素和氧氟沙星联合使用对铜绿假单胞菌的两株临床分离株（PSA 9258和PSA 9263）的协同潜力。采用药效学模型，利用两种不同的消除半衰期（T1/2）模拟单药、双药或三药联合的一室药代动力学。在补充阳离子的穆勒-欣顿肉汤中进行每个重复实验24小时。协同、无差异和拮抗分别定义为在24小时实验期间的任何时间点，细菌计数的平均log10 CFU/ml（CFU = 菌落形成单位）减少≥2.0、≥0至≤2或≤0。模拟氧氟沙星（峰浓度[CP]=6μg/ml；T1/2 = 5.5小时）与头孢他啶（CP = 80μg/ml；T1/2 = 2小时）联合的时间-浓度-杀菌曲线研究，导致PSA 9258和9263的细菌计数平均分别减少2.18和1.81 log CFU/ml。模拟的氧氟沙星药代动力学参数（CP = 6μg/ml；T1/2 = 5.5小时）与妥布霉素（CP = 8μg/ml；T1/2 = 2小时）联合，PSA 9258和9263的细菌计数平均分别减少2.26和0.6 log CFU/ml。时间-浓度-杀菌曲线结果与棋盘法协同实验不一致，棋盘法协同实验表明氧氟沙星/妥布霉素联合（部分抑菌浓度=2.0/2.5）存在拮抗作用，氧氟沙星/头孢他啶联合（部分抑菌浓度=1.0/1.0）无差异。在二次实验中，将浓度为最低抑菌浓度四分之一和等于最低抑菌浓度的妥布霉素（T1/2 = 2小时）和头孢他啶（T1/2 = 2小时）与氧氟沙星（CP = 6μg/ml；T1/2 = 5.5小时）联合。当氧氟沙星与等于最低抑菌浓度的妥布霉素联合时，细菌计数平均减少3.74和5.59 CFU/ml。这些结果表明，临床上可达到的氧氟沙星浓度与最低抑菌浓度等效的妥布霉素联合，可能会增强抗铜绿假单胞菌活性。
