Scaglione F, Mouton J W, Mattina R, Fraschini F
University of Milan School of Medicine, Milan, Italy.
Antimicrob Agents Chemother. 2003 Sep;47(9):2749-55. doi: 10.1128/AAC.47.9.2749-2755.2003.
During the last decade some studies have shown that the area under the curve (AUC)/MIC ratio is the pharmacodynamic index that best predicts the efficacies of quinolones, while other studies suggest that the predictive value of the peak concentration/MIC (peak/MIC) ratio is superior to the AUC/MIC ratio in explaining clinical and microbiological outcomes. In classical fractionated dose-response studies with animals, it is difficult to differentiate between the AUC/MIC ratio and the peak/MIC ratio because of colinearity. Three different levofloxacin and ciprofloxacin dosing regimens were studied in a neutropenic mouse pneumonia model. The different regimens were used with the aim of increasing the AUC/MIC ratio without changing the peak/MIC ratio and vice versa. The first regimen (RC) consisted of daily doses of 5 up to 160 mg/kg of body weight divided into one, two, or four doses. In the second regimen (R0), mice were given 1.25 mg/kg every hour from 1 to 23 h, while the dose given at 0 h was 2.5, 5, 10, 20, 40, or 80 mg/kg. In the third regimen (R11), mice also received 1.25 mg/kg every hour from 0 to 23 h; but in addition, they also received 2.5, 5, 10, 20, 40, or 80 mg/kg at 11 h. The level of protein binding was also evaluated. The results indicate that the unbound fraction (f(u)) was concentration dependent for both levofloxacin and ciprofloxacin and ranged from approximately 0.67 to 0.88 for both drugs between concentrations of 0.5 and 80 mg/liter. The relationships between the AUC/MIC ratio and the number of CFU were slightly better than those between the peak/MIC ratio and the number of CFU. There was no clear relationship between the amount of time that the concentration remained above the MIC and effect (R(2) < 0.1). For both drugs, the peak/MIC ratio that resulted in a 50% effective concentration was lower for the R0 and R11 dosing regimens, indicating the importance of the AUC/MIC ratio. The same was true for the static doses. Survival studies showed that for mice treated with the low doses the rate of survival was comparable to that for the controls, but with the higher doses the rate of survival was better for mice receiving the R0 regimen. We conclude that for quinolones the AUC/MIC ratio best correlates with efficacy against pneumococci and that the effect of the peak/MIC ratio found in some studies could be partly explained by concentration-dependent protein binding.
在过去十年中，一些研究表明曲线下面积（AUC）/最低抑菌浓度（MIC）比值是最能预测喹诺酮类药物疗效的药效学指标，而其他研究则表明，在解释临床和微生物学结果方面，峰浓度/MIC（峰/MIC）比值的预测价值优于AUC/MIC比值。在经典的动物分次剂量反应研究中，由于共线性，很难区分AUC/MIC比值和峰/MIC比值。在中性粒细胞减少小鼠肺炎模型中研究了三种不同的左氧氟沙星和环丙沙星给药方案。使用不同方案的目的是在不改变峰/MIC比值的情况下提高AUC/MIC比值，反之亦然。第一种方案（RC）包括每日剂量为5至160mg/kg体重，分为1、2或4次给药。在第二种方案（R0）中，小鼠从1至23小时每小时给予1.25mg/kg，而在0小时给予的剂量为2.5、5、10、20、40或80mg/kg。在第三种方案（R11）中，小鼠同样从0至23小时每小时接受1.25mg/kg；但此外，它们在11小时还接受2.5、5、10、20、40或80mg/kg。还评估了蛋白结合水平。结果表明，左氧氟沙星和环丙沙星的游离分数（f(u)）均呈浓度依赖性，在0.5至80mg/L的浓度范围内，两种药物的游离分数约为0.67至0.88。AUC/MIC比值与菌落形成单位（CFU）数量之间的关系略优于峰/MIC比值与CFU数量之间的关系。浓度维持在MIC以上的时间与效应之间没有明显关系（R²<0.1）。对于两种药物，R0和R11给药方案导致50%有效浓度的峰/MIC比值较低，表明AUC/MIC比值的重要性。静态剂量也是如此。生存研究表明，对于低剂量治疗的小鼠，生存率与对照组相当，但对于高剂量，接受R0方案的小鼠生存率更高。我们得出结论，对于喹诺酮类药物，AUC/MIC比值与抗肺炎球菌的疗效最相关，并且在一些研究中发现的峰/MIC比值的效应可能部分由浓度依赖性蛋白结合来解释。
