Bédos J P, Azoulay-Dupuis E, Moine P, Muffat-Joly M, Veber B, Pocidalo J J, Vallée E
Clinique de Réanimation des Maladies Infectieuses, Hôpital Bichat-Claude Bernard, Paris, France.
J Pharmacol Exp Ther. 1998 Jul;286(1):29-35.
We looked for associations between pharmacokinetic (Pk) and pharmacodynamic (Pd) parameters of ciprofloxacin (CPFX) and sparfloxacin (SPFX) and the in vivo efficacy of these antimicrobials in an immunocompetent mouse model of severe Streptococcus pneumoniae pneumonia. Bacterial killing curves recorded in the lungs during the 24 h after single subcutaneous injections of the fluoroquinolones (FQs) in doses ranging from 6.25 to 200 mg/kg were compared with mean Pk/Pd parameters in the serum of the same mice. The impact of the dosing interval on the antimicrobial dose response was evaluated based on the survival of mice treated for 3 days with CPFX (25-200 mg/kg) or SPFX (6.25-50 mg/kg) administered at various intervals from 3 to 24 h. Bacterial killing curves showed that the maximal bacterial decrease achieved in the lungs was correlated, similarly for both FQs, with the area under the curve (AUC) above the minimal inhibitory concentration (MIC) (overall correlation: r = 0.968, P < 10(-4)). CPX attained higher maximal bactericidal effect values, a steeper killing slope and a shorter time to maximal bactericidal effect in comparison with SPX for the highest doses tested. The lower MIC of SPFX compared with CPFX (0.25 vs. 0.75 microgram/ml) and its higher AUC/dose ratio (resulting from a lower serum peak but a longer half-life) translated into a greater area under the bactericidal curve. In the dose fractionation experiments, the Pk/Pd parameter most closely correlated with the survival rate for both FQs was the daily AUC/MIC ratio (r = 0.976, P < 10(-4)). When the AUC/MIC ratio was greater than 160, the probability of a clinical cure was 100%, independently of the dosage schedule.
我们在免疫功能正常的重症肺炎链球菌肺炎小鼠模型中，研究了环丙沙星（CPFX）和司帕沙星（SPFX）的药代动力学（Pk）和药效学（Pd）参数与这些抗菌药物体内疗效之间的关联。将单次皮下注射剂量范围为6.25至200mg/kg氟喹诺酮类药物（FQs）后24小时内记录的肺部细菌杀灭曲线，与同一小鼠血清中的平均Pk/Pd参数进行比较。基于以3至24小时的不同间隔给予CPFX（25 - 200mg/kg）或SPFX（6.25 - 50mg/kg）治疗3天的小鼠存活率，评估给药间隔对抗菌药物剂量反应的影响。细菌杀灭曲线表明，肺部实现的最大细菌减少量与两种FQs相似，均与高于最低抑菌浓度（MIC）的曲线下面积（AUC）相关（总体相关性：r = 0.968，P < 10(-4)）。对于所测试的最高剂量，与SPX相比，CPX达到更高的最大杀菌效应值、更陡的杀灭斜率和更短的达到最大杀菌效应的时间。与CPFX相比，SPFX的MIC较低（0.25对0.75微克/毫升），且其AUC/剂量比更高（由于血清峰浓度较低但半衰期较长），这转化为更大的杀菌曲线下面积。在剂量分割实验中，与两种FQs存活率最密切相关的Pk/Pd参数是每日AUC/MIC比（r = 0.976，P < 10(-4)）。当AUC/MIC比大于160时，临床治愈的概率为100%，与给药方案无关。
