Zelenitsky Sheryl, Ariano Robert, Harding Godfrey, Forrest Alan
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Antimicrob Agents Chemother. 2005 Oct;49(10):4009-14. doi: 10.1128/AAC.49.10.4009-4014.2005.
Pseudomonas aeruginosa causes serious infections whose outcome is highly dependent on antimicrobial therapy. The goal of this study was to predict the relative efficacies of three ciprofloxacin dosing regimens for P. aeruginosa infection using clinical outcome-based Monte Carlo simulations (MCS) with "real patient" demographics, pharmacokinetics, MICs, and pharmacodynamics (PDs). Each cohort consisted of 1,000 simulated study subjects. Three ciprofloxacin dosing regimens were studied, including (i) the recommended standard dose of 400 mg given intravenously (i.v.) every 12 h (q12h), (ii) the recommended high dose of 400 mg i.v. q8h, and (iii) a novel, PD-targeted regimen to attain a fAUC/MIC value of >86. Probability of target attainment (PTA) and probability of cure (POC) were determined for each regimen. POC with the standard dose was at least 0.90 if pathogen MICs were < or =0.25 microg/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 microg/ml, respectively. Predicted cure rates in these MIC categories were significantly higher at 0.72 and 0.40 with the high dose and 0.91 and 0.72 with the PD-targeted regimen(P < 0.0001). Analyses based on the local susceptibility profile produced PTA and POC estimates of 0.44 and 0.74 with the standard ciprofloxacin dose, 0.58 and 0.81 with the high dose, and 0.84 and 0.93 with the PD-targeted regimen, respectively. In conclusion, as demonstrated by clinical outcome-based MCSs, the highest recommended ciprofloxacin dose of 400 mg i.v. q8h should be used in the treatment of P. aeruginosa infection to improve PD target attainment and clinical cure. However, even this appears ineffective if pathogen MICs are 1 mug/ml, warranting the consideration of a lower MIC breakpoint, < or =0.5 microg/ml.
铜绿假单胞菌可引发严重感染，其感染结果高度依赖于抗菌治疗。本研究的目的是使用基于临床结果的蒙特卡洛模拟（MCS），结合“真实患者”的人口统计学、药代动力学、最低抑菌浓度（MIC）和药效学（PD）数据，预测三种环丙沙星给药方案对铜绿假单胞菌感染的相对疗效。每个队列由1000名模拟研究对象组成。研究了三种环丙沙星给药方案，包括：（i）推荐的标准剂量，即每12小时静脉注射（i.v.）400毫克（q12h）；（ii）推荐的高剂量，即每8小时静脉注射400毫克；（iii）一种新的、以PD为靶点的方案，以达到fAUC/MIC值>86。确定了每种方案的目标达成概率（PTA）和治愈概率（POC）。如果病原体MIC≤0.25微克/毫升，标准剂量的POC至少为0.90，但如果MIC分别为0.5或1微克/毫升，则POC仅为0.59或0.27。在这些MIC类别中，高剂量方案的预测治愈率显著更高，分别为0.72和0.40，而以PD为靶点的方案为0.91和0.72（P<0.0001）。基于当地药敏谱的分析得出，环丙沙星标准剂量的PTA和POC估计值分别为0.44和0.74，高剂量为0.58和0.81，以PD为靶点的方案为0.84和0.93。总之，基于临床结果的MCS表明，治疗铜绿假单胞菌感染时应使用推荐的最高环丙沙星剂量，即每8小时静脉注射400毫克，以提高PD靶点达成率和临床治愈率。然而，如果病原体MIC为1微克/毫升，即使是这个剂量似乎也无效，因此有必要考虑将较低的MIC断点设定为≤0.5微克/毫升。
