Vourli Sophia, Tsala Marilena, Kotsakis Stathis, Daikos George L, Tzouvelekis Leonidas, Miriagou Vivi, Zerva Loukia, Meletiadis Joseph
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462, Athens, Greece.
Laboratory of Bacteriology, Hellenic Pasteur Institute, 11521, Athens, Greece.
J Pharm Sci. 2016 Apr;105(4):1513-8. doi: 10.1016/j.xphs.2016.02.008.
Dose optimization is required to increase carbapenem's efficacy against carbapenemase-producing isolates. Four clinical Klebsiella pneumoniae isolates were used: one susceptible to meropenem with minimum inhibitory concentration (MIC) 0.031 mg/L and 3 verona integron-borne metallo bete-lactamase-1-producing isolates with MICs 8, 16, and 128 mg/L. The human pharmacokinetics of short (0.5-h) and prolonged (3-h) infusion regimens of 1 g meropenem every 8 h were simulated in an in vitro pharmacokinetic-pharmacodynamic model. Time-kill curves were constructed for each isolate and dosing regimen, and the %T > MIC associated with maximal bactericidal activity was estimated. The percentage of pharmacodynamic target attainment for isolates with different MICs was calculated for 350 ICU, surgical, and internal medicine patients. The isolates with MIC ≤8 mg/L were killed with both dosing regimens. The %T > MIC corresponding to maximal bactericidal activity was ∼40%. The percentages of target attainment were >90%, 61%-83%, 23%-33%, and <3% with the short infusion regimen and >90%, 98%-99%, 55%-79%, and <5% with the prolonged infusion regimen for isolates with MIC ≤2, 4, 8, and ≥16 mg/L, respectively. The lowest target attainment rates were observed for the ICU patients and the highest for internal medicine patients. The prolonged infusion regimen was more effective than the short infusion regimen against isolates with MIC 4-8 mg/L.
需要进行剂量优化，以提高碳青霉烯类药物对产碳青霉烯酶分离株的疗效。使用了4株临床肺炎克雷伯菌分离株：1株对美罗培南敏感，最低抑菌浓度（MIC）为0.031 mg/L，以及3株产 Verona 整合子介导的金属β-内酰胺酶-1的分离株，MIC分别为8、16和128 mg/L。在体外药代动力学-药效学模型中模拟了每8小时静脉输注1 g美罗培南的短时间（0.5小时）和延长时间（3小时）输注方案的人体药代动力学。为每种分离株和给药方案构建了时间-杀菌曲线，并估计了与最大杀菌活性相关的%T > MIC。计算了350例重症监护病房（ICU）、外科和内科患者中不同MIC分离株的药效学目标达成百分比。MIC≤8 mg/L的分离株在两种给药方案下均被杀死。对应最大杀菌活性的%T > MIC约为40%。对于MIC≤2、4、8和≥16 mg/L的分离株，短时间输注方案的目标达成百分比分别>90%、61%-83%、23%-33%和<3%，延长时间输注方案的目标达成百分比分别>90%、98%-99%、55%-79%和<5%。ICU患者的目标达成率最低，内科患者的目标达成率最高。对于MIC为4-8 mg/L的分离株，延长时间输注方案比短时间输注方案更有效。
