Jaruratanasirikul Sutep, Thengyai Suriyan, Wongpoowarak Wibul, Wattanavijitkul Thitima, Tangkitwanitjaroen Kanyawisa, Sukarnjanaset Waroonrat, Jullangkoon Monchana, Samaeng Maseetoh
Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand
Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
Antimicrob Agents Chemother. 2015;59(6):2995-3001. doi: 10.1128/AAC.04166-14. Epub 2015 Mar 9.
Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.
危重症患者在严重脓毒症和脓毒性休克早期的病理生理变化会导致抗生素的药代动力学（PK）模式改变，这是影响治疗成功的重要因素。本研究的目的是：（i）揭示群体PK参数；（ii）评估美罗培南的达标概率（PTA）。在9例严重脓毒症和脓毒性休克患者的最初24小时内，每8小时给予1 g美罗培南后进行PK研究，并进行蒙特卡洛模拟以确定达到40%暴露时间（游离血浆药物浓度保持高于最低抑菌浓度的时间，即fT>MIC）和80% fT>MIC的PTA。这些患者中美罗培南的分布容积（V）和总清除率（CL）分别为23.7升和7.82升/小时。对于最低抑菌浓度为4 μg/ml的病原体，每8小时静脉输注1 g共1小时以及每8小时静脉输注0.5 g共4小时的美罗培南给药方案达到40% fT>MIC的PTA分别为92.52%和90.29%。对于免疫功能低下宿主中最低抑菌浓度为2 μg/ml的病原体，每8小时静脉输注2 g共1小时和共4小时的美罗培南给药方案达到80% fT>MIC的PTA分别为84.32%和94.72%。这些发现表明，美罗培南的V较之前在健康受试者中的研究结果更大，CL更低。对于该患者群体中危及生命的感染，可能需要最大推荐剂量，即每8小时2 g美罗培南进行治疗。
