Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients
Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients
复制标题
DOI：
10.1128/aac.00554-15
复制
发表时间：
2015-12-01
影响因子：
4.9
通讯作者：
Giamarellou, Helen
中科院分区：
文献类型：
--
作者：
Karaiskos, Ilias;Friberg, Lena E.;Giamarellou, Helen
在广泛耐药（XDR）革兰氏阴性菌感染的时代，粘菌素作为危重患者的最后治疗手段已经恢复。最近的研究集中在粘菌素的最佳给药策略上，已经证明了在治疗开始时负荷剂量的必要性（D。Plachouras，M.卡尔瓦宁湖e. Friberg，E. Papadomichelakis，A.安东尼亚杜岛桑加里斯岛Karaiskos湾Poulakou，F. Kontopidou，A.阿马甘岛汽车和H. Giamarellou，Antimicrob Agents Chemother 53：3430 - 3436，2009，http：//dx·doi·org/10·1128/AAC·01361 - 08; A. F.穆罕默德岛Karaiskos，D. Plachouras，M. Karvanen，K.庞蒂基斯，B。Jansson，E. Papadomichelakis，A. Antoniadou，H. Giamarellou，A.阿马甘岛汽车和L. e. Friberg，Antimicrob Agents Chemother 56：4241 - 4249，2012，http：//dx·doi·org/10.1128/AAC.06426-11; S.M. Garonzik，J. Li，V. Thamlikitkul，D.L. Paterson，S. Shoham，J. Jacob，F. P. Silveira，A. Forrest和R. L. Nation，Antimicrob Agents Chemother 55：3284 - 3294，2011，http：//dx·doi·org/10·1128/AAC·01733 - 10）。在19例疑似或微生物学记录的由XDR革兰氏阴性菌株引起的感染的重症患者中，给予9 MU甲磺酸粘菌素（CMS）（类似于270 mg粘菌素碱活性）的负荷剂量，维持剂量为4.5 MU，每12小时一次，24小时后开始。排除了接受肾脏置换的患者。CMS输注时间为30 min或1 h。在负荷剂量后和第5次或第6次给药后进行重复采血。采用液相色谱-串联质谱法测定粘菌素浓度和测定的CMS（水解为粘菌素后测定，包括部分磺甲基化衍生物）。在NONMEM中使用新数据结合既往研究数据进行群体药代动力学分析。测量的多粘菌素E甲磺酸酯浓度通过4个房室分布和磺甲基基团的去除来描述，而粘菌素处置遵循1房室模型。负荷剂量后（最长时间为8 h），观察到的最大粘菌素A加B浓度平均值为2.65 mg/L。与既往研究相比，本研究中测得的A和B型多粘菌素E甲磺酸盐和多粘菌素的可用性显著较高，这解释了本研究中浓度高于预期的原因。肌酐清除率是多粘菌素E甲磺酸盐清除率的时变协变量。急性肾损伤的发生率为20%。
Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241-4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S.M. Garonzik, J. Li, V. Thamlikitkul, D.L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (similar to 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.