Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study.
Dose-dependent artificial prolongation of prothrombin time by interaction between daptomycin and test reagents in patients receiving warfarin: a prospective in vivo clinical study.
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DOI：
10.1186/s12941-017-0203-3
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发表时间：
2017-04-11
影响因子：
5.7
通讯作者：
Yotsuyanagi H
中科院分区：
文献类型：
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作者：
Saito M;Hatakeyama S;Hashimoto H;Suzuki T;Jubishi D;Kaneko M;Kume Y;Yamamoto T;Suzuki H;Yotsuyanagi H
达托霉素与凝血酶原时间（PT）的某些检测试剂相互作用，导致PT人为延长。这种延长在体外高浓度达托霉素的情况下尤其突出。然而，这种延长在临床环境中是否重要以及评估PT的最佳时机仍不清楚。在日本的一所大学医院，对接受达托霉素治疗确诊或疑似耐药革兰氏阳性细菌感染的患者进行了一项前瞻性临床研究。使用9种PT试剂检测达托霉素峰和谷时的PT。线性回归分析用于检查达托霉素浓度的差异和PT-国际标准化比值（PT-INR）的相对变化。35例患者接受达托霉素（6 mg/kg）。达托霉素谷浓度和峰浓度的平均值±标准差分别为13.5 ± 6.3和55.1 ± 16.9 μg/mL。12例患者（34%）接受华法林治疗。使用5种PT试剂时，与谷值时的PT-INR相比，达托霉素峰浓度时的PT-INR延长的受试者比例显著，尽管平均相对变化小于10%。没有参与者在临床上表现出任何出血迹象。观察到一种试剂的PT呈线性、剂量依赖性延长[未校正系数β 3.1 × 10−3/μg/mL; 95%置信区间（CI）2.3 × 10−5-6.3 × 10−3; p = 0.048]。当根据华法林使用情况对患者进行分层时，在华法林使用者中观察到两种PT试剂的显著线性关系（校正系数β，6.4 × 10−3/μg/mL; 95% CI 3.5 × 10−3-9.3 × 10−3; p < 0.001;校正系数β，8.3 × 10−3/μg/mL; 95% CI 4.4 × 10−3-1.2 × 10−2; p < 0.001）。在非华法林使用者中，任何PT试剂均未观察到这种线性关系。我们发现，高浓度的达托霉素可通过与某些PT试剂相互作用而导致PT-INR人为延长。这种变化在临床上可能不可忽略，特别是在接受高剂量达托霉素的华法林使用者中。在达托霉素谷浓度而不是峰浓度时测量PT可能更好。
Daptomycin has been reported to cause artificial prolongation of prothrombin time (PT) by interacting with some test reagents of PT. This prolongation was particularly prominent with high concentrations of daptomycin in vitro. However, whether this prolongation is important in clinical settings and the optimal timing to assess PT remain unclear. A prospective clinical study was conducted with patients who received daptomycin for confirmed or suspected drug-resistant, gram-positive bacterial infection at a university hospital in Japan. PT at the peak and trough of daptomycin was tested using nine PT reagents. Linear regression analyses were used to examine the difference in daptomycin concentration and the relative change of PT-international normalized ratios (PT-INR). Thirty-five patients received daptomycin (6 mg/kg). The mean ± standard deviation of the trough and peak concentrations of daptomycin were 13.5 ± 6.3 and 55.1 ± 16.9 μg/mL, respectively. Twelve patients (34%) received warfarin. With five PT reagents, a significant proportion of participants experienced prolongation of PT-INR at the daptomycin peak concentration compared to the PT-INR at the trough, although the mean relative change was less than 10%. None of the participants clinically showed any signs of bleeding. A linear, dose-dependent prolongation of PT was observed for one reagent [unadjusted coefficient β 3.1 × 10−3/μg/mL; 95% confidence interval (CI) 2.3 × 10−5–6.3 × 10−3; p = 0.048]. When patients were stratified based on warfarin use, this significant linear relationship was observed in warfarin users for two PT reagents (adjusted coefficient β, 6.4 × 10−3/μg/mL; 95% CI 3.5 × 10−3–9.3 × 10−3; p < 0.001; and adjusted coefficient β, 8.3 × 10−3/μg/mL; 95% CI 4.4 × 10−3–1.2 × 10−2; p < 0.001). In non-warfarin users, this linear relationship was not observed for any PT reagents. We found that a higher concentration of daptomycin could lead to artificial prolongation of PT-INR by interacting with some PT reagents. This change may not be clinically negligible, especially in warfarin users receiving a high dose of daptomycin. It may be better to measure PT at the trough rather than at the peak daptomycin concentration.