伏立康唑血药浓度监测的临床应用

目的：通过动态监测患者伏立康唑血药谷浓度，探讨安全有效的伏立康唑临床精准合理应用策略。方法：采用液质联用方法动态检测64例患者，共103份血液标本伏立康唑的药物谷浓度；观察患者治疗期间的疗效和不良反应的发生情况；进一步分析药物浓度与患者临床反应的相关性。结果：（1）使用推荐剂量的伏立康唑治疗后，39/64例（61%）患者谷浓度在1.5~5.5 μg·mL^-1，中位数为2.62（1.53~5.33）μg·mL^-1；18/64例（28%）患者的谷浓度<1.5 μg·mL^-1，中位数为0.975（0.16~1.49）μg·mL^-1；7/64例（11%）患者谷浓度>5.5 μg·mL^-1，中位数为6.03（5.58~9.38）μg·mL^-1。（2）谷浓度<1.5 μg·mL^-1的患者与谷浓度≥ 1.5 μg·mL^-1的患者治疗无效的比率分别为61%和33%。谷浓度低者较谷浓度高者治疗无效的比率更高，2组具有统计学差异（P=0.050）。对11/18例谷浓度<1.5 μg·mL^-1且治疗无效的患者调整剂量后，患者谷浓度均增加至1.5 μg·mL^-1以上，且疗效获得改善。（3）64例患者中21例（33%）发生不良反应，谷浓度>5.5 μg·mL^-1的患者与谷浓度≤ 5.5 μg·mL^-1的患者在治疗过程中不良反应的发生率分别为71%和28%。谷浓度高者较谷浓度低者发生不良反应的风险显著增加，差异具有统计学意义（P=0.034）。其中9例在伏立康唑减量后消失，7例未调整剂量对症处理后好转，5例因不良反应较重停药。结论：伏立康唑血药浓度个体间差异较大，根据动态监测患者血药谷浓度指导临床用药，有助于提高疗效和安全性，从而有益于推进抗真菌治疗的精准医疗水平。

Therapeutic drug monitoring for voriconazole in patients with invasive fungal infections

OBJECTIVE To determine the plasma concentrations of voriconazole of inpatients, and access the association between the trough concentration and clinical efficacy and adverse drug reactions.METHODS A total of 103 measurements by high pressure liquid chromatography were performed in 64 patients. Clinical efficacy and adverse drug reactions were observed during the pharmacotherapy period.RESULTS Trough concentration was 1.5-5.5 μg·mL^-1 in 39/64 cases (61%), the median was 2.62 (1.53-5.33) μg·mL^-1; <1.5 μg·mL^-1 in 18/64 cases (28%), the median was 0.975 (0.16-1.49) μg·mL^-1; >5.5 μg·mL^-1 in 7/64 cases (11%), the median was 6.03 (5.58-9.38) μg·mL^-1. Lack of response to therapy was more frequent in patients with voriconazole levels <1.5 μg·mL^-1 (61%) than in those with voriconazole levels ≥ 1.5 μg·mL^-1 (12%) (P=0.050). Blood levels ≥ 1.5 μg·mL^-1 were reached after increasing the voriconazole dose, with complete or partial resolution of infection in all 11/18 cases. The incidences of adverse drug reaction with voriconazole trough blood levels >5.5 μg·mL^-1 and ≤ 5.5 μg·mL^-1 were 71% and 28%. The risk of adverse drug reaction with voriconazole trough blood levels >5.5 μg·mL^-1 was significantly increased (P=0.034). 21/64 cases (33%) occurred adverse reactions, and 9 cases improved after dose reduction, 7 cases improved after treatment, 5 cases discontinued voriconazole because of severe adverse reactions.CONCLUSION Voriconazole plasma concentration is largely different between individuals, while therapeutic drug monitoring improves the efficacy and safety of therapy in patients with invasive fungal infections.