老年重症耐甲氧西林金黄色葡萄球菌感染患者替考拉宁的药动学研究和药效学评价

目的 探讨耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）肺部感染老年患者替考拉宁的药动学差异与药效学评价。方法 研究纳入2018年9月—2019年8月诊断为MRSA肺部感染患者50例，治疗前下呼吸道痰液标本培养提示为MRSA感染并对替考拉宁敏感。所有患者予静脉输注替考拉宁，前3剂400 mg，每12 h给药1次，维持剂量400 mg每24 h给药1次。将达到稳态后第5次给药前测得C_min≤10 μg·mL^-1的患者维持剂量方案更改为600 mg qd。注射用替考拉宁400 mg或600 mg溶于100 mL 0.9%氯化钠注射液，给药时间为30 min，疗程为14~21 d。按规定时间采集静脉血2 mL，采用HPLC检测血药浓度，使用DAS 3.0软件处理，求出各例患者的药动学参数。将达稳态后第5次给药前测得C_min>10 μg·mL^-1的药动学参数设为A；对于C_min≤10 μg·mL^-1的患者，将维持剂量调整为600 mg qd，并将调整剂量后第5次给药前测得C_min>10 μg·mL^-1的药动学参数设为B。按照APACHE II评分和SOFA评分将患者分为重症和非重症2组。结合PK/PD原理，比较2组患者在C_min处于10~20 μg·mL^-1和20~30 μg·mL^-1以及AUC/MIC≥345和<345的临床治疗有效率、细菌清除率及不良反应发生情况。结果 替考拉宁药动学以二室模型描述最佳。负荷剂量相同时，维持剂量为400 mg的A组与维持剂量为600 mg的B组药动学参数比较如下：C_max[（32.28±15.16） mg·L^-1vs（65.73±28.96） mg·L^-1]，t_1/2[（86.24±10.61） h vs（70.51±11.78） h]，V_d[（2.73±1.32） L·kg^-1vs（2.58±1.02） L·kg^-1]，CL[（0.11±0.05） L·h^-1·kg^-1vs（0.13±0.06） L·h^-1·kg^-1]，AUC_（0~t）[（2 698.16±1 603.25） mg·h·L^-1vs（4 076.85±1 873.09） mg·h·L^-1]，AUC_（0~∞）[（4 509.33±2 786.54） mg·h·L^-1vs（7 193.58±4 109.81） mg·h·L^-1]，差异有统计学意义（P<0.05）。患者SOFA评分≤5和>5的临床有效率为65.71%和53.33%，细菌清除率分别为65.79%和47.37%。APACHEII评分≤15和>15的临床有效率分别为63.64%和58.82%，细菌清除率分别为63.16%和52.63%。结论 MRSA肺部感染老年患者替考拉宁的药动学存在较大差异，结合PK/PD原理，能够为个体化治疗提供科学的给药方案。

Pharmacokinetics and Pharmacodynamic Evaluation of Teicoplanin in Elderly Patients with Severe Methicillin-resistant Staphylococcus Aureus Infection

OBJECTIVE To investigate the pharmacokinetic differences and pharmacodynamic evaluation of teicoplanin in elderly patients with methicillin-resistant Staphylococcus aureus(MRSA) pulmonary infection. METHODS The 50 patients diagnosed with MRSA pulmonary infection from September 2018 to August 2019, the culture of lower respiratory tract sputum specimens before treatment indicated MRSA infection and sensitivity to teicoplanin. All patients were given intravenous teicoplanin, the first three doses of 400 mg, once every 12 h, and a maintenance dose of 400 mg once every 24 h. The maintenance dose regimen for patients with C_min ≤ 10 μg·mL^-1measured before the fifth dose after reaching steady state was changed to 600 mg qd. Teicoplanin 400 mg or 600 mg for injection was dissolved in 100 mL 0.9% sodium chloride injection, the administration time was 30 min, and the course of treatment is 14-21 d. The 2 mL of venous blood was collected at the specified time, the blood drug concentration was detected by HPLC, and the DAS 3.0 software was used for processing to obtain the pharmacokinetic parameters of each patient. After reaching steady state, the pharmacokinetic parameter of C_min>10μg·mL^-1measured before the fifth dose was set to A. For patients with C_min ≤ 10 μg·mL^-1, the maintenance dose was adjusted to 600 mg qd, and set the pharmacokinetic parameter of C_min>10 μg·mL^-1 as B before the fifth dose after adjusting the dose. Patients were divided into severe and non severe groups according to APACHE II score and SOFA score. Comparison of clinical treatment efficiency, bacterial clearance rate and adverse reactions between the two groups at C_min of 10-20 μg·mL^-1and 20-30 μg·mL^-1, AUC/MIC ≥ 345 and <345 combined with PK/PD principle. RESULTS The pharmacokinetics of teicoplanin was best described by two compartment model. The loading dose was the same, the pharmacokinetic parameters of group A with 400 mg maintenance dose and group B with 600 mg maintenance dose were as follows:C_max was[(32.28±15.16)mg·L^-1vs (65.73±28.96)mg·L^-1], t_1/2 was[(86.24±10.61)h vs (70.51±11.78)h], V_d was[(2.73±1.32)L·kg^-1vs (2.58±1.02)L·kg^-1], CL was[(0.11±0.05)L·h^-1·kg^-1vs (0.13±0.06)L·h^-1·kg^-1], AUC_(0-t)was[(2 698.16±1 603.25)mg·h·L^-1vs (4 076.85±1 873.09)mg·h·L^-1], AUC_(0~∞) was[(4 509.33±2 786.54)mg·h·L^-1vs (7 193.58±4 109.81)mg·h·L^-1], the difference was statistically significant (P<0.05). The clinical effective rates of patients with SOFA scores ≤ 5 and >5 were 65.71% and 53.33%, and the bacterial clearance rates were 65.79% and 47.37%. The clinical effective rates of APACHE II scores ≤ 15 and >15 were 63.64% and 58.82%, and the bacterial clearance rates were 63.16% and 52.63%. CONCLUSION The pharmacokinetics of teicoplanin in elderly patients with MRSA pulmonary infection is quite different. Combined with PK/PD principle, it can provide a scientific dosing plan for the individualized treatment.