临床药师指引下万古霉素给药方案优化及血药浓度监测研究：附7年数据分析

Research of optimal dosing regimens and therapeutic drug monitoring for vancomycin by clinical pharmacists：analysis of 7-year data

目的探讨临床药师指引在优化万古霉素给药方案及血药浓度监测（TDM）中的有效性及安全性，以促进万古霉素的个体化给药。方法采用回顾性研究方法，收集2011年1月至2017年10月在上海交通大学医学院附属瑞金医院进修期间收治的应用万古霉素的住院患者信息，根据是否接受临床药师指引用药分为非药师干预组及药师干预组。药师干预组患者万古霉素用药采用个体化指引方案，即临床药师依据万古霉素使用指南，针对每位患者的病理生理状态、病情，帮助临床医师制定该患者的万古霉素TDM及个体化用药方案等，血药浓度不达标者分别采用单纯增加给药剂量或24 h持续输注方案；非药师干预组仅由临床医师根据万古霉素说明书或临床经验确定给药方案。记录患者万古霉素给药情况、TDM情况、微生物学培养情况、肾功能、30 d病死率、住院时间等信息。以＂血药浓度达稳态后于下一次用药前1 h内采样进行TDM＂定义为TDM时机合理；依据2009年美国感染病协会（IDSA）发布的万古霉素应用指南判定初始给药方案的合理性。结果共收集258例患者的临床资料，其中非药师干预组158例，药师干预组100例。药师干预组TDM时机的合理性较非药师干预组显著提高〔87.0%（87/100）比69.6%（110/158），P〈0.01〕，首次谷浓度监测时间为用药后3 d的比例较非药师干预组明显增加〔51.0%（51/100）比37.3%（53/142），P〈0.05〕。与非药师干预组比较，药师干预组TDM时机合理患者初始给药方案的合理率和稳态谷浓度达标率显著增加〔87.4%（76/87）比68.2%（75/110），51.7%（45/87）比30.9%（34/110），均P〈0.01〕，根据TDM结果优化用药方案的比例较高〔54.0%（47/87）比15.5%（17/110），P〈0.01〕，目标浓度达标率提高〔70.1%（61/87）比32.7%（36/110），P〈0.01〕，血药浓度低于目标浓度及高于目标浓度比例均显著下降〔27.6%（24/87）比46.4%（51/110），2.3%（2/87）比20.9%（23/110），均P〈0.01〕；药师干预组无一例患者发生急性肾损伤（AKI），而非药师干预组AKI发生率为6.4%（7/110），两组比较差异有统计学意义（P〈0.01）。两组微生物学培养、30 d病死率及住院时间比较差异无统计学意义。药师干预组87例患者中，有42例因万古霉素谷浓度未达标而调整治疗方案，其中22例采用单纯增加给药剂量法，20例采用万古霉素24 h持续输注法。与单纯增加给药剂量比较，万古霉素24 h持续输注可明显提高稳态（谷）浓度（mg/L：18.0±6.7比12.5±5.8，P〈0.05），并能显著降低万古霉素日均剂量（mg/kg：27.1±7.1比36.6±9.2，P〈0.01）。结论在临床药师指引下采用以TDM为主的优化万古霉素个体化给药方案，可提高患者万古霉素浓度监测时机的准确性以及目标稳态（谷）浓度达标率，降低万古霉素诱导的AKI发生率。

ObjectiveTo investigate the effectiveness and safety of clinical pharmacists-directed vancomycin dosing and therapeutic drug monitoring （TDM）, and to promote the individualized medication of vancomycin.MethodsInformation of hospitalized patients treated by vancomycin admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2011 to October 2017 was collected retrospectively during study period, the patients were divided into pharmacists intervention and non-pharmacists intervention groups according to pharmacist-directed vancomycin dosing guideline or not. The individualized dosing regimen of vancomycin for the patients in pharmacists intervention group was guided by clinical pharmacists, this guideline was that pharmacists offered the TDM guidance, made the individualized dosage regimen of vancomycin, etc., which based on the patients＇ pathophysiology, condition, and the adjustments of increased dose or 24-hour continuous infusion vancomycin were made for patients if the steady-state trough concentrations fell below the target level. Vancomycin dosage was made for patients in the non-pharmacists intervention group by physicians only based on vancomycin instructions or clinical experience. The vancomycin dosing, TDM, microorganism culture, renal function, 30-day mortality rate, and length of hospital stay were recorded. The appropriateness of TDM for vancomycin was defined as a blood collection within 1 hour of the next scheduled dose after steady state achieved. The rationality of the initial dosing regimen was determined based on the vancomycin application guidelines issued by Infectious Diseases Society of America （IDSA） in 2009.ResultsA total of 258 patients were enrolled, and there were 158 patients in the non-pharmacists intervention group and 100 in pharmacists intervention group. The appropriateness of TDM for vancomycin in pharmacists intervention group was significantly improved as compared with that in non-pharmacists intervention group [87.0% （87/100） vs. 69.6% （110/158）, P 〈 0.01], the percentage of first trough serum concentrations drawn on day 3 after steady state achieved was significantly increased [51.0% （51/100） vs. 37.3% （53/142）, P 〈 0.05]. Compared with the non-pharmacists intervention group, the percentages of patients who received appropriate initial dosing and attained the initial target therapeutic range in pharmacists intervention group were significantly increased [87.4% （76/87） vs. 68.2% （75/110）, 51.7% （45/87） vs. 30.9% （34/110）, both P 〈 0.01], the percentage of patients whose vancomycin dosing regimen was adjusted based on TDM results was also significantly increased [54.0% （47/87） vs. 15.5% （17/110）, P 〈 0.01], the rate of vancomycin serum concentrations reaching the standard was increased [70.1% （61/87） vs. 32.7% （36/110）, P 〈 0.01], and a lower number of patients in sub- or supra-therapeutic range was observed in pharmacists intervention group [27.6% （24/87） vs. 46.4% （51/110）, 2.3% （2/87） vs. 20.9% （23/110）, both P 〈 0.01]. In addition, a lower incidence of vancomycin-induced acute kidney injury （AKI） was observed in pharmacists intervention group as compared with that in non-pharmacists intervention group [0 （0/87） vs. 6.4% （7/110）, P 〈 0.01]. No significant difference was observed in the microorganism culture, 30-day mortality rate or length of hospital stay between the two groups. Among the 87 patients in pharmacists intervention group, the vancomycin dosing was adjusted for 42 patients who did not attain the target therapeutic range, increasing the dose of vancomycin was made for 22 patients, 24-hour continuous infusion was made for 20 patients. Compared with the only increasing vancomycin dose group, vancomycin continuous infusion for 24 hours could significantly increase the serum trough concentration （mg/L： 18.0±6.7 vs. 12.5±5.8, P 〈 0.05）, and reduce daily dosage （mg/kg： 27.1±7.1 vs. 36.6±9.2, P 〈 0.01）.ConclusionsThe implementation of a pharmacist-directed vancomycin dosing guideline based on TDM optimized vancomycin dosing regimen, improved the accuracy and timeliness of TDM for vancomycin, achieved a higher percentage of levels within the therapeutic range, and a lower incidence of vancomycin-induced AKI.