蒙特卡洛模拟评价和优化产超广谱β-内酰胺酶大肠埃希菌血流感染抗菌药物给药方案

目的： 评价和优化某院产超广谱β-内酰胺酶大肠埃希菌（ESBLs-EC）血流感染抗菌药物给药方案。方法： 收集该院2019年产ESBLs-EC血流感染对亚胺培南西司他丁、哌拉西林钠他唑巴坦、头孢吡肟、头孢他啶和阿米卡星耐药监测报告,确定亚胺培南西司他丁、哌拉西林钠他唑巴坦、头孢吡肟、头孢他啶和阿米卡星治疗方案,根据各抗菌药物的药动学/药效学（PK/PD）模型,运用蒙特卡洛模拟（MCS）计算5种抗菌药物不同给药方案的达标概率（PTA）和累积反应分数（CFR）,评价疗效和优化出最佳初始给药方案。结果： 亚胺培南西司他丁1 g q12h、1 g q8h和1 g q6h,哌拉西林钠他唑巴坦4.5 g q8h和4.5 g q6h共5种给药方案的CFR ≥ 90%,而头孢吡肟、头孢他啶和阿米卡星所有给药方案CFR均小于90%。结论： 该院产ESBLs-EC血流感染时,经验选择可用亚胺培南西司他丁1 g q12h,哌拉西林钠他唑巴坦4.5 g q8h,不推荐头孢吡肟、头孢他啶和阿米卡星经验性治疗,临床经验性治疗与模拟结果基本一致,个体化治疗则应根据MIC值调整给药方案。     

英夫利西单抗失应答的被动治疗药物监测在炎症性肠病治疗中的药物经济学系统评价

目的： 英夫利西单抗（infliximab,IFX）用于炎症性肠病（inflammatory bowel disease,IBD）治疗可能出现药物失应答,对于IFX失应答,临床采用传统经验增加药物剂量策略或根据治疗药物监测（therapeutic drug monitoring,TDM）策略。为评价其经济性,本研究系统评价IBD患者IFX失应答的被动TDM策略与传统经验增加剂量策略的药物经济学价值。方法： 计算机检索PubMed等中英文数据库于1998-2020年发表的IFX失应答的被动TDM策略与传统经验增加剂量比较的经济性评价文献,根据事先确定的纳入与排除标准筛选文献,再按照卫生经济学评价报告标准共识（CHEERS）清单评估,系统评价2种策略经济性。结果： 纳入的7项研究中,4项临床研究及3项模型研究,其中6项研究显示,被动TDM给药与传统经验给药具相似有效性,采用被动TDM策略支付更低医疗费用。一项研究发现不检测策略较被动TDM更有效而鉴于证据有限需谨慎看待可能不具成本效果。对7项研究进行质量评估,其中5项（71.4%）均在好至优秀等级。结论： 现有证据显示,IBD患者IFX失应答的被动TDM策略较传统经验增加剂量可节省成本或更具成本效果。     

肺移植术后早期他克莫司血药浓度及影响因素分析

目的：探讨肺移植受者术后早期他克莫司（tacrolimus,Tac）血药浓度的特点及其影响因素,为肺移植受者术后早期的个体化治疗提供依据。方法：收集2019年1月-2020年9月在某中心行肺移植术的69例肺移植受者的病历资料,对肺移植受者术后30 d内他克莫司的血药浓度与性别、年龄、临床指标及合并唑类抗真菌药进行相关性分析。结果：术后30 d内他克莫司的浓度波动范围较大,达到目标浓度的次数仅占总监测次数的29.7%;年龄、红细胞压积、总胆红素、合并使用伏立康唑和泊沙康唑与他克莫司标准化血药浓度显著相关;合并使用伏立康唑和泊沙康唑后,他克莫司的平均剂量分别降低52.8%和32.5%。结论：肺移植早期影响他克莫司药物浓度的因素较多,需密切监测,且需根据年龄、临床指标和合并唑类抗真菌药的变化及时调整剂量。     

PK/PD模型结合蒙特卡洛模拟评价和优化耐碳青霉烯类铜绿假单胞菌抗菌药物给药方案

目的： 评价和优化耐碳青霉烯类铜绿假单胞菌感染抗菌药物给药方案。方法： 收集中山市人民医院2019年耐碳青霉烯类铜绿假单胞菌对头孢他啶、头孢吡肟、哌拉西林钠他唑巴坦和阿米卡星耐药监测报告,确定头孢他啶、头孢吡肟、哌拉西林钠他唑巴坦和阿米卡星治疗方案,根据各抗菌药物的PK/PD模型,运用蒙特卡洛模拟计算4种抗菌药物不同给药方案的达标概率（PTA）和累积反应分数（CFR）,评价疗效和优化出最佳初始给药方案。结果： 4种抗菌药物15种给药方案CFR均<90%。当最低抑菌浓度（MIC）≤ 2 μg·mL^-1时,4种抗菌药物常规剂量下的给药方案均能达到满意的治疗效果,当MIC ≤ 16 μg·mL^-1时,可目标性选择头孢他啶2 g（q8h）、头孢吡肟2 g（q8h）和哌拉西林钠他唑巴坦4.5 g（q8h）给药方案治疗,当MIC=32 μg·mL^-1时,只有哌拉西林钠他唑巴坦4.5 g（q6h）给药方案PTA>90%,当MIC>32 μg·mL^-1时,所有给药方案PTA均<90%。4种抗菌药物MIC值的敏感相关性为范围-88.9%~-96.7%。结论： 在CRPA感染经验性治疗时,单药治疗并不能达到满意的抗感染治疗效果,应考虑联合用药,可选用较高剂量和增加给药频次的抗假单胞菌β内酰胺类抗菌药联合阿米卡星。MIC值是影响4种抗菌药物治疗效果的最主要因素,临床上应重视细菌耐药的培养,可根据MIC值调整给药方案进行目标治疗。     

基于群体药代动力学模型仿真探索氨磺必利有效浓度范围

目的:以群体药动学模型仿真为基础,探索氨磺必利有效浓度范围,解决临床实际应用中血药浓度超过治疗参考范围的问题。方法:回顾性收集广州医科大学附属脑科医院2019至2020年接受氨磺必利治疗的精神科患者的治疗药物监测(therapeutic drug monitoring,TDM)数据及相关病历资料,采用非线性混合效应模型对氨磺必利血药浓度数据进行拟合分析,通过协变量筛选评估获得最终模型,模拟仿真各种剂量下氨磺必利血药浓度分布范围。结果:121名患者的330个血药浓度数据的68%可信区间血药浓度范围是185.59~650.94ng·mL^-1,采用建立的一室模型[最终模型:CL/F=61.1×(AGE/32)^-0.624,L·h^-1],模拟仿真发现当给药剂量在200~400mg·d^-1时,氨磺必利的平均血药浓度范围在《神经精神科治疗药物监测共识指南(2017版)》推荐有效浓度范围(100~320ng·mL^-1)内,在给药剂量400~800mg·d^-1时,平均血药浓度为300~600ng·mL^-1。结论:可根据临床治疗情况,将氨磺必利有效浓度范围暂定100~600ng·mL^-1,对应的推荐给药剂量为200~800mg·d^-1。     

妊娠期癫痫患者左乙拉西坦药动学行为变化

目的：系统研究左乙拉西坦（levetiracetam,LEV）在妊娠期癫痫患者体内药动学行为变化,并探究基于LEV血药浓度监测,调整妊娠期癫痫患者的给药方案。方法：回顾性收集2017年1月至2021年7月于中国医科大学附属盛京医院就诊并进行LEV血药浓度监测的妊娠期癫痫患者的临床病历资料,计算孕前至产后LEV的表观清除率（CL）,分析妊娠期癫痫患者LEV的给药方案,并探究妊娠期合并用药对LEV体内药动学行为的影响。结果：对17例单用LEV治疗的妊娠期癫痫患者138次血药浓度监测数据的回顾性分析表明,妊娠期LEV的CL显著增加,与孕前基线相比,在妊娠早期、中期及晚期分别增加了86.39%（P<0.01）、148.30%（P<0.01）和134.69%（P<0.01）,分娩后迅速下降,于产后6周左右恢复至孕前水平。不同妊娠时期LEV给药剂量存在差异,妊娠中、晚期给药剂量较孕前分别增加了44.93%（P<0.01）和96.07%（P<0.01）。妊娠期合用具酶诱导作用的抗癫痫药能够诱导LEV代谢,使LEV的CL增加。结论：妊娠期癫痫患者LEV体内药动学行为变化显著,其CL于妊娠中期达到峰值,分娩后迅速降低。与具酶诱导作用的抗癫痫药合用会增加LEV的CL。定期监测LEV血药浓度可为妊娠期癫痫患者的药物治疗管理提供指导。     

基于人工智能的药物治疗推荐功能介绍及应用效果分析

目的：介绍基于人工智能的药物治疗推荐功能并对其应用效果进行评价。方法：通过对智能药物推荐功能的技术方案、医学知识库构建、推荐模型等进行介绍,并以临床具体病例为示例,对系统功能进行展示,最后以智能药物治疗推荐的正确率、功能上线后某三甲医院抗菌药物医嘱合理率作为评价指标,对其应用效果进行评价。结果：通过大数据信息抽取以及不同知识角度的知识融合,可以更加完善、高效地构建医学知识库。临床智能药物推荐功能可以在不同场景下给出个体化的药物治疗方案,且推荐正确率高达85.16%。将该功能嵌入某三甲医院抗菌药物合理使用预警系统后,抗菌药物处方合理率由90.47%提升至95.35%。结论：基于人工智能的药物治疗推荐功能对促进临床合理用药有较大帮助,可以提升并优化临床诊疗质量。     

低治疗指数/严格剂量药物的等效性评价和临床合理使用

目的： 总结低治疗指数/严格剂量药物（narrow therapeutic index/critical dose drugs，NTI/CD Drugs）仿制药在临床使用中可能存在的风险以指导临床合理用药。方法： 通过文献调研，从NTI/CD药物生物等效性评价和临床评价研究角度，以抗癫痫药、免疫抑制剂、心血管系统药物为代表进行总结分析。结果： NTI/CD药物原研药和仿制药临床是否等效仍存在较大争议。结论： 临床治疗过程中，NTI/CD药物的替换应尽量避免。NTI/CD药物仿制药的审批制度有待进一步完善。     

伏立康唑在肝硬化患者中的治疗药物监测及用药安全性评价

目的：探讨伏立康唑在肝硬化患者中的血药谷浓度（C_min）的分布特征及影响浓度变异的因素，并对其进行用药安全性评价。方法：患者使用的维持剂量有减半维持剂量（A组）和标准维持剂量（B组），采用HPLC法测定伏立康唑血药浓度。收集伏立康唑用药相关信息，采用多元线性回归探讨影响伏立康唑C_min的因素。结果：本研究共监测了53例肝硬化病患者的74个血药浓度。A组患者伏立康唑C_min为（4.02±1.94）μg·mL^-1，B组患者伏立康唑C_min为（6.89±4.57）μg·mL^-1。其中A组中有30.8%的C_min高于治疗窗上限，B组有63.4%的C_min高于治疗窗上限。多元线性回归分析结果表明A组患者中伏立康唑C_min与白蛋白值、INR值、合并使用肝毒性药物和CYP2C19抑制剂具有显著相关性。研究中并没有发现对B组血药浓度有影响的因素。伏立康唑在A组和B组中的不良反应发生率分别为11.4%和38.9%。结论：减半维持剂量在肝硬化患者中仍具有较高的血药浓度。肝硬化患者使用伏立康唑应密切监测血药浓度，从而保证伏立康唑治疗的安全性和有效性。     

1例体外膜氧合治疗患者美罗培南和伏立康唑血浆浓度偏低的病例分析

目的探讨体外膜氧合(ECMO)对抗菌药物药动学的影响,为ECMO患者使用抗菌药物剂量提供参考。方法分析1例ECMO治疗期间美罗培南和伏立康唑血浆浓度监测结果。结果 ECMO可能使伏立康唑血浆浓度降低,而对美罗培南药动学影响小。结论脂溶性药物或蛋白结合率高的药物更易被ECMO管路和膜氧合器吸附,导致血浆浓度降低。     

Altered Pharmacokinetics and Dosing of Liposomal Amphotericin B and Isavuconazole during Extracorporeal Membrane Oxygenation

Drug pharmacokinetics may be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). Ensuring the optimized effective dosing of antimicrobials on ECMO remains a challenge. To date, limited data are available regarding the optimal use of amphotericin and triazoles during ECMO. We report a case of altered pharmacokinetics, insufficient liposomal amphotericin B and isavuconazole levels, and the need for escalated doses during ECMO in a patient with severe acute respiratory distress syndrome secondary to pulmonary blastomycosis. A 2-fold increase in the standard total daily dose of both drugs was necessary to overcome low serum concentrations thought to be secondary to drug loss from ECMO circuit sequestration. These findings have important implications for optimizing antimicrobial therapy in patients receiving ECMO to maximize therapeutic efficacy. The use of therapeutic drug monitoring for patients receiving antimicrobial therapy with concurrent ECMO may facilitate appropriate drug dosing to achieve adequate serum concentrations and optimize favorable patient outcomes. Further studies exploring antimicrobial pharmacokinetics during ECMO are needed to inform dosing recommendations in critically ill patients.     

临床药师参与 1 例嵌合抗原受体 T 细胞治疗后继发肺毛霉菌病的抗 感染治疗

目的:探讨儿科临床药师在肺毛霉菌感染治疗中的作用。 方法:临床药师通过参与 1 例儿童嵌合抗原受体 T 细胞治疗 后继发肺部毛霉菌感染药物治疗,结合抗真菌药物的药动学/ 药效学(PK/ PD)特点、血药浓度监测结果,实施个体化给药治疗。 结果:患儿在两性霉素 B 胆固醇硫酸酯复合物联合泊沙康唑治疗 6 周后临床症状好转,影像学改善,泊沙康唑血药浓度达标,两 性霉素 B 胆固醇硫酸酯复合物治疗过程中未出现严重不良反应。 结论:对于少见的儿童肺毛霉菌感染,两性霉素 B 联合泊沙 康唑治疗可能有效     

Evaluation of Altered Drug Pharmacokinetics in Critically Ill Adults Receiving Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a life‐support modality used in patients with refractory cardiac and/or respiratory failure. A significant resurgence in the use ECMO has been seen in recent years as a result of substantial improvements in technology and survival benefit. With expanding ECMO use, a better understanding of how ECMO affects drug pharmacokinetics (PK) is necessary. The vast majority of PK studies in patients receiving ECMO have been conducted within neonatal or pediatric populations or within a controlled environment (e.g., in vitro or ex vivo). Because of significant differences in absorption, distribution, metabolism, and excretion, it may be inappropriate to extrapolate these PK data to adults. Thus, the aims of this review are to evaluate the changes in drug PK during ECMO and to summarize the available PK data for common drugs used in the adult critically ill patients during ECMO support. A search of the PubMed (1965–July 2016), EMBASE (1965–July 2016), and Cochrane Controlled Trial Register databases was performed. All relevant studies describing PK alterations during ECMO in ex vivo experiments and in adults were included. Evaluation of the data indicated that drug PK in adults receiving ECMO support may be significantly altered. Factors influencing these alterations are numerous and have intricate relationships with each other but can generally be classified as ECMO circuit factors, drug factors, and patient factors. Commonly used drugs in these patients include antimicrobials, sedatives, and analgesics. PK data for most of these drugs are generally lacking; however, recent research efforts in this patient population have provided some limited guidance in drug dosing. With an improved understanding of altered drug PK secondary to ECMO therapy, optimization of pharmacotherapy within this critically ill population continues to move forward.     

A systematic review on pharmacokinetic changes in critically ill patients: role of extracorporeal membrane oxygenation

Objective

Several factors including disease condition and different procedures could alter pharmacokinetic profile of drugs in critically ill patients. For optimizing patient''s outcome, changing in dosing regimen is necessary. Extracorporeal Membrane Oxygenation (ECMO) is one of the procedures which could change pharmacokinetic parameters.The aim of this review was to evaluate the effect of ECMO support on pharmacokinetic parameters and subsequently pharmacotherapy.

Method

A systematic review was conducted by reviewing all papers found by searching following key words; extracorporeal membrane oxygenation, ECMO, pharmacokinetic and pharmacotherapy in bibliography database.

Results

Different drug classes have been studied; mostly antibiotics. Almost all of the studies have been performed in neonates (as a case series). ECMO support is associated with altered pharmacokinetic parameters that may result in acute changes in plasma concentrations with potentially unpredictable pharmacological effect. Altreation in volume of distribution, protein binding, renal or hepatic clearance and sequestration of drugs by ECMO circuit may result in higher or lower doses requirement during ECMO. As yet, definite dosing guideline is not available.ECMO is extensively used recently for therapy and as a procedure affects pharmacokinetics profile along with other factors in critically ill patients. For optimizing the pharmacodynamic response and outcome of patients, drug regimen should be individualized through therapeutic drug monitoring whenever possible.     

Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) may affect the pharmacokinetics of certain drugs. The objectives of this study were to determine (1) the pharmacokinetics of gentamicin in neonates on ECMO and compare them to reported values for a similar patient population not on ECMO, (2) if the pharmacokinetics of gentamicin differ between venous-venous and venous-arterial bypass, and (3) if the pharmacokinetics of gentamicin are affected by oxygenator surface area (0.6 m2 vs 0.8 m2 oxygenators). The medical records of 29 term neonates who received gentamicin while on ECMO were reviewed. Data collected included gentamicin dosage, peak and trough serum concentrations determined at steady state, duration of treatment, time on ECMO, daily weights, and pertinent laboratory values. An initial dosage of gentamicin 2.5 mg/kg every 18 hours is suggested for term neonates on ECMO. Dosage adjustments should be based on gentamicin serum concentrations, and modifications may also be required after ECMO.     

Pharmacoeconomic analysis of caspofungin versus liposomal amphotericin B as empirical antifungal therapy for neutropenic fever.

PURPOSE: An analysis was conducted that evaluated and compared the cost differences between caspofungin and liposomal amphotericin B when the medications were used as empirical antifungal therapy for persistent fever during neutropenia. METHODS: Rates of drug use and impaired renal function (IRF) were based on data from published studies. IRF was defined as a doubling of the serum creatinine level or, if the creatinine level was elevated at enrollment, an increase of at least 1 mg/dL. The estimates of the costs for drug acquisition and treating IRF were derived using published data and applied to compare caspofungin with liposomal amphotericin B. Sensitivity analyses were performed by varying the IRF and relative acquisition costs to assess the effect of these factors on the cost differences. RESULTS: The acquisition costs per patient were 6942 dollars for liposomal amphotericin B and 3996 dollars for caspofungin. The estimated cost per patient from IRF was 3173 dollars for liposomal amphotericin B and 793 dollars for caspofungin. Combining drug acquisition and IRF costs, the overall treatment cost per patient for caspofungin was 5326 dollars less than for liposomal amphotericin B. In sensitivity analyses of drug costs, the price of liposomal amphotericin B would have to be 23.95 dollars per vial for the overall treatment costs to be equal. CONCLUSION: Comparison of cost estimates derived from published data revealed that a combined estimate of acquisition costs and costs related to the treatment of IRF was lower for caspofungin than for liposomal amphotericin B for empirically treating patients with neutropenic fever.     

Clinical use of systemic antifungal agents

The chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects, and drug interactions of amphotericin B, flucytosine, ketoconazole, and miconazole are reviewed. Amphotericin B, a heptaene compound with poor water solubility, disrupts the fungal cell wall by binding to ergosterol. Ketoconazole and miconazole, imidazole derivatives, are poorly water soluble and inhibit the synthesis of ergosterol. Flucytosine is a readily water-soluble, fluorinated pyrimidine agent that may be metabolized to fluorouracil. The pharmacokinetics of amphotericin B is unique and has not yet been clearly defined. After oral administration, absorption of flucytosine from the gastrointestinal tract is rapid and nearly complete. In adults, oral administration of ketoconazole produces peak concentrations of drug one to two hours after the dose. Miconazole is administered only intravenously and distributes well into most tissues. Amphotericin B remains the drug of choice for most systemic mycoses. Dosing of amphotericin B is often empiric and patient specific. Flucytosine is rarely used alone; the combination of flucytosine and amphotericin B exerts synergistic killing of many fungi. Ketoconazole is effective for treating many chronic fungal infections. Miconazole is seldom used because of the availability of agents that are equally effective, less toxic, or both. Nephrotoxicity can occur with amphotericin B therapy, while flucytosine is associated with gastrointestinal and hematologic toxicities. Ketoconazole is much less toxic than any of the other agents, while miconazole has a high incidence of adverse effects. In addition to the need for more effective and less toxic agents, research is needed to clearly define the pharmacokinetics and pharmacodynamics of currently available antifungal drugs.     

Effects of antifungal drugs on proliferation signals in Candida albicans

The sensitivity of Candida albicans to antifungal drugs when cultured under aerobic and anaerobic conditions was measured. Ciclopirox olamine and siccanin were more effective under aerobic than under anaerobic conditions. Terbinafine, neticonazole and amphotericin B showed the same antifungal activity under both aerobic and anaerobic conditions. None of these antifungal activities were affected by the pH conditions. Terbinafine inhibited the elongation of hyphae, while neticonazole and amphotericin B induced proliferation of the yeast form. The expression of RAS1, EFG1 and CPH1 mRNAs was inhibited by these drugs. These results suggested that the inhibition of hyphal formation might be caused by disruption of the RAS1-signal pathway.     

某三甲综合医院治疗药物监测中危急值的回顾性分析

目的：探讨2019-2020年间,河南省人民医院常规开展的13种治疗药物监测项目的危急值数据所呈现的特点及对个体化用药的启示。方法：通过查询该院危急值报告记录与处置登记本和瑞美实验室管理系统（LIS）,对近2年在TDM中出现的危急值的项目、科室来源、患者基本情况等进行统计,使用SPSS 21.0和EXCEL 2019进行数据分析。结果：共出现危急值4 152例（发生率8.7%）,危急值发生率前三位的项目为：苯妥英（64.5%）、地高辛（28.6%）和万古霉素（24.8%）;危急值构成比前三位的项目为：伏立康唑（24.0%）、他克莫司（19.3%）和丙戊酸（13.6%）;科室来源前三位为：感染科、移植科和神经内科;从患者的基本资料来看,危急值发生率较高的为中青年男性患者。在TDM中出现危急值的原因众多,其中患者依从性较差和样本采集时间错误是出现假阳性结果的主要原因之一。结论：定期对TDM中出现的危急值数据进行回顾性的统计分析,不仅有利于提高患者的个体化治疗效果,保障用药安全,还有利于检测科室的查缺补漏,为危急值的持续性改进提供了证据支持。     

外阴阴道假丝酵母菌病致病菌种分布及药敏分析

目的：探讨外阴阴道假丝酵母菌病的致病菌种及其在体外对常用抗真菌药物的敏感性。方法采用科玛嘉真菌培养鉴定和ATBFUNCUS药敏试剂盒对310例外阴阴道假丝酵母菌病患者临床标本进行菌种分析和药敏试验。结果310例外阴阴道假丝酵母菌病的致病菌主要为白假丝酵母菌265例,占85.48%,非白假丝酵母菌45例,其中热带假丝酵母菌32例,占10.32%,光滑假丝酵母菌9例,占2.9%,克柔假丝酵母菌4例,占11.30%。4种抗真菌药物的敏感性为两性霉素B（100%）、5-氟胞嘧啶（99.03%）、氟康唑（86.45%）、伊曲康唑（79.68%）。结论外阴阴道假丝酵母菌病的主要致病菌为白假丝酵母菌。不同菌种对常用抗真菌药物的敏感性存在差异,应根据药敏结果选择合理的抗真菌药物。