替考拉宁在不同人群中的药动学及给药方案分析

目的对替考拉宁在不同人群中的药动学及给药方案进行综述,以期为其在国内的临床合理应用提供参考。方法查阅国内外相关文献,归纳替考拉宁在健康志愿者、新生儿和儿童ICU患者、老年人、连续流动时腹膜透析的肾终末期患者、慢性肾功能衰竭患者等人群中的药动学及给药方案。结果与结论替考拉宁具有抗菌优势和低毒性等特点,因而在临床应用上有着广阔的前景,替考拉宁在国内人群中的药动学需要进一步研究。     

基于药动学理论脓毒症患者替考拉宁个体化给药分析

目的 探讨临床药师利用药动学理论指导脓毒症患者替考拉宁个体化给药的可行性。方法 临床药师通过参与1例脓毒症抗感染治疗案例,结合监测结果和患者药动学分析,为临床提供药物处置对策和监护建议。结果 临床药师在2次会诊中,结合监测结果对患者进行抗菌药物药动学分析,提出替考拉宁个体化的处置对策和监护计划,保障个体化给药的实施。结论 临床药师对脓毒症患者药动学改变进行全面评估,配合治疗药物监测手段,能够辅助临床医生做好个体化用药工作。     

替考拉宁在临床抗感染治疗中的探讨与实践

替考拉宁是临床上常用的治疗各种严重革兰氏阳性菌特别是多重耐药金黄色葡萄球菌和肠球菌感染的糖肽类抗菌药物。但由于影响其抗感染疗效的因素较多,导致临床疗效个体差异显著,在一定程度上增加了临床应用的难度。本文通过查阅近年来国内外相关文献,分别从替考拉宁的化学结构和药理作用特点、药效学特点、药动学特点、药动学/药效学(PK/PD)参数特点及在特殊人群中的应用进行归纳与总结,为优化替考拉宁在抗感染治疗中的应用,实现个体化治疗提供理论依据。     

替考拉宁国外儿童药动学数据在国内儿童中的外推适用性考察和剂量优化

目的：考察替考拉宁国外儿童药动学数据在国内汉族儿童中的跨种族外推适用性,为临床个体化给药提供参考依据。方法：收集85例国内汉族儿童的监测数据和临床资料,参考已发表的国外儿童替考拉宁药动学模型,采用外推方法获取我国汉族儿童群体的药动学模型,用拟合优度（Goodness-of-fit）、直观预测检验法（VPC）、正态化预测分布误差（NPDE）对最终模型的预测性能进行验证。结果：本研究获取的我国汉族儿童替考拉宁药动学参数为：V₁（中央室分布容积）=（7.83±5.14）L,V₂（周边室分布容积）=（15.13±9.75）L,CL（表观清除率）=（0.32±0.21）L·h^-1,CL₂（周边室清除率）=（0.23±0.11）L·h^-1。拟合优度、直观预测检验和NPDE结果表明,外推模型稳定,预测结果可靠。模拟结果显示,按说明书6 mg·kg^-1,或10 mg·kg^-1,每日一次维持剂量给药,稳态谷浓度很难达到15~30 mg·L^-1的目标浓度范围,维持剂量应提高为15 mg·kg^-1,每日一次。结论：该研究通过模型外推成功获取了替考拉宁在我国汉族儿童群体的药动学参数,模拟结果提示说明书儿童维持剂量偏低。     

替考拉宁在肾功能不全及采用连续肾脏替代疗法患者中个体化用药的研究进展

替考拉宁作为糖肽类抗菌药,在治疗革兰阳性菌感染疾病方面发挥重要作用。但在临床应用中,其负荷剂量不当会导致治疗无效或产生不良反应,尤其对于肾功能不全及采用连续肾脏替代疗法（CRRT）的患者,替考拉宁的药动学/药效学（PK/PD）参数发生显著变化,且个体差异较大,干扰了临床给药剂量的精准,导致无法达到理想的疗效。因此,通过探讨替考拉宁在老年、儿童、低蛋白血症、体外膜肺氧合（ECMO）及行不同CRRT模式的肾功能不全患者体内PK特征与疗效的相关性,对替考拉宁的用药方案进行了综述,为临床个体化用药提供参考。     

成年患者替考拉宁群体药动学研究

目的：构建中国成年患者替考拉宁（teicoplanin,TEC）群体药动学（population pharmacokinetics,PPK）模型,探讨TEC药动学参数的影响因素。方法：收集患者的用药信息、血药总浓度、性别、年龄、血清肌酐水平等信息,采用非线性混合效应模型法（nonlinear mixed effect model,NONMEM）建立替考拉宁PPK模型。用图形法、非参数自举法（bootstrap）、正态化预测分布误差法（normalized predictive distribution error,NPDE）进行模型评价。结果：共收集111例成年患者的149个替考拉宁血浆总浓度数据,建立了替考拉宁的一房室PPK模型：CL （L·h^-1）=1.26×（eGFR/82）^0.431,V（L）=83.1,协变量分析显示肌酐清除率（CKD-EPI公式）是影响替考拉宁清除率的重要因素,未发现影响替考拉宁表观分布容积的因素。经验证,最终模型具有良好的拟合优度、稳健率及预测性能。结论：临床可根据患者肌酐清除率（CKD-EPI公式）制定个体化给药方案。     

中枢神经系统耐甲氧西林金黄色葡萄球菌感染治疗方案选择

万古霉素、替考拉宁、利奈唑胺是临床常用的治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的抗菌药物,由于其不同的药代动力学及不良反应特点导致其在临床应用中的侧重点各有不同。由于血脑屏障的存在,中枢神经系统感染尤其是MRSA感染的治疗尤为困难。该研究从药代动力学方面分析了替考拉宁在中枢神经系统感染中的应用以及从药物疗效、药物经济学及药物不良反应三个方面比较了万古霉素脑室给药和利奈唑胺外周静脉给药对于中枢神经系统MRSA感染的优劣,为临床颅内感染治疗方案的选择提供借鉴意义。     

临床药师参与肾脏替代治疗患者替考拉宁个体化药物治疗分析

摘要：为探讨替考拉宁在肾衰竭患者连续肾脏替代治疗（CRRT）下的清除情况,优化替考拉宁首剂负荷剂量和维持剂量,临床药师通过2例CRRT患者替考拉宁治疗药物监测（TDM）协助医师制定和优化替考拉宁的给药剂量。同时测定替考拉宁在CRRT上机时和下机时的血药浓度、滤出液浓度和尿液浓度,计算该药物的滤过系数和清除比率,为不同CRRT方式提供用药剂量参考。经个体化用药调整后血培养转阴,评估患者抗感染疗效好,未出现药物相关不良反应。因此对于重症感染推荐CRRT患者采用替考拉宁高负荷剂量,建议结合TDM结果、CRRT模式及治疗剂量、残余肾功能进行维持剂量调整。     

生理药动学模型预测阿戈美拉汀口服给药的体内药动学过程

目的:建立阿戈美拉汀在人体内的生理药动学(PBPK)模型,预测其口服给药后的体内药动学过程。方法:测定不同基因型群体的健康男性空腹口服阿戈美拉汀后的血药浓度,采用Gastro PlusTM软件建立阿戈美拉汀口服给药的PBPK模型,并进行模型的优化和验证。结果:模型拟合阿戈美拉汀的药-时曲线与实测值比较R2均>0.95。预测阿戈美拉汀口服给药后绝对生物利用度为1%~7%;给药后其在人体内广泛分布,各组织/器官的暴露量以肝、脑和红骨髓中为最高,约为血中药物暴露量的2~4倍;食物、年龄、性别均可对阿戈美拉汀口服给药后的药动学过程产生一定的影响。结论:该试验所建立的PBPK模型可较好模拟阿戈美拉汀的体内药动学过程。     

替考拉宁与阿米卡星在烧伤患者痂下组织液中的药动学研究

目的:考察替考拉宁和阿米卡星在早期严重烧伤患者痂下组织液(STF)中的药动学参数。方法:选取20名严重烧伤的患者为研究对象,在烧伤后24 h接受500mg替考拉宁(10例)或400 mg阿米卡星(10例)静脉滴注,在滴注结束后1、2、4、8、24、48、96、144、192、240 h时收集STF样品;另取健康志愿受试者12例收集血清作对照组。用TDx免疫分析仪测定样品中抗生素浓度,并计算替考拉宁和阿米卡星药动学参数。结果:STF及血清中替考拉宁和阿米卡星药-时曲线均符合两室模型。替考拉宁在STF中的药动学参数为:t1/2α(3.74±2.64)h、t1/2β(92.18±11.73)h,V c(25.64±5.68)L、AUC(1 279.42±256.12)μg·h/ml,CLs(0.404 8±0.078 8)L/h。阿米卡星在STF中的药动学参数为:t1/2α(4.35±1.66)h、t1/2β(80.04±9.52)h、V c(13.17±1.32)L,AUC(1 802.49±285.68)μg·h/ml,CLs(0.227 2±0.038 3)L/h。结论:单剂量静脉滴注结束后24h替考拉宁和阿米卡星在STF的浓度仍高于常见致病菌的最低抑菌浓度。提示在烧伤早期使用强效抗生素可在STF中获得有效而持久的抗菌浓度,有利于在创面基底和创周形成有效的抗生素屏障,防止烧伤创面感染性细菌侵入。     

Multicomponent antibiotic substances produced by fermentation: Implications for regulatory authorities,critically ill patients and generics

Teicoplanin and polymyxin E (colistin) are antibiotics consisting of multiple, closely related subcomponents, produced by fermentation. The principal components comprise a complex mixture of chemically related, active substances (teicoplanin A_2-1–A_2-5 and polymyxin E_1–2, respectively), which might be required to be present in specific ratios to ensure optimal antibacterial and clinical efficacy. These subcomponents differ in their fatty acid and amino acid composition and, as such, the lipophilic and protein binding characteristics differ between components. This has therapeutic implications for critically ill patients, as the volume of distribution of the teicoplanin A₂ and polymyxin E analogues at the onset of an intravenous infusion may impact on expected pharmacokinetics and influence outcome.     

高龄下呼吸道感染患者的替考拉宁血药浓度监测及安全性评价

目的探讨替考拉宁在高龄下呼吸道感染患者中的血药浓度与临床疗效、不良反应之间的关系。方法高龄下呼吸道感染病例52例,用替考拉宁治疗5—24d,观察患者疗效、给药前后肝肾功能指标及不良反应情况;监测患者替考拉宁的谷浓度。结果替考拉宁的谷浓度为（17．1±10．1）mg·L^-1,治疗有效组和无效组在血药浓度等方面差异无统计学意义;给药前后肝、肾功能指标差异无统计学意义。结论替考拉宁在治疗下呼吸道感染患者时,血药浓度与疗效之间未见显著相关性,临床应用时应在血药浓度的监测下行个体化治疗。     

Optimal teicoplanin loading regimen to rapidly achieve target trough plasma concentration in critically ill patients

Teicoplanin is used for the treatment of Methicillin‐resistant Staphylococcus aureus infection. It has been demonstrated that conventional loading regimen was insufficient for teicoplanin to achieve target trough plasma concentration (C_min > 10 mg/L). Therefore, a Chinese expert group recommended an optimal loading dose regimen of teicoplanin to treat severe Gram‐positive infection. However, there was no report about the teicoplanin concentration, and the safety and efficacy of teicoplanin therapy in Chinese patients since the consensus was published. The objective of this study was to compare the teicoplanin C_min and clinical response in critically ill Chinese patients after the administration of conventional or optimal loading regimen, and to reveal the potential factors that may affect teicoplanin C_min in addition to loading regimen. Fifty‐five patients were retrospectively divided into two groups based on teicoplanin loading regimen: (a) CD group (conventional loading dose group, n = 18, loading dose was 400 mg); (b) OD group (optimal loading dose group, n = 37, loading dose was 800 mg). Initially, three loading doses were administered every 12 hours, while the fourth loading dose was injected 24 hours after the third dose. The maintenance dose was 400 mg (CD group) or 800 mg (OD group), respectively. The mean teicoplanin C_min on day 2 and day 4 in the OD group was significantly higher than those in the CD group, which were 14.75 ± 5.93 mg/L vs 8.26 ± 4.87 mg/L (P < .001) and 14.90 ± 5.20 mg/L vs 9.13 ± 4.75 mg/L (P = .019), respectively. The percentages of patients in the OD group achieving the target teicoplanin C_min on day 2 and day 4 were also significantly higher than those in the CD group, which were 83.7% vs 33.3% (P < .001) and 82.4% vs 28.6% (P = .0013), respectively. Furthermore, multivariate linear regression analysis showed that body‐weight exerted significant effect on teicoplanin C_min in the OD group. The percentage of favourable clinical response in the OD group was significantly higher than that in the CD group (83.8% vs 55.6%, P = .025). There was no difference between teicoplanin adverse effects in the two groups. The study demonstrated that the optimal loading dose regimen of teicoplanin can rapidly reach target C_min, and result in a good clinical efficacy and low adverse effect in critically ill Chinese patients.     

替考拉宁临床应用及药学监护横断面调查

目的 替考拉宁是用于治疗革兰氏阳性菌感染的糖肽类抗菌药物,掌握住院患者替考拉宁临床应用及其药学监护情况,可为完善药学监护方案提供参考。方法 采用横断面调查方法,针对中日友好医院出院时间为2018年1月1日至12月31日的,且在住院期间接受替考拉宁治疗的全部183例住院患者的药学监护数据进行分析。结果 183例患者以肺部感染为主,占71.58%。97例（53.01%）患者给予了负荷剂量;维持给药方案采用最多的为0.4g qd（32.24%）。共有35例（19.13%）患者监测替考拉宁血药谷浓度,共监测40例次,平均血药谷浓度（7.77±4.31）mg?L?1;血药谷浓度超过10 mg?L?1的只有11例次,占总例次的27.50%;不同维持剂量下的平均血药谷浓度有随给药剂量增大而升高的趋势,但各维持剂量组血药谷浓度值之间没有统计学差异（P=0.122）。结论 住院患者的替考拉宁治疗剂量整体不足,大部分谷浓度没有达到有效阈值,这点应该是临床感染性指标改善欠佳的主要原因。     

Teicoplanin in perspective A critical comparison with vancomycin

Teicoplanin is a new glycopeptide antibiotic with a chemical structure related to vancomycin. The proposed advantages of teicoplanin over vancomycin are discussed. These include lower incidence of side-effects, lower toxicity (especially in combination with aminoglycosides), lower dosage frequency and the possibility of intramuscular administration. There is only a limited number of studies comparing both agents; more studies are still needed before firm conclusions can be drawn. Therapeutic drug monitoring is not usually necessary for teicoplanin; the situation is not clear for vancomycin. There is some doubt whether the incidence of resistance is as infrequent for teicoplanin as it is for vancomycin. Teicoplanin appears to be a promising alternative to vancomycin, but more data are needed on the relative clinical efficacy and the development of resistance to both drugs.     

Teicoplanin in perspective

Teicoplanin is a new glycopeptide antibiotic with a chemical structure related to vancomycin. The proposed advantages of teicoplanin over vancomycin are discussed. These include lower incidence of side-effects, lower toxicity (especially in combination with aminoglycosides), lower dosage frequency and the possibility of intramuscular administration. There is only a limited number of studies comparing both agents; more studies are still needed before firm conclusions can be drawn. Therapeutic drug monitoring is not usually necessary for teicoplanin; the situation is not clear for vancomycin. There is some doubt whether the incidence of resistance is as infrequent for teicoplanin as it is for vancomycin. Teicoplanin appears to be a promising alternative to vancomycin, but more data are needed on the relative clinical efficacy and the development of resistance to both drugs.     

危重症患者万古霉素给药方案调整的研究进展

万古霉素是目前临床耐甲氧西林金葡菌感染治疗的一线药物,准确建立和适时调整万古霉素给药方案是临床治疗的关键,针对危重症患者特殊的病理生理状态的个体化治疗尤为重要。本文综述影响危重症患者万古霉素药动学性质的各因素和方案调整。     

替考拉宁在重症肺炎患者中的血药浓度监测与应用分析

目的：评价分析替考拉宁在重症肺炎患者中的血药浓度范围及临床疗效。方法：前瞻性纳入某院重症医学科重症肺炎且需使用替考拉宁治疗的患者,给予替考拉宁常规负荷剂量（400 mg,q 12 h,3剂）以及维持剂量（400 mg,qd）,给药后第5天收集替考拉宁稳态谷浓度血样,运用高效液相色谱法监测其浓度,统计分析血药浓度与临床疗效、细菌学有效率以及不良反应的相关性。采用SPSS19.0对本研究数据进行处理。结果：替考拉宁在4~100 μg·mL^-1范围内线性关系良好,标准曲线回归方程为：Y=6 471.14X-2 065.43,R²=0.999 6,平均日内精密度和日间精密度RSD为3.35%和4.66%,稳定性试验RSD为5.13%。平均提取回收率和方法回收率为82.71%和98.34%。共62例重症肺炎患者纳入本研究,替考拉宁平均稳态谷浓度为（11.98±4.82）μg·mL^-1,总体临床有效率为64.52%,细菌学有效率为66.13%,7例（11.29%）出现肾功能损伤,4例（6.45%）出现肝功能损伤。质量浓度<10 μg·mL^-122例,占35.48%,浓度<15 μg·mL^-1的45例,占72.58%。Logistic回归分析显示替考拉宁谷浓度与细菌学有效率以及肾毒性分别具有独立相关性,并确定目标谷浓度范围为9~17 μg·mL^-1。结论：对于重症肺炎患者,为保证临床疗效建议适当增加替考拉宁给药剂量,必要时可开展血药浓度监测,使其有效浓度维持在9~17 μg·mL^-1范围。     

替考拉宁在特殊人群中药动学研究进展

替考拉宁是临床治疗耐甲氧西林金黄色葡萄球菌等耐药革兰阳性菌感染的首选药物之一。本文分别对近年来替考拉宁在老年人、儿童，重症感染、肾功能不全、低白蛋白血症、严重烧伤、血液肿瘤患者等特殊人群中的药动学研究进展进行综述，考察特殊病理生理状态对其疗效和安全性的影响，为临床合理用药提供参考。