1例血液滤过患者万古霉素持续滴注给药的病例分析

临床药师参与1例经血液滤过治疗患者的导管相关感染、肺感染的诊疗过程.分析万古霉素持续滴注的药代与药动学、不良反应的发生率、稳定性等方面因素.提出对于该患者建议使用持续滴注方式给药并同时进行血药浓度监测使患者的感染得到控制.通过探讨万古霉素持续滴注给药方式的适宜性,可为相关人群的安全用药提供科学依据.     

130例万古霉素血清药物浓度检测与用药结果分析

目的:探讨万古霉素血清药物浓度检测方法,分析对于万古霉素临床应用的重要影响.方法:选取我院2013年9月~2015年12月收治的130例耐药革兰氏阳性菌感染患者作为研究对象,使用万古霉素进行治疗,通过对万古霉素血清药物浓度的检测,分析应用效果.结果:血清药物浓度为10~20μg/mL的万古霉素,治疗效果更为显著.万古霉素血清药物浓度越高,不良反应发生率越高.结论:通过万古霉素血清药物浓度检测,合理控制万古霉素的用药剂量,可以获得更好的治疗效果.     

340例万古霉素血药浓度监测及临床用药合理性分析

目的：评价340例万古霉素血药浓度监测及其临床用药情况.方法：提取本院2003年1月-2006年2月使用万古霉素并监测血药浓度的住院患者病历340份,对其临床资料进行统计分析.结果：本院住院患者使用万古霉素有效率为81.2%,不合理使用占27%,首次治疗药物监测结果在有效治疗窗内的仅占45.6%.药物利用指数（DUI）为0.61,不良反应发生率（ADR）为6.2%.结论：本院住院患者万古霉素使用基本合理,但应注意万古霉素血药浓度的监测要密切结合临床,实现个体化给药.     

腹膜透析相关腹膜炎患者万古霉素血药浓度监测结果分析

目的:分析腹膜透析(腹透)相关腹膜炎患者万古霉素血药浓度结果及特点,为腹透患者合理使用万古霉素提供参考.方法:收集2015年1月-2020年12月我院第一医学中心监测万古霉素血药浓度的腹透相关腹膜炎患者的病例资料,回顾性分析万古霉素血药浓度的分布情况、临床治疗方案,探讨血药浓度与治疗方案的关系.结果:万古霉素治疗腹透相...     

万古霉素和去甲万古霉素所致白细胞减少的病例分析及药学监护

目的 研究万古霉素和去甲万古霉素所致的白细胞减少的临床特点.方法 收集我院2008年1月至2013年3月发生的万古霉素及去甲万古霉素相关的白细胞减少病例,总结用药剂量、发生时间、不良反应症状及转归.结果 共收集与万古霉素或去甲万古霉素相关的白细胞减少11例.患者发生白细胞减少不良反应的中位数时间为用药后14 d,经过停药及对症治疗后所有患者在1周内恢复,中位数时间为3 d.结论 万古霉素及去甲万古霉素可以引起白细胞减少的不良反应,其机制与免疫介导或骨髓抑制有关,停药并经对症治疗后可恢复.     

体外膜肺氧合对危重患者体内万古霉素药动学与剂量的影响

万古霉素是治疗耐甲氧西林金黄色葡萄球菌(MRSA)感染的首选药物。因存在肾毒性风险,万古霉素治疗剂量存在个体差异,且与患者体内万古霉素药动学密切相关。基于抗菌药物及时、合理使用的重要性,该文结合国内外指南、专家共识及以往相关研究,综述使用体外膜肺氧合(ECMO)期间万古霉素体内药动学与剂量变化,以期为使用ECMO的危重患者安全合理使用万古霉素提供参考。     

万古霉素鞘内注射用于神经外科术后颅内感染患者治疗的临床效果

目的 观察万古霉素鞘内注射用于神经外科术后颅内感染患者治疗的临床效果.方法 回顾性分析2018年11月—2020年11月阳江市人民医院收治的86例接受神经外科手术治疗后出现颅内感染的患者临床资料,根据万古霉素给药方式不同分为观察组和对照组,各43例.对照组予注射用盐酸万古霉素静脉滴注治疗,观察组予注射用盐酸万古霉素鞘内...     

神经外科术后患者肾功能亢进对万古霉素血药浓度及疗效的影响

目的 研究神经外科术后患者肾功能亢进对万古霉素血药浓度及疗效的影响.方法 回顾性分析解放军总医院医疗保障中心神经外科2019年1—6月择期手术后进行万古霉素治疗药物监测的患者,分为肾功能正常组和肾功能亢进组,比较2组患者的基本情况、万古霉素使用情况、血药浓度情况和预后情况.结果 共纳入患者104例,其中肾功能正常组78...     

万古霉素与肝事件风险Meta分析

目的 对已经发表的万古霉素与肝事件风险随机对照临床试验进行Meta分析,探讨万古霉素与肝事件风险的关系.方法 全面搜索和审查被MEDLINE、PubMed、国际药学文摘和Cochrane图书馆收录的从1950年1月-2010年6月发表的使用万古霉素联合或不联合其他治疗与非万古霉素治疗报告肝事件的随机对照研究论文,并提取和审查数据.对选定的研究用Jadad评分法进行评估,影响的大小用95％CI风险比(RR)和NNH表示,发表偏倚的影响用漏斗图和Egger's检验评估.结果 20个随机对照试验,共7419例病例符合研究纳入标准.接受万古霉素治疗的患者肝事件特别是血清转氨酶水平升高的发生率高于接受非万古霉素治疗组(汇集RR=1.95;95％ CI 1.62,2.36；P＜0.001),但大部分风险事件是轻至中度.肝事件报告明显增加与发表偏倚无明显相关.结论 建议对使用万古霉素的患者进行肝事件风险的连续监测.     

95例特重度烧伤患者治疗用万古霉素不同血药浓度对临床疗效与安全性的影响

目的:分析特重度烧伤患者治疗用万古霉素不同血药浓度对临床疗效与安全性的影响,旨在为临床治疗提供参考.方法:选取医院2018年12月-2020年5月收治的特重度烧伤患者95例临床资料,分析其万古霉素静脉滴注治疗后不同血药浓度患者不良反应发生情况及临床疗效.结果 .95例治疗用万古霉素患者中,血药浓度＞20 mg,/L的不良反应发生率高于≥10～20 mg/L与＜10 mg/L(P＜0.05),但不同血药浓度产生的临床疗效经组间比较其差异均无统计学意义(P＞0.05).结论:特重度烧伤患者万古霉素用药治疗后,监测其血药浓度以调整用药剂量,使其血药浓度维持在安全治疗窗区间,尽量减少个体差异对疗效的影响,从而确保其疗效和用药的安全性.     

颅内感染新生儿万古霉素脑脊液渗透率及相关因素分析

目的:监测颅内感染新生儿万古霉素血药浓度、脑脊液浓度、脑脊液渗透率并分析其影响因素,为制定个体化抗感染治疗方案提供依据。方法:收集我院2016年2月至2018年7月因细菌性脑膜炎入住新生儿科并使用万古霉素抗感染治疗的患儿临床资料,监测万古霉素血药浓度和脑脊液浓度,计算其渗透率,应用SPSS17.0统计学软件进行相关因素分析。结果:万古霉素平均血药浓度为11.72(9.54~15.22)mg/L,脑脊液浓度2.32(1.90~3.09)mg/L,渗透率23.02(14.49~33.33)%。万古霉素血药浓度与日龄、矫正胎龄、体质量、血肌酐水平相关(P<0.05);万古霉素脑脊液渗透率与脑脊液白细胞计数和蛋白水平相关(P<0.05)。结论:万古霉素的药动学在新生儿不同个体间差异较大,应根据年龄、体质量和血肌酐水平调整用药剂量,并严密监测血药浓度和脑脊液浓度。     

Assessment of Epithelial Lining Fluid Partitioning of Systemically Administered Monoclonal Antibodies in Rats

For systemically administered monoclonal antibodies (mAbs) with pharmacological targets in the epithelial lining fluid (ELF), information on the partitioning of mAb between plasma and ELF is instrumental for dose predictions. Bronchoalveolar lavage (BAL) combined with measurements of urea as indicator of sample dilution is often used to estimate ELF concentrations of a drug. However, unbalanced extraction of mAb and urea could potentially lead to a systematic bias in the back-calculated ELF concentration. In the present study 0.5, 1, or 4 mL phosphate-buffered saline was instilled to lungs of rats to obtain lavage samples after systemic dosing of mAb and tool small molecule (n≥4/group). Furthermore, extraction of urea, mAb and the small molecule was assessed by repeatedly lavaging the lung (n = 4). There was no statistically significant difference in the calculated partitioning into ELF between the evaluated instillation volumes. Repeated BAL demonstrated that urea and the small molecule were extracted from other sources than the ELF. In contrast, there was limited to none in-flow of mAb into the lavage fluid. The unbalanced extraction of urea and mAb could theoretically result in underestimated ELF concentrations and the calculated partitioning of 0.17±0.062 might therefore constitute a lower boundary for the true partitioning.     

万古霉素对老年患者肾毒性的观察及血药浓度监测的意义

目的 探讨老年患者使用万古霉素治疗过程中进行肾毒性观察及血药浓度监测的意义。方法 对69例明确有金黄色葡萄球菌感染的老年住院患者予万古霉素500mg或去甲万古霉素400mg静滴，每8小时1次，平均疗程11d，观察用药前后肾功能指标的变化。31例患者在药物治疗过程中监测万古霉素血药浓度，根据检查结果调整治疗方案。结果 65例老年患者在应用万古霉素前后血清肌酐、血尿素氮、内生肌酐清除率的变化差异无统计学意义（P〉0．05）。结论 老年患者应用万古霉素大多数是安全的，根据内生肌酐清除率调整用药剂量及（或）进行血药浓度监测，进行个体化给药，可以提高该药应用的安全性和有效性。     

万古霉素高谷浓度给药方案的研究

目的建立万古霉素谷浓度为10～20μg·mL-1的给药设计方案。方法 采用Matxke方法估算药物动力学参数,以目标谷浓度为10～20μg·mL-1,利用药物动力学参数设计给药方案,比较预测谷浓度与实际谷浓度的差别并计算AUC0～24/MIC。结果43例患者的预测谷浓度为(15.25±1.60)μg·mL-1,实际谷浓度为(14.47±2.46)μg·mL-1,预测谷浓度的ME为0.78μg·mL-1(95%CI:0.13～1.42),MAE为1.57μg·mL-1(95%CI:1.09～2.06),RMAE为2.21μg·mL-1(95%CI:1.41～2.79)。预测谷浓度与实际谷浓度具有相关性(P<0.001,r=0.535);43例患者中有41例(95.35%)患者的实际谷浓度在10～20μg·mL-1。患者实际日剂量明显高于说明书推荐剂量(P<0.001)。当MIC≤1μg·mL-1时,43例患者中有42例(97.67%)患者的AUC0～24/MIC均可>400。结论本研究建立的给药方案可以满足谷浓度为10～20μg·mL-1的要求。     

万古霉素血药浓度监测应用调查及分析

目的 通过对154例患者434例次万古霉素血药浓度监测,结合疗效、不良反应及药敏结果进行统计分析,为临床合理应用万古霉素提供依据.方法 收集本院2012年154例434例次万古霉素血药浓度的监测结果,结合临床病历资料、病原学检查、肾功能指标、合并用药及发生的不良反应情况进行汇总分析,同时分析万古霉素的最低抑菌浓度（MIC）与疗效的关系.结果 434例次万古霉素血药浓度的监测结果中,血药谷浓度10～20 μg·mL^-1共有214例次（占49.29％）,＜10 tg·mL^-1共有81例（占18.69％）,＞20 μg·mL^-1共有139例（占32.02％）;单独使用万古霉素共12例（占7.79％）,联合使用一种抗感染药物共40例（占24.03％）,联合使用两种或两种以上抗感染药物共102例（占68.18％）;不良反应发生率为32.47％.结论 应加强对万古霉素临床治疗药物的监测,根据测得的血药浓度对给药剂量进行适当的调整,实现个体化给药,从而达到提高疗效、降低毒性发生率,实现合理用药的目的.     

Possible Extraction of Drugs from Lung Tissue During Broncho-alveolar Lavage Suggest Uncertainty in the Procedure's Utility for Quantitative Assessment of Airway Drug Exposure

Following inhaled dosing, broncho-alveolar lavage (BAL) is often used for sampling epithelial lining fluid (ELF) to determine drug concentration in the lungs. This study aimed to explore the technique's suitability. Urea is typically used to estimate the dilution factor between the BAL fluid and physiological ELF, since it readily permeates through all fluids in the body. As representatives of permeable small molecule drugs with high, medium and low tissue distribution properties, propranolol, diazepam, indomethacin and AZD4721 were infused intravenously to steady state to ensure equal unbound drug concentrations throughout the body. The results showed that propranolol had higher unbound concentrations in the ELF compared to the plasma whilst this was not the case for the other compounds. Experiments with different BAL volumes and repeated lavaging indicated that the amount of drug extracted is very sensitive to experimental procedure. In addition, the results show that the unbound concentrations in ELF compared to plasma differs dependent on molecule class and tissue distribution properties. Overall data suggests that lavaging can remove drug from lung tissue in addition to ELF and highlights significant uncertainty in the robustness of the procedure for determining ELF drug concentrations.     

氨溴索对肺耐甲氧西林金黄色葡萄球菌感染患者肺部万古霉素浓度的影响

目的:研究氨溴索对肺部耐甲氧西林金黄色葡萄球菌(MRSA)感染患者血液与肺部万古霉素浓度的影响,评价两药联用的合理性。方法:44例肺部MRSA感染患者经纳入后随机分为2组:A组患者入组后即给万古霉素1.0g,ivd,q12h。B组患者入组后即给药万古霉素1.0g,ivd,q12h,联合使用氨溴索60 mg,iv,q12h。于第4个万古霉素给药剂量之前以咳痰或负压吸痰采集痰液样本,同时收集患者血清。采用荧光偏振免疫法(FPIA法)测定万古霉素浓度。结果:A组、B组患者痰液中万古霉素质量浓度分别为(1.8±2.1)μg.mL-1,(3.6±3.1)μg.mL-1,2组差异有显著性(P<0.05);A组、B组患者万古霉素血药质量浓度分为(15.7±2.5)μg.mL-1,(14.7±2.8)μg.mL-1,2组差异无显著性(P>0.05)。结论:万古霉素与氨溴索联合使用可增加肺部MRSA感染患者痰液中万古霉素浓度,不影响血液中万古霉素的浓度。     

Differences in Surfactant Lipids Collected from Pleural and Pulmonary Lining Fluids

Purpose The type and relative importance of saturated and unsaturated phospholipid components of surfactant within the epithelial lining fluid (ELF) of the inner and outer surfaces of the lung is not known. Methods Seven healthy dogs were anesthetized and a bronchoalveolar lavage (BAL) was performed, immediately followed by a pleural lavage (PL). Lipid was extracted from lavage fluid and then analyzed for saturated, primarily dipalmitoylphosphatidylcholine (DPPC), and unsaturated phosphatidylcholine (PC) species using high-performance liquid chromatography (HPLC) with combined fluorescence and ultraviolet detection. Dilution of ELF in lavage fluids was corrected for using the urea method. Results DPPC (494.7 ± 213.9 μg/mL) was the predominant PC present in ELF collected from the alveolar surface. In contrast, significantly higher (p = 0.028) proportions of unsaturated PC species were measured in PL fluid (∼105 μg/mL), particularly stearoyl-linoleoyl-phosphatidylcholine (SLPC), which could not be measured in fluid collected from the alveoli, compared to DPPC (2.6 ± 2.0 μg/mL). Conclusions This study indicates that unsaturated PC species seem to be more important than saturated species, particularly DPPC, in the pleural cavity, which has implications for surfactant replenishment following pleural disease or thoracic surgery.     

Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents

Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of nelfinavir and saquinavir in ELF are undetectable, whereas tipranavir and lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these protease inhibitors were co-administrated with ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of anti-infective agents, the knowledge of drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens.     

Proposal of membrane transport mechanism of protein-unbound ulifloxacin into epithelial lining fluid determined by improved microdialysis

Microdialysis method (MD) is useful for sampling protein-unbound substances in vivo. Generally in the MD, a reference compound is used to correct differences in drug permeation clearance through a dialysis membrane in vivo and in vitro. No reference compound was, however, used for determination of a protein-unbound drug concentration in the epithelial lining fluid (ELF). In this study, we firstly examined the propriety of endogenous urea as a reference compound to determine the protein-unbound ulifloxacin concentrations in rat ELF by MD. Endogenous urea was used to correct differences in the permeation clearance in vivo and in vitro which reflect the differences in the extent of contact between a tip probe and ELF in vivo and in vitro. The results showed that our MD is applicable to determine the various concentrations of ulifloxacin and urea, and that we can use endogenous urea as a reference compound even if the extent of the contact between a tip of the probe and the ELF is small. In addition, use of urea concentrations does not affect drug distribution from plasma to ELF because we used endogenous urea. These results support usefulness of endogenous urea as a reference compound to determine protein-unbound drug concentration in ELF by MD. In addition, our results also suggest the existence of certain distribution mechanisms which cause the high penetration ulifloxacin into ELF. Our MD can help progress in pharmacokinetic-pharmacodynamic analysis of various antibiotics in the case where the concentrations in ELF are not equal to that in plasma.