治疗药物浓度监测下万古霉素治疗血流感染6例

目的探讨增大万古霉素剂量治疗血流感染的可行性。方法入选2013年7月1日—12月31日革兰阳性菌血流感染并使用万古霉素治疗的成人患者,检测万古霉素血药浓度并根据患者的治疗反应及血药浓度监测结果,调整万古霉素给药方案,同时记录患者的临床相关资料,分析治疗药物浓度监测下增大万古霉素剂量,治疗甲氧西林耐药凝固酶阴性葡萄球菌(MRCNS)血流感染患者的有效性及安全性。结果本研究中血流感染病原菌均为MRCNS,除1株人葡萄球菌的万古霉素MIC值为1 mg/L,其余菌株的万古霉素MIC值均为2 mg/L。常规剂量(2 g/d,或1.5 g/d)万古霉素的谷浓度平均值为(3.84±1.42)mg/L,高剂量(3 g/d)万古霉素谷浓度平均值为(9.13±4.88)mg/L。常规剂量时平均万古霉素曲线下面积(AUC)与MIC浓度比值(AUC/MIC)为152±39,高剂量用药时平均AUC/MIC为197±44。6例患者中有1例出现了肾功能损害。6例患者在使用万古霉素后3例临床和细菌学治愈,3例无效。结论万古霉素治疗肾功能正常的MRCNS血流感染患者时,建议在治疗药物浓度监测下调整患者个体化的给药方案,以达到目标治疗浓度。     

中国成人万古霉素给药剂量的商榷

目的探讨中国成人万古霉素每日2g给药方案，能否达到10--20mg／L的目标血药浓度。方法回顾性分析交通大学医学院附属瑞金医院2011年9月至2012年12月收治的使用万古霉素且进行血药浓度监测的122例住院患者临床资料，分析给药剂量、年龄、性别、体重、合并用药等与血药谷浓度的相关性。结果按说明书给药的患者中，62．1％血药谷浓度低于目标血药谷浓度。年龄是患者用药后血药浓度是否能够达到目标值的独立危险因素，对于符合说明书剂量给药的患者，年龄〈60岁者中70．0％低于目标血药浓度；年龄≥60岁者中，62．5％达到或高于目标血药浓度。结论临床医师和药师需审慎地评估患者的给药剂量，尤其应该考虑年龄的独立影响因素。     

下呼吸道感染的病原菌分布及药敏分析

目的了解下呼吸道感染病原菌分布及耐药情况，指导临床合理用药。方法采集2004-2006年期间病房送检的下呼吸道标本，用VITEK—AMS全自动微生物分析仪进行鉴定及药敏实验。结果445例阳性下呼吸道标本中共分离细菌498株，53例为混合感染，主要是革兰阴性杆菌，占59．6％（297／498），以铜绿假单胞菌、肺炎克雷伯菌、鲍曼／溶血不动杆菌、大肠埃希菌、嗜麦芽假单胞菌、阴沟肠杆菌为主；革兰阳性球菌占29．8％，（148／498），以金黄色葡萄球菌为主；真菌占10．4％（43／498）。革兰阴性杆菌对亚胺培南耐药率最低，为0．0％～25．6％，其次是妥布霉素和哌拉西林／他唑巴坦。对革兰阳性球菌耐药率最低是万古霉素，均为0．0％，其次是呋喃妥因。肺炎克雷伯菌、大肠埃希菌、阴沟肠杆菌超广谱β-内酰胺酶（ESBLs）产生率为19．0％、62．0％、33．3％。耐苯唑西林葡萄球菌（MRS）为88．3％～97．3％。结论下呼吸道感染病原菌以革兰阴性杆菌为主，但革兰阳性球菌和真菌有上升趋势，多数病原菌耐药问题严重，应加强病原学及耐药性监测，以便指导临床合理用药。     

重症监护病房细菌性血流感染监测中C反应蛋白和降钙素原的临床意义

目的探讨C反应蛋白（CRP）和降钙素原（PCT）在重症监护病房细菌性血流感染监测中的临床意义。方法回顾性分析北京世纪坛医院重症监护病房进行血液培养的154例患者临床资料,根据血培养结果分为阳性组（n=78）和阴性者（n=76）;血培养采血当日测定CRP和PCT结果,并对两组数据进行比较。血培养阳性组按革兰阳性菌（n=17）与阴性菌（n=61）再次分组,并对两小组患者的CRP和PCT水平进行比较。结果血培养阳性组CRP[中位数124（11-217）mg／L]显著高于阴性组[中位数62．3（7．39-200）mg／L,Z=-5．394,P〈0．01];阳性组PCT[中位数6．59（0．21～100）μg／L]亦显著高于阴性组[中位数0．44（0．07-60．34）μg／L,Z=-8．896,P〈0．01]。革兰阳性菌组CRP[中位数119（34．8～217）mg／L]与革兰阴性菌组[中位数126（11～205）mg／L]差异无统计学意义;但革兰阴性菌组PCT[中位数6．99（1．55～100）μg／L]显著高于革兰阳性菌组[中位数2．04（0．21～46．69）μg／L,Z=-2．663,P〈0．053。结论在重症监护病房细菌性血流感染的监测CRP和PCT具有一定参考价值;与革兰阳性菌血流感染相比,革兰阴性菌血流感染的PCT值更高。     

蒲公英体外抑菌活性的研究

目的：探讨中药蒲公英的体外抑菌活性。方法：采用微量肉汤稀释法,对临床常见203株分离菌进行体外最小抑菌浓度（MIC）测定。结果：蒲公英对葡萄球菌MIC50为15．6mg／L、MIC90 31．25mg／L;肺炎链球菌MIC50为250mg／L、MIC90 250mg／L;B溶血性链球菌MIC50为125mg／L、MIC90 500mg／L;阴性杆菌MIC50为62．5-500mg／L、MIC90 125～1000mg／L。结论：蒲公英在体外对临床常见感染菌,尤其是革兰阳性、阴性球菌有较好的抑菌活性。     

老年患者万古霉素血药谷浓度110例次分析

目的分析老年患者万古霉素谷浓度与肾功能及药物剂量之间的关系,为老年患者合理使用万古霉素提供参考。方法选取2015年11月至2016年4月在首都医科大学附属北京友谊医院住院并进行万古霉素血药浓度监测的老年患者,回顾性分析其临床资料、肾功能、万古霉素剂量与谷浓度监测结果。结果共纳入老年患者38例,共计110例次万古霉素谷浓度检测结果,谷浓度均值(20.41±8.85)mg/L,其中低于10 mg/L者10.0%,10~20 mg/L者40.9%,高于20 mg/L者49.1%。不同性别、不同年龄段老年患者万古霉素谷浓度水平无统计学差异(P0.05)。54.9%老年患者接受万古霉素初始剂量为1.0 g/d,对应谷浓度为(14.33±5.32)mg/L,接受1.5 g/d和2.0 g/d初始剂量的谷浓度相近,分别为(22.83±8.58)和(20.76±9.74)mg/L。肾小球滤过率(GFR)≥60 ml/min的老年患者万古霉素谷浓度为(17.20~20.92 mg/L),GFR 30~59 ml/min的患者谷浓度升至(26.87±11.02)mg/L,GFR 15~29 ml/min者用药量减少,但谷浓度仍超标(24.58±8.69 mg/L)。结论该院多数应用万古霉素治疗的老年患者达到有效治疗浓度,万古霉素1.0 g/d是比较稳妥的初始给药剂量,GFR60 m L/min的老年患者万古霉素剂量应酌减。     

万古霉素在重症感染中的治疗药物监测现状及前景

万古霉素被誉为治疗革兰阳性菌感染的最后一道防线,也是推荐的一线用药。因其治疗窗窄,重症患者需监测药物浓度以指导临床安全用药。传统上基于万古霉素谷浓度的治疗药物监测已被临床广泛接受。2009年美国传染病学会(IDSA)指南建议,对于重症患者目标谷浓度为15～20 mg/L。近十余年国内外学者对于该治疗浓度的安全性及有效性评价不一。2020年更新指南提出,肾损伤风险最小、最准确且最佳的给药方法是通过曲线下面积(AUC)指导给药剂量和监测,提倡个体化目标AUC/最低抑菌浓度(MIC)比值为400～600 mg/(h·L)。由此可见目前就万古霉素临床监测指标存在争议。因此,本文就万古霉素治疗重症感染过程中进行治疗浓度监测的手段及策略进行综述,对指导临床合理用药具有重要意义,有助于临床医师制定个体化给药方案,最大程度减少或避免药物毒性。     

万古霉素在持续性静-静脉血液滤过时的药代动力学研究

目的：研究持续性静-静脉血液滤过（CVVH）时万古霉素的药代动力学特点，指导临床合理用药。方法：应用荧光偏振免疫分析仪测定万古霉素应用不同阶段的血药浓度，计算其药代动力学参数。结果：万古霉素在该患者体内的药代动力学符合开放型二室模型。用药3d主要药代参数：峰浓度（Cmax)=22.18mg/l，谷浓度（Cmin)=5.82mg/L，半衰期（T1/2）=5.75h，总体分布容积（Vd)=21.92,L,总体清除率（CL）=3.49L/h。用药16d主要药代参数；Cmax=38.70mg/L,Cmin=16.50mg/L,T1/2=33.32h,Vd=12.92L,CL=0.38L/h。结论：CVVH可以清除万古霉素，用药时应考虑多种影响因素，并监测血药浓度以提高疗效，减少药物对肾脏的损伤。     

抗菌新药左奥硝唑体外抗厌氧菌活性研究

目的测定芹奥硝唑对临床分离375株厌氧菌的体外抗菌活性。方法根据CLSI2012年版M11A8标准,采用琼脂稀释法测定芹奥硝唑对375株临床分离厌氧菌的最低抑菌浓度（MIC）,并与奥硝唑、甲硝唑和右奥硝畔3种同类药物进行比较。结果芹奥硝唑对大多数厌氧菌的体外抗菌活性强,与甲硝唑、奥硝唑及右奥硝唑相仿或略强。左奥硝唑对厌氧革兰阴性菌中的脆弱拟杆菌、多形拟杆菌的抗菌活性强,其MIC90值分别为0．5、1mg／L;对厌氧革兰阳性杆菌中的艰难梭菌活性强、产气荚膜梭杆菌活性相仿,其MIC90值分别为0．25、2mg／L;对厌氧革兰阳性球菌中的大消化链球菌也具有良好的抗菌活性,其M1C90值为1mg／L。但左奥硝唑和其同类药物对厌氧革兰阴性球菌中的韦荣球菌抗菌活性均较差。结论左奥硝唑对厌氧革兰阴性杆菌、革兰阳性杆菌、革兰阳性球菌均具有较强的抗菌活性,与甲硝唑、奥硝唑及右奥硝唑相仿或略强。提示左奥硝唑具有良好的抗厌氧菌应用前景。     

老年患者泌尿系统感染致病菌及其耐药性分析

目的调查老年患者泌尿系统感染致病菌及其耐药性，为临床合理使用抗生素提供依据。方法对428例老年患者中段尿标本进行细菌培养及耐药性监测。结果共检测出病原菌435株，其中革兰阴性杆菌占61．8％，革兰阳性球菌占25．1％，真菌占10．3％；老年女性革兰阴性杆菌的感染率显著高于男性（P〈0．01）；革兰阴性及阳性细菌中分别以大肠埃希菌（39．1％）和肠球菌属（16．3％）最多。产超广谱β-内酰胺酶（ESBLs）的大肠埃希菌对亚胺培南、哌拉西林-他唑巴坦、呋喃妥因、氨卞西林-舒巴坦、阿米卡星的耐药率低；肠球菌属细菌对万古霉素、利奈唑烷均100％敏感；葡萄球菌属细菌耐甲氧西林株达90．6％。结论老年患者泌尿系统感染以革兰阴性菌为优势菌株，细菌耐药性监测对指导临床合理用药具有重要意义。     

Vancomycin population pharmacokinetics in neonates

BACKGROUND: Recently the value of vancomycin therapeutic drug monitoring, as well as the required therapeutic range, has been subject of debate, resulting in new recommendations. This study was performed to incorporate these new insights in an up-to-date dosing scheme for neonates of various gestational ages. METHODS: In this retrospective study with prospective validation, 108 newborns with suspected central line-related septicemia during the first month of life received 30 mg/kg/day vancomycin divided into two doses regardless of gestational or postconceptional age. Trough and peak vancomycin serum concentrations were determined before and after the third dose. Vancomycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Model parameters were evaluated and then used to simulate vancomycin dosing for different dose and dose interval combinations. Targets were a trough concentration between 5 and 15 mg/L and a peak below 40 mg/L. In the prospective study, the optimal scheme was tested in 22 patients. RESULTS: Of the 108 patients, 34.3% of measured trough concentrations and 17.6% of peak concentrations were outside the desired therapeutic range. The model that best fitted the data included clearance and volume per kilogram and was independent of gestational age. Simulation of various dosing schemes showed that a dosing schedule of 30 mg/kg/day, irrespective of gestational age, in three doses was optimal, and this scheme was prospectively tested. Mean trough concentrations before the second dose were 8.2 +/- 2.2 mg/L versus a predicted trough of 8.9 +/- 2.5 mg/L. No peak levels higher than 40 mg/L were found. CONCLUSIONS: The use of the proposed schedule leads to adequate vancomycin trough serum concentrations, and there is no need for routine monitoring of peak serum concentrations.     

Optimizing the Clinical Use of Vancomycin

The increasing number of infections produced by beta-lactam–resistant Gram-positive bacteria and the morbidity secondary to these infections make it necessary to optimize the use of vancomycin. In 2009, the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Disease Pharmacists published specific guidelines about vancomycin dosage and monitoring. However, these guidelines have not been updated in the past 6 years. This review analyzes the new available information about vancomycin published in recent years regarding pharmacokinetics and pharmacodynamics, serum concentration monitoring, and optimal vancomycin dosing in special situations (obese people, burn patients, renal replacement therapy, among others). Vancomycin efficacy is linked to a correct dosage which should aim to reach an area under the curve (AUC)/MIC ratio of ≥400; serum trough levels of 15 to 20 mg/liter are considered a surrogate marker of an AUC/MIC ratio of ≥400 for a MIC of ≤1 mg/liter. For Staphylococcus aureus strains presenting with a MIC >1 mg/liter, an alternative agent should be considered. Vancomycin doses must be adjusted according to body weight and the plasma trough levels of the drug. Nephrotoxicity has been associated with target vancomycin trough levels above 15 mg/liter. Continuous infusion is an option, especially for patients at high risk of renal impairment or unstable vancomycin clearance. In such cases, vancomycin plasma steady-state level and creatinine monitoring are strongly indicated.     

老年人尿路感染常见病原菌耐药性分析

目的研究老年人尿路感染的常见病原菌及其对常用抗生素的耐药性，以指导临床用药。方法采用Vitek-Ams System和Kirby-Bauer法对267例尿路感染的老年患者标本进行细菌培养并检测其对多种抗生素的耐药性。结果共检出病原菌310株，其中革兰阴性杆菌201株（66．1％），主要为大肠埃希菌137株（45．1％）、铜绿假单胞菌25株（8．2％）、肺炎克雷伯菌19株（6．3％）、变形杆菌13株（4．3％）。革兰阴性杆菌对第3代头孢菌素的耐药率较高，可能与产超广谱B内酰胺酶菌株的增多有关，亚胺培南是治疗革兰阴性杆菌感染最有效的药物。革兰阳性球菌76株（23．0％），层析万古霉素仍然是治疗革兰阳性球菌感染最有效的药物。真菌33株（10．9％），对两性霉素B耐药率为0。结论老年人尿路感染病原菌耐药性严重，持续耐药监测对抗生素的合理应用，提高疗效，减缓耐药菌株的发生与发展有重要意义。     

万古霉素对脓毒症患者肾功能的影响

目的 探讨脓毒症患者万古霉素治疗时急性肾损伤（AKI）发生的原因.方法 51例耐甲氧西林金黄色葡萄球菌（MRSA）感染的脓毒症患者,初始使用万古霉素2 g/d,分4次给药,5个半衰期后监测万古霉素谷、峰血药浓度,根据血药浓度调整万古霉素使用剂量,记录7d内万古霉素使用总剂量.检查记录使用万古霉素前及治疗7d后C反应蛋白（CRP）、最高体温,记录治疗7d中脑钠肽（BNP）、中心静脉压（CVP）、乳酸平均值.根据血药浓度调整万古霉素每日使用剂量.万古霉素治疗7d中根据48 h SCr增加超过26.4μmol/L确定为AKI,并分组为AKI组（n=28）和非AKI组（n=23）,比较两组之间万古霉素血药浓度、乳酸、CRP、BNP、CVP、当日最高体温的差异.结果 使用万古霉素5个半衰期后所有患者平均谷浓度（9.18 ±6.15） μg/ml,峰浓度（25.73 ±20.30） μg/ml,调整剂量5d后平均谷浓度（10.26±5.10）μg/ml,峰浓度（23.52±6.83） μg/ml.A组与B组之间万古霉素血药浓度差异无统计学意义.两组之间CRP、BNP、CVP、乳酸、最高与最低体温差值均有统计学差异.结论 使用适当剂量万古霉素治疗脓毒血症时AKI的发生与否可能与感染控制效果及患者血容量是否充足有关.     

The characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia

ObjectiveThis study was designed to investigate the characteristics and impact indicator of vancomycin pharmacokinetics in cancer patients complicated with severe pneumonia.MethodsFifty-seven cancer patients complicated with severe pneumonia were included in this research. Vancomycin serum trough concentrations were measured using the fluorescence polarization immunoassay (FPIA) method. The Bayesian estimator was used to calculate the pharmacokinetic parameters.ResultsThe average initial therapeutic dose of vancomycin was 15.18 ± 3.29 mg/kg (q12 h). Our study shows that vancomycin initial trough concentrations measured in cancer patients are significantly reduced (6.54 ± 3.11 mg/L; p < 0.0001) compared with the recommended standard vancomycin trough concentration (10–15 or 15–20 mg/L). Meanwhile, the clearance (CL) and volume of distribution (Vd) of vancomycin was increased significantly in cancer patients. Multivariate linear regression analysis revealed that Cys-C was the most important variable for vancomycin trough concentration (r² = 0.439). The relationships between vancomycin trough concentrations and Cys-C were further evaluated after the 57 patients were grouped by cut-off point (1.44 mg/L) of the serum Cys- C levels before vancomycin was administered. Compared with group Early group (Cys-C>1.44 mg/L), Delayed group (Cys-C≤1.44 mg/L) had much lower trough concentrations. Meanwhile, CL and CLcr were significantly increased in Delayed group (Cys-C≤1.44 mg/L). Although the clinical outcomes were similar between two groups, the duration of vasoactive agent in Early group was considerably shorter compared with Delayed group (χ² = 4.213; p < 0.05).ConclusionsThe serum trough concentration of vancomycin was significantly reduced in cancer patients complicated with severe pneumonia. Higher dosage regimen is needed to ensure clinical effectiveness. The Cys-C level measured prior to administration of vancomycin is suggested to be the most suitable parameter to predict whether vancomycin trough concentration is up to standard dosage. Especially for patients with baseline Cys-c less than 1.44 mg/L, it is more likely to need higher dosage algorithm.     

In-vitro comparison of the post-antibiotic effect of vancomycin and teicoplanin

The post-antibiotic effect (PAE) of teicoplanin was compared with that of vancomycin for five selected Gram-positive cocci. Two concentrations of each antibiotic were investigated, with the test organisms being exposed to each for both 1 and 2 h. At a concentration of 25 mg/l, teicoplanin had a greater PAE than vancomycin for the methicillin resistant staphylococci and Enterococcus faecalis strains tested. At a concentration of 5 mg/l, teicoplanin gave equal effects to those of vancomycin except for the strain of methicillin-resistant Staphylococcus aureus (MRSA) tested. The variation in the antibiotic exposure time gave only small changes in the PAE, except for the MRSA tested.     

Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial

Several single-center studies have suggested that higher doses of vancomycin, aimed at producing trough concentrations of >15 mg/liter, are associated with increased risk of nephrotoxicity. We prospectively assessed the relative incidence of nephrotoxicity in relation to trough concentration in patients with documented methicillin-resistant Staphylococcus aureus (MRSA) infections at seven hospitals throughout South Carolina. Adult patients receiving vancomycin for at least 72 h with at least one vancomycin trough concentration determined under steady-state conditions were prospectively studied. The relationship between vancomycin trough concentrations of >15 mg/ml and the occurrence of nephrotoxicity was assessed using univariate and multivariate analyses, controlling for age, gender, race, dose, length of therapy, use of other nephrotoxins (including contrast media), intensive care unit (ICU) residence, episodes of hypotension, and comorbidities. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or a ≥ 50% increase from the baseline for two consecutive measurements. MICs of vancomycin for the MRSA isolates were also determined. A total of 288 patients were studied between February 2008 and June 2010, with approximately one-half having initial trough concentrations of ≥ 15 mg/ml. Nephrotoxicity was observed for 42 patients (29.6%) with trough concentrations >15 mg/ml and for 13 (8.9%) with trough concentrations of ≤ 15 mg/ml. Multivariate analysis revealed vancomycin trough concentrations of >15 mg/ml and race (black) as risk factors for nephrotoxicity in this population. Vancomycin trough concentrations of >15 mg/ml appear to be associated with a 3-fold increased risk of nephrotoxicity.     

血浆Th17细胞相关因子与25-羟基维生素D检测对宫颈癌的临床价值

目的：探讨宫颈癌患者Th17细胞相关因子与25-羟基维生素D检测的临床价值。方法收集宫颈癌患者68例,其中腺癌28例、鳞状细胞癌40例,选取年龄与其相匹配的50例健康体检者作为对照组。分析25羟维生素D与白介素17（IL-17）、白介素6（IL-6）在各组间的差异及其相关性。结果宫颈癌患者血浆25-羟基维生素D浓度为（24.50±6.80）ng/ml,低于健康对照组（35.10±8.70）ng/ml,宫颈癌患者血浆IL-17浓度为550（350,705）ng/L,IL-6浓度为480（390,620）ng/L,均低于健康对照组,差异有统计学意义（P均＜0.05）;腺癌患者血浆25-羟基维生素D、IL-17、IL-6浓度与鳞状细胞癌患者比较,差异无统计学意义（P＞0.05）;宫颈癌患者血浆IL-6、IL-17与25-羟基维生素D存在相关性（r分别=0.37、0.40, P均＜0.05）。结论宫颈癌患者血浆25-羟基维生素D与Th17细胞相关因子浓度检测对治疗和预后监测具有一定临床价值。     

革兰阳性球菌耐药性监测

目的监测和探讨从感染患者中分离出的革兰阳性球菌的耐药情况。方法收集2007年1～12月分离的非重复阳性球菌420株，采用国际标准琼脂稀释法测定最小抑菌浓度。结果耐甲氧西林金黄色葡萄球菌（MRSA）和耐甲氧西林表皮葡萄球菌（MRSE）分别占40％（24／60）和70％（49／70）。未发现MRSA或MRSE对万古霉素和替考拉宁耐药菌株。耐青霉素肺炎链球菌的总耐药率为32．5％（耐药2．5％，中敏30％）。肠球菌40株，耐青霉素粪肠球菌占40％，而屎肠球菌对青霉素100％耐药。粪肠球菌和屎肠球菌对高浓度庆大霉素耐药率分别为55％（30％～86％）和78％（50％～100％）。未发现对万古霉素、替考拉宁耐药的肠球菌。结论大部分抗菌药物耐药率与国内报道一致，替考拉宁和万古霉素对革兰阳性球菌仍然保持很高的抗菌活性。