肠球菌的临床感染与耐药性分析

目的了解温州医学院附属第一医院临床分离主要肠球菌的分布及其对常用抗菌药物的耐药现状,以指导临床合理用药。方法对2008年至2011年临床分离的635株粪肠球菌和屎肠球菌的标本来源和药敏结果进行回顾性分析。结果各种临床标本中两种肠球菌的分布比例存在差异,总体以尿液标本所占比例最多,且屎肠球菌的总体分离率高于粪肠球菌。粪肠球菌对利奈唑胺、氨苄西林、万古霉素、呋喃妥因和替考拉宁的耐药率都在5．0％以下,对莫西沙星和青霉素G的耐药率也仅为7．0％和6．7％;屎肠球菌对莫西沙星、左旋氧氟沙星、环丙沙星、氨苄西林、青霉素G和红霉素的耐药率都在90．0％以上,对利奈唑胺、万古霉素、替考拉宁和奎奴敏感。粪肠球菌的多重耐药株占总数的26．4％,屎肠球菌的多重耐药株占总数的78．2％。结论粪肠球菌和屎肠球菌对15种抗菌药物的耐药情况不同,屎肠球菌具有更高的耐药率和更广的耐药谱。临床应根据药敏试验的结果合理选择抗菌药物,以防止耐药菌株的产生和播散。     

重庆市1264株粪肠球菌和屎肠球菌耐药性监测

【摘 要】 目的 了解2011年中国重庆市主要7所教学医院临床分离粪肠球菌和屎肠球菌对各类抗菌药物的耐药性。方法 重庆市主要7所教学医院(6所综合性医院,1所儿童医院)按统一方案、采用统一的材料、方法和判断标准(CLSI 2011年版)进行粪肠球菌和屎肠球菌的耐药性监测。数据用WHONET 5.5软件按照CLSI 2011年版折点进行分析。结果 共分离到非重复粪肠球菌589株、屎肠球菌675株,对利奈唑胺、万古霉素、替考拉宁仍极敏感,耐药率<2%,万古霉素耐药粪肠球菌和屎肠球菌检出率分别为0.3%、0.7%。粪肠球菌对青霉素、氨苄西林、呋喃妥因的耐药率较低,分别为14.8%、8.6%和5.1%,对高浓度庆大霉素的耐药率分别为46.9%;屎肠球菌耐药性明显高于粪肠球菌,对青霉素和氨苄西林耐药率接都在90％左右。儿童和成人耐药率存在一定差别。结论 本市医院肠球菌感染以屎肠球菌为主, 粪肠球菌次之,两者耐药性明显不同, 监测其耐药情况对指导临床用药具有重要意义。     

肠球菌属细菌感染耐药性分析

目的了解中国医科大学附属盛京医院肠球菌属细菌的临床分布及耐药情况,为指导临床制定合理有效治疗方案提供理论依据。方法收集2017年1月1日至2017年12月31日我院门诊、住院患者肠球菌属细菌病原学资料,回顾性分析其菌种分布、标本分布、科室来源及其耐药特征。结果共分离出466株肠球菌属细菌,其中粪肠球菌211株(45.28%)、屎肠球菌255株(54.72%)。肠球菌属细菌均以尿液标本为最主要的来源,其次为全血标本,并且来源于尿液标本的肠球菌属细菌对临床常用抗生素的耐药率普遍高于非尿液标本肠球菌属细菌耐药率。儿科为屎肠球菌最主要的分布科室,而粪肠球菌则主要分布于泌尿外科。耐药性方面,除四环素、利福平和喹努普汀/达福普汀外,屎肠球菌对受检的其余18种抗生素的耐药性均高于粪肠球菌,但对喹努普汀/达福普汀无耐药性,而粪肠球菌对此种抗生素的耐药率却为100.00%。二者对克林霉素的耐药率均为100.00%。共检出耐万古霉素肠球菌7株(1.50%),耐替考拉宁肠球菌6株(1.28%),未发现对替加环素、利奈唑胺耐药菌株。结论屎肠球菌在肠球菌属细菌中占主要地位,且耐药率方面明显高于粪肠球菌,耐糖肽类抗生素菌株的出现需引起临床的高度警惕,应进一步加强耐药菌株的监测,并对临床应用抗生素加以规范。     

两种肠球菌致重症患者尿路感染的耐药性比较

目的研究粪肠球菌和屎肠球菌致重症患者尿路感染现状并对其耐药特征进行比较分析,为临床合理选用抗菌药物,有效预防和控制感染提供依据。方法对2011年1月至2014年12月福建医科大学附属第二医院重症监护室尿路感染患者分离的172株肠球菌进行分析,用法国生物梅里埃Vitek2-Compact微生物鉴定仪鉴定肠球菌,K-B纸片扩散法进行药敏试验,利用WHONET 5.6软件分析处理试验数据。结果 172株肠球菌中,粪肠球菌和屎肠球菌分别占68.0%和32.0%;药敏试验表明两种肠球菌对利奈唑胺、万古霉素、替考拉宁都较敏感(耐药率5.0%),未检出对替加环素耐药的菌株,除这4种药物外,对其余12种抗菌药物差异存在统计学意义(χ2=36.15,P0.05)。4年间粪肠球菌除对四环素、替加环素外,屎肠球菌除对四环素、庆大霉素(高浓度)、替加环素外,对其余抗菌药物的耐药率的变化均呈显著升高的趋势(χ2=16.71,P0.05)。结论从该院重症患者尿液标本中分离出的肠球菌多重耐药严重,对大多数抗菌药物的耐药率呈逐年升高的趋势,两种肠球菌的耐药性存在菌种差异,临床应加强细菌监测,治疗肠球菌感染时首选利奈唑胺、万古霉素、替考拉宁、替加环素。     

屎肠球菌的临床分布与耐药性分析

目的了解医院屎肠球菌的临床分布和耐药情况,为临床抗感染的预防与治疗提供参考。方法回顾性分析1999年1月至2011年12月临床标本中分离的1161株屎肠球菌;用WHONET5．6软件分析耐药率变迁。结果临床分离的1161株屎肠球菌,在同期分离的1944株肠球菌属中占59．72％。主要分离自尿液和血液,分别占40．91％和26．87％;主要分离自外科病区、内科病区、ICU和儿科病区的菌株,分别占29．37％、25．15％、13．95％和13．53％;屎肠球菌对多种抗菌药物耐药,对万古霉素、替考拉宁和利奈唑胺的耐药率较低,分别为1．04％、0．94％和1．85％。结论屎肠球菌在临床的分离率逐年增加,已成为医院内感染的主要病原菌之一,其多药耐药和高耐药现象相当严重,目前万古霉素、替考拉宁和利奈唑胺仍然是治疗肠球菌属引起感染的有效药物。     

肝硬化患者肠球菌感染及体外药敏监测

目的研究肝硬化患者肠球菌感染的现状及药敏特点,以加强对肝硬化肠球菌感染的认识,指导用药。方法留取标本进行细菌培养、鉴定及药敏试验。结果所有纳入研究范围的肝硬化患者共检出肠球菌112株,其中粪肠球菌89株,占79.5%,比例最高,屎肠球菌占14.3%,居第2位。腹水中检出肠球菌64株,占57.1%,其次为痰和尿液,分别为38.1%和14.4%。肠球菌对红霉素、奈替米星的耐药率超过80%,对青霉素G、氨苄西林、呋喃妥因的敏感率超过70%,对左氧氟沙星的敏感率为58.9%,对头孢唑啉、头孢派酮的敏感率分别只有25.0%和33.0%,检出高耐氨基糖苷类肠球菌(HLAR)58株,占51.8%,未检出耐万古霉素和替考拉宁肠球菌,但检出万古霉素中介肠球菌4株,占3.6%。结论肠球菌是肝硬化患者医院感染的重要致病菌,尤以粪肠球菌和屎肠球菌为主,屎肠球菌的耐药率高于粪肠球菌,万古霉素和替考拉宁是治疗肠球菌感染的首选药物。     

血流感染粪肠球菌和屎肠球菌的临床分布及耐药研究

回顾性分析上海市某三甲医院血培养阳性标本中粪肠球菌和屎肠球菌的临床分布及对抗菌药物的耐药特征,为临床治疗其所致感染奠定基础。收集上海市某三甲医院2012年2月—2016年9月血流感染患者血液标本中的粪肠球菌和屎肠球菌,采用法国生物梅里埃公司的VITEK 2Compact全自动细菌鉴定和药敏分析系统进行细菌鉴定及药敏测定,研究细菌临床分布特点及对常用抗菌药物的耐药特征。共分离获得30株粪肠球菌和17株屎肠球菌。粪肠球菌样本主要来自泌尿科、消化科和血液科,所占比例分别为13.33%、16.67%和10.00%。粪肠球菌对青霉素、氨苄西林、环丙沙星、左氧氟沙星、四环素和红霉素的耐药率分别为13.33%、10.00%、36.67%、33.33%、66.67%和60.00%。屎肠球菌样本主要来自消化科(29.41%),其对以上抗菌药物的耐药率分别为88.24%、82.35%、88.24%、76.47%、23.53%和70.59%。屎肠球菌对青霉素、氨苄西林、环丙沙星和左氧氟沙星的耐药率显著高于粪肠球菌,而对四环素的耐药率显著低于粪肠球菌。两者均对替加环素、利奈唑胺和万古霉素敏感,但万古霉素对屎肠球菌的最低抑菌浓度显著低于粪肠球菌。结果提示,屎肠球菌对青霉素、氨苄西林、环丙沙星、左氧氟沙星的耐药率高于屎肠球菌,对万古霉素敏感,且其万古霉素最低抑菌浓度低于粪肠球菌。本研究为治疗这两种细菌所致感染的经验性用药提供了数据支持。     

肠球菌属细菌的临床分布与耐药性分析

目的了解2012-2017年临床分离肠球菌的分布特征及耐药性,为临床合理用药提供依据。方法采用全自动微生物分析仪进行菌株鉴定及药敏试验,对肠球菌的临床分布与耐药情况进行统计分析。结果共分离出1 432株肠球菌,其中粪肠球菌为603株(42.11%),屎肠球菌为596株(41.62%)。肠球菌属细菌标本来源以尿液、胆汁和全血为主,分别占39.66%、34.50%和11.59%,其中粪肠球菌主要来自普外科、泌尿外科和ICU,而屎肠球菌主要来自ICU、普外科和消化内科。肠球菌总体对红霉素的耐药率最高(67.81%),其次为四环素(47.49%)、环丙沙星(47.00%)和左旋氧氟沙星(46.44%),对利奈唑胺和万古霉素的耐药率较低,分别为4.89%和1.19%。粪肠球菌对奎奴普丁/达福普汀、四环素的耐药率分别为83.91%和64.01%,明显高于屎肠球菌(均P0.05)。屎肠球菌对红霉素、青霉素G、氨苄西林、喹诺酮类的耐药率均超过85.00%,且均高于粪肠球菌(均P0.05)。粪肠球菌和屎肠球菌对利奈唑胺的耐药率分别为6.80%和2.18%,对万古霉素的耐药率分别为0.66%和0.67%。结论肠球菌感染病原菌以粪肠球菌和屎肠球菌为主,肠球菌属细菌对万古霉素和利奈唑胺仍然保持较高的敏感性,不同种的肠球菌其耐药性差异显著。     

某三甲医院儿童和成年女性尿培养病原菌分布和耐药性分析

摘要 目的：了解尿路感染儿童和成年女性尿培养病原菌种类和耐药性的差异,为临床合理选用抗菌药物提供依据。方法：分别收集2018年1月~2019年12月期间在我院住院的尿路感染儿童的尿培养标本1618份和尿路感染成年女性的尿培养标本1044份,分析其病原菌的分布和耐药性。结果：1618份儿童尿培养标本中分离出267株病原菌,居首位的病原菌是屎肠球菌,占43.82%（117/267）;1044份成年女性尿培养标本中分离出139株病原菌,居首位的病原菌是粪肠球菌,占28.78%（40/139）。在两种人群尿培养病原菌中大肠埃希菌和肺炎克雷伯菌构成比均分别为第二位和第三位。儿童尿培养屎肠球菌对青霉素G、氨苄西林、环丙沙星等喹诺酮类药物的耐药率高于成年女性尿培养粪肠球菌,对克林霉素、奎奴普丁/达福普汀、四环素的耐药率低于成年女性尿培养粪肠球菌（P＜0.05）;未发现对高浓度庆大霉素、高浓度链霉素、利奈唑胺、万古霉素、替加环素耐药的肠球菌。儿童尿培养大肠埃希菌对氨苄西林/舒巴坦、头孢吡肟的耐药率均高于成年女性尿培养大肠埃希菌（P＜0.05）。儿童尿培养肺炎克雷伯菌对头孢哌酮/舒巴坦、氨苄西林/舒巴坦、哌拉西林/他唑巴坦、氨曲南、厄他培南、亚胺培南、美洛培南、呋喃妥因、头孢唑啉等头孢菌素类药物的耐药率高于成年女性尿培养肺炎克雷伯菌（P＜0.05）。结论：尿路感染儿童和成年女性尿培养病原菌均以肠球菌为主,大肠埃希菌和肺炎克雷伯菌构成比分别为第二位和第三位,两种人群尿培养主要病原菌耐药性均有不同程度的差异,临床医生应根据尿培养和药敏结果合理用药。     

190株肠球菌的鉴定及药敏分析

目的了解黑龙江省医院肠球菌的菌种分布及对常用抗生素耐药性的现状。方法对2004年8月至2006年6月检出的190株肠球菌的菌种鉴定及药敏结果进行回顾性分析。结果粪肠球菌(46.3%)分离率下降;屎肠球菌(33.2%)、鹑鸡肠球菌(13.7%)分离率增加。耐药株检出率屎肠球菌为85.1%,粪肠球菌为75.0%,鹑鸡肠球菌为70.2%。青霉素和呋喃妥因对粪肠球菌引起的感染有一定的疗效,万古霉素,替考拉宁是治疗肠球菌引起感染的最佳选择。结论肠球菌已成为引起临床感染的重要致病菌,它的天然耐药和多重耐药的特性使得临床可选治疗药物范围狭窄。应防止耐万古霉素肠球菌株的产生。     

Antibiotic resistance and genotypic characterization by PFGE of clinical and environmental isolates of enterococci

Fifty-four Enterococcus faecalis and 20 Enterococcus faecium isolates from clinical and non-human sources in Rome, Italy, were characterized by antibiotic resistance and pulsed field gel electrophoresis (PFGE). Resistance to vancomycin, teicoplanin, ampicillin, and ciprofloxacin was more frequent in E. faecium than in E. faecalis, whereas high-level resistance to aminoglycoside was found primarily in E. faecalis. Multi-resistance was found primarily among clinical isolates, but was also observed among environmental isolates. Common genotypes shared among clinical and environmental isolates were observed, however, the majority of isolates occurred as unique, source-specific clones. Several PFGE types were associated with shared features in their antibiotic resistance patterns; evidences of clonal spread between and within wards were also noted. This is the first report indicating clonal relatedness between human and environmental enterococci isolated in Italy.     

Susceptibility to antimicrobial agents and genotypic relatedness of enterococcal strains isolated from patients and hospital environment

The aim of this study was to evaluate antibiotic susceptibility of Enterococcus sp. strains isolated from two hospitals in ?ód?, during 2005-2006. The second goal was to determine possible transmission of these strains within hospital wards by using melting profile PCR. Enterococcal strains were identified to species according standard microbiological methods. There was isolated 159 strains of E. faecalis, 51 strains of E. faecium and two E. avium, 1 E. durans. Susceptibility to antimicrobial agents was tested by disc diffusion method. None of these strains was resistant to vancomycin, teicoplanin or linezolid. There was high percentage of strains resistant to aminoglicosides, 22% of E. faecalis strains, and 54.9% of E. faecium strains, respectively. Additionally it was shown that 11.7% of E. faecium is resistant to chinuprisin-dalfopristin. The strains with similar pattern of resistance to antibiotics and fenotypic characteristics were genotyped by mpPCR. This technique was useful to confirm relatedness of bacterial strains suspected of being spread within hospital wards.     

胆总管结石患者胆汁病原菌分布特点及耐药性分析

目的:探讨胆总管结石患者胆汁病原菌的分布特点以及耐药性的分析。方法:选择2016年6月-2017年6月期间我院收治的胆总管结石合并胆道感染患者160例为研究对象,所有患者均进行逆行内镜胰胆管造影(ERCP)并抽取胆汁标本,进行细菌培养和耐药性实验,评价分析胆汁病原菌的分布特点及耐药性情况。结果:160例患者中有117例(73.13%)检出病原菌,共培养出病原菌130株,其中有13例患者为两种病原菌同时感染。革兰阴性菌有95株(73.08%)、革兰阳性菌有31株(23.85%)、真菌有4株(3.08%)。比例由高到低的前六位病原菌依次为:大肠埃希菌、肺炎克雷伯菌、阴沟肠杆菌、屎肠球菌、铜绿假单胞菌、粪肠球菌。革兰阴性菌对亚胺培南、阿米卡星、美罗培南、他唑巴坦、头孢吡肟等三四代头孢菌素耐药率较低,对头孢曲松、环丙沙星、左氧氟沙星、哌拉西林、氨苄西林等耐药率较高。革兰阳性菌对替拉考宁、万古霉素、利奈唑胺等耐药率较低,对四环素、环丙沙星、左氧氟沙星、克林霉素、氨苄西林等耐药率较高。真菌对酮康唑、伊曲康唑、氟康唑等耐药率较低,对两性霉素B耐药率较高。结论:胆总管结石患者胆汁病原菌主要为革兰阴性菌、其次为革兰阳性菌,各病原菌对各种抗菌药物表现出不同的耐药性,因此在临床治疗时应参考药敏试验结果进行合理选择治疗药物。     

Antimicrobial activity of mupirocin, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline against vancomycin-resistant enterococci (VRE) from clinical isolates in Korea (1998 and 2005)

It is a hot clinical issue whether newly approved antimicrobial agents such as daptomycin, linezolid, quinupristin/dalfopristin (synercid) and tigecycline are active enough to be used for infections caused by vancomycin resistant bacteria. We performed susceptibility tests for mupirocin, which is in widespread clinical use in Korea, and four new antimicrobials, daptomycin, linezolid, quinupristin/dalfopristin and tigecycline, against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium isolated from Korean patients in 1998 and 2005 to evaluate and compare the in vitro activity of these antimicrobials. Among these agents, quinupristin/dalfopristin, which is rarely used in hospitals in Korea, showed relatively high resistance to several vancomycin-resistant enterococci (VRE) isolated in 2005. Likewise, daptomycin, linezolid and tigecycline have not yet been in clinical use in Korea. However, our results showed that most of the 2005 VRE isolates were already resistant to linezolid and daptomycin (highest minimum inhibitory concentration (MIC) value >100 microg/ml). Compared with the other four antimicrobial agents tested in this study, tigecycline generally showed the greatest activity against VRE. However, four strains of 2005 isolates exhibited resistance against tigecycline (MIC >12.5 microg/ml). Almost all VRE were resistant to mupirocin, whereas all E. faecium isolated in 1998 were inhibited at concentrations between 0.8 to approximately 1.6 microg/ml. In conclusion, resistances to these new antimicrobial agents were exhibited in most of VRE strains even though these new antibiotics have been rarely used in Korean hospitals.     

Characterization of glycopeptides, aminoglycosides and macrolide resistance among Enterococcus faecalis and Enterococcus faecium isolates from hospitals in Tehran

The prevalence of glycopeptides, aminoglycosides and erythromycin resistance among Enterococcus faecalis and Enterococcus faecium was investigated. The susceptibility of 326 enterococcal hospital isolates to amikacin, kanamycin, netilmicin and tobramycin were determined using disk diffusion method. The minimum inhibitory concentration (MIC) of vancomycin, teicoplanin, gentamicin, streptomycin, and erythromycin were determined by microbroth dilution method. The genes encoding aminoglycoside modifying enzymes described as AMEs genes, erythromycin-resistant methylase (erm) and vancomycin-resistant were targeted by multiplex-PCR reaction. High level resistance (HLR) to gentamicin and streptomycin among enterococci isolates were 52% and 72% respectively. The most prevalent of AMEs genes were aac (6')-Ie aph (2") (63%) followed by aph (3')-IIIa (37%). The erythromycin resistance was 45% and 41% of isolates were positive for ermB gene. The ermA gene was found in 5% of isolates whereas the ermC gene was not detected in any isolates. The prevalence of vancomycin resistant enterococci (VRE) was 12% consisting of E. faecalis (6%) and E. faecium (22%) and all of them were VanA Phenotype. The results demonstrated that AMEs, erm and van genes are common in enterococci isolated in Tehran. Furthermore our results show an increase in the rate of vancomycin resistance among enterococci isolates in Iran.     

Antimicrobial susceptibility of<Emphasis Type="Italic">Enterococcus</Emphasis> species isolated from slovak bryndza cheese

Three hundred and ten enterococcal isolates (178 Enterococcus faecium, 68 E. durans, 49 E. faecalis, 8 E. italicus, 3 E. gallinarum, 3 E. casseliflavus, and 1 E. hirae) from Slovak Bryndza cheese were evaluated for susceptibility to nine antimicrobial agents (vancomycin, teicoplanin, ampicillin, streptomycin, gentamicin, erythromycin, rifampicin, nitrofurantoin, and ciprofloxacin). All enterococcal isolates from Bryndza cheese were susceptible to ampicillin, streptomycin, gentamicin, vancomycin, and teicoplanin as determined by the disk diffusion method. Vancomycin resistance genes vanA and vanB were not detected. Resistance rates of enterococcal isolates to rifampicin, erythromycin, ciprofloxacin, and nitrofurantoin were 24, 26, 2, and 1 %, respectively. Thirty-six % of E. faecium isolates and 22 % of the E. faecalis isolates were resistant to erythromycin. Resistance to rifampicin was similar in E. faecium (31 %) and E. faecalis (29 %). Both E. faecium and E. faecalis strains showed the same resistance to ciprofloxacin (2 %). E. durans isolates showed low levels of resistance to rifampicin, erythromycin, ciprofloxacin, and nitrofurantoin (1-4 %). Forty-eight (30 %) of the E. faecium isolates, two (3 %) of the E. durans isolates, and six (12 %) of the E. faecalis isolates exhibited multidrug resistance. The highest frequency of resistant enterococci was observed in Bryndza produced in winter season.     

肠球菌血流感染研究进展

摘要：近年来,随着肠球菌感染发生率的增加,有关肠球菌血流感染、尿路感染和腹腔感染的研究也逐渐增多,其中肠球菌血流感染病死率显著增加,预后不佳。临床上肠球菌感染以屎肠球菌和粪肠球菌为主。年龄、性别、致病菌种类及耐药情况、治疗方案的选择等均与肠球菌血流感染的发生和预后密切相关。此外,耐万古霉素肠球菌血流感染的治疗用药——达托霉素和利奈唑胺血药浓度及剂量的选择也被广泛关注。遵守临床操作规程,合理选择抗生素的种类及剂量浓度,严格监测药物使用情况,可减少血流感染的发生率,改善预后。现对肠球菌血流感染的发生及预后危险因素、治疗药物的选择进行综述,以期为肠球菌血流感染患者的临床治疗提供指导。     

泌尿外科住院患者泌尿系感染病原菌分布及其耐药性分析

了解泌尿外科住院患者泌尿系感染病原菌的分布及其对常用抗菌药物的耐药情况。对泌尿外科泌尿系感染住院患者的消毒中段尿培养结果进行回顾性分析,尿培养菌株的鉴定、药敏分析和统计分析采用VITEK2全自动微生物仪。3 a中泌尿外科泌尿系感染住院患者共分离到细菌1 233株,其中革兰阴性杆菌772株,占62.61%,革兰阳性球菌353株,占28.63%,真菌82株,占6.65%。菌株数居前5位的细菌依次为:大肠埃希菌、肠球菌属、洋葱伯克霍尔德菌、假丝酵母菌属和变形杆菌。分离大肠埃希菌产ESBLs率为66.18%,粪肠球菌中未发现VRE菌株,屎肠球菌VRE为0.8%。未发现对美洛培南耐药的大肠埃希菌,对肠埃希菌耐药率在10%以下的有亚胺培南、阿米卡星、哌拉西林/他唑巴坦和呋喃妥因。洋葱伯克霍尔德菌和铜绿假单胞菌对所监测的抗菌药物均有不同程度的耐药。未发现对万古霉素、替考拉宁及氨苄西林耐药的粪肠球菌。泌尿系感染的病原菌以大肠埃希菌和肠球菌为主,非发酵革兰阴性杆菌及假丝酵母菌所占比例超过20%,不容忽视,病原菌的耐药率较高,临床医生应根据尿培养和药敏试验结果合理使用抗菌药物。