Synthesis and evaluation of novel 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols as antifungal agents

A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[(4-substitutedphenyl)-piperazin-1-yl]-propan-2-ols have been designed and synthesized on the basis of the structure-activity relationships and antimycotic mechanism of azole antifungal agents. Their structures were confirmed by elemental analysis, IR, MS, (1)H NMR and (13)C NMR. Results of preliminary antifungal tests against six human pathogenic fungi (Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, inherently fluconazole-resistant Candida krusei, Candida glabrata) in vitro showed that all title compounds exhibited activity against fungi tested to some extent except against C. tropicalis. Compound 5b showed higher activity against C. albicans, C. parapsilosis and C. krusei than fluconazole, and its MIC values were determined to be 0.5microg/mL, 1microg/mL and 4microg/mL, respectively. Compound 5k showed higher activities against Torulopsis glabrata than fluconazole (with the MIC value of 2microg/mL). Compounds 5a, 5c, 5f, 5g, 5i exhibited higher activities against C. parapsilosis than fluconazole (with the MIC values of 2microg/mL, 2microg/mL, 2microg/mL, 1microg/mL and 2microg/mL, respectively).     

医院内真菌感染的分布及药物敏感性分析

目的了解医院内真菌感染分布及药物敏感情况,为预防真菌感染、合理使用抗真菌药物提供依据。方法常规培养分离出真菌,然后接种在科玛嘉显示培养基进行显色,并用法国生物梅里埃公司生产的API20CAUX酵母菌鉴定到种,利用ATB FUNGUS3真菌药敏板条进行MIC法药敏试验。结果湖南省肿瘤医院2008年6月-2011年6月期间,真菌感染来源的主要病区依次是胸部内科(35.2%)、重症监护病房(29.0%)、老干内科(17.4%);真菌感染的标本主要来自痰(69.6%),其次,尿液占9.2%,大便和分泌物各占7.4%、6.8%;在500株真菌中,白色假丝酵母菌占54.6%,其次是热带假丝酵母菌25.8%、近平滑假丝酵母菌9.2%、克柔假丝酵母菌8.2%;500株真菌中,23.08%白色念珠菌(63/273),30.0%非白念(68/227)对5-氟胞嘧啶不敏感;30.8%非白念(70/227)对氟康唑不敏感,其中87.8%克柔念珠(36/41)对氟康唑耐药;17.2%非白念(39/227)对伊曲康唑不敏感;8.4%非白念(19/227)对伏立康唑不敏感;8.8%非白念(20/227)对两性霉素B不敏感。所有白色念珠菌对氟康唑、伊曲康唑、伏立康唑、两性霉素B均敏感。结论临床感染的真菌仍以白色念珠菌为主,非白色念珠菌的感染有上升趋势,药敏结果显示非白念对5-氟胞嘧啶、氟康唑、伊曲康唑产生了较强的耐药性;因此,常规开展真菌药敏试验,进行耐药性监测,可以为预防真菌感染、合理使用抗真菌药物提供依据。     

老年下呼吸道感染患者痰分离真菌种类及药物敏感性

目的了解老年患者下呼吸道痰标本中真菌种类分布及药物敏感性,为预防真菌感染及针对性诊治提供依据。方法收集2010年1月—2014年10月云南亚高原地区3所医院老年患者下呼吸道标本分离的真菌,对其进行鉴定和药物敏感性试验。结果1 887株真菌中,白假丝酵母菌最多,占65.18%,同时,分离出毛霉菌属（0.69%）、构巢曲霉菌（0.16%）等少见菌株;分离的菌株对制霉菌素、两性霉素B和伊曲康唑的敏感率较高,分别为100.00%、90.14%和88.98%;对氟康唑和咪康唑的耐药率较高,分别为34.29%和36.62%;5种常见酵母菌对制霉菌素均敏感,但白假丝酵母菌、光滑假丝酵母菌对氟康唑、咪康唑的耐药率达35.94%~40.88%,白假丝酵母菌对5 氟胞嘧啶的耐药率为19.51%。结论对老年人临床抗真菌治疗需要考虑真菌类别及药敏结果。     

大学生口腔念珠菌分离株药物敏感性分析

目的 探讨在校大学生口腔念珠菌对常用抗真菌药物的敏感性.方法 选取云南省某高校在校学生1179名,采集其口腔咽拭子,分离疑似念株菌84株.采用微量液基稀释法,测定念珠菌对氟康唑、酮康唑、氟胞嘧啶和两性霉素B等4种常用抗真菌药物的敏感性,以最低抑菌浓度(MIC值)进行判定.结果 84株念珠菌对上述4种药物敏感性的几何均数分别为3.175,0.070,0.272和0.43 mg/L;耐药率分别为8.3%,9.5%,7.1%和8.3%;非白色念珠菌对酮康唑和两性霉素B的耐药率均高于白色念珠菌(P<0.05);有3株念株菌对2种或2种以上药物同时耐药.结论 在校大学生口腔念珠菌中存在一定程度的耐药株和交叉耐药现象,尤其是非白色念珠菌.     

2-Acylhydrazino-5-arylpyrrole derivatives: synthesis and antifungal activity evaluation

The synthesis and antifungal activity of 2-acylhydrazino-5-arylpyrroles 21-62 are described. Pyrrole derivatives 21-62 were evaluated for their antifungal activity towards Candida albicans ATCC 10231 and three Candida non-albicans isolated from clinical specimens. Most of them showed very good antifungal activities against Candidae, having MIC values in the 0.39-3.12 microg/mL range and enhanced inhibition potency as compared to that of fluconazole. In addition, some of the most active compounds were tested for cytotoxic activities against breast (MCF-7), lung (H-460), and central nervous system (SF-268) human cancer cell lines with the NCI anticancer drug screen. The activity of pyrroles described in this paper, along with the low toxicity, shows promise for the future development of non-toxic new antimycotic agents. The relationship between functional group variation and biological activity of the evaluated compounds is also discussed.     

243株假丝酵母菌属MIC结果分析

目的分析临床常见假丝酵母菌属对常用抗真菌药物的耐药性。方法采用法国生物梅里埃公司提供的ATB FUNGS 2试验板条,测定243株临床常见假丝酵母菌属的最低抑菌浓度（MIC）值。结果243株假丝酵母菌属以白色假丝酵母菌为主,占64.6%,其他依次为光滑假丝酵母菌（14.4%）、热带假丝酵母菌（11.1%）、近平滑假丝酵母菌（5.8%）、克柔假丝酵母菌（4.1%）;上述5种常见假丝酵母菌对5-氟胞嘧啶、两性霉素B、氟康唑和伊曲康唑4种抗真菌药物均产生了耐药性,其中克柔假丝酵母菌耐药率较高,对4种抗真菌药物的耐药率分别为20.0%、50.0%、30.0%和40.0%;上述5种常见假丝酵母菌对伊曲康唑耐药率均较对氟康唑高。结论临床常见假丝酵母菌属对常用抗真菌药物已具有一定的耐药性,应加强监测与控制。     

Susceptibilities of Candida species to amphotericin B and fluconazole: the emergence of fluconazole resistance in Candida tropicalis.

OBJECTIVE: To determine the susceptibilities of Candida species isolated from Taiwan to amphotericin B and fluconazole. DESIGN: Prospective surveillance study. METHODS: Each hospital was asked to submit up to 10 C. albicans and 40 non-albicans Candida species during the collection period, from April 15 to June 15, 1999. One isolate was accepted from each episode of infection. The broth microdilution method was used to determine susceptibilities to amphotericin B and fluconazole. RESULTS: Only 3 of 632 isolates, one each of C. famata, C. krusei, and C. tropicalis, were resistant to amphotericin B. A total of 53 (8.4%) of 632 clinical yeast isolates, consisting of 4% C. albicans, 8% C. glabrata, 15% C. tropicalis, and 70% C. krusei, were resistant to fluconazole. In contrast, no C. parapsilosis isolate was resistant to fluconazole. Isolates from tertiary-care medical centers had higher rates of resistance to fluconazole than did those from regional and local hospitals (11.4% vs 6.6%). Isolates from different sources showed different levels of susceptibility to fluconazole. All of the isolates with the exception of C. tropicalis and C. krusei isolated from blood were susceptible to fluconazole. A pattern of co-resistance to both amphotericin B and fluconazole was observed. CONCLUSIONS: Non-albicans Candida species had higher rates of resistance to fluconazole than did C. albicans (44 of 395 [11.2%] vs 9 of 237 [3.8%]; P = .002). The increasing rate of fluconazole resistance in C. tropicalis (15%) is important because C. tropicalis is one of the most commonly isolated non-albicans Candida species.     

呼吸道标本分离的假丝酵母菌分布及耐药性

目的调查近年住院患者呼吸道标本分离的假丝酵母菌属菌种分布及耐药性变化趋势，为临床合理使用抗真菌药物提供依据。方法对青岛中心医疗集团所属各医院2007-2011年38 326例住院患者送检的呼吸道标本，采用沙保罗培养法培养；VITEX32全自动细菌培养系统YBC鉴定卡或FUNGS CA20进行酵母菌鉴定；ATB FUNGUS 3真菌药敏试验板进行药敏试验。应用WHONET5.4软件对药敏结果进行分析。结果38 326份送检标本共分离假丝酵母菌属2 745株（7.16%），其中白假丝酵母菌2 036株(74.17%)，热带假丝酵母菌348株(12.68%)，光滑球拟酵母菌118株(4.30%)，副秃发酵母菌57株（2.08%)，克柔假丝酵母菌57株（2.08%)，其他假丝酵母菌129株（4.70%）。假丝酵母菌属对常用抗真菌药物的耐药率从高至低依次为伊曲康唑、氟康唑、伏立康唑、氟胞嘧啶、两性霉素B。经χ2检验，所有假丝酵母菌对氟胞嘧啶、两性霉素B、氟康唑的耐药率，2007-2011年无变化（两两比较，P＞0.05）；对伊曲康唑、伏立康唑的耐药率，2007-2011年有所上升（两两比较，P＜0.05）。结论呼吸道感染的假丝酵母菌属以白假丝酵母菌为主；对抗真菌药物已出现不同程度的耐药，并呈增加趋势。     

念珠菌属的分布及其对五种抗真菌药物的耐药性分析

目的检测念珠菌对5种抗真菌药物体外敏感性，了解念珠菌耐药性变化趋势。方法用沙氏培养基进行真菌分离，采用念珠菌显色培养基作菌种鉴定，用ATBFUNGUS3药敏试剂盒测定抗真菌药物对临床分离的念珠菌最低抑菌浓度（MIC）。结果白色念珠菌的耐药率为最低，它除对伊曲康唑耐药率为10．8％外，其余均低于5．4％；而以克柔念珠菌的耐药率最高，它对氟康唑和伊曲康唑的耐药率大于33.3％。结论不同念珠菌对常用抗真菌药物耐药性存在差异，白色念珠菌对抗真菌药物的耐药性要低于非白色念珠菌。因此真菌的培养鉴定和药敏试验对临床合理选择抗真菌药物十分重要。     

80株生殖道白念珠菌的药物敏感性研究

目的 为了解生殖道白念珠菌对五种抗真菌药物的敏感性及是否存在交叉耐药性，了解对抗真菌药物的耐药率，使临床医师能选择敏感的药物控制白念珠菌感染。方法 采用NCCLS M27-A推荐方法检测80株临床分离的生殖道白念珠菌对五种抗真菌药物的最低抑菌浓度(MIC80)。结果 80株临床分离生殖道白念珠菌对五种抗真菌药物的敏感率分别从41．3％至87．5％不等，而耐药率从0％至26．2％不等。且10株同时对氟康唑、咪康唑耐药，2株同时对氟康唑、酮康唑耐药，有1株同时对咪康唑、酮康唑耐药。结论 发现白念珠菌对两性霉素B最敏感，而对唑类药物耐药率较高，且唑类药物之间存在交叉耐药性。     

245例女性阴道假丝酵母菌病的真菌分布及耐药性分析

目的 探讨女性阴道假丝酵母菌病的真菌分布及耐药性,为临床治疗提供依据.方法 对临床从阴道分泌物中分离出的245株假丝酵母菌属采用科玛嘉假丝酵母菌显色培养基和YBC鉴定卡进行鉴定,并采用Rosco纸片扩散法对5种抗真菌药物进行药物敏感试验.结果 245株假丝酵母菌属中白色假丝酵母菌193株占78.8％、光滑假丝酵母菌33株占13.5％、热带假丝酵母菌10株占4.1％、克柔假丝酵母菌6株占2.5％、其他假丝酵母菌3株占1.2％;在5种抗真菌药物中,耐药率最高的是伊曲康唑为33.1％(x2=99.20,P＜0.05),氟康唑耐药率为27.8％、酮康唑为18.8％、两性霉素B为7.4％、5-氟胞嘧啶为4.9％.结论 女性阴道假丝酵母菌感染以白色假丝酵母菌为主,对抗真菌药物有不同程度耐药,临床应重视药敏试验,合理用药.     

62例真菌菌血症回顾性研究

目的研究真菌菌血症临床特点、可能的相关因素、病原谱及药敏特点,为真菌菌血症防治提供依据。方法回顾性地研究医院2003-2004年发生的62例真菌菌血症。结果95.2%的真菌菌血症为医院感染;59例长期应用广谱抗菌药物(95.1%)、中心静脉置管(46.8%)、气管切开及机械通气(38.7%);分离出的病原菌依次为白色假丝酵母菌(16株)、近平滑假丝酵母菌(12株)、光滑假丝酵母菌(11株)、热带假丝酵母菌(10株);对氟康唑敏感性均>90%(热带假丝酵母菌除外)。结论非白色假丝酵母菌感染导致的真菌菌血症逐渐增多,广谱抗菌药物的应用及中心静脉置管与真菌菌血症相关性可能更强,氟康唑对除热带假丝酵母菌、克柔假丝酵母菌外的多种真菌有良好的抗菌活性。     

深部真菌感染的菌群分布及耐药性

目的了解医院感染患者深部真菌感染的菌群分布及4种抗真菌药物的体外抗菌活性,为临床合理应用抗真菌药物提供帮助。方法常规培养分离真菌,用VITEK全自动微生物分析仪鉴定到种,药敏试验采用Rosco抗真菌药敏纸片扩散法及NCCLS M27-A肉汤稀释法。结果医院感染患者分离的9种156株深部真菌,以白色假丝酵母菌和热带假丝酵母菌为主,分别占57.69%、31.41%;临床感染标本的分离率以呼吸内科、心血管外科、神经内科为主,分别占26.28%、12.18%、9.62%;感染标本来源以呼吸道和泌尿道为主,占71.15%和16.67%;Rosco纸片扩散法对氟康唑、两性霉素B、伊曲康唑、酮康唑的耐药率分别为:23.08%、2.56%、12.18%、17.31%,MIC90分别为64.0、2.0、8.0、16.0mg/L。结论医院感染患者的深部真菌菌株以白色假丝酵母菌和热带假丝酵母菌为主,念珠菌属对常用抗真菌药物的耐药性有一定的差异,两性霉素B的抗菌活性最强,氟康唑的耐药性越来越高,临床应根据药敏试验结果合理应用抗真菌药物。     

Characteristics of candidaemia with Candida-albicans compared with non-albicans Candida species and predictors of mortality

Candidaemia due to non-albicans Candida species is increasing in frequency. We describe 272 episodes of candidaemia, define parameters associated with Candida albicans and other Candida species, and analyse predictors associated with mortality. Patients with C. albicans (55%) had the highest fatality rate and frequently received immunosuppressive therapy, while patients with Candida parapsilosis (16%) had the lowest fatality and complication rates. Candida tropicalis (16%) was associated with youth, severe neutropenia, acute leukaemia or bone marrow transplantation, Candida glabrata (10%) was associated with old age and chronic disease, and Candida krusei (2%) was associated with prior fluconazole therapy. The overall fatality rate was 36%, and predictors of death by multi-variate analysis were shock, impaired performance status, low serum albumin and congestive heart failure. Isolation of non-albicans Candida species, prior surgery and catheter removal were protective factors. When shock was excluded from analysis, antifungal therapy was shown to be protective. Unlike previous concerns, infection with Candida species other than C. albicans has not been shown to result in an increased fatality rate.     

140株深部假丝酵母菌属感染的临床特点及耐药性分析

目的 了解湘雅医院深部假丝酵母菌属感染的临床特点、菌种分布和耐药情况,为临床合理应用抗真菌药物提供依据.方法 收集2007年8月～2008年3月临床分离的假丝酵母菌属140株,采用法国生物梅里埃公司VITEK 2全自动鉴定仪及配套酵母样真菌鉴定卡YST作假丝酵母菌属菌种鉴定,用ATBTM FUNGUS 3真菌药敏卡对假丝酵母菌属进行5种常用抗真菌药物体外敏感试验,并对此140例感染者的病例进行资料统计分析.结果 假丝酵母菌属感染的主要真菌有5种,其中以白色假丝酵母菌最多,占52.8%;其他依次为热带假丝酵母菌占17.9%,光滑假丝酵母菌占14.3%,近平滑假丝酵母菌占7.8%,克柔假丝酵母菌占4.3%,其他假丝酵母菌占2.9%;140株假丝酵母菌属对两性霉素B、氟康唑、依曲康唑、伏立康唑和5-氟胞嘧啶的耐药率分别为2.1%、2.9%、9.3%、0.7%和2.9%.结论 假丝酵母菌属感染主要由白色假丝酵母菌和热带假丝酵母菌引起,对伏立康唑、两性霉素B和5-氟胞嘧啶有较高的体外敏感性;广谱抗菌药物、免疫抑制剂和抗肿瘤药物的广泛应用,增加了假丝酵母菌属的感染机会,应加强对其进行耐药性监测,以指导临床合理使用抗菌药物.     

Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives

A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were prepared under mild reaction conditions and tested for their antifungal activity. Pharmacomodulation at N(1), C(2) and C(5) of the indole ring and at the level of the alkyl chain (R(1)) was carried out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were obtained in satisfactory yields by CO(2) elimination from the intermediate carbamates. All of the compounds were evaluated in vitro against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B, fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted significant antifungal activity against C. albicans, with MIC in the range of 1-6 microg mL(-1). As regards inhibitory activity against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 microg mL(-1) in contrast to the reference drugs, amphotericin B and itraconazole, whose MIC(90) and MIC(80) values were 0.14 and 0.50 microg mL(-1), respectively. The most potent compound, 45a, exhibited MIC value (8 +/- 1 microg mL(-1)) 16-fold higher than that of itraconazole.     

Synthesis, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles

The synthesis and antimicrobial activity of a new series of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazole derivatives 3-12 were described. The in vitro antimicrobial activity of the compounds was determined against some Gram-positive, Gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicated that the synthesized compounds possessed a broad spectrum of activity with MIC values 500-15.625 microg/ml. In the series, the most active compound against Candida krusei and Candida albicans isolate is 8 with MIC value 31.25 microg/ml. However, it is one dilution less potent than the compared fluconazole. Some of the screened compounds exhibit significant activity, having MIC value as 31.25 microg/ml in Pseudomonas aeruginosa having same activity as Rifampicin. Furthermore, considering the worth of developing new antibacterial agents against drug-resistant P. aeruginosa the present study explores the structure-activity relationship analysis of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles using 3D-common features pharmacophore hypotheses approach.     

1312株酵母菌的鉴定及其药敏分析

目的 分析临床标本中酵母菌的菌种分布及其对5种常用抗真菌药物的敏感性,帮助临床合理使用抗真菌药物. 方法 采用显色培养基和VITEK 32的YST鉴定卡对2009-2010年海口市人民医院临床送检的标本进行分离鉴定,并用ATB FUNGUS 3进行体外药物敏感性检测及耐药分析. 结果 1312株酵母菌中,其中白色念珠菌最多为825株(62.9％),其次为热带念珠菌206株(15.7％)和光滑念珠菌198株(15.1％).体外药敏检测结果显示氟康唑、伏立康唑对白色念珠菌、近平滑念珠菌、热带念珠菌的敏感率达90％以上;伊曲康唑对白色念珠菌和近平滑念珠菌敏感率大于80％;两性霉素B对各念珠菌的敏感率都大于95％. 结论 1312株酵母菌中白色念珠菌的比例最高,其次为热带念珠菌和光滑念珠菌.体外药敏检测结果显示氟康唑、伏立康唑和两性霉素B的敏感率较好.     

儿童假丝酵母感染状况分析及药物敏感性研究

目的:探讨儿童假丝酵母的感染情况,分析其对常用抗真菌药物的敏感性,为真菌感染的治疗和预防提供依据。方法:收集临床假丝酵母感染患儿标本77例,进行菌株的分离、鉴定。并从患儿年龄、基础疾病及标本来源、检出病原菌种类、菌株药物敏感性等方面进行分析。结果:真菌感染患儿的平均年龄为6岁。标本主要来源于咽拭子,白假丝酵母的分离率最高(63.6%),其次为光滑假丝酵母、热带假丝酵母、克柔假丝酵母和其他假丝酵母。药物敏感性实验结果表明,假丝酵母对两性霉素B(AmB)、5-氟胞嘧啶(5-FC)的敏感性较高。其中,白假丝酵母对AmB、5-FC、氟康唑(FCZ)及伊曲康唑(ICZ)的敏感率依次为100.0%、91.9%、83.7%、69.4%;对ICZ、FCZ、5-FC的耐药率依次为4.1%、2.0%、2.0%。结论:儿童真菌感染以白假丝酵母最多见,分离菌株对FCZ和ICZ的耐药性较高,临床医生应高度重视,并根据药物敏感性实验结果进行治疗和预防。     

Antifungal activity of the honeybee products against Candida spp. and Trichosporon spp

Honeybee products (honey, royal jelly, pollen, and propolis) were evaluated for their ability to inhibit the growth of 40 yeast strains of Candida albicans, Candida glabrata, Candida krusei, and Trichosporon spp. The broth microdilution method was used to assess the antifungal activity of honeybee products against yeasts. Fluconazole was selected as the antifungal control agent. Using the broth microdilution method, minimal inhibitory concentration ranges with regard to all isolates were 5-80% (vol/vol), 0.06-1?μg/mL, 0.002-0.25?μg/mL, 0.006-0.1?μg/mL, and 0.02-96?μg/mL for honey, royal jelly, pollen, propolis, and fluconazole, respectively. The antifungal activities of each product decreased in the following order: propolis >pollen?>?royal jelly?>?>?honey. This study demonstrated that honeybee products, particularly propolis and pollen, can help to control some fluconazole-resistant fungal strains.