侵袭性真菌感染的分子诊断现状

近年来陧袭性真菌感染的发病率不断升高,侵袭性真菌感染的早期、准确诊断对于合理选用抗真菌药物,提高抗真菌疗效至关重要：另外,及时诊断侵袭性真菌感染可以减少经验性抗真菌治疗,降低抗真菌药物的选择性压力,     

白念珠菌生物膜耐药机制及中药治疗的研究进展

近几年来,由于临床诊治时滥用抗生素、糖皮质激素等药物,导致各种真菌对抗真菌药物的耐药性日渐增强,后续治疗可供选择药物愈来愈少,这类真菌感染性问题的解决迫在眉睫。临床上经常使用的抗真菌药物主要有氟康唑、伏立康唑、酮康唑等。其中氟康唑常被选作治疗真菌感染的药物,但长期使用,不但会导致耐药性大大增加,而且在耐受氟康唑类药物后真菌也会对其他抗真菌药物产生一系列交叉耐药性[1]。因此,目前有许多中药研究是在与氟康唑类药物协同作用的基础上进行抗耐药试验的[2-5]。     

294株白念珠菌药物敏感试验及耐药性分析

近年来,随着临床使用大量抗生素、免疫抑制剂和糖皮质激素治疗严重感染、肿瘤及自身免疫病,人体菌群失调和真菌感染发生率持续升高.同时,抗真菌药物的频繁应用亦造成真菌耐药性日益增多,真菌感染成为医院感染的主要病原体之一.真菌感染中以白念珠菌（Candida albicans）比例最高,本文对本院2012年1～12月送检的临床标本常规培养分离,共分离的白念珠菌294株,其药物敏感试验及耐药性分析如下.     

侵袭性曲霉病的临床诊断评价

近20年来随着肿瘤大剂量化疗、造血干细胞和实体器官移植的发展,机会性真菌感染发病率逐年增加,其中侵袭性曲霉病是肿瘤和移植患者死亡的重要原因。尽管不断有新的抗真菌药物问世,侵袭性曲霉病总体治愈率仅为50％左右^[1]。主要原因是早期诊断困难,导致抗真菌治疗的延误。2002年欧洲癌症-侵袭性真菌感染治疗研究协作组和美国国立变态反应和感染病研究院真菌病研究组（EORTC／MSG）提出根据宿主因素、临床特征、真菌学证据及组织病理,将侵袭性真菌病的诊断分为3级,即确诊、拟诊和疑诊,为临床研究和流行病学研究制定出规范的诊断标准^[2]。     

三唑类抗真菌新药泊沙康唑和伏立康唑简介

随着侵袭性真菌感染的发病率和死亡率逐年增多,新近问世的新型抗真菌药物也越来越多。新一代广谱三唑类抗真菌药物泊沙康唑和伏立康唑,在体内和体外均有较强的抗真菌活性,临床上用其来预防和治疗侵袭性真菌感染。两药具有共有的作用机制,在抗真菌活性、药物代谢及安全性方面有着各自特点。分子结构上泊沙康唑和伏立康唑优于原有药物伊曲康唑和氟康唑,从而具备更强、更广的抗菌谱。两药的研发和应用表明抗真菌药物研究正朝着高效、广谱、低毒的方向发展,成为治疗各种类型真菌感染新的有力手段。然而,两药在临床研究和血药浓度监测方面仍待深入探究。本文将从分子结构、作用机制、适应症和药代动力学方面介绍两药,并对两药在未来的临床应用进行展望,为临床应用提供帮助。     

几种新型抗真菌药物简介

脂质型二性霉素B,新型唑类药物如伏立康唑,以及作用于真菌细胞壁的药物如卡泊芬净和米卡芬净的问世,反映了抗真菌药物研究向高效、广谱、低毒的方向发展的一个特点,无疑为各种类型真菌感染的药物治疗提供了新型的有力的手段;与传统的抗真菌药物如脱氧胆酸二性霉素B和氟康唑等相比,这些药物临床疗效好,毒副作用低,对于系统性真菌感染的防治具有重大意义,文中就这方面的信息做了简介。     

念珠菌分离鉴定及耐药性分析

目的 了解念珠菌在临床标本中的分布情况及常用抗真菌药物的敏感性,为临床使用抗真菌药提供依据.方法 对2003年至2005年各种临床标本中分离的244株念珠菌进行鉴定,用真菌药敏卡做念珠菌对8种抗真菌药物的药敏试验,结合临床资料综合分析.结果 痰液标本念珠菌检出率最高达60.7%,其次是分泌物为19.3%.共分离白色念珠菌142株,占58.2%,热带念珠菌54株,占22.1%,敏感性较高的药物是5-FC、NYS、AMB,灰黄霉素耐药率最高,达到70%以上.结论 肿瘤,免疫功能低下,病情严重,意识障碍,长期卧床的患者念珠菌感染以白色念珠菌为主,长期使用抗生素是患者真菌感染的主要原因,真菌药敏试验可为临床治疗提供依据.     

天然植物抗假丝酵母菌活性成分的研究

临床真菌感染的发病率和死亡率逐年上升,其中以假丝酵母菌为代表的侵袭性真菌感染尤为严重,目前主要抗真菌药物的耐药性日趋严重,且多数具有毒副作用,寻找安全有效的新型抗真菌药物迫在眉睫。天然植物中抗真菌活性成分来源广泛,具有低毒、广谱、作用途径多样化等优点,成为新型抗真菌药物的一个重要研究方向。本文主要综述了近年来从天然植物中筛选抗假丝酵母菌活性成分的研究。     

院内150例真菌感染及其耐药性分析

目的研究院内真菌感染的特点及耐药状况。方法对临床标本分离的真菌,用TAB Expression鉴定仪鉴定,E—test抗真菌药敏试纸条进行药敏试验。结果150株真菌共有14个种,以白色念珠菌为主．占45．3％。各种真菌对6种抗真菌药物均有不同程度的耐药。结论院内真菌感染呈上升趋势,并且产生一定的耐药株。     

天然化合物抗真菌活性研究进展

近年来,真菌感染患者的发病率和死亡率持续上升,但现有抗真菌药物种类依然非常少,并且耐药现象的出现使临床可选择的抗真菌药物变得更加有限.因此,对新的抗真菌药物的开发迫在眉睫,从天然产物中寻找新型高效的抗真菌药物成为目前的研究热点之一.从天然产物中筛选出具有抗真菌活性的天然化合物,有助于扩大治疗真菌感染疾病的可选药物种类,减少耐药的发生.该文归纳现有报道的具有抗真菌活性的化合物,根据其不同来源及不同化学结构进行分类,阐明不同类别天然化合物的抗真菌作用机制,为开发新型高效抗真菌药物提供前体结构及抗真菌新靶点.     

The role of antifungal susceptibility testing in the management of patients with invasive mycoses

The availability of standardized antifungal susceptibility testing methodologies as well as the definition of interpretative breakpoints have made possible the establishment of useful correlations between in vitro testing data and clinical results with antifungal drugs such as fluconazole and itraconazole in patients with oropharyngeal candidiasis. The results obtained in these studies, however, can not be extrapolated to other organisms or clinical syndromes. Although there has been some recent progress, the interpretations of in vitro and in vivo results obtained in patients suffering cryptococcosis or invasive candidiasis needs to be further defined in order to establish meaningful clinical-laboratory correlations. Furthermore, the method needs to be fully standardized in case of filamentous fungi. It can be anticipated that the development, standardization and validation of in vitro antifungal susceptibility testing will guide clinicians in the management of patients with invasive mycoses.     

The fungal cell wall as a target for the development of new antifungal therapies

In the past three decades invasive mycoses have globally emerged as a persistent source of healthcare-associated infections. The cell wall surrounding the fungal cell opposes the turgor pressure that otherwise could produce cell lysis. Thus, the cell wall is essential for maintaining fungal cell shape and integrity. Given that this structure is absent in host mammalian cells, it stands as an important target when developing selective compounds for the treatment of fungal infections. Consequently, treatment with echinocandins, a family of antifungal agents that specifically inhibits the biosynthesis of cell wall (1-3)β-D-glucan, has been established as an alternative and effective antifungal therapy. However, the existence of many pathogenic fungi resistant to single or multiple antifungal families, together with the limited arsenal of available antifungal compounds, critically affects the effectiveness of treatments against these life-threatening infections. Thus, new antifungal therapies are required. Here we review the fungal cell wall and its relevance in biotechnology as a target for the development of new antifungal compounds, disclosing the most promising cell wall inhibitors that are currently in experimental or clinical development for the treatment of some invasive mycoses.     

Present and future of voriconazole in the treatment of invasive mycoses: the inseparable binomial diagnosis-treatment

Two milestones have characterized the last decades in Medical Mycology: the continuous increase in incidence of invasive mycoses and the discovery of new antifungal drugs that have allowed the successful treatment of these severe infections. This monography presents the most relevant studies on the present situation of invasive mycoses, its diagnosis and treatment, as well as data confirming the important role of voriconazole in their treatment.     

Clinical application of antifungal pharmacodynamics

Studies of pharmacodynamics are used to develop dosing regimens that maximize safety and efficacy in clinical practice. Antifungal pharmacodynamics is a growing field, and studies are increasingly moving from the in vitro phase to animal models to clinical evaluations. Preclinical studies that determine pharmacodynamic predictors of efficacy and safety provide valuable data in the determination of a dosage regimen, but evaluations of antifungal pharmacodynamic parameters in vivo are less common. This article reviews areas where antifungal pharmacodynamics has been evaluated in clinical trials to develop principles that may be used in the pharmacotherapy of invasive mycoses.     

Update on Amphotericin B Pharmacology and Dosing for Common Systemic Mycoses

Amphotericin B (AMB) has been used for nearly five decades in the treatment of life-threatening mycoses. While triazoles and echinocandins have largely supplanted the routine use of AMB for common Candida and Aspergillus infections, this prototypical broad-spectrum agent or its lipid formulations are still preferred by many clinicians as the initial empiric antifungal therapy for severely immunosuppressed patients, and remain the preferred treatment in combination with 5-fluorocytosine for cryptococcal meningioencephalitis. This article reviews progress over the last decade in understanding the pharmacology and clinical dosing of AMB formulations for common systemic mycoses, including invasive candidiasis, cryptococcosis, aspergillosis and mucormycosis.     

Aspectos actuales de las enfermedades invasivas por hongos filamentosos

Invasive fungal infections have become a major cause of morbimortality in intensive care patients, persons suffering from cancer or immune deficiencies, and other diseases with impaired immunity. Candida albicans remains the most frequent fungal pathogen, but advances in the diagnosis, prevention and treatment of invasive candidiasis are leading to important etiological changes. Among the emerging invasive mycoses, are those caused by filamentous fungi, such as Aspergillus, Lomentospora/Scedosporium, Fusarium or the Mucorales. Invasive aspergillosis is difficult to diagnose, and although there are diagnostic tools available, their use is not widespread, and their effectiveness vary depending on the group of patients. Clinical suspicion in high-risk patients, radiological diagnosis and the use of biomarkers, such as 1,3-β-D-glucan and galactomannan, can be of great help. However, diagnostic resources are limited in other mycoses, but radiology, pathological studies and the microbiological diagnosis can be useful. The high mortality of these mycoses requires early empirical antifungal treatment in many cases. Voriconazole is the first choice for treatment of the majority of aspergillosis, scedosporiasis, fusariosis and other hyalohyphomycoses. The treatment of mucormycoses, Lomentospora prolificans infections or mycoses by dematiaceous fungi are more complicated. Amphotericin B is active against many mucoralean fungi, but the combination of two or more antifungal agents could be a therapeutic alternative in many amphotericin B-refractory mycoses. Current clinical challenges include improving the diagnosis and the treatment of these mycoses, along with improving the adequate prevention in patients at high risk of suffering from them.     

In vitro antifungal activity of voriconazole: New data after the first years of clinical experience

Voriconazole has been developed to meet the increasing need for new and useful antifungal agents for the treatment of invasive mycoses. This review describes the spectrum of voriconazole antifungal activity based on data from in vitro studies published during the last three years. This survey demonstrates that voriconazole has a broad antifungal spectrum against the most common fungal pathogens being its action fungistatic for Candida and fungicidal for Aspergillus and other filamentous fungi. Overall, more than 95% of all Candida isolates tested are susceptible to voriconazole and less than 3% are resistant. Similar or even better activity rates have been described for Aspergillus, Cryptococcus and most of yeasts and moulds of medical importance. We also discuss the limitations related to the azole cross-resistance observed in some Candida glabrata isolates, the poor activity of voriconazole against Scedosporium prolificans, its activity against fungal biofilms and the great potential usefulness of combination of voriconazole with other antifungal drugs.     

Clinical efficacy of new antifungal agents

Several new options are now available for treating serious fungal infections. All three echinocandin agents currently available have been shown in randomized, blinded clinical trials to be efficacious in treating candidemia and invasive candidiasis. By contrast, the demonstrated efficacy of the echinocandins for the treatment of invasive aspergillosis has been based on historically controlled salvage treatment trials in patients failing or intolerant of other therapies. The new triazole agents, voriconazole and posaconazole, have a broad spectrum of antifungal activity. Voriconazole has become the agent of choice for invasive aspergillosis. On the basis of compassionate treatment data, posaconazole appears to be effective for treatment of zygomycosis. These agents have also been shown to be effective in the treatment of non-Aspergillus mould infections, several of the endemic mycoses and serious Candida infections.     

In vitro antifungal activity of voriconazole against dermatophytes and superficial isolates of Scopulariopsis brevicaulis

We have studied the in vitro antifungal activity of voriconazole, fluconazole and itraconazole against 252 clinical isolates of dermatophytes and Scopulariopsis brevicaulis by a standardized agar diffusion method (NeoSensitabs). Several important factors such as temperature (28 degrees C vs. 35 degrees C) and incubation time (2-10 days vs. 18-74 h) were adapted to dermatophytes and Scopulariopsis requirements. Voriconazole showed an excellent activity against most species of dermatophytes, higher than itraconazole and fluconazole. However, S. brevicaulis isolates were highly resistant to all azoles used in this study. Voriconazole might be an interesting antifungal alternative to refractory superficial mycoses.     

In vitro antifungal activity of anidulafungin

Anidulafungin is a new and very useful pharmacological tool for the treatment of invasive mycoses. The antifungal spectrum of anidulafungin reaches the most common pathogenic fungi. Anidulafungin is especially active against the genera Candida and Aspergillus. Its antifungal mechanism is based on the inhibition of the beta-1,3-D-glucan synthesis, an essential molecule for the cell wall architecture, with different consequences for Candida and Aspergillus, being anidulafungin fungicide for the former and fungistatic for the latter. This review describes the in vitro antifungal spectrum of anidulafungin based in the scientific and medical literature of recent years. We can underline that most than 99% of Candida isolates are susceptible to < or = 2 microg/ml of anidulafungin. MIC are very low (< or =0.125 microg/ml) for most clinical isolates of the species Candida albicans, Candida glabrata, Candida tropicalis and Candida krusei while Candida parapsilosis and Candida guilliermondii isolates are susceptible to anidulafungin concentrations < or = 2 microg/ml. An excellent activity of anidulafungin has been also described against Aspergillus, Pneumocystis and other fungi. However, its activity is very low against Cryptococcus and the Zygomycetes. The excellent activity of anidulafungin has made this antifungal a first line therapeutic indication for candidemia and invasive candidiasis in non-neutropenic patients.