卡泊芬净治疗55例恶性血液病患者侵袭性真菌感染的安全性研究

目的:评价卡泊芬净治疗血液病患者侵袭性真菌感染的疗效及安全性。方法:采用回顾性分析法统计本院2005年8月—2006年9月住院患者使用卡泊芬净的疗效和不良事件。结果:55例病历分析中显示卡泊芬净总有效率为57.1%,药物相关的不良反应发生率低且较轻。结论:卡泊芬净抗菌谱广,疗效确切,安全性好,是血液病患者抗真菌经验治疗的较为理想药物。     

A comparative evaluation of properties and clinical efficacy of the echinocandins

With the increase in prevalence of fungal infections, newer antifungal agents are needed to effectively treat invasive disease, and at the same time minimize adverse effects from therapy. The echinocandins comprise a novel class of antifungals; their mechanism of action involves inhibiting 1,3-β-D-glucan synthase, which is essential in cell wall synthesis for certain fungi. All three echinocandins are US FDA-approved for the treatment of esophageal candidiasis. Caspofungin and anidulafungin are licensed for the treatment of candidemia, and other select forms of invasive candidiasis. Micafungin is at present the only echinocandin approved for prophylaxis of fungal infections in hematopoietic stem cell transplants; whereas caspofungin is approved for empiric therapy of febrile neutropenia. Although all three echinocandins are active against Aspergillus, only caspofungin is presently approved for salvage therapy in invasive aspergillosis. Combination therapy with echinocandins plus other licensed antifungal therapy shows promise in treating invasive aspergillosis. This article will explore the similarities and differences among the echinocandins.     

棘白菌素的临床用药进展

棘菌素类抗真菌药物靶向作用于真菌细胞壁,具有独特的抗真菌效应。该类抗真菌药物如卡泊芬净（caspofungin）、米卡芬净（micafungin）和阿尼芬净（anidulafungin）对念珠菌属、曲霉菌属以及某些对唑类药物耐药的真菌菌种具有良好的抗菌活性。本文主要综述棘白菌素类药物临床应用进展。     

Emerging echinocandins for treatment of invasive fungal infections

The echinocandins are a new class of antifungals, developed in response to the need for safe and effective antifungals for the treatment of invasive fungal infections. These agents work by inhibiting 1,3-beta-d-glucan synthase, an enzyme essential for production of cell walls in select fungi. Echinocandins appear to demonstrate favourable activity in vitro against a variety of yeasts (including both Candida albicans and non-albicans Candida) as well as select moulds (including Aspergillus spp.) In general, all echninocandins demonstrate a favourable safety profile and require once-daily parenteral administration. Caspofungin is the first of these agents to be available in the US, and is approved for empirical antifungal therapy in febrile neutropenic patients, candidaemia and select forms of invasive candidiasis, and for management of invasive aspergillosis in patients refractory to or intolerant of other therapies. Micafungin was recently approved by the FDA for treatment of oesophageal candidiasis, and for the prophylaxis of fungal infections in haematopoietic stem cell transplant recipients. Emerging data indicate micafungin may have an important role in the treatment of invasive forms of candidiasis. Anidulafungin is an echinocandin approved in the US for treatment of candidaemia and oesophageal candidiasis. Aminocandin (HMR-3702, IP-960) is an investigational agent, with published experience limited to in vitro studies and animal models of infection.     

新型抗深部真菌感染药物——棘白霉素类

棘白霉素类(卡泊芬净、米卡芬净、阿尼芬净)抗真菌药是最新型的1种广谱抗真菌药,作用于真菌细胞壁,对于念珠菌属以及曲霉菌属均有效,使用安全性较高。该文主要综述了棘白霉素类药物的作用机制、适应证、抗菌谱、药动学、药物相互作用及不良反应。     

卡泊芬净用于侵袭性真菌病的药物经济学系统评价

目的:系统评价卡泊芬净用于侵袭性真菌病(invasive fungal disease,IFD)治疗的经济性,为医院药品和医保目录遴选提供循证依据.方法:计算机检索PubMed、Embase、Cochrane Library、万方数据、中国生物医学文献数据库、中国知网和卫生技术评估相关网站,查询建库至2021年10月公...     

Recent advances and challenges in the treatment of invasive fungal infections

The frequency of invasive fungal infections (IFIs) has increased over the last decade with the rise in at-risk populations of patients. The morbidity and mortality of IFIs are high and management of these conditions is a great challenge. With the widespread adoption of antifungal prophylaxis, the epidemiology of invasive fungal pathogens has changed. Non-albicans Candida, non-fumigatus Aspergillus and moulds other than Aspergillus have become increasingly recognised causes of invasive diseases. These emerging fungi are characterised by resistance or lower susceptibility to standard antifungal agents. Invasive infections due to these previously rare fungi are therefore more difficult to treat. Recently developed antifungal agents provide the potential to improve management options and therapeutic outcomes of these infections. The availability of more potent and less toxic antifungal agents, such as second-generation triazoles and echinocandins, has led to considerable improvement in the treatment of IFIs. This article reviews the changing spectrum of invasive mycosis, the properties of recently developed antifungal agents and their role in the management of these infections.     

侵袭性真菌感染风险评分系统的建立及效能分析

目的:建立一个识别侵袭性真菌感染(invasive fungal infection,IFI)高风险人群的风险评分系统,并验证其有效性.方法:对模型组103例病人的病例资料进行单因素及logistic多重回归分析,筛选出IFI的危险因素并分别赋值,建立IFI风险评分系统.运用该评分系统计算41例IFI病人的综合得分,比较各得分组IFI实际发生率的差异,运用接收者工作特征曲线(receiver operating characteristic curve,ROC)评价该评分系统的效能.结果:糖尿病、胃肠道手术、血液系统恶性肿瘤、机械通气治疗>3 d、广谱抗生素治疗>5 d、深静脉导管植入是IFI的危险因素.模型组和验证组中得分越高的病例发生IFI的几率越大,且高、中、低得分组的IFI发生率的差异有统计学意义(P<0 05).模型组ROC曲线下面积为0 816,验证组ROC曲线下面积为0 811.结论:该评分系统能够有针对性地帮助临床医师识别IFI高风险人群,指导对病人的及时治疗.     

Recent advances in the treatment of life-threatening,invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative.

Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole.

Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.     

The echinocandin antifungals: an overview of the pharmacology,spectrum and clinical efficacy

For over four decades, the principal target of antifungal therapy has been the fungal cell membrane sterol ergosterol. Although this has proven to be a successful and relatively selective antifungal target, collateral toxicity to mammalian cells (amphotericin B) and drug interactions (azoles) have been by-products of agents that target the fungal cell membrane. In the 1970s, the echinocandins were identified during the screening of fungal fermentation products for new antibiotic agents. These agents were subsequently shown to inhibit production of β(1,3)-glucan, a key structural component of the fungal cell wall. Subsequent chemical modification of these natural products has led to the development of safer, semi-synthetic β(1,3)-glucan synthase inhibitors with enhanced microbiological and clinical efficacy against infections caused by Candida and Aspergillus species. In this review, the pharmacology, spectrum and clinical efficacy of the three leading β(1,3)glucan synthase inhibitors (caspofungin, micafungin and anidulafungin), which have completed phase III clinical trials, will be discussed and a perspective for the role of these agents in the management of life-threatening mycoses will be offered.     

棘白霉素类抗真菌药的研究进展

棘白霉素类抗真菌药是一类新型抗真菌药，作用于真菌细胞壁，对于念珠菌属以及曲霉菌属均有效，而且安全性较高。目前开发的品种有卡泊芬净、米卡芬净、阿尼芬净，均已通过FDA认证上市。现从作用机制、抗菌活性、药动学、临床评价、药物相互作用和不良反应等几方面对其做一综述。     

Anidulafungin and voriconazole in invasive fungal disease: pharmacological data and their use in combination

The incidence of invasive fungal infections has been increasing since the 1980s due to a growing population of immunocompromised and critically ill patients with associated risk factors including immunosuppressive chemotherapy, prolonged periods on intensive care units and infection with HIV. Persons who are severely immunocompromised are particularly vulnerable to infection from molds and yeasts that are often found naturally in the environment. In recent years, several new systemic antifungal agents have been released, significantly increasing options for the treatment of the most serious fungal infections. Newly available drugs as those in the echinocandin class include caspofungin, micafungin and anidulafungin, as well as the newer generation triazoles, voriconazole and posaconazole. In this review, the in vitro and in vivo activity of anidulafungin and voriconazole, both new antimycotic substances with a different mode of action, are analyzed.     

儿童深部真菌感染的治疗

目的：探讨儿童深部真菌感染的治疗。方法：回顾性分析14例经病原学检查确诊的儿童深部真菌感染的临床资料。结果：14例患儿中11例为新隐球菌脑膜炎，3例为新隐球茵全身感染；13例给予抗真菌治疗，其中2例单用氟康唑(F1u)，另11例用二性霉素B(AMB)或脂质体二性霉素B(L-AMB)联合氟康唑或5-氟胞嘧啶(5-FC)，3例治愈。7例好转。结论：新隐球菌是儿童深部真菌感染的常见病原，AMB联合5-FC或Flu是治疗儿童深部真菌感染的主要方案。     

Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections

Background:

Voriconazole is a broad-spectrum, second-generation triazole antifungal agent with demonstrated efficacy in the treatment of invasive fungal infections caused by Aspergillus spp. and Candida spp. Given the characteristically poor prognosis of patients with invasive fungal infections and the protracted duration of treatment required, therapeutic monitoring of voriconazole is, in theory, an attractive method to optimize antifungal therapy.

Objective:

To determine the utility of therapeutic drug monitoring for voriconazole.

Methods:

A previously published decision-making algorithm was used to assess the currently available literature on therapeutic drug monitoring of voriconazole.

Results:

Several analytical methods can be used to quantify plasma or serum concentrations of voriconazole. Reasons for therapeutic monitoring of this drug include wide variability both within and between individuals secondary to drug properties, drug–drug interactions, and disease states. Furthermore, voriconazole follows nonlinear pharmacokinetics with saturable hepatic clearance. Another potential factor in favour of therapeutic drug monitoring for voriconazole is genetic polymorphism of CYP2C19, whereby patients who are homozygous for poor metabolism (about 19% of non-Indian Asians) can have 4-fold greater exposure to voriconazole. The concentrations of this drug are also greater in patients with hepatic impairment. Drug–drug interactions with other substrates of CYP2C9, CYP2C19, and CYP3A4 can also alter voriconazole concentrations. However, the correlations between plasma concentrations of voriconazole and its efficacy and toxicity are not well defined. Although lower and upper target thresholds of 0.25–2 mg/L and 4–6 mg/L, respectively, have been suggested, studies to date have not been appropriately designed or powered to reveal any definitive association.

Conclusions:

Routine therapeutic drug monitoring of voriconazole is not recommended except in certain circumstances, such as lack of response to therapy or evidence of toxicity, in which case selective monitoring of voriconazole concentrations may be of clinical utility.     

伏立康唑治疗儿童侵袭性肺部真菌感染疗效观察

目的：探讨伏立康唑治疗儿童侵袭性肺部真菌感染（IPFI）的临床效果及安全性。方法：收集我院儿科呼吸病房2018年2月至2019年1月收治的IPFI患儿88例,采用随机数表法分为伏立康唑组和米卡芬净组各44例,分别选用伏立康唑和米卡芬净进行治疗,疗程均为4~6周,比较两组患儿的临床疗效与不良反应发生率。结果：伏立康唑组总有效率93.18%,高于米卡芬净组的77.27%;临床症状消退时间、痰培养转阴时间、影像学病灶吸收时间均短于米卡芬净组（P均<0.05）,两组不良反应发生率比较差异无统计学意义（P>0.05）。结论：伏立康唑治疗儿童IPFI的临床疗效优于米卡芬净,且用药安全,可作为儿童IPFI的有效抗真菌药物在临床上推广应用。     

CYP2C19基因多态性对侵袭性真菌感染重症患者伏立康唑血药浓度的影响

目的:研究CYP2C19基因多态性与侵袭性真菌感染重症患者伏立康唑标准化血药浓度的关系,为临床合理用药提供参考。方法:运用PCR-RFLP方法对患者CYP2C19 2(681G→A)和CYP2C19 3(636 G→A)位点进行基因型分析;使用HPLC法检测49名侵袭性真菌感染患者的伏立康唑血药浓度;并对伏立康唑血药浓度检测结果、药物疗效和不良反应与基因分型结果进行统计学分析。结果:49名患者中,同时分析CYP2C19两个位点,共有5种双位点基因型组合,包括强代谢型(extensive metabolizer,EM)的681GG-636GG、中等代谢型(intermediate metabolizer,IM)的681GA-636GG和681GG-636GA以及慢代谢型(poor metabolizer,PM)的681AA-636GG和681GA-636GA,其分布频率分别为14.29%,53.06%,8.16%,14.29%和10.2%。EM组、IM组和PM组的标准化血药浓度存在显著性差异(P<0.05),且PM组显著高于IM组,IM组显著高于EM组(P<0.05)。此外,基因多态性对各组间的药物疗效(P<0.05)和不良反应(P<0.05)均具有显著性影响。结论:CYP2C19基因多态性对伏立康唑血药浓度、疗效和不良反应产生显著影响,表明药物遗传学研究对伏立康唑临床合理用药具有重要的指导意义。     

CD64与G实验联用在诊断侵袭性真菌感染中的检测价值分析

目的 观察和分析全血中性粒细胞CD64与血浆G实验联合检测在诊断侵袭性真菌感染(IFI)中的价值.方法 选取100例疑似IFI住院患者作为研究对象,根据是否被最终诊断为IFI将其分为病例组(41例)和对照组(59例),对2组患者全血中性粒细胞CD64水平和G实验[血浆(1,3)-β-D葡聚糖]水平进行观察和比较.结果 病例组患者全血中性粒细胞CD64水平显著高于对照组(t=5.564,P＜0.01),全血中性粒细胞CD64检测诊断IFI的受试者工作特征曲线下面积为0.782;全血中性粒细胞cd64检测与G实验检测结果具有相关性(x2=72.074,P＜0.01),诊断IFI的Kappa值为0.848(t=8.490,P＜0.01),McNemar检验结果显示P=0.688;单独应用全血中性粒细胞CD64检测与单独应用G实验检测的敏感性均显著低于联合检测(x2=6.011、10.818,P＜0.05),三种方法诊断IFI的特异性差异无统计学意义(x2=1.883,P＞0.05).结论 全血中性粒细胞CD64检测在诊断IFI中具有一定的价值,联合应用全血中性粒细胞CD64检测和G实验可提高针对IFI的诊断敏感性.     

侵袭性真菌感染的经验性和抢先治疗

侵袭性真菌感染（invasive fungal infection, IFI）更趋常见,其原因除广谱抗生素的应用以及肿瘤放疗和化疗、造血干细胞移植、器官移植和免疫功能缺陷患者增多等外,最主要的是新的诊断真菌感染的临床实验室技术、尤其是半乳甘露聚糖试验和（1,3）-β-D-葡聚糖试验的应用逐渐普及,为临床诊断IFI提供了坚实的基础。此外,IFI的影像学特征也成为诊断IFI的一个重要条件。与经验性抗真菌治疗相比,这些实验室和影像学检查的阳性结果可提高诊断的可靠性,由此为真菌感染治疗提供更多的依据,同时减少抗真菌药物的滥用。     

Amphotericin B lipid complex for the treatment of invasive fungal infections

Amphotericin B lipid complex (ABLC; Abelcet^®, Enzon Pharmaceuticals) has become the dominant marketed lipid amphotericin B compound to emerge since the approval of these agents from the mid-1990s onwards. This agent is a 1:1 combination of amphotericin B and a lipid moiety consisting of dimyristoyl phosphatidylcholine and dimyrisoyl phosphatidylcholine, which exists in a ribbon-like molecular structure. ABLC undergoes rapid reticuloendothelial uptake from the circulation and achieves significantly higher tissue concentrations in the liver, spleen and lung compared to comparably dosed conventional amphotericin B. ABLC is approved by the FDA for all mycoses in amphotericin B-intolerant or -refractory infection. Randomised, controlled trials of amphotericin B have shown comparable efficacy in candidiasis and an improved outcome in invasive aspergillosis versus historical controls. ABLC has demonstrated a reduced incidence of nephrotoxicity and infusion reactions versus amphotericin B. Comparative studies against other lipid formulations are quite limited and have shown variable differences in infusion toxicity, nephrotoxicity, hepatotoxicity and clinical efficacy. Postapproval experience has shown substantial efficacy for less common mycotic pathogens including zygomycosis. The precise position of ABLC versus both other lipid formulations and expanding formulary of new antifungal agents is in flux. Future studies which examine its clinical efficacy, role in combination therapy, toxicity and cost-effectiveness in these complex patients are needed.     

Anidulafungin: an evidence-based review of its use in invasive fungal infections

Introduction:

Anidulafungin is a new echinocandin antifungal agent with indications for use in esophageal candidiasis and candidemia. The mortality and morbidity associated with fungal infections in healthcare facilities necessitates the development of new treatment options for these diseases.

Aims:

This review assesses the pharmacology and evidence for the use of anidulafungin in the treatment of serious fungal infections.

Evidence review:

There is substantial evidence that anidulafungin is a potent antifungal agent with activity against a broad range of fungal species. Likewise, evidence supports that anidulafungin is a well-tolerated antifungal agent. Clinical studies provide sufficient evidence for regulatory approval for esophageal candidiasis and candidemia, and limited evidence suggests that anidulafungin may be superior to fluconazole for candidemia and invasive candidiasis. The introduction of anidulafungin into clinical practice adds a third option for therapy in the echinocandin class. Research into its efficacy in other fungal infections is ongoing, and further studies into the impact of anidulafungin on economic outcomes will be beneficial.

Place in therapy:

Current evidence supports the use of anidulafungin in the management of candidemia, esophageal candidiasis, and invasive candidiasis, as demonstrated by the successful results in large multicenter clinical trials.