棘白菌素类抗真菌药的研究新进展

近年来棘白菌素类抗真菌药发展很快,有多个广谱、低毒、高效的新化合物进入临床研究.本文综述了棘白菌素类抗真菌药研究的最新进展,介绍了三个新药物：卡波芬净,米卡芬净,安多芬净,并与其他抗真菌药作对比,均显示其独特优点.     

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。     

抗真菌药

棘白菌素类抗真菌药 棘白菌素(echinocandine)是新型抗菌机制的抗真菌药.本类药物中已上市的为卡泊芬净,尚在临床研究阶段的有阿尼芬净和米卡芬净.     

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。     

卡泊芬净治疗IFI的临床研究进展

卡泊芬净为棘球白素类抗真菌药，也是第一个在全世界范围使用的棘球白素，目前已在75个国家被广泛使用。卡泊芬净可以抑制真菌细胞壁上β1，3葡聚酶的合成。在体内外均有抗假丝酵母属和曲霉属真菌的能力。其药代动力学特点允许每日1次用药，药物交叉反应很少。患耐受性好。上市5年中安全性极好。     

新药述评棘白菌素类抗真菌药米卡芬净的药理与临床评价

采卡芬净（FK463）是第2个棘白菌素类抗真菌药物，在体内、外对曲霉菌、念珠菌均有抗新活性。现对其药理作用、药动学、临床评价以及不良反应等做一综述。     

新型棘白菌素类抗真菌药阿尼芬净

阿尼芬净(anidulafungin,VER-002;LY303366),是第三代棘白菌素类的半合成抗真菌药,是两性霉素B的衍生物,由美国Vicuron制药公司研制,同其他棘白菌素类抗真菌药比较,分布容积更大,抗菌谱更广,目前在美国处于Ⅲ期临床试验阶段.介绍阿尼芬净的作用机制、药效学、药动学和临床评价.     

新型抗真菌药卡泊芬净的临床应用

目前适于全身抗真菌感染的药物主要有：多烯类（两性霉素B）、吡咯类（酮康唑、伊曲康唑、氟康唑、伏立康唑）、氟嘧啶类（5-氟尿嘧啶）等3类。丙烯胺类如特比萘芬因疗效低不宜单独给药，仅与吡咯类联用于耐吡咯类的霉菌感染。这些药物都有治疗价值，但存在疗效欠佳或难以耐受的不良反应等问题，加上耐药菌株的出现，因此临床上迫切需要开发出高效、低毒、广谱的抗真菌药。卡泊芬净即是新一类抗真菌药。     

棘白菌素类抗真菌药临床应用研究进展

棘白菌素类（echinocandins）是21世纪初开发的最新型的一类广谱抗真菌药,其通过抑制真菌细胞壁的β-（1,3）-D-葡聚糖的合成,破坏真菌细胞壁的完整性,导致真菌细胞溶解死亡,是一种具有全新作用机理的抗真菌药物,对很多耐唑类药物的真菌仍具有良好的抗菌活性。因其通过干扰真菌细胞壁的合成而产生抗真菌作用,而人体细胞没有细胞壁,所以该类药对人体的毒性较低,是迄今为止安全性最高的一类抗真菌药物,具有抗菌谱广、抗真菌作用强、半衰期长、不良反应少、患者耐受性好等特点。该类药对念珠菌为杀菌剂,对曲霉菌属于抑菌剂,无交叉耐药性,是目前用于治疗全身性真菌感染的一线药物。目前国外已上市的棘白菌素类抗真菌药有三种：卡泊芬净、米卡芬净和阿尼芬净,其中卡泊芬净已在国内上市。本文对棘白菌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等进行简要综述。     

棘白菌素类抗真菌药不良反应文献分析

目的 了解棘白菌素抗真菌药致药品不良反应类型及特点，为临床合理使用棘白菌素类抗真菌药提供参考和依据。方法 通过文献检索，收集《中国期刊全文数据库》、Pubmed等中英文数据库2000年—2022年6月棘白菌素类抗真菌致不良反应相关文献，剔除不符合要求的文献，进行归类整理与分析。结果 共检索到文献114篇，报道卡泊芬净、米卡芬净、阿尼芬净所致药物不良反应共2 870例。其中，报道卡泊芬净所致药物不良反应1 407例；米卡芬净所致药物不良反应734例；阿尼芬净所致药物不良反应729例。以引起消化系统、全身性反应、皮肤及附件不良反应多见。结论 临床注意合理选用棘白菌素抗真菌药，应尽可能避免或减少药物不良反应的发生，从而保障患者用药安全有效。     

The echinocandins

The changing pattern in fungal infections has driven the need to expand the targets of antifungal activity. The echinocandins are the newest addition to the arsenal against fungal infections. Three echinocandins have been approved by the United States Food and Drug Administration: caspofungin, micafungin, and anidulafungin. These agents have a broad spectrum of activity and are similar to each other with respect to in vitro activity against Candida sp, with micafungin and anidulafungin having similar minimum inhibitory concentrations (MICs) that are generally lower than the MIC of capsofungin. The MICs of the echinocandins are highest against Candida parapsilosis; however, whether this will affect clinical outcomes is unknown. Several case reports have identified clinical failure due to elevated MICs with caspofungin or micafungin against Candida albicans, Candida krusei, and C. parapsilosis. Resistance to the echinocandin class was present in some but not all of the isolates. Empiric therapy with one of the echinocandins for candidemia or invasive candidiasis in patients with neutropenia and those without neutropenia appears to be appropriate when one factors in mortality rate, the increasing frequency of non-albicans Candida infections, and the broad spectrum, safety, and fungicidal effect of the echinocandins. After speciation of the organism, continued therapy with an echinocandin can and should be reevaluated. The echinocandins demonstrate similar in vitro and in vivo activity against Aspergillus sp, but only caspofungin is approved for treatment in patients who are intolerant of or refractory to other therapies. Voriconazole and amphotericin B have demonstrated synergy with the echinocandins. The clinical response to combination therapy has been variable; however, the mortality rate appears to be lower with combination therapy than monotherapy. Large controlled trials are needed to determine the role of combination therapy for invasive aspergillosis. Micafungin and anidulafungin generally have a lower frequency of adverse reactions compared with caspofungin. Phlebitis (3.5-25% of patients) and elevated liver enzyme levels (1-15%) occur more often with caspofungin compared with micafungin and anidulafungin (< 8%). Overall, the three echinocandins are relatively safe and effective agents for the treatment of Candida infections.     

Echinocandin antifungal drugs in fungal infections: a comparison

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2?μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC??) values are typically <2?μg/mL but 100-fold higher MIC?? values are seen with Candida parapsilosis (1-2?μg/mL) and Candida guilliermondii (1-4?μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2?μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35?mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.     

New agents for the treatment of systemic fungal infections--current status

Systemic antifungal chemotherapy is enjoying its most dynamic era. More antifungal agents are under development than ever before, including agents in entirely new classes. Major goals of current investigations are to identify compounds with a wide spectrum of activity, minimal toxicity and a high degree of target specificity. The antifungal drugs in development include new azoles {voriconazole, posaconazole (formerly SCH-56592), ravuconazole (formerly BMS-207147)}, lipid formulations of amphotericin B, a lipid formulation of nystatin, echinocandins {anidulafungin (formerly, LY-303366, VER-002), caspofungin (formerly MK-991), micafungin (formerly FK-463)}, antifungal peptides other than echinocandins, and sordarin derivatives. This discussion reviews the currently available antifungal agents and summarises the developmental issues that surround these new systemic antifungal drugs.     

Update on antifungals targeted to the cell wall: focus on β-1,3-glucan synthase inhibitors

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targeted respectively to chitin synthase (nikkomycins), β-1,3-glucan synthase (echinocandins) and mannoproteins (pradimicins/benanomicins), have entered clinical development. While nikkomycins and pradimicins/benanomicins are no longer in development, echinocandins have emerged as potentially clinically useful and three compounds, caspofungin (MK-991, L-743,872), micafungin (FK-463) and anidulafungin (LY-303366) are in late clinical development (Phase II and III).     

Update on antifungals targeted to the cell wall: focus on beta-1,3-glucan synthase inhibitors

Currently available antifungal drugs for serious infections are either fungistatic and vulnerable to resistance (azoles) or fungicidal but toxic to the host (polyenes). Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development. Three classes of such compounds, targeted respectively to chitin synthase (nikkomycins), beta-1,3-glucan synthase (echinocandins) and mannoproteins (pradimicins/benanomicins), have entered clinical development. While nikkomycins and pradimicins/benanomicins are no longer in development, echinocandins have emerged as potentially clinically useful and three compounds, caspofungin (MK-991, L-743,872), micafungin (FK-463) and anidulafungin (LY-303366) are in late clinical development (Phase II and III).     

The safety of anidulafungin

The echinocandins are a new class of antifungal that have shown promising results in treating a variety of fungal infections. Anidulafungin is the newest approved echinocandin and may have some advantages over existing antifungals. It has activity against a broad range of fungi. It is unique because it undergoes a process of slow chemical degradation rather than being metabolised. Studies evaluating the use of anidulafungin in combination with other commonly used drugs have not demonstrated any significant drug–drug interactions or adverse events. Thus far, anidulafungin appears to have an excellent safety profile with few adverse events. Based on early clinical experience, it appears that anidulafungin will be a valuable and safe asset in the management of serious and difficult-to-treat fungal infections.     

Safety and interactions of new antifungals in stem cell transplant recipients

Introduction: Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Considerable progress in treating IFDs has been achieved over the last years, through the availability of new, effective drugs. However, many of these newer antifungal agents have some limitations, such as their variable toxicity and unique predisposition for pharmacokinetic drug-drug interactions. Areas covered: This article reviews the literature evaluating the safety profile of the lipid formulations of Amphotericin B, echinocandins, and second-generation triazoles. It also discusses the possible drug-drug interactions with some drugs commonly used in allogeneic HSCT. Expert opinion: Nephrotoxicity is the most frequent side effect of lipid formulations of Amphotericin B, which may cause a reduced clearance of the renally eliminated calcineurin inhibitors used for the control of Graft Versus Host Disease. Second-generation triazoles are characterized by a limited toxicity profile, but also by frequent drug-drug interactions with other drugs metabolized by the hepatic enzymes. The echinocandins are characterized by a very low toxicity profile and negligible interactions with other drugs. Such pharmacological knowledge is crucial in the daily care of allogeneic HSCT patients.     

The safety of anidulafungin

The echinocandins are a new class of antifungal that have shown promising results in treating a variety of fungal infections. Anidulafungin is the newest approved echinocandin and may have some advantages over existing antifungals. It has activity against a broad range of fungi. It is unique because it undergoes a process of slow chemical degradation rather than being metabolised. Studies evaluating the use of anidulafungin in combination with other commonly used drugs have not demonstrated any significant drug-drug interactions or adverse events. Thus far, anidulafungin appears to have an excellent safety profile with few adverse events. Based on early clinical experience, it appears that anidulafungin will be a valuable and safe asset in the management of serious and difficult-to-treat fungal infections.     

Caspofungin

Available systemically effective antifungal agents for the treatment of invasive fungal infections are few. With the increasing recognition of a need for newer antifungal drugs, caspofungin has been introduced as the first member of a new class of compounds called echinocandins. This paper reviews the chemistry and mechanism of action of caspofungin, its activity in vitro and in animal models, and clinical pharmacokinetics,clinical efficacy and safety in patients.     

Echinocandins in the management of invasive fungal infections, Part 2.

PURPOSE: The chemistry, pharmacology, spectrum of activity, resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse effects, drug interactions, dosage and administration, cost, and place in therapy of echinocandins are reviewed. SUMMARY: Three echinocandins are currently available: caspofungin, micafungin, and anidulafungin. The principal mechanism of action of the echinocandins is the noncompetitive inhibition of beta-(1,3)-D-glucan synthase, an essential component of the cell wall of many fungi that is not present in mammalian cells. Echinocandins exhibit fungicidal activity against Candida species, including triazole-resistant isolates, and fungistatic activity against Aspergillus species. While fungistatic against mold, echinocandins may hold promise for the treatment of these pathogens when given in combination with amphotericin B or broad-spectrum triazoles, such as voriconazole. To date, resistance to echinocandins has been reported in only two patients. Echinocandins exhibit concentration-dependent activity against Candida species. In clinical trials, caspofungin has demonstrated efficacy in treating candidemia, esophageal candidiasis, and febrile neutropenia. Micafungin has demonstrated efficacy as antifungal prophylaxis in hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis. Anidulafungin received approved labeling from the Food and Drug Administration in February 2006. Clinical efficacy data will be forthcoming. CONCLUSION: Echinocandins are fungicidal against yeast and fungistatic against mold. Their limited toxicity profile and minimal drug-drug interactions make them an attractive new option for the treatment of invasive fungal infections. Their cost may limit their use as initial therapy for patients with fungemia in medical centers or intensive care units with a high rate of triazoleresistant Candida infections.