Micafungin for the prophylaxis and treatment of Candida infections

Invasive fungal infection is a significant cause of morbidity and mortality worldwide. The incidence of these infections is steadily increasing. In addition, strains resistant to many commonly used antifungal agents are becoming more prevalent. Many new antifungals have become commercially available in recent years, which have vastly improved the ability to treat these infections effectively. Micafungin is one of three commercially available echinocandins available for use in the USA. This class of agents possess a unique mechanism of action that helps to reduce toxicity while maintaining potent antifungal activity. Micafungin is currently approved for the treatment of esophageal candidiasis in adults and is the only in its class approved for the prophylaxis of Candida infection in patients who have undergone hematopoietic stem cell transplantation. It was also recently approved in the USA for the treatment of candidemia and other forms of invasive candiaisis (acute disseminated candiaisis, Candida peritonitis and abscess). In general, micafungin is well tolerated and has favorable safety and drug-interaction profiles.     

Update on new antifungal therapy

Increases in rates as well as morbidity and mortality associated with fungal infections have necessitated the need for additional antifungal agents. Recent research has resulted in the introduction of 3 new antifungal agents: micafungin, anidulafungin, and posaconazole. Micafungin and anidulafungin, both potent inhibitor of 1,3-beta-D-glucan synthase, are the second and third available agents in the echinocandins class that are available in clinical practice. Posaconazale, a potent inhibitor of ergosterol synthesis, is a new agent in the triazole class that has shown promising clinical efficacy in the treatment and prophylaxis of invasive fungal infections due to Candida as well as molds. This article reviews the clinical efficacy as well as the approved uses and dosages associated with the use of these new antifungal agents. Other considerations, such as precautions, administration techniques, potential drug interactions, and common adverse effects associated with the use of these agents, are also reviewed.     

Micafungin: the US perspective

Invasive fungal infections cause considerable morbidity and mortality in nosocomial settings and amongst immunocompromised hosts. Invasive candidiasis and aspergillosis remain the most common invasive fungal infections, with Candida spp. constituting the fourth most common bloodstream infection in the USA. Currently available antifungal therapies include the polyene, antimetabolite, allylamine, azole and echinocandin drug classes. Micafungin, approved in March 2005 by the Food and Drug Administration for use in the USA, has shown safety and efficacy for the treatment of candidiasis and aspergillosis in clinical trials in Japan, Europe and South Africa. Micafungin holds promise as a first-line treatment option for candidiasis, as well as prophylaxis against invasive fungal infections during periods of neutropenia in high-risk patients.     

Echinocandin antifungals: review and update

The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-beta-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas) was the first approved echinocandin, followed recently by micafungin (Mycamine) and anidulafungin (Eraxis). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.     

Echinocandin antifungals: review and update

The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-β-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas^®) was the first approved echinocandin, followed recently by micafungin (Mycamine^®) and anidulafungin (Eraxis^®). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.     

Caspofungin acetate for treatment of invasive fungal infections

OBJECTIVE: To briefly discuss the changing epidemiology of fungal infections and review currently available agents; provide a review of caspofungin; and discuss its pharmacology, pharmacokinetics, dosing guidelines, safety and efficacy, and role in the treatment of invasive fungal infections as it relates to current antifungal therapy. DATA SOURCES: A MEDLINE (1966 to August 2002) database search using key words caspofungin, echino candins, fungal infections, and invasive aspergillosis, was completed to identify relevant articles including reviews, recent studies, treatment guidelines, and data from Merck and Company. STUDY SELECTION: In vitro studies and all clinical trials were evaluated to summarize the clinical efficacy and safety of caspofungin. DATA SYNTHESIS: The incidence of fungal infections is increasing as the population at risk expands. Cost, resistance, and morbidity and mortality are key issues. Adding to the antifungal armamentarium is necessary to address these therapeutic dilemmas. Caspofungin is the first member of a new class of antifungal agents, the echinocandins, to be approved for clinical use. Caspofungin is classified as a glucan synthase inhibitor and represents a class of agents with a novel mechanism of action. Unlike currently available agents (polyenes, pyrimidines, azoles) that exert their effect on the fungal cell membrane, the echinocandins are the first agents to inhibit fungal cell wall synthesis. Caspofungin exhibits activity against Aspergillus spp. and Candida spp., including non-albicans species. Data from clinical trials demonstrate that caspofungin is effective in patients with invasive aspergillosis as well as candida esophagitis. Its Food and Drug Administration-approved indication is limited to invasive aspergillosis refractory to or intolerant of current therapy. CONCLUSIONS: Caspofungin has activity against Aspergillus spp. as well as a variety of Candida spp. Clinical data support its usefulness in the treatment of invasive aspergillosis and select candida infections. As additional clinical data become available, it seems likely that the therapeutic role of caspofungin will expand.     

Optimal use of existing and new antifungal drugs

Clinicians are increasingly aware that fungal pathogens are a significant cause of morbidity and mortality in hospitalized patients. Historically, these infections occurred in severely immunocompromised patients who were undergoing treatment for hematological malignancy or solid organ transplantation. Currently, however, systemic fungal infections are commonly seen in debilitated patients who are being nursed in intensive care or high-dependency units. These infections are mostly caused by Candida albicans but there is a growing proportion of strains of non- albicans Candida spp, some with reduced susceptibility to commonly used antifungals. The limited armamentarium of antifungal agents to date has meant that amphotericin B continues to be considered the most effective therapeutic agent albeit with a poor record of treatment-limiting side effects. The past decade has seen some encouraging developments in antifungal therapy. Three lipid formulations of amphotericin B showing reduced toxicity compared with the desoxycholate formulation are now licensed. There are three investigational triazoles currently undergoing evaluation that should prove important additions to existing members of this class. The echinocandin caspofungin is the first of a new class of antifungal agents with a novel mode of action, which has recently been approved for use in the United States.     

Anidulafungin: is it a promising option in the treatment of pediatric invasive fungal infections?

Cases of invasive fungal infections are increasing globally due to an increase in the immunosuppressed population, the use of broad-spectrum antibiotics and the invasive instrumentation of patients in intensive care units. Ongoing emergence of resistance and problems with toxicity have resulted in the need for the development of new antifungal agents. Anidulafungin, the most recently developed echinocandin, is approved by the US FDA for treatment of candidemia, other forms of Candida infection and esophageal candidiasis in non-neutropenic adult patients, but it is not currently licensed for pediatric usage. The drug is projected to be distinctive owing to its unique pharmacokinetics and is already listed in adult antifungal treatment guidelines. In this article, anidulafungin will be reviewed with a focus on pediatric patients.     

Candida infections in the intensive care unit: epidemiology, risk factors and therapeutic strategies

This article reviews the epidemiology, predisposing risk factors and outcome of systemic Candida spp. infections in the intensive care unit setting. Incidence of systemic Candida infections in patients requiring intensive care has increased substantially in recent years; while diagnosis of serious Candida infection may be difficult, the clinical conditions which predispose patients to these infections are now better understood and effective antifungal therapies are becoming increasingly available. Severe fungal infections are generally associated with poor outcomes in these patients. Patients at highest risk for Candida infection may be potential candidates for early, presumptive therapy. In this article we review antifungal treatment, including the use of polyenes, azoles and echinocandines, and the role of prophylaxis.     

Micafungin use in children

Invasive fungal infections (IFIs) are one of the major reasons for morbidity and mortality in immunocompromised children. The majority of IFIs are caused by Candida and Aspergillus species. Early diagnosis and prompt initiation of appropriate antifungal therapy is essential for favorable outcome. Micafungin is a member of the echinocandins, a novel class of antifungal agents that target the biosynthesis of β-1,3-D-glucan, a key fungal cell wall component. It has concentration-dependent fungicidal activity against Candida species and fungistatic activity against Aspergillus species. Although optimal dosing of micafungin in children has not been established, the recommended dosage in children is 2 mg/kg/day (100 mg/day if >40 kg bodyweight) for invasive candidiasis, 1 mg/kg/day (50 mg/day if >40 kg bodyweight) for the prophylaxis of Candida infections in patients with anticipated prolonged and severe neutropenia or in allogeneic hematopoietic stem cell transplantation recipients. Micafungin has a favorable safety and drug-drug interaction profile. The most common adverse effects in children are diarrhea, epistaxis, abdominal pain, headache, nausea, vomiting, fever, chills, elevation of alanine aminotransferase/aspartate aminotransferase values, hypokalemia, thrombocytopenia, mucositis, and rash. Because of its different mechanisms of action, micafungin shows promise as part of the prophylactic and therapeutic management of IFIs, but larger prospective and comparative trials are needed for widespread use in children.     

Caspofungin: an overview

The echinocandins are a novel class of antifungal agents that have come into use over the past 10 years. The mechanism of action of these lipopeptide agents is via noncompetitive inhibition of the synthesis of 1,3-beta-glucans, which are fungal cell wall constituents. All agents of this class are only available in an intravenous formulation. The first approved agent of this class was caspofungin (Cancidas). Caspofungin is a therapeutic option for patients with candidal esophagitis and deep-seated candidal infections, and is an alternative therapy for Aspergillus infections, especially in the salvage setting. In addition, it is a therapeutic option for the empiric therapy of febrile neutropenia. The usefulness of this agent in treating less common fungal infections has been cited in anecdotal reports. One major limitation of this drug is the lack of an oral formulation. Caspofungin may be considered as a component of combination antifungal regimens. Caspofungin represents a significant advance in the care of patients with serious fungal infections.     

Caspofungin: an overview

The echinocandins are a novel class of antifungal agents that have come into use over the past 10 years. The mechanism of action of these lipopeptide agents is via noncompetitive inhibition of the synthesis of 1,3-β-glucans, which are fungal cell wall constituents. All agents of this class are only available in an intravenous formulation. The first approved agent of this class was caspofungin (Cancidas^®). Caspofungin is a therapeutic option for patients with candidal esophagitis and deep-seated candidal infections, and is an alternative therapy for Aspergillus infections, especially in the salvage setting. In addition, it is a therapeutic option for the empiric therapy of febrile neutropenia. The usefulness of this agent in treating less common fungal infections has been cited in anecdotal reports. One major limitation of this drug is the lack of an oral formulation. Caspofungin may be considered as a component of combination antifungal regimens. Caspofungin represents a significant advance in the care of patients with serious fungal infections.     

Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend^®, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan^®, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

结核患者深部真菌的分离鉴定及耐药分析

目的观察和评价结核患者深部真菌的分离培养及耐药情况。方法依据美国临床实验室标准化委员会(NCCLS)推出的酵母菌的液体培养基稀释法抗真菌药物敏感试验标准方案(M-27)进行结果判断,采集2100份标本进行分离培养并对268份深部真菌进行鉴定和耐药分析。结果深部真菌的分离率为12.8%(268/2100),其中白念珠菌为70.5%(189/268),热带念珠菌为16.8%(45/268),克柔念珠菌为7.8%(21/268),光滑念珠菌为3.3%(9/268),并对7种抗真菌药物均出现不同程度的耐药,其中发现对7种抗真菌药物全耐药的白念珠菌9株,热带念珠菌2株。结论结核患者的深部真菌感染较严重并存在耐药倾向,应早诊断、早治疗。     

Micafungin: a therapeutic review

In recent decades, the incidence of aspergillosis, candidiasis and clinically important deep mycoses has been increasing, with advances in transplantation medicine and anticancer chemotherapy. Micafungin (FK463, Fujisawa Healthcare) has been developed as a novel type of antifungal agent, which inhibits 1,3-beta-D-glucan synthase in the fungal cell wall. Micafungin, one of the echinocandins, exhibits extremely high antifungal activity against Aspergillus spp. and Candida spp. in vitro. It is also characterized by a linear pharmacokinetic profile and a much lower prevalence of adverse reactions than amphotericin B. Micafungin is quite useful in the treatment of deep mycoses. In clinical studies in Japan, micafungin was found to be highly effective against aspergillosis (57.1% overall efficacy rate) and candidiasis (78.6%). Micafungin is expected to increase the efficacy rate of treatment in patients with severe aspergillosis or candidiasis when used in combination with amphotericin B or mold azoles.     

Bench-to-bedside review: <Emphasis Type="Italic">Candida</Emphasis> infections in the intensive care unit

Invasive mycoses are life-threatening opportunistic infections and have emerged as a major cause of morbidity and mortality in critically ill patients. This review focuses on recent advances in our understanding of the epidemiology, diagnosis and management of invasive candidiasis, which is the predominant fungal infection in the intensive care unit setting. Candida spp. are the fourth most common cause of bloodstream infections in the USA, but they are a much less common cause of bloodstream infections in Europe. About one-third of episodes of candidaemia occur in the intensive care unit. Until recently, Candida albicans was by far the predominant species, causing up to two-thirds of all cases of invasive candidiasis. However, a shift toward non-albicans Candida spp., such as C. glabrata and C. krusei, with reduced susceptibility to commonly used antifungal agents, was recently observed. Unfortunately, risk factors and clinical manifestations of candidiasis are not specific, and conventional culture methods such as blood culture systems lack sensitivity. Recent studies have shown that detection of circulating β-glucan, mannan and antimannan antibodies may contribute to diagnosis of invasive candidiasis. Early initiation of appropriate antifungal therapy is essential for reducing the morbidity and mortality of invasive fungal infections. For decades, amphotericin B deoxycholate has been the standard therapy, but it is often poorly tolerated and associated with infusion-related acute reactions and nephrotoxicity. Azoles such as fluconazole and itraconazole provided the first treatment alternatives to amphotericin B for candidiasis. In recent years, several new antifungal agents have become available, offering additional therapeutic options for the management of Candida infections. These include lipid formulations of amphotericin B, new azoles (voriconazole and posaconazole) and echinocandins (caspofungin, micafungin and anidulafungin).     

Recent advances in antifungal pharmacotherapy for invasive fungal infections

Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.     

How to select an antifungal agent in critically ill patients

Fungal infections are common in critically ill patients and are associated with increased morbidity and mortality. Candida spp are the most commonly isolated fungal pathogens. The last 2 decades have seen an increased incidence of fungal infections in critical illness and the emergence of new pathogenic fungal species and also the development of more effective (better bioavailability) and safer (less toxicity, fewer drug interactions) drugs. The distinction between colonization and infection can be difficult, and problems diagnosing infection may delay initiation of antifungal treatment. A number of factors have been identified that can help to distinguish patients at high risk for fungal infection. The antifungal agents that are most frequently used in the intensive care unit are the first- and second-generation azoles and the echinocandins; amphotericin B derivatives (mainly the liposomal agents) are less widely used because of adverse effects. The choice of antifungal agent in critically ill patients will depend on the aim of therapy (prophylaxis, pre-emptive, empiric, definitive), as well as on local epidemiology and specific properties of the drug (antifungal spectrum, efficacy, toxicity, pharmacokinetic/pharmacodynamic properties, cost). In this article we will review all these aspects and propose an algorithm to guide selection of antifungal agents in critically ill patients.     

Micafungin: a therapeutic review

In recent decades, the incidence of aspergillosis, candidiasis and clinically important deep mycoses has been increasing, with advances in transplantation medicine and anticancer chemotherapy. Micafungin (FK463, Fujisawa Healthcare) has been developed as a novel type of antifungal agent, which inhibits 1,3-β-D-glucan synthase in the fungal cell wall. Micafungin, one of the echinocandins, exhibits extremely high antifungal activity against Aspergillus spp. and Candida spp. in vitro. It is also characterized by a linear pharmacokinetic profile and a much lower prevalence of adverse reactions than amphotericin B. Micafungin is quite useful in the treatment of deep mycoses. In clinical studies in Japan, micafungin was found to be highly effective against aspergillosis (57.1% overall efficacy rate) and candidiasis (78.6%). Micafungin is expected to increase the efficacy rate of treatment in patients with severe aspergillosis or candidiasis when used in combination with amphotericin B or mold azoles.