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: 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.     

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.     

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.     

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.     

Inhibition of HIV by chemokine receptor antagonists: exciting new targets,complex development

The prevalence of invasive fungal infections is increasing and the infections are becoming a major problem in immunocompromised children and neonates. Fortunately, there has been a recent surge in the development of new antifungal agents. Caspofungin, the first licensed echinocandin, is a novel class of antifungal and is approved for use in children 3 months of age or older for the treatment of invasive candidiasis, salvage therapy for invasive aspergillosis and as empirical therapy for febrile neutropenia. This article reviews the published data on the use of caspofungin in immunocompromised children and neonates with invasive fungal infections.     

Caspofungin therapy in immunocompromised children and neonates

The prevalence of invasive fungal infections is increasing and the infections are becoming a major problem in immunocompromised children and neonates. Fortunately, there has been a recent surge in the development of new antifungal agents. Caspofungin, the first licensed echinocandin, is a novel class of antifungal and is approved for use in children 3 months of age or older for the treatment of invasive candidiasis, salvage therapy for invasive aspergillosis and as empirical therapy for febrile neutropenia. This article reviews the published data on the use of caspofungin in immunocompromised children and neonates with invasive fungal infections.     

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.     

Management of invasive fungal infections: a role for polyenes

The spectrum of invasive fungal infections (IFIs) continues to evolve with the emergence of rare and resistant fungal pathogens. Clinicians are faced with difficult diagnostic and treatment challenges in the management of immunocompromised patients at high risk of developing IFIs. Early and appropriate antifungal therapy is essential for a successful outcome when treating invasive mycoses. The armamentarium of antifungal drugs continues to grow; the three main classes of commonly administered drugs are the polyenes, azoles and echinocandins. The newer triazoles and the echinocandins have changed primary treatment options for some fungal infections, such as aspergillosis and candidiasis. However, despite their toxic potential, the oldest antifungal drugs, polyenes, remain useful in the treatment of IFIs because of their broad-spectrum activity, low rates of resistance and established clinical record, particularly in immunocompromised patients with breakthrough fungal infections. This review highlights important issues in the treatment of IFIs for consideration by clinicians.     

Fungal infections and their treatment in the intensive care unit

PURPOSE OF REVIEW: To describe and bring together recent development in the diagnosis and treatment of both community-acquired and opportunistic fungal infections in the intensive care unit. RECENT FINDINGS: The past few years have brought major advances to both the diagnosis and treatment of fungal infections. The development of newer therapeutic modalities to supplement existing treatment options includes a new class of antifungal agents, the echinocandins. Newer and improved agents of the azole class have arrived as well as better delineation for the role of liposomal amphotericins. Newer, nonculture-based diagnostic tests have allowed earlier, more timely diagnosis of opportunistic fungal infections, allowing more rapid initiation of therapy. SUMMARY: Improved diagnostic tests and newer antifungal agents have been introduced, leading to earlier diagnosis and treatment.     

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.     

Antifungal prophylaxis and therapy in patients with hematological malignancies and hematopoietic stem cell transplant recipients

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.     

Antifungal prophylaxis and therapy in patients with hematological malignancies and hematopoietic stem cell transplant recipients

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.     

The value of amphotericin B in the treatment of invasive fungal infections

Over the last 20 years, there has been an increase in the total number of invasive fungal infections (IFIs) and in infections caused by rare and emerging pathogens. This is due in part to the growing population of immunocompromised patients at risk of developing fungal infections. Three classes of antifungal agents are widely used for the treatment of systemic fungal infections: polyenes, azoles, and echinocandins. Polyenes were the first antifungal agents developed and have a long-standing history in the treatment of IFIs. The use of conventional amphotericin B has been limited because of toxic side effects, which have been reduced by the lipid formulations of amphotericin B. Treatment options for invasive mycoses have expanded with the recent introduction of the second-generation triazoles (voriconazole and posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin). Despite the increased number of antifungal drugs, resistance issues present a problem in the treatment of IFIs. Although some fungal pathogens display innate resistance, others have developed resistance secondary to selective pressure. This article briefly reviews the changing epidemiology of fungal infections and associated risk factors, resistance issues with commonly administered antifungal agents, and treatment options for IFIs, with a focus on polyenes.     

Combination antifungals: an update

Invasive fungal infections are an important cause of morbidity and mortality in specific patient populations. There has been an impressive increase in the antifungal armamentarium, yet optimal therapies for many invasive fungal infections remain unknown. Genomic sequencing of a number of pathogenic fungi will pave the way to discovering additional newer targets for antifungal drug design. These new discoveries, plus the existing repertoire of antifungal agents, create the need to effectively model single and combination antifungal agents. Future therapies may also include the use of cell-stress pathway inhibitors in combination with existing antifungal agents. This review focuses on combination antifungal therapy against Cryptococcus neoformans, Candida and Aspergillus species. Combination therapy is only supported by randomized clinical trials for cryptococcal meningitis. We review data from in vitro and animal model studies as well as insights from clinical trials to discuss current thoughts and highlight the gaps in our knowledge surrounding combination antifungal therapy.     

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.     

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.     

Current challenges in the management of invasive fungal infections

The incidence of invasive fungal infections (IFIs) has increased over the past two decades, as the populations of patients at risk have continued to rise. Early and accurate diagnosis and the subsequent usage of appropriate antifungal therapy are difficult, which leads to a high mortality rate in patients with IFI. Along with the widespread use of antifungal prophylaxis, the epidemiology of invasive fungal pathogens has changed. Non-albicans Candida, Non-fumigatus Aspergillus, and molds other than Aspergillus have become more common pathogens causing invasive diseases, and most of these emerging fungi are resistant to or less susceptible than others to standard antifungal agents. Therefore, invasive infections due to these previously rare fungi are more difficult to treat. Advances in more potent and less toxic antifungal agents, such as second-generation triazoles and echinocandins, may potentially improve the outcomes of these infections. Recent advances in detecting fungal cell-wall components and genomic DNA also allow earlier diagnosis. This article reviews the changing spectrum of invasive fungal infections and the introduction of recent advances in diagnostic tools and antifungal agents.     

Combination antifungals: an update

Invasive fungal infections are an important cause of morbidity and mortality in specific patient populations. There has been an impressive increase in the antifungal armamentarium, yet optimal therapies for many invasive fungal infections remain unknown. Genomic sequencing of a number of pathogenic fungi will pave the way to discovering additional newer targets for antifungal drug design. These new discoveries, plus the existing repertoire of antifungal agents, create the need to effectively model single and combination antifungal agents. Future therapies may also include the use of cell-stress pathway inhibitors in combination with existing antifungal agents. This review focuses on combination antifungal therapy against Cryptococcus neoformans, Candida and Aspergillus species. Combination therapy is only supported by randomized clinical trials for cryptococcal meningitis. We review data from in vitro and animal model studies as well as insights from clinical trials to discuss current thoughts and highlight the gaps in our knowledge surrounding combination antifungal therapy.