echinocandin-b and Mycoses

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.

Topics: Anidulafungin; Antifungal Agents; Aspergillus; Candida albicans; Caspofungin; Cryptococcus; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Mycoses; Peptides, Cyclic

Neonates with gastrointestinal diseases and extremely preterm infants are at highest risk for developing invasive fungal infections. Candida species are commensal organisms that colonize skin and mucosal surfaces as well as adhere to catheter surfaces. Due to the immature immune system of neonates including compromise of the developing barrier defenses of the skin or mucosal membranes, Candida can invade into the bloodstream and disseminate, often making these infections difficult to eradicate. Treatment of bloodstream infections uniquely involves both starting antifungal therapy and removing central venous catheters. Liposomal amphotericin formulations and echinochandins are currently being studied in neonates. Prevention for high risk patients is now feasible with fluconazole prophylaxis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Therapy, Combination; Echinocandins; Fluconazole; Fungal Proteins; Humans; Infant, Newborn; Mycoses; Peptides, Cyclic; Treatment Outcome

Invasive fungal infections have increased in frequency and severity over the past two decades as a result of an increasing number of immunocompromised patients. This new age of opportunistic fungal infections extends to pediatric patients. The last decade has seen the development of several new antifungal agents for the treatment of these infections. However, there is a paucity of data on the treatment of invasive fungal infections in children. This review provides a brief overview of the current state of antifungal therapy for children, discussing the important antifungal classes and the differences in mechanisms of action and resistance, pharmacology, and efficacy and safety data in pediatric patients outside the neonatal period.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Azoles; Caspofungin; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Flucytosine; Fungal Proteins; Humans; Infant; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Triazoles

Novel therapies to treat invasive fungal infections have revolutionised the care of patients with candidiasis, aspergillosis and other less common fungal infections. Physicians in the twenty first century have access to safer versions of conventional drugs (i.e., lipid amphotericin B products), extended-spectrum versions of established drugs (i.e., voriconazole), as well as a new class of antifungal agents; the echinocandins. The increased number of options in the antifungal armamentarium is well timed, as the incidence of both invasive candidiasis and invasive aspergillosis, and the financial burden associated with these infections, have increased significantly in the past several decades. The increasing incidence of fungal infections has risen in parallel with the increase in critically ill and immunocompromised patients. Candida is the fourth most common bloodstream isolate, approximately 50% of which are non-albicans species. Estimates suggest there to be 9.8 episodes of invasive candidiasis per 1000 admissions to surgical intensive care units, with attributable mortality at 30% and cost per episode of US44,000 dollars. The burden of candidiasis is even higher in the paediatric population, with Candida being the second most common bloodstream infection. The increase in non-albicans candidiasis mandates the introduction of new antifungal agents capable of treating these often azole-resistant isolates. In addition, there has been a rise in the incidence of invasive aspergillosis, the most common invasive mould infection following haematopoietic stem cell transplantation, with an estimated incidence of 10 - 20%. The mortality associated with invasive aspergillosis has increased by 357% since 1980. Unfortunately, the overall survival rate among patients treated with amphotericin B, and even voriconazole, remains suboptimal, as evidenced by the failure of treatment in 47% of patients in the landmark voriconazole versus amphotericin B trial. Given the increasing incidence and suboptimal outcomes of these serious fungal infections, novel therapies represent an opportunity for significant advancement in clinical care. The current challenge is to discover the optimal place for the echinocandins in the treatment of invasive fungal infections.

Topics: Anidulafungin; Animals; Antifungal Agents; Caspofungin; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Mycoses; Peptides, Cyclic

Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period. Prophylaxis by fluconazole has dramatically reduced the frequency of early Candida infections. Caspofungin has recently been shown to offer an excellent alternative to amphotericin B (with less toxicity) or fluconazole (with a broader spectrum) for therapy of systemic Candida infections. Aspergillus infections occur in 15% to 20% of allogeneic hematopoietic cell transplant patients, most frequently in the post-engraftment period; they are associated with a severe diminution of cell-mediated immune responses by graft-versus-host disease and prolonged corticosteroid use. Voriconazole, a recently introduced broad-spectrum azole, has excellent activity against Aspergillus and is generally well tolerated. Voriconazole currently offers the best prospect for success and tolerance as a first-line treatment for aspergillosis. Second-line therapies include lipid formulations of amphotericin B, caspofungin, or intravenous itraconazole. Unfortunately, early initiation of therapy for aspergillosis is frequently not possible because of inaccurate diagnostics. One new diagnostic, the galactomannan assay, has recently been approved, and others are in development; these offer promise for earlier diagnosis without the need for invasive procedures. It is hoped that these new therapies and new diagnostics will usher in a new era of antifungal therapy.

Topics: Antifungal Agents; Azoles; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Nucleosides; Peptides; Peptides, Cyclic; Polyenes

Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Liposomes; Mycoses; Neoplasms; Neutropenia; Peptides, Cyclic; Randomized Controlled Trials as Topic; Survival Analysis; Triazoles

Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Candidiasis; Deoxycholic Acid; Drug Combinations; Echinocandins; Fungal Proteins; Humans; Immunocompromised Host; Mycoses; Peptides; Peptides, Cyclic; Phosphatidylcholines; Phosphatidylglycerols; Triazoles

Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.

Topics: Anti-Bacterial Agents; Antifungal Agents; Drug Design; Echinocandins; Flucytosine; Fungal Proteins; Humans; Immunocompromised Host; Molecular Structure; Mycoses; Peptides; Peptides, Cyclic; Polyenes; Triazoles

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 beta(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 beta(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 beta(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.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Clinical Trials as Topic; Drug Administration Schedule; Echinocandins; Fungal Proteins; Fungi; Humans; Microbial Sensitivity Tests; Mycoses; Peptides; Peptides, Cyclic; Treatment Outcome

Fungal infection remains a major hurdle in solid organ transplantation. A variety of new antifungal agents have become available and new diagnostic tools are in development. This conference was convened to review current approaches to the prevention and treatment of fungal infection in transplantation. Among the keys to successful management of fungal infection are identification of patients at risk for infection (stratification), eradication or control of established infection in advance of transplantation, the demonstration of cure by radiologic and histopathologic means, and the use of surgical debridement, reduction in immune suppression, and fungicidal therapies whenever possible. The absence of sensitive diagnostic tools and standardization of antifungal susceptibility testing for the filamentous fungi are identified as major impediments to care in this area.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Azoles; Causality; Echinocandins; Fungal Proteins; Fungi; Humans; Mycoses; Organ Transplantation; Peptides; Peptides, Cyclic; Postoperative Complications; Risk Factors; Time Factors; Transplantation; Virus Diseases

In our search for natural products with a broad spectrum of antifungal activity as lead compounds for novel treatments for mycoses, we have isolated echinocandin-type lipopeptide FR901379 and lipopeptidolactone FR901469, as novel water-soluble antifungal agents that inhibit the synthesis of 1,3-beta-glucan, a key component of the fungal cell wall. Since the cell wall is a feature unique to fungi and is not present in nonfungal eukaryotic cells, inhibitors of the synthesis of fungal cell wall components such as 1,3-beta-glucan have potential for selective toxicity to fungi and not to the host. In this short review, we describe efforts directed at synthetic modification of FR901469 and FR901379 with the ultimate goal of identifying new entities with suitable profiles as development candidate compounds. The main thrust of our work to date has been replacement of the highly flexible lipophilic side chains of the natural products with a view to reducing the hemolytic potential associated with these compounds, and to enhance chemical stability and/or in vivo antifungal efficacy. As a result of these efforts, we recently discovered a novel analog, FK463 (micafungin). Micafungin is currently in phase III clinical trials worldwide as a parenteral agent for various mycoses, and a new drug application (NDA) was recently filed in Japan.

Topics: Anti-Bacterial Agents; Antifungal Agents; Biological Products; Depsipeptides; Drug Design; Echinocandins; Fungal Proteins; Fungi; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Molecular Structure; Mycoses; Peptides; Peptides, Cyclic

Topics: Amphotericin B; Anidulafungin; Animals; Anti-Bacterial Agents; Antifungal Agents; Echinocandins; Fungal Proteins; Humans; Mycoses; Peptides; Peptides, Cyclic

A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

Topics: Aminoglycosides; Amphotericin B; Animals; Anthracyclines; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cell Wall; Chitin; Echinocandins; Fungal Proteins; Fungi; Glucans; Mice; Mycoses; Peptides; Peptides, Cyclic; Pyrimidine Nucleosides

Topics: Antifungal Agents; Dose-Response Relationship, Drug; Drug Industry; Echinocandins; Fungal Proteins; Humans; Mycoses; Peptides, Cyclic

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Animals; Antifungal Agents; Caspofungin; Child; Child, Preschool; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Infant; Infant, Newborn; Lipopeptides; Lipoproteins; Micafungin; Middle Aged; Mycoses; Peptides, Cyclic; Pyrimidines; Thiazoles; Treatment Outcome; Triazoles; Voriconazole