micafungin and Aspergillosis

The frequency of invasive fungal infections, and specifically invasive aspergillosis, has increased in the last few decades. Despite the development of new antifungal agents, these infections are associated with high mortality, ranging from 40% to 80%, depending on the patient and the localization of the infection. To reduce these figures, several therapeutic strategies have been proposed, including combination therapy. Most of the available data on the efficacy of these combinations are from experimental models, in vitro data and retrospective observational studies or studies with a small number of patients that have included both patients in first-line treatment and those receiving rescue therapy; in addition there are many patients with possible forms of aspergillosis and few with demonstrated or probable forms. To date, there is no evidence that combination therapy has significantly higher efficacy than monotherapy; however, combination therapy could be indicated in severe forms of aspergillosis, or forms with central nervous involvement or extensive pulmonary involvement with respiratory insufficiency, etc. Among the combinations, the association of an echinocandin--the group that includes micafungin--with voriconazole or liposomal amphotericin B seems to show synergy. These combinations are those most extensively studied in clinical trials and therefore, although the grade of evidence is low, are recommended by the various scientific societies.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Caspofungin; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Echinocandins; Forecasting; Fungemia; Guinea Pigs; Humans; Invasive Pulmonary Aspergillosis; Lipopeptides; Meningitis, Fungal; Micafungin; Mice; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Triazoles

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.

Topics: Adolescent; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis, Invasive; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; Drug Dosage Calculations; Early Diagnosis; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycological Typing Techniques; Neutropenia; Transplantation, Homologous

Increases in the rates of fungal infections, as well as their associated morbidity and mortality has led to a need for additional antifungal agents. The most common serious fungal agents in immunosuppressed and critically ill patients are Candida spp. and Aspergillus spp., although other emerging fungi must be considered. Rational, early systemic antifungal treatment should be based on diagnostic imaging techniques and conventional mycological and non-culture-based procedures. While the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex. In addition to the available antifungal armamentarium, recent research has resulted in the introduction of three new antifungal agents: micafungin, anidulafungin, and posaconazole. This article provides an update, based on the latest scientific evidence, of the clinical efficacy, pharmacokinetics, safety and dosing of antifungal drugs administered in the management of Candida spp., Aspergillus spp., Cryptococcus spp., Zygomycetes, Scedosporium spp. and Fusarium spp.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; Candidiasis; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Early Diagnosis; Echinocandins; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Mycoses; Randomized Controlled Trials as Topic; Salvage Therapy; Treatment Outcome; Triazoles

Echinocandins act by inhibiting 1,3-beta-D-glucan synthesis in the fungal cell wall. The three licensed agents in this class, namely anidulafungin, caspofungin and micafungin, have a favourable pharmacological profile. These agents are narrow spectrum with clinically relevant activity against Candida and Aspergillus spp. Several trials have established the non-inferiority of these agents over existing agents in the treatment of invasive fungal infections. Caspofungin is also licensed for empirical antifungal therapy of presumed fungal infections in patients with febrile neutropenia. This paper reviews the literature on echinocandins.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Caspofungin; Clinical Trials as Topic; Echinocandins; Humans; Lipopeptides; Micafungin

Invasive fungal infections cause significant morbidity and mortality in immunocompromised children. The prevalence of invasive aspergillosis (IA) is increasing as a reflection of the rising numbers of immunocompromised patients and the increasing use of aggressive immunosuppressive treatment regimes for hematologic malignancies and transplantation. IA is almost exclusively seen in severely immunocompromised or critically ill children, including those with the classic risk factors (particularly neutropenia, hematopoietic stem cell transplant or solid-organ transplantation, hematological malignancies, use of systemic immunosuppressive agents or cytotoxic therapies). Early treatment improves survival rates, but the diagnosis of aspergillosis remains difficult and, while IA has been relatively well-characterized in adults, far fewer studies have described optimal treatment for the pediatric population. This article reviews and compares the newer, less-invasive diagnostic techniques that are becoming available and focuses on the data specifically from pediatric trials regarding efficacy, safety and pharmacokinetics of the antifungals used for IA.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Child; Echinocandins; Fungal Vaccines; Genomics; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Pyrimidines; Risk Factors; Triazoles; Voriconazole

Micafungin is an echinocandin antifungal drug recently approved for the treatment of candidiasis. The possibility of its clinical use against other invasive mycoses, has aroused the interest of numerous investigators in evaluating its efficacy in different animal models.. To critically review the current data on the use of micafungin in the treatment of invasive mycoses in animal models.. We searched the PubMed/Medline data base (National Library of Medicine) from 2005 to 2008, both inclusive, on the use of micafungin in the experimental treatment of the fungal infection.. Seven, of a total of 18 articles reviewed, were done in animal models of candidiasis and six in animal models of pulmonary or SNC aspergillosis. Similarly to the other echinocandins, caspofungin and anidulafungin, micafungin seems to exert a fungicidal activity against Candida albicans and Candida glabrata and a fungistatic activity against Aspergillus fumigatus. The paradoxical effect observed in lung tissue the experimental caspofungin treatment of aspergillosis has not been seen in the case of micafungin. The available data demonstrate a higher efficacy of micafungin versus fluconazole in the experimental treatment of C. albicans infections caused by strains susceptible in vitro to both drugs. To improve the efficacy of micafungin in the treatment of C. glabrata and A. fumigatus infections, several authors have tested different combined therapies, the combination of micafungin with amphotericin B being that showed the best results.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Drug Evaluation, Preclinical; Echinocandins; Fusarium; Immunocompromised Host; Lipopeptides; Micafungin; Mice; Mucormycosis; Mycoses; Rabbits; Rats; Rhizopus; Saccharomycetales; Trichosporon

Micafungin is one of three echinocandins, a novel class of antifungal agents active against 1,3-beta-D glucan in the fungal cell wall. It is a favorable safety profile have made it an attractive option in the treatment of invasive Candida and Aspergillus infections. Available studies have shown that younger children have lower C(max), shorter t(1/2) and faster clearance than adults.

Topics: Adolescent; Antifungal Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Multiple, Fungal; Echinocandins; Female; Fungemia; Humans; Infant; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests

Micafungin is a echinocandin. It inhibits beta-1,3-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp., as well as several but not all pathogenic molds. Results from in vitro studies, animal models, small clinical trials, hint at possible future indications such as invasive aspergillosis and empirical viantifungal therapy, although currently there is little information published.. To describe published data of micafungin as treatment against invasive mold infections, specially analysing its role in the inmunodepressed host and critical care setting.. A systematic review of literature using the principal medical search engines was performed. Terms such as micafungin, aspergillosis, zygomycosis, invasive fungal infections, emerging fungal infections, antifungal treatment or therapy, antifungal prophylaxis, empiric or pre-emptive therapy were crossed. Febrile neutropenia patients were excluded.. Several studies in these setting were identified and were described in this review. Although there were no blinded randomized clinical trials published, treatment or prophylaxis of invasive aspergillosis and other invasive mould infections with micafungin described in open clinical studies were analyzed.. Micafungin could play a future important role as a primary or rescue therapy, alone or in combination, in the treatment or prophylaxis of invasive fungal infections caused by moulds. New randomized clinical trials are needed to confirm their efficacy.

Topics: Adult; Animals; Antifungal Agents; Aspergillosis; Candidiasis; Child; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation, Preclinical; Echinocandins; Fluconazole; Forecasting; Fungemia; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Multicenter Studies as Topic; Mycoses; Organ Transplantation; Postoperative Complications; Premedication; Prospective Studies; Randomized Controlled Trials as Topic; Zygomycosis

To review the mechanism of action, antifungal spectrum of activity, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of the echinocandins.. A MEDLINE search (1982-May 2009) was conducted for articles published in the English language using the key words caspofungin, micafungin, anidulafungin, and echinocandins.. Medicinal chemistry, in vitro, and animal studies, as well as human trials were reviewed for information on the pharmacodynamics, pharmacokinetics, efficacy, and safety of each echinocandin. Clinical trials were reviewed and included to compare and contrast the available echinocandins.. Three echinocandin antifungal agents are currently approved for use in the US: caspofungin, micafungin, and anidulafungin. The echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell wall of several fungi. The echinocandins display fungistatic activity against Aspergillus spp. and fungicidal activity against most Candida spp., including strains that are fluconazole-resistant. The echinocandins have been shown to be efficacious for the treatment of esophageal candidiasis, candidemia, and invasive candidiasis. In addition, caspofungin has demonstrated efficacy as empiric treatment of febrile neutropenia and salvage therapy for the treatment of invasive aspergillosis, and it is the only echinocandin approved for use in pediatric patients. Micafungin is the only echinocandin approved for use as prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation. Overall, resistance to echinocandins is still rare, and all agents are well tolerated, with similar adverse effect profiles and few drug-drug interactions.. Echinocandins, the newest addition to the arsenal of antifungals, offer potential advantages over other classes of agents. Clinicians should assess their distinguishing characteristics, including route of metabolism, drug interaction profile, and approved indications for use, when determining which agent to include on a formulary.

Topics: Anidulafungin; Animals; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Child; Clinical Trials as Topic; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Mycoses

Serious infections caused by opportunistic molds remain a major problem for public health. Immune deficiency following organ transplantation and aggressive cancer treatment has greatly increased the incidence of systemic mycoses, and invasive aspergillosis in patients with AIDS is associated with significant morbidity and mortality. Amphotericin B is the first-line therapy for systemic infection because of its broad-spectrum and fungicidal activity. However, considerable side effects limit its clinical utility. The echinocandins are large lipopeptide molecules that inhibit the synthesis of 1,3-beta-D-glucan, a key component of the fungal cell wall. Three echinocandins have reached the market, and some others are in early clinical development. Caspofungin was the first echinocandin to be licensed for clinical use in most countries. Micafungin is licensed for clinical use in Japan, China, Taiwan, Jordan, Korea, Hong-Kong and the US, and anidulafungin is currently licensed in the US. The novel class of echinocandins represents a milestone in antifungal drug research that has further expanded our therapeutic options. Studies to date have shown that micafungin exhibits extremely potent antifungal activity against clinically important fungi, including Aspergillus and azole-resistant strains of Candida. In animal studies, micafungin is as efficacious as amphotericin B with respect to improvement of survival rate. Micafungin is also characterized by a linear pharmacokinetic profile and substantially fewer toxic effects. Micafungin is a poor substrate for the cytochrome P450 enzymes, and compared to azoles, fewer drug interactions are described. No dose adjustments of the drug are required in the presence of mycophenolate mofetil, cyclosporin, tacrolimus, prednisolone, or sirolimus. Strategies using this new echinocandin agent will benefit a large number of patients with severe immune dysfunction.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Cell Wall; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Hematopoietic Stem Cell Transplantation; Hemolytic Agents; Humans; Lipopeptides; Lipoproteins; Micafungin; Mice; Mycoses; Opportunistic Infections; Peptides, Cyclic; Structure-Activity Relationship

Micafungin is a relatively broad-spectrum antifungal agent available for clinical use in the US and Japan. By inhibiting the production of beta-1,3-glucan, an essential fungal cell wall component, micafungin has reduced toxicity to mammalian cells while maintaining potent antifungal activity against many pathogenic fungi including polyene- and azole-resistant isolates. Indeed, micafungin has been shown to be efficacious in the treatment of infections caused by Candida and Aspergillus species in clinical trials without the associated toxicities of amphotericin B formulations and drug interactions that occur with the azoles. In this review, the pharmacology, spectrum of activity, clinical efficacy and safety profile of micafungin are discussed.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Candida; Candidiasis; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Fungi; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

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-beta-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.

Topics: Anidulafungin; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Caspofungin; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Echinocandins; Enzyme Inhibitors; Glucosyltransferases; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Treatment Outcome

Micafungin, a potent inhibitor of 1,3-beta-D-glucan synthase, has become the second available agent in the echinocandins class that is approved for use in clinical practice. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans species of Candida, and Aspergillus species, as well as several but not all pathogenic molds. If anything, its in vitro activity appears to be superior to that of caspofungin, although the clinical relevance of this observation is unclear. The clinical role of micafungin appears to be similar to that of caspofungin, although clinical data are still lacking at this stage, with initial approval only for treatment of esophageal candidiasis and prophylaxis in subjects with neutropenia. Pharmacokinetic and pharmacodynamic studies and reports of adverse effects and safety have reported similar but not identical results to those of other agents in the echinocandin class. Factors such as acquisition costs and the potential for resistance development may be more relevant to its widespread use than in vitro and in vivo data comparisons with caspofungin.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Clinical Trials as Topic; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins; Enzyme Inhibitors; Glucosyltransferases; Humans; Lipopeptides; Lipoproteins; Micafungin; Mice; Microbial Sensitivity Tests; Peptides, Cyclic

Micafungin, a new class of the antifungal agent "echinocandin" released in 2002, and voriconazole, a new triazole antifungal agent released in 2005 in Japan have in vitro activities against Aspergillus spp. Results of large-scale clinical trials in Europe and the United States showed voriconazole to have superior efficacy against invasive pulmonary aspergillosis in comparison with conventional amphotericin B, and caspofungin, a member of the echinocandins, was effective as an empirical antifungal therapy in patients with persistent fever and neutropenia. In this way, choices of therapeutic medicine for aspergillosis are increasing more and more, and it is expected that the method of treatment will change greatly in future. On the other hand, we need to establish a new standard therapy for aspergillosis to avoid the clinical disruption caused by the variety of pharmaceutical choice caused. In this report, we describe the role of new antifungal agents for non-fumigatus Aspergillus infections, and the breakthrough in counteracting fungal infection using these new drugs.

Topics: Antifungal Agents; Aspergillosis; Caspofungin; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

The incidence of fungal infections has increased globally, and the introduction of the newer triazoles and echinocandin antifungals is a more-than-welcome and long overdue development. In this report, we review the clinical trials evaluating the therapeutic efficacy of these new antifungal agents and examine possible gaps in coverage. Voriconazole has become the primary treatment for most forms of invasive aspergillosis in a number of centers, posaconazole offers a broad antifungal spectrum, and echinocandins are fungicidal against most Candida species. Moreover, the new agents are active against some fungi that are resistant to amphotericin B, may have a role in the management of fever and neutropenia, and provide exciting options for combination antifungal therapy. However, significant questions remain, including the management of breakthrough infections and treatment failures and the efficacy of the new antifungal agents against less common fungi.

Topics: Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Cryptococcosis; Echinocandins; Fever; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Neutropenia; Peptides, Cyclic; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

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.. 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.. 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.

Topics: Anidulafungin; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Catheterization; Critical Care; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Transplants

Micafungin is a new drug in the echinocandin class and is currently being investigated in Phase III clinical trials. Like other echinocandins, it inhibits 1,3-beta-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp. Micafungin sodium is available for intravenous administration only. It has a favorable safety and drug-drug interaction profile. Micafungin has been approved by the US FDA for treatment of esophageal candidiasis and for antifungal prophylaxis during the pre-engraftment phase in patients undergoing hematopoietic stem cell transplantation. Considering the competitive pricing as well as the good tolerability and efficacy, at present micafungin seems to be another choice for both of these indications. Current research has proven micafungin sodium to add a rational and effective option to the antifungal armamentarium, especially in esophageal candidiasis refractory to fluconazole treatment, in those intolerant to triazoles or in patients needing concomitant therapy interacting with triazoles. In addition to the current indications, recent uncontrolled clinical trials have demonstrated a marked success in the treatment of candidemia and invasive candidiasis. Results from in vitro studies, animal models, small clinical trials, as well as the obvious comparison with the more established caspofungin, hint at possible future indications such as invasive aspergillosis and empirical antifungal therapy. However, preclinical data on micafungin is inconsistent and published well-designed clinical studies are scarce. More controlled and sufficiently scaled trials are imperative in order to establish micafungin as a reliable and safe option in clinical practice.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Candida; Candidiasis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Proteoglycans

Invasive fungal infections are important causes of morbidity and mortality in hospitalised patients. Current therapy with amphotericin B and antifungal triazoles has overlapping targets and is limited by toxicity and resistance. Echinocandins are a new class of antifungal drugs, which inhibit the synthesis of 1,3-beta-D-glucan. This homopolysaccharide is an important component of the cell wall of many pathogenic fungi, providing osmotic stability and functioning in cell growth and cell division. Micafungin, which is a member of the echinocandin class, exhibits in vitro fungicidal or fungistatic activity against a variety of fungal pathogens which include Candida and Aspergillus species but not Cryptococcus, Fusarium or Zygomycetes. Micafungin demonstrates linear pharmacokinetics, which are not altered by drugs metabolised through the P450 enzyme system. The preclinical and clinical data strongly support the development of micafungin for treatment of proven or suspected mucosal and invasive Candida infections in immunocompetent and immunocompromised patients. This paper reviews the preclinical and clinical pharmacology of micafungin and its potential role for treatment of fungal invasive infections in patients.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Disease Models, Animal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Mycoses; Peptides, Cyclic; Randomized Controlled Trials as Topic

Micafungin (MCFG) is a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3-beta-D-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner, and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itraconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9%, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective in aspergillosis and candidiasis, with no tolerability problems.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Echinocandins; Fungal Proteins; Glucosyltransferases; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Mice; Microbial Sensitivity Tests; Peptides, Cyclic

Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis (IA) remains unacceptably high. Aspergillus fumigatus still accounts for the majority of cases of IA; however less susceptible to antifungals non-fumigatus aspergilli began to emerge. Antifungal drug resistance of Aspergillus might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, has brought resistance testing to the forefront of clinical mycology. In addition, molecular biology has started to shed light on the mechanisms of resistance of A. fumigatus to azoles and the echinocandins, while genome-based assays show promise for high-throughput screening for genotypic antifungal resistance. Several problems remain, however, in the study of this complex area. Large multicenter clinical studies--point prevalence or longitudinal--to capture the incidence and prevalence of antifungal resistance in A. fumigatus isolates are lacking. Correlation of in vitro susceptibility with clinical outcome and susceptibility breakpoints has not been established. In addition, the issue of cross-resistance between the newer triazoles is of concern. Furthermore, in vitro resistance testing for polyenes and echinocandins is difficult, and their mechanisms of resistance are largely unknown. This review examines challenges in the diagnosis, epidemiology, and mechanisms of antifungal drug resistance in A. fumigatus.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Naphthalenes; Peptides, Cyclic; Terbinafine; Triazoles

Micafungin, an echinocandin antifungal agent with a novel mechanism of action, inhibits beta-(1,3)-D-glucan synthase interfering with fungal cell wall synthesis. It shows excellent antifungal activity against a broad range of Candida spp., including azole-resistant strains, and Aspergillus spp. in in vitro and animal studies. In HIV-positive patients, intravenous micafungin 50-150 mg/day dose-dependently eradicated endoscopically confirmed oesophageal candidiasis, with micafungin 100 and 150 mg/day being more effective than micafungin 50 mg/day and as effective as fluconazole 200 mg/day in a double-blind trial. In nonblind trials, micafungin (monotherapy or combination therapy) was effective against invasive aspergillosis, candidiasis and candidaemia in paediatric and adult patients with newly diagnosed or refractory infections. Micafungin 50 mg/day provided significantly better antifungal prophylaxis than fluconazole 400 mg/day in 882 haematopoietic stem cell transplant recipients in a randomised, double-blind trial. Respective overall success rates were 80% and 73.5%. Micafungin is generally well tolerated. Adverse events were not dose- or infusion-related with micafungin 12.5-900 mg/day; no histamine-like reactions occurred. Micafungin was as well tolerated as fluconazole, with numerically fewer micafungin recipients discontinuing treatment (4.2% vs 7.2%).

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic

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.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis, Oral; Child; Clinical Trials as Topic; Drug Interactions; Echinocandins; Fungi; HIV Infections; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, beta-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH (0.5-0.7 mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0-1.5 mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.

Topics: Amphotericin B; Aspergillosis; Candidiasis; Echinocandins; Fluconazole; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Neutropenia; Peptides, Cyclic; Practice Guidelines as Topic

Combination therapy with amphotericin B and flucytosine is considered to be the treatment of choice for cryptococcal infections. However, for other infections and combinations of antifungal infections, the data are less clear-cut. The concurrent use of amphotericin B with an azole has elicited controversy, given the potential of antimicrobial antagonism. The results of one recent candidemia study suggest that the potential antagonism may not be an issue; the combination of amphotericin B and fluconazole provided more effective clearance of Candida from the bloodstream than did fluconazole used alone. Several in vitro and animal studies have shown antagonism between the azoles and amphotericin B for aspergillosis. However, introduction of the new class of agents that target beta-glucan synthase (echinocandins) has invigorated the prospects of combination therapy. The echinocandins and polyenes are not antagonistic, and there is evidence that the echinocandins may provide additive to synergistic activity in combination with triazoles. For patients whose aspergillosis is progressing despite monotherapy, the addition of a second agent, such as an echinocandin, may be reasonable.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Caspofungin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Triazoles; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Biomarkers; Diagnosis, Differential; Echinocandins; Glucans; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Pyrimidines; Serologic Tests; Triazoles; Voriconazole

The development of newer antifungal drugs is creating new potential combination therapies to combat the dismal mortality rate associated with invasive aspergillosis (IA). The efficacy of combination therapy for IA has not been established; sparse data on combination or sequential antifungal therapy depict interactions ranging from synergy to antagonism. We reviewed data from all published in vitro studies, animal model studies, and clinical reports and recent abstracts on combination and sequential antifungal therapy for IA from 1966-2001. Among cases of IA during 1966-2001, 249 were treated with 23 different antifungal combinations. Amphotericin B plus 5-fluorocytosine was the most commonly used (49% of cases), followed by amphotericin B plus itraconazole (16%) or plus rifampin (11%). Combination therapy resulted in improvement in 63% of patients, generally with amphotericin B plus 5-fluorocytosine or rifampin and indifference with amphotericin B plus itraconazole. In 27 in vitro reports, we found synergy (in 36% of reports), additivity (in 24%), indifference (in 28%), and antagonism (in 11%). Amphotericin B plus 5-fluorocytosine and amphotericin B plus rifampin showed generally positive interactions and amphotericin B plus itraconazole showed results that were largely indifferent. Eighteen animal model reports demonstrated synergy (in 14% of reports), additivity (in 20%), indifference (in 51%), and antagonism (in 14%). In general, amphotericin B plus 5-fluorocytosine, amphotericin B plus rifampin, and amphotericin B plus itraconazole showed indifferent results, whereas amphotericin B plus micafungin showed positive interactions. Thirty-four cases treated during 1990-2001 with sequential therapy, excluding amphotericin B followed by itraconazole, showed improvement in 68% of cases. Improvement was noted with amphotericin B or itraconazole followed by voriconazole but not with itraconazole followed by amphotericin B.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Treatment Outcome

The echinocandins are large lipopeptide molecules that are inhibitors of beta-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides; Peptides, Cyclic; Treatment Outcome

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candida; Cell Wall; Drug Design; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Fungi; Glucosyltransferases; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Membrane Proteins; Micafungin; Peptides, Cyclic; Schizosaccharomyces pombe Proteins

Few studies have assessed the efficacy and safety of micafungin in patients with proven or probable invasive aspergillosis (IA). This was the aim of the current study, which was conducted in 22 hospitals in China, where micafungin was approved for treatment of IA in 2006.. This was a non-comparative, phase IV open-label study (NCT02646774). Eligible patient were adults with proven or probable IA. Efficacy endpoints included rates of overall treatment success (primary endpoint) and clinical improvement, fungal clearance, mortality, and the site of Aspergillus infection (all secondary endpoints). Safety endpoints included incidences of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and adverse drug reactions (ADRs). These endpoints were reported descriptively with associated 95% confidence intervals (CI); no hypotheses were tested.. The study was discontinued early due to low patient recruitment, which did not allow for the planned sample size to be reached. In total, 68 patients were enrolled: 42 into the full analysis set (for efficacy) and 61 into the safety analysis set. All patients were Han Chinese; the majority were male (n = 26; 61.9%) and ≤60 years of age (n = 35; 83.3%). Rates of overall treatment success, clinical improvement, fungal clearance, and mortality were 45.2% (n = 19/42; 95% CI: 29.85-61.33); 59.5% (n = 25/42; 95% CI: 43.28-74.37), 80.0% (n = 4/5; 95% CI: 28.36-99.49), and 7.1% (n = 3/42; 95% CI: 1.50-19.48), respectively. All patients were diagnosed with pulmonary Aspergillus infection. Overall, 155 TEAEs and 8 SAEs were reported by 37 (60.7%) and 7 (11.5%) patients. The most common TEAEs were decreased platelet count and fatigue (both n = 5; 8.2%) and the most common SAEs were intracranial hemorrhage and lung infection (n = 3; 4.9% and n = 2; 3.3%). Eight ADRs (n = 6; 9.8%) were reported but all were completely remitted or remitting during follow-up.. Results suggest that micafungin is efficacious and well-tolerated in patients with proven or probable IA in China. However, these findings should be interpreted with care, due to the small number of patients included in this study. Further comparative trials should be used to confirm the efficacy and safety of micafungin in patients with proven or probable IA.

Topics: Adult; Aged; Antifungal Agents; Aspergillosis; China; Dose-Response Relationship, Drug; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Treatment Outcome; Young Adult

Invasive aspergillosis remains associated with significant morbidity and mortality, necessitating new options for salvage therapy. The objective of this study was to evaluate the efficacy and safety of micafungin as salvage monotherapy in patients with invasive aspergillosis. Patients with proven or probable invasive aspergillosis, who were refractory or intolerant to previous systemic antifungal therapy, were randomised 2 : 1 to receive 300 mg day(-1) intravenous micafungin monotherapy or an intravenous control monotherapy [lipid amphotericin B (5 mg kg(-1) day(-1)), voriconazole (8 mg kg(-1) day(-1)) or caspofungin (50 mg day(-1))] for 3-12 weeks. Patients underwent final assessment 12 weeks after treatment start. Seventeen patients with invasive aspergillosis (proven, n = 2; probable, n = 14; not recorded, n = 1) participated in the study (micafungin arm, n = 12; control arm, n = 5). Three patients each in the micafungin (25.0%; 95% CI: 5.5-57.2) and control arm (60.0%; 95% CI: 14.7-94.7) had successful therapy at end of treatment as assessed by an Independent Data Review Board. Eleven patients died; six due to invasive aspergillosis. No deaths were considered related to study treatment. During this study it became increasingly common to use combination treatment for salvage therapy. Consequently, enrolment was low and the study was discontinued early. No clear trends in efficacy and safety can be concluded.

Topics: Administration, Intravenous; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Caspofungin; Drug Therapy, Combination; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Treatment Outcome; Voriconazole

The safety and efficacy profile of caspofungin and micafungin in Japanese patients with fungal infections were directly compared in this prospective, randomized, double-blind study. The proportion of patients who developed significant drug-related adverse event(s) (defined as a serious drug-related adverse event or a drug-related adverse event leading to study therapy discontinuation) was compared in 120 patients [caspofungin 50 mg, or 50 mg following a 70-mg loading dose on Day 1 (hereinafter, 70/50 mg) group: 60 patients; micafungin 150 mg: 60 patients]. The overall response rate was primarily evaluated in the per-protocol set (PPS) population. The proportion of patients who developed significant drug-related adverse events was 5.0 % (3/60) in the caspofungin group and 10.0 % (6/60) in the micafungin group [95 % confidence interval (CI) for the difference: -15.9 %, 5.2 %]. The favorable overall response in the PPS population for patients with esophageal candidiasis, invasive candidiasis, and chronic pulmonary aspergillosis including aspergilloma was 100.0 % (6/6), 100.0 % (3/3), and 46.7 % (14/30) in the caspofungin group, and 83.3 % (5/6), 100.0 % (1/1), and 42.4 % (14/33) in the micafungin group, respectively. In Japanese patients with Candida or Aspergillus infections, there was no statistical difference in the safety between caspofungin and micafungin. Consistent with other data on these two agents, the efficacy of caspofungin and micafungin was similar.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Humans; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Treatment Outcome

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Bacterial; Aspergillosis; beta-Glucans; Candidiasis, Invasive; Chemical and Drug Induced Liver Injury; Early Diagnosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Mannans; Micafungin; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count <500 cells/mm(3)) at onset of treatment. Successful response was seen in 25/98 (26%); an additional 12 patients achieved stable disease. Response was seen in 2/9 (22%) in de novo treatment, 21/87 (24%) in refractory patients, and 2/2 (100%) in toxicity failure patients. Additionally, response was seen in 22 of the 90 (24%) patients treated with combination therapy, and in 3 of 8 (38%) patients who were treated with micafungin alone. No significant differences in responses were found based on type of HSCT, GVHD status, site of IA, or Aspergillus species, and no significant toxicity was seen. Micafungin was well tolerated, even at high doses, and is a reasonable option for treatment of IA in this high-risk patient population.

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus; Child; Drug Therapy, Combination; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Invasive Pulmonary Aspergillosis; Lipopeptides; Micafungin; Treatment Outcome

The clinical efficacy of micafungin (MCFG) in surgery, emergency, and intensive-care medicine has been studied in only a limited number of cases. We conducted a multicenter postmarketing study to evaluate MCFG efficacy and safety in Japan. MCFG was given to patients with a temperature exceeding 37.5 degrees C, either with a proven fungal infection based on mycological or histopathological examination, or those who were regarded as having probable or possible fungal infections (patients who had at least one high-risk factor for the development of a systemic fungal infection and for whom fungi had been detected at multiple sites by surveillance culture or a positive beta-D-glucan test). Efficacy was evaluated using the AKOTT algorithm created by our group (AKOTT is an acronym created from the first letter of the surname of each of the five members of the evaluation committee). Of the 180 patients enrolled, 68 were excluded by exclusion criteria or for other reasons, and 112 (58 with proven candidiasis, 1 with proven aspergillosis, and 53 with suspected fungal infection) were evaluated for efficacy. MCFG was administered at a mean daily dose of 104 mg for a mean duration of 14.2 days. It was effective in 72 p 72 patients, ineffective in 28, and the effect was undeterminable in 12, for an overall clinical efficacy 72.0%. MCFG was effective in 78.6% of those with proven candidiasis and in 65.1% with suspected fungal infection, but it was ineffective in the 1 patient with aspergillosis. MCFG eradicated 77.6% (52/67) of fungi isolated. There were 69 drug-related adverse reactions, mainly abnormal hepatic function tests, in 37 of 178 patients evaluated for safety. One adverse reaction, skin eruption, had a probable causal relationship with drug treatment. In conclusion, MCFG had high clinical efficacy and safety in the treatment of deep-seated fungal infections in surgery, emergency, and intensive-care medicine, indicating good potential as a firstline drug for both targeted and empirical therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Antifungal Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Drug Eruptions; Echinocandins; Emergency Service, Hospital; Female; Humans; Intensive Care Units; Japan; Lipopeptides; Liver Diseases; Male; Micafungin; Middle Aged; Postoperative Complications; Product Surveillance, Postmarketing; Treatment Outcome

Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA).. A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel.. Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA.. Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Aspergillosis; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Humans; Infant; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic

The efficacy and safety of micafungin (FK463), which is a new lipopeptide antifungal agent of the echinocandin class and is active against both Aspergillus and Candida species, were investigated in patients with deep-seated mycosis in this study. 70 patients were treated with micafungin 12.5-150 mg/d intravenously for up to 56 d. The overall clinical response rates were 60% (6/10) in invasive pulmonary aspergillosis, 67% (6/9) in chronic necrotizing pulmonary aspergillosis, 55% (12/22) in pulmonary aspergilloma, 100% (6/6) in candidemia, and 71% (5/7) in esophageal candidiasis. The response rates for patients with prior antifungal treatment which was considered ineffective or toxic, were similar to rates for patients without prior treatment. Mycological eradication was observed in patients infected with Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Candida albicans, Candida glabrata, or Candida krusei. Adverse events related to micafungin were reported in 21 patients (30%), and there was no dose-related occurrence of any adverse event. It is concluded that treatment with micafungin as monotherapy seems to be effective and safe in patients with deep-seated mycosis.

Topics: Adult; Aged; Antifungal Agents; Aspergillosis; Candidiasis; Dose-Response Relationship, Drug; Drug Administration Schedule; Echinocandins; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Mycoses; Peptides, Cyclic; Severity of Illness Index; Treatment Outcome

The echinocandins are large lipopeptide molecules that are inhibitors of beta-(1,3)-glucan synthesis, an action that damages fungal cell walls. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp and fungistatic against Aspergillus spp. They are not active at clinically relevant concentrations against Zygomycetes, Cryptococcus neoformans, or Fusarium spp. No drug target is present in mammalian cells. The first of the class to be licensed was caspofungin, for refractory invasive aspergillosis (about 40% response rate) and the second was micafungin. Adverse events are generally mild, including (for caspofungin) local phlebitis, fever, abnormal liver function tests, and mild haemolysis. Poor absorption after oral administration limits use to the intravenous route. Dosing is once daily and drug interactions are few. The echinocandins are widely distributed in the body, and are metabolised by the liver. Results of studies of caspofungin in candidaemia and invasive candidiasis suggest equivalent efficacy to amphotericin B, with substantially fewer toxic effects. Absence of antagonism in combination with other antifungal drugs suggests that combination antifungal therapy could become a general feature of the echinocandins, particularly for invasive aspergillosis.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Clinical Trials as Topic; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides; Peptides, Cyclic; Treatment Outcome

Topics: Antibodies, Fungal; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Brain Diseases; Diagnosis, Differential; Humans; Male; Micafungin; Middle Aged; Treatment Outcome; Voriconazole

The molecular epidemiology and antifungal susceptibility of Aspergillus nidulans species complex has not been well studied. To evaluate the genetic diversity and antifungal susceptibility patterns of clinical and environmental isolates of A. nidulans complex. Sixty clinical and environmental isolates of Aspergillus section Nidulantes were collected from five countries (Iran, The Netherlands, Spain, Portugal and Greece). The species were molecularly identified by sequencing of β-tubulin gene. The genetic diversity of A nidulans complex isolates (n = 54) was determined with a microsatellite genotyping assay. Antifungal susceptibility profile was determined using EUCAST method. The isolates were classified as A nidulans (46.7%), A spinulosporus (26.6%), A quadrilineatus (10%), A pachycristatus (3.3%), A rugulosus (3.3%), A unguis (5%), A creber, (1.7%), A olivicola (1.7%) and A sydowii (1.7%). Thirty-four sequence types (STs) were identified among the 54 A nidulans complex isolates. A high level of genetic diversity was found among A nidulans sensu stricto strains but low diversity was found among A spinulosporus strains. Amphotericin B showed high MICs to all species. The most active azole was posaconazole (GM = 0.64 mg/L), while itraconazole showed the highest MICs among azoles (GM = 2.95 mg/L). A spinulosporus showed higher MICs than A nidulans sensu stricto for all antifungals except for micafungin and anidulafungin. Interspecies variations may result in differences in antifungal susceptibility patterns and challenge antifungal therapy in infections caused by A nidulans. Differences in the distribution of STs or persistence of multiple STs might be related to the sources of isolation and niche specialisation.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Aspergillus nidulans; Azoles; Cross Infection; Environmental Microbiology; Genetic Variation; Greece; Humans; Iran; Micafungin; Microbial Sensitivity Tests; Microsatellite Repeats; Molecular Epidemiology; Netherlands; Phylogeny; Phylogeography; Portugal; Spain; Tubulin

Fungal infections are a major cause of morbidity and mortality in the haematological patients. These infections are mainly due to Candida spp. and Aspergillus spp. Mortality by these infections is high, but rates have descended in the latest series due to better antifungal agents. Echinocan-dins are, in vitro, very active against Candida and Aspergillus spp. The objective of the study is to analyse the efficacy and safety of micafungin in the antifungal prophylaxis of haema-tological patients on chemotherapy.. A multicentre, observational retrospective study was performed in 7 Haematology Depart-ments in Spain. Patients admitted to these departments with chemotherapy or immunosuppressive treatment, and who had received antifungal prophylaxis with micafungin between 1 January 2009 and 31 December 2014 were included.. There were 5 cases of probable or proven fun-gal infection (4.8%) according to the 2008 EORTC criteria: 2 proven, 3 probable. The types of fungal infection were 3 as-pergillosis and 2 candidiasis. There were no drop-outs from the prophylaxis with micafungin due to toxicity.. Micafungin is an antifungal agent which, used in prophylaxis, has demonstrated good efficacy and an excellent toxicity profile, making it an apparently interesting option in patients requiring antifungal prophylaxis during their hospitalisation episode.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Candidiasis; Female; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Lymphoma; Male; Micafungin; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Young Adult

Topics: Adolescent; Adult; Allografts; Aspergillosis; Candidiasis; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Micafungin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Voriconazole

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Diagnosis, Differential; Echocardiography; Endocarditis; Fatal Outcome; Female; Heart Atria; Humans; Micafungin; Middle Aged; Myxoma; Voriconazole

To investigate the performance of the routine serum galactomannan (sGM) assay in the diagnosis of invasive aspergillosis (IA) in high-risk haematology patients receiving prophylaxis with micafungin.. Retrospective study including all haematological patients who received prophylaxis with micafungin during high-risk IA episodes (neutropenic patients after chemotherapy for acute myeloid leukaemia/myelodysplastic syndrome; allogeneic haematopoietic stem-cell transplantation during early neutropenic phase or graft-versus-host disease requiring high prednisone doses) and for whom at least one sGM result was available. Episodes were classified as follows: true-positive (positive GM in the context of IA), false-positive (positive GM result in patients who had no evidence of IA), true-negative (negative GM test results and no IA), or false-negative (negative GM test in the context of IA). Non-evaluable patients were excluded.. Among 146 evaluable episodes, four were true-positive in the context of probable breakthrough IA (incidence of breakthrough IA, 2.7%); 111/146 high-risk episodes (76%) were considered true-negative and 31/146 (21.2%) were considered false-positive. No false-negative episodes were detected. All but one of the false-positive episodes were detected in surveillance GM tests, leading to high-resolution CT scans in eight cases (8/31; 25.8%), all of which were negative. The positive predictive and negative predictive values of sGM for surveillance and diagnostic approaches were 3.2% (1/31) and 100% (110/110) and 75% (3/4) and 100% (1/1), respectively.. Surveillance of asymptomatic patients receiving prophylaxis with micafungin using sGM is unnecessary, because the results are either negative or false-positive. However, sGM remains useful in the diagnosis of breakthrough IA in symptomatic patients during prophylaxis.

Topics: Adult; Antibiotic Prophylaxis; Aspergillosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Lipopeptides; Male; Mannans; Micafungin; Retrospective Studies

Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus.

Topics: Aged; Antifungal Agents; Aspergillosis; Central Nervous System Fungal Infections; Chronic Disease; Echinocandins; Female; Humans; Itraconazole; Lipopeptides; Micafungin; Paranasal Sinus Diseases; Radiography

Limited data are available about the safety and efficacy of micafungin in children. A postmarketing surveillance study was conducted to assess the safety and effectiveness of micafungin, an echinocandin antifungal, in pediatric patients. A prospective multicenter postmarketing observational study was carried out between October 2006 and September 2008 in Japan. Pediatric patients under 16 years received an intravenous infusion of micafungin at a dose of 1 mg/kg for candidiasis and 1 to 3 mg/kg for aspergillosis, with the option of increasing the dose if required to 6 mg/kg once daily. All adverse events were recorded. A total of 201 pediatric patients were enrolled. There were 55 adverse drug reactions reported among 42 of 190 patients evaluated for safety (22.1%); the most frequently reported adverse drug reaction was hepatobiliary disorders. No adverse drug reactions were reported in 18 neonates (aged below 4 wk). The overall clinical response rate in 91 patients evaluated for efficacy was 86.8%. The response rate in neonates was 90.0%, and there were no differences in the response rate by age. Micafungin was found to have sufficient safety and effectiveness for the treatment of fungal infections in pediatric patients with various backgrounds.

Topics: Adolescent; Antifungal Agents; Asian People; Aspergillosis; Candidiasis; Child; Child, Preschool; Echinocandins; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin

Voriconazole is a triazole antifungal agent superior to amphotericin B in the treatment of invasive aspergillosis. It is generally well tolerated and has excellent oral bioavailability, providing significant benefit in the treatment of invasive fungal infections. There have been numerous reports of dermatologic reactions to this agent, including erythroderma, cheilitis, Stevens-Johnson syndrome, discoid lupus erythematosus, pseudoporphyria, squamous cell carcinoma, and photosensitivity reactions. Pseudoporphyria, a dermatologic condition mimicking porphyria cutanea tarda, has been described as an adverse effect of voriconazole use. Clinical findings include photosensitivity, vesicles, bullae, milia, and scarring in sun-exposed areas. Photo-onycholysis is a phenomenon of nail discoloration and onycholysis that has been described in the setting of a phototoxic drug reaction and pseudoporphyria. Implicated drugs have most commonly been tetracyclines, fluoroquinolones, and psoralens; others have been reported as well. We report a case of a pediatric patient with leukemia who developed symptoms consistent with pseudoporphyria and later photo-onycholysis while being treated with voriconazole. To our knowledge, this is the first reported case of pseudoporphyria due to voriconazole in a pediatric patient and the first reported case of photo-onycholysis as a consequence of voriconazole use.

Topics: Ankle; Aspergillosis; Blister; Catheter-Related Infections; Cefepime; Cephalosporins; Cheilitis; Child; Cicatrix; Clindamycin; Dermatitis, Phototoxic; Echinocandins; Humans; Hypokalemia; Immunocompromised Host; Levofloxacin; Lipopeptides; Magnesium Deficiency; Male; Micafungin; Onycholysis; Photosensitivity Disorders; Porphyrias; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Vancomycin; Voriconazole

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae.

Topics: Albumins; Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Culture Media; Echinocandins; Humans; Hyphae; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Voriconazole

Abstract An 88-year-old man underwent uneventful phacoemulsification and aspiration with an implantation of a preloaded acrylic intraocular lens. Six months later, he developed endophthalmitis with negative aqueous cultures, and the inflammation was refractory to conventional antibacterial therapies. He was treated successfully with vitrectomy and removal of the IOL and the entire lens capsule. A combination of intravitreal voriconazole and systemic micafungin were prescribed, and the inflammation was resolved. As best we know, this is the first case of Aspergillus tubingenesis endophthalmitis that followed the implantation of a preloaded intraocular lens.

Topics: Aged, 80 and over; Antifungal Agents; Aspergillosis; Aspergillus; Device Removal; Drug Therapy, Combination; Echinocandins; Endophthalmitis; Eye Infections, Fungal; Humans; Intravitreal Injections; Lens Implantation, Intraocular; Lipopeptides; Male; Micafungin; Phacoemulsification; Postoperative Complications; Pyrimidines; Triazoles; Visual Acuity; Vitrectomy; Voriconazole

Micafungin inhibits 1,3-β-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive fungal infections. However, little is known about the immunomodulatory activity of micafungin in these infections.. We evaluated the immunomodulatory activity of escalating doses of micafungin in murine and human polymorphonuclear neutrophils (PMNs) in vitro and in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors.. Micafungin was able to regulate PMN cytokine response to Aspergillus fumigatus conidia by decreasing the expression of tumour necrosis factor-α and increasing that of interleukin-10 (IL-10). In vivo, the therapeutic efficacy of micafungin was strictly dose-dependent, with the maximum activity observed at the highest dose, concomitant with reduced inflammatory pathology. The anti-inflammatory activity of micafungin required IL-10 and occurred through signalling via the TLR2/dectin-1 and TLR3/TRIF pathways.. Together, these findings suggest that the therapeutic efficacy of micafungin in aspergillosis is orchestrated by the activation of innate immune receptors affecting the inflammatory/anti-inflammatory balance during infection.

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Bacterial Load; Cells, Cultured; Echinocandins; Female; Histocytochemistry; Humans; Immunologic Factors; Lipopeptides; Lung; Micafungin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophils; Treatment Outcome

Micafungin, an antifungal echinocandin, has been indicated for pediatric patients with invasive fungal infection (IFI) in Japan and Europe. Its efficacy in immunocompromised pediatric patients with IFI, however, has not been fully investigated.. The safety and efficacy of micafungin as an antifungal therapy were analyzed in nine consecutive severe immunocompromised patients with IFI.. Three patients with proven or probable Candida infections had complete response to micafungin therapy. Of the other six patients with proven, probable or possible Aspergillus infection, four had complete response and one had partial response to micafungin treatment. No severe adverse events were observed.. In this small series, micafungin was effective for IFI caused by both Candida and Aspergillus species and no severe adverse events were observed in these immunocompromised patients.

Topics: Adolescent; Antifungal Agents; Aspergillosis; Candidiasis; Child; Child, Preschool; Cohort Studies; Echinocandins; Female; Humans; Immunocompromised Host; Infant; Lipopeptides; Male; Micafungin; Treatment Outcome

Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Cunninghamella; Deoxycholic Acid; Drug Combinations; Drug Interactions; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mucormycosis; Nitriles; Pyridines; Triazoles

KB425796-C is a novel antifungal metabolite produced by the newly isolated bacterial strain Paenibacillus sp. No. 530603. This compound is a 40-membered macrocyclic lipopeptidolactone consisting of 12 amino acids and a 3-hydroxy-15-methylpalmitoyl moiety. KB425796-C displayed antifungal activity against micafungin-resistant fungi and was fungicidal to Trichosporon asahii in vitro. In a murine systemic infection model of T. asahii, KB425796-C showed excellent efficacy upon i.p. administration at 32 mg kg(-1). In addition, KB425796-C induced morphological changes in the hyphae of Aspergillus fumigatus and had fungicidal effects in combination with micafungin. In a mouse model of septic A. fumigatus infection, although non-treated mice survived for a maximum of only 6 days, the survival rate of micafungin-treated mice (0.1 mg kg(-1)) increased to 20%, while the survival rate of mice treated with a combination of micafungin (0.1 mg kg(-1)) and KB425796-C (32 mg kg(-1)) increased to 100% during the 31-day post-infection period. Our findings suggest that KB425796-C is a good candidate for the treatment of aspergillosis in combination with micafungin.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Depsipeptides; Disease Models, Animal; Drug Resistance, Fungal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Female; Injections, Intraperitoneal; Lipopeptides; Micafungin; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Paenibacillus; Sepsis; Survival Rate; Trichosporon; Trichosporonosis

Given the recent increase in aspergillosis caused by species other than Aspergillus fumigatus, micafungin, caspofungin, and liposomal amphotericin B (L-AmBi) were investigated as monotherapy or combination therapy for murine systemic or pulmonary Aspergillus flavus infection. Treatment for 3 or 6 days was begun at 24 h (intravenous [i.v.], 2.8 × 10(4) conidia) or 2 h (intranasal, 4.1 × 10(6) to 6.75 × 10(6) conidia) postchallenge as follows: 5 or 10 mg/kg L-AmBi, 10 mg/kg caspofungin, 15 mg/kg micafungin, L-AmBi plus echinocandin, L-AmBi on days 1 to 3 and echinocandin on days 4 to 6, or echinocandin on days 1 to 3 and L-AmBi on days 4 to 6. Mice were monitored for survival, fungal burden, serum or tissue cytokines, and lung histopathology. In the systemic infection, micafungin or caspofungin was more effective than L-AmBi in prolonging survival (P < 0.05), and L-AmBi was associated with significantly elevated serum levels of interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), and IL-12 (P < 0.05). In contrast, L-AmBi was significantly more effective than the echinocandins in reducing fungal growth in most tissues (P < 0.05). Concomitant therapies produced significantly enhanced survival, reduction in fungal burden, and low levels of proinflammatory cytokines, while antagonism was seen with some sequential regimens. In comparison, in the pulmonary infection, L-AmBi was significantly better (P < 0.05) than caspofungin or the combination of L-AmBi and caspofungin in prolonging survival and reducing lung fungal burden. Caspofungin stimulated high lung levels of IL-1α, tumor necrosis factor alpha (TNF-α), and IL-6, with extensive tissue damage. In summary, systemic A flavus infection was treated effectively with L-AmBi plus micafungin or caspofungin provided that the drugs were administered concomitantly and not sequentially, while pulmonary A. flavus infection responded well to L-AmBi but not to caspofungin.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus flavus; Caspofungin; Chemokine CCL3; Drug Administration Schedule; Drug Therapy, Combination; Echinocandins; Female; Interleukin-12; Interleukin-1alpha; Interleukin-6; Lipopeptides; Lung; Micafungin; Mice; Survival Rate; Tumor Necrosis Factor-alpha

We investigated the triazole, amphotericin B, and micafungin susceptibilities of 196 A. fumigatus clinical isolates in Nagasaki, Japan. The percentages of non-wild-type (non-WT) isolates for which MICs of itraconazole, posaconazole, and voriconazole were above the ECV were 7.1%, 2.6%, and 4.1%, respectively. A G54 mutation in cyp51A was detected in 64.2% (9/14 isolates) and 100% (5/5 isolates) of non-WT isolates for itraconazole and posaconazole, respectively. Amphotericin B MICs of ≥2 μg/ml and micafungin minimum effective concentrations (MECs) of ≥16 μg/ml were recorded for two and one isolates, respectively.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Itraconazole; Japan; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Mutation; Pyrimidines; Sequence Analysis, DNA; Triazoles; Voriconazole

Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach.. We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate.. IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality.. The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis; Cohort Studies; Echinocandins; Female; Humans; Lipopeptides; Lung Transplantation; Male; Micafungin; Middle Aged; Mycoses; Risk; Time Factors; Triazoles

In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.

Topics: Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Leukemia; Lipopeptides; Micafungin; Mycoses; Neutropenia; Opportunistic Infections; Pyrimidines; Triazoles; Voriconazole

The frequency of invasive fungal sinusitis (IFS) has increased in recent years with the use of steroids, onset of diabetes mellitus, and the administration of antibacterial agents. We report on the clinical features and outcomes of four patients with IFS involving the cavernous sinus and orbit. Prognostic factors facilitating an early diagnosis are described, and the usefulness of combination therapy involving systemic administration of antifungal agents and surgical intervention is discussed.. We treated four patients with IFS between March 2003 and November 2007 at Ehime University Hospital. Patients were two males and two females, aged from 61 to 74 years (mean 67.8 years).. With regard to clinical symptoms, headache was observed in all patients, and cranial nerve paralysis (visual disturbance, blindness, cheek paresthesia) was seen in 3 patients. β-D-Glucan levels in four patients were high compared with normal values. Aspergillus was histopathologically identified from biopsy specimens in all patients. One patient was complicated with Candida in addition to the Aspergillus infection. Orbital exenteration and ESS were performed in 2 patients as surgical debridement. In all patients, systemic administration of antifungal agents was initiated after surgery.. All patients received strategic treatment with surgery and systemic administration of anti-fungal agents. The single fatality was due to brain infarction caused by the spread of Aspergillus, and the remaining three patients are still alive. Our observations in these patients suggest that early diagnosis and strategic treatment may improve the prognosis of IFS.

Topics: Aged; Antifungal Agents; Aspergillosis; Biopsy; Blindness; Brain Infarction; Candidiasis; Cavernous Sinus; Combined Modality Therapy; Debridement; Early Diagnosis; Echinocandins; Fatal Outcome; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Lipopeptides; Magnetic Resonance Imaging; Male; Maxillary Sinusitis; Micafungin; Middle Aged; Orbit Evisceration; Orbital Diseases; Postoperative Complications; Pyrimidines; Sphenoid Sinusitis; Tomography, X-Ray Computed; Triazoles; Voriconazole

Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Echinocandins; Iron Chelating Agents; Lipopeptides; Micafungin; Mice; Mice, Inbred BALB C; Mucormycosis; Polyenes; Rhizopus

The safety and efficacy of micafungin were evaluated in a Japanese post-marketing survey involving 1,142 patients with deep mycosis caused by Candida or Aspergillus. The overall clinical response was 83.0%, and the respective responses for patients with candidiasis or aspergillosis were 86.3 and 70.8%. With regard to drug reactions, 562 adverse reactions were observed in 28.5% of patients. Among the 83 serious adverse drug reactions reported by 53 patients, a causal relationship with micafungin was assessed as definite or probable for 6 reactions in 5 patients. Age and baseline hepatic and renal function status did not affect the incidence of adverse reactions, although incidence increased significantly in proportion to the severity of mycosis and daily dose (p < 0.01). In multiple logistic regression analysis, neither baseline hepatic impairment nor increased daily dose of micafungin affected the incidence of hepatobiliary disorders, however, the severity of mycosis was found to correlate significantly with hepatobiliary disorders (p = 0.031). Taken together, our post-marketing findings show that micafungin is effective against deep mycosis caused by Candida or Aspergillus in patients across a range of backgrounds.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aspergillosis; Aspergillus; Candida; Candidiasis; Echinocandins; Female; Humans; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Risk Factors; Treatment Outcome

We aimed to evaluate the efficacy of a combination of amphotericin B (AMB) and micafungin (MCFG) against 25 clinical isolates of Aspergillus species in vitro. We examined fungal growth in the presence of these drugs using a checkerboard method with the tetrazolium salt: 2,3-bis (2- methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxyanilide inner salt (XTT) to determine the efficacy of an AMB/MCFG combination in inhibition of filamentous fungal growth, evaluated based on 50% reduction of metabolic activity. The fractional inhibitory concentration index showed that the drugs synergistically inhibited 36% of the isolates. Activity was judged as indifferent for 64% isolates; antagonistic interaction was not detected. The AMB/MCFG combination was more effective than AMB alone when sub-inhibitory concentrations of AMB were used. This report demonstrates the efficacy of AMB/MCFG combination for inhibiting the growth of Aspergillus species in vitro, warranting the extension of such studies to animal models.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Echinocandins are a new class of antifungal agents with a specific mechanism of action. These drugs inhibit the enzyme 1,3β-D-glucan synthetase which is responsible for the formation of 1,3β-D-glucan, an essential fungal cell wall component. They have a good activity against Candida species and Aspergillus. Three agents are available at the present time or under development : caspofungin, micafungin and anidulafungin. These drugs require intravenous administration. Efficacy, safety, rare drugs interactions and specificity of action are advantages for therapy of invasive fungal infections. In France, micafungin and caspofungin are approved for a pediatric use.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Candidiasis, Invasive; Caspofungin; Child; Echinocandins; Evidence-Based Medicine; Humans; Injections, Intravenous; Lipopeptides; Micafungin; Mycoses; Treatment Outcome

We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Transplantation

Aminocandin (IP960; HMR3270; NXL201) is a new echinocandin with broad-spectrum in vitro activity against Aspergillus and Candida spp. We compared the activity of aminocandin with that of amphotericin B (AmB), itraconazole (ITC) and caspofungin (CAS) in murine models of disseminated aspergillosis against three strains of A. fumigatus, two of which were fully susceptible (AF293 and A1163) and one was resistant to ITC (AF91). Mice were rendered temporarily neutropenic or persistently neutropenic with cyclophosphamide and were infected intravenously 3 days later. Temporarily neutropenic mice were treated with either intraperitoneal (i.p.) AmB (5mg/kg/dose), oral (p.o.) ITC (25mg/kg/dose), intravenous (i.v.) aminocandin (0.25-10mg/kg/dose), i.p. aminocandin (1mg/kg/dose) or solvent control for 9 days. Mice were euthanised 11 days post infection and the kidneys and liver were removed for quantitative culture. Following infection with AF293, only aminocandin 5mg/kg i.v. yielded 100% survival. Aminocandin 1mg/kg i.v., AmB 5mg/kg i.p. or ITC 25mg/kg p.o. were equivalent (P>0.05). Aminocandin 5mg/kg was superior to aminocandin 0.25mg/kg (P<0.0001) as well as all controls (P<0.0001) in reducing mortality. Following infection with AF91, only aminocandin at 5mg/kg and 1mg/kg i.v. yielded 100% survival, which was superior to ITC, aminocandin 0.25mg/kg and controls (all P<0.0001). In the persistently neutropenic model with A1163, aminocandin, CAS and micafungin (2-10mg/kg) were all effective at prolonging survival, with some impact on reducing culture burdens, even with alternate-day dosing (4mg/kg). The only fungicidal regimen was aminocandin 5mg/kg, which sterilised 40% and 50% of mice following infection with AF293 and AF91, respectively. Aminocandin at doses of > or =1mg/kg is highly effective in reducing mortality and organ burden in disseminated infection caused by ITC-susceptible and -resistant A. fumigatus.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Caspofungin; Colony Count, Microbial; Disease Models, Animal; Echinocandins; Injections, Intraperitoneal; Injections, Intravenous; Itraconazole; Kidney; Lipopeptides; Liver; Male; Micafungin; Mice; Survival Analysis; Treatment Outcome

While anti-cancer chemotherapy has improved the survival of patients with hematologic malignancies, it has also exposed such patients to the risk of life-threatening infection due to neutropenia. In intensive chemotherapy for leukemia, invasive aspergillosis resulting in death is infrequently observed. In such cases, aggressive diagnostic and therapeutic intervention is required. Herein, we report a case of Aspergillus liver abscesses in a patient with acute monoblastic leukemia. The patient presented with febrile neutropenia and concomitantly with an elevated serum beta-D: -glucan level during chemotherapy. The abscesses were finally diagnosed by liver biopsy. Although antifungal monotherapy of voriconazole or liposomal amphotericin B, both of which are recommended for invasive aspergillosis, showed a poor response, when combined with micafungin, an echinocandin, both had a highly favorable effect against the infection. Therefore, our clinical experience suggests that the serum test is useful for the rapid diagnosis of invasive aspergillosis, especially in deep tissues, and that combination antifungal therapy with micafungin should be considered when initial monotherapy for fungal infection shows an insufficient effect.

Topics: Antifungal Agents; Aspergillosis; Drug Therapy, Combination; Echinocandins; Hepatitis; Humans; Leukemia, Monocytic, Acute; Lipopeptides; Liver Abscess; Male; Micafungin; Middle Aged

This study presents in vitro susceptibility data for clinical (n = 48) and environmental (n = 31) isolates of Aspergillus terreus against nine antifungal agents. The methodology of the European Committee on Antimicrobial Susceptibility Testing was applied. Posaconazole and anidulafungin had the lowest and amphotericin B the highest MICs. No differences in susceptibility patterns were observed between environmental and clinical isolates.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; DNA, Fungal; Humans; Microbial Sensitivity Tests; Soil Microbiology

The in vitro antifungal activities of micafungin in comparison to caspofungin, fluconazole, itraconazole, voriconazole, and amphotericin B were evaluated against 93 Candida and 23 Aspergillus isolates recovered from pediatric patients with fungal infections. MICs were determined by the CLSI M27-A2 and M38-A for Candida and Aspergillus species, respectively. Micafungin showed potent activity against Candida albicans, Candida tropicalis, and Candida glabrata with a MIC range of <= 0.002 to 0.015mug/ml. In contrast, micafungin demonstrated higher MIC levels against Candida parapsilosis with a MIC range of 0.12 to 2 mug/ml. Micafungin showed potent antifungal activity against Aspergillus species tested with a MIC range of 0.004 to 0.015 mug/ml. Overall, micafungin had excellent in vitro antifungal activities against Candida and Aspergillus species recovered from pediatric patients with fungal infections.

Topics: Adolescent; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Female; Humans; Infant; Infant, Newborn; Japan; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests

A pharmacokinetic (PK)-pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections.. Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK-PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration-time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L).. Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required.. These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100-150 mg once daily for treatment), and on the basis of these results we propose a PK-PD-based dosing strategy for Aspergillus infections. A regimen of 200-250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.

Topics: Adult; Aged; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Models, Statistical; Plasma

We determined the in vitro activities of anidulafungin, caspofungin, and micafungin against 526 isolates of Aspergillus spp. (64 A. flavus, 391 A. fumigatus, 46 A. niger, and 25 A. terreus isolates) collected from over 60 centers worldwide from 2001 through 2007. Susceptibility testing was performed according to the CLSI M38-A2 method. All three echinocandins--anidulafungin (50% minimum effective concentration [MEC50], 0.007 microg/ml; MEC90, 0.015 microg/ml), caspofungin (MEC50, 0.015 microg/ml; MEC90, 0.03 microg/ml), and micafungin (MEC50, 0.007 microg/ml; MEC90, 0.015 microg/ml)-were very active against Aspergillus spp. More than 99% of all isolates were inhibited by < or = 0.06 microg/ml of all three agents.

Topics: Anidulafungin; Antifungal Agents; Aspergillosis; Aspergillus; Caspofungin; Echinocandins; Humans; Inhibitory Concentration 50; Lipopeptides; Micafungin; Microbial Sensitivity Tests

The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including Candida species (MIC range, 0.00025 to 0.0078 microg/ml), Cryptococcus neoformans (MIC range, 0.0039 to 0.0625 microg/ml), and Aspergillus species (MIC range, 0.0156 to 4 microg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent Candida albicans strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some Candida and Aspergillus species and against Cryptococcus neoformans. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg.kg(-1).dose(-1), respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Benzamidines; Candida albicans; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycoses; Specific Pathogen-Free Organisms; Treatment Outcome

SPK-843, a new polyene antifungal, exhibited dose-dependent efficacy on murine pulmonary aspergillosis models. SPK-843 doses of higher than 1.0 mg/kg of body weight exhibited no renal toxicities and a tendency toward better survival prolongation than the estimated maximum tolerated doses of amphotericin B (Fungizone) (1.0 mg/kg) and liposomal amphotericin B (AmBisome) (8.0 mg/kg).

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus flavus; Disease Models, Animal; Dose-Response Relationship, Drug; Echinocandins; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Mice; Polyenes; Treatment Outcome

Aspergillus fumigatus is a leading cause of death in immunocompromised patients and a frequent colonizer of the respiratory tracts of asthma and cystic fibrosis (CF) patients. Biofilms enable bacteria and yeasts to persist in infections and can contribute to antimicrobial resistance. We investigated the ability of A. fumigatus to form biofilms on polystyrene (PS) and human bronchial epithelial (HBE) and CF bronchial epithelial (CFBE) cells. We developed a novel in vitro coculture model of A. fumigatus biofilm formation on HBE and CFBE cells. Biofilm formation was documented by dry weight, scanning electron microscopy (SEM), and confocal scanning laser microscopy (CSLM). The in vitro antifungal activities of seven antifungal drugs were tested by comparing planktonic and sessile A. fumigatus strains. A. fumigatus formed an extracellular matrix on PS and HBE and CFBE cells as evidenced by increased dry weight, SEM, and CSLM. These biofilms exhibited decreased antifungal drug susceptibility and were adherent to the epithelial cells, with fungi remaining viable throughout 3 days. These observations might have implications for treatment of A. fumigatus colonization in chronic lung diseases and for its potential impact on airway inflammation, damage, and infection.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biofilms; Bronchi; Cells, Cultured; Cystic Fibrosis; Drug Resistance, Fungal; Epithelial Cells; Humans; Microbial Sensitivity Tests; Microscopy, Confocal; Microscopy, Electron, Scanning; Respiratory Tract Infections

We report 2 pediatric cases of cerebral fungal infection. A patient with severe aplastic anemia developed an Aspergillus species brain abscess and pulmonary aspergillosis after peripheral blood stem cell transplantation. Despite administration of micafungin, amphotericin B, and flucytosine, the patient died 2 months after the transplantation because of underlying pulmonary aspergillosis. Another patient with acute myelogenous leukemia developed a huge brain abscess with histopathologic findings suspicious of mucormycosis. This patient was cured with combination therapy of antifungal agents and intensive surgery, without sequelae. It is important to perform aggressive multimodality treatment, when indicated, including surgical intervention, even if in myelosuppression.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Central Nervous System Fungal Infections; Child; Drug Combinations; Echinocandins; Fatal Outcome; Female; Flucytosine; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Magnetic Resonance Imaging; Male; Micafungin; Mucormycosis; Peripheral Blood Stem Cell Transplantation; Remission Induction; Treatment Outcome

Treatment options for primary cutaneous aspergillosis in neonates are limited by the lack of pharmacokinetic and safety data of newer antifungal agents that are effective against Aspergillus spp. We report the successful treatment of cutaneous aspergillosis in an extremely low-birth-weight preterm infant with liposomal amphotericin B, voriconazole and micafungin, and provide pharmacokinetic profiles for voriconazole and micafungin.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Dermatomycoses; Echinocandins; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

The rising incidence of pulmonary aspergillosis is a major clinical concern. However, only a limited number of antifungal drugs are available in Japan that are effective for pulmonary Aspergillus infections. Micafungin (MCFG), a newly developed echinocandin family antifungal drug, has potent antifungal activity in vitro, but few reports detailing its clinical effectiveness have been published to date. A retrospective study was performed using data from nine patients (seven males and two females) with chronic invasive forms of pulmonary aspergillosis, who were treated with either MCFG alone or together with other antifungal drugs between April 2003 and March 2004. The overall efficacy of the treatments was evaluated in the terms of clinical, mycological, serological and radiological responses. The average age of the patients was 61.9 (20-83) years old. Four patients received only MCFG and the remaining five patients were treated with MCFG in combination with amphotericin B (AMB) only (1 patient), itraconazole (ITC) only (2 patients) or AMB backed up by ITC during AMB discontinuation periods (2 patients). The mean duration of MCFG administration was 59.2 (28-96) days. Overall, the treatment was judged to have been effective for seven of nine patients. No patient's condition deteriorated in response to treatment. Administration of MCFG alone was judged to have been effective in three of four patients. No notable adverse effects were documented during MCFG administration. These data suggest that MCFG may be an effective and safe antifungal drug for the treatment of chronic invasive forms of pulmonary aspergillosis.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Chronic Disease; Drug Therapy, Combination; Echinocandins; Female; Humans; Itraconazole; Japan; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic; Radiography; Retrospective Studies; Treatment Outcome

While invasive pulmonary aspergillosis usually occurs in immunocompromised hosts, it has been described after influenza virus infection in healthy individuals. The first case was a 76-year-old previously healthy woman admitted because of chest pain, cough, sputum, fever, and a chest radiograph abnormality. A transbronchial biopsy specimen showed fungal hyphae. Amphotericin B (AMPH) and Itraconazole (ITCZ) were given, and she improved gradually. A viral test showed a titre of 1/128 to influenza A. Case 2 was a 72-year-old previously healthy man admitted because of cough, fever, chest pain and a consolidation and cavitation on the chest radiograph. Antibiotics were ineffective. Cavitation with a halo sign appeared on the contralateral lung. Because his daughter was infected with Influenza B, we suspected he had been infected with IPA following influenza infection. AMPH and ITCZ and Micafungin sodium were given. His respiratory failure worsened, and on the tenth hospital day he required artificial ventilation; his condition improved gradually, (extubation after 40 days.) A viral test showed a titre of 1/128 to influenza B. IPA must be considered for the differential diagnosis of complications of influenza virus infection.

Topics: Aged; Alphainfluenzavirus; Amphotericin B; Antifungal Agents; Aspergillosis; Betainfluenzavirus; Diagnosis, Differential; Drug Therapy, Combination; Echinocandins; Female; Humans; Influenza, Human; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Peptides, Cyclic

A 35-year-old man developed invasive pulmonary aspergillosis (IPA) with severe neutropenia after umbilical cord stem cell transplantation for chronic myelogenous leukemia. Filamentous fungus isolated from his sputum was identified as Aspergillus terreus. Despite systemic amphotericin B (AMPH) administration, IPA progressed. However, intravenous administration of micafungin (MCFG) and oral itraconazole improved clinical data and symptoms, although he later died of massive hemoptysis. Examination of the in vitro susceptibility of this A. terreus isolate to MCFG revealed a good minimum inhibitory concentration and good time-kill assay results compared to AMPH. Thus, MCFG might be useful for IPA caused by A. terreus.

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus; Drug Therapy, Combination; Echinocandins; Humans; Itraconazole; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Neutropenia; Opportunistic Infections; Peptides, Cyclic; Sputum; Stem Cell Transplantation

A 59-year-old man was admitted to our hospital with a diagnosis of acute myeloid leukemia in September 2004. He developed invasive pulmonary aspergillosis (IPA) and candidiasis, which were improved by administration of micafungin and amphotericin B (AMPH-B). He received reduced-intensity unrelated cord-blood transplantation without induction chemotherapy. He developed grade IV graft-versus-host disease (GVHD) and the administration of steroids against GVHD was prolonged. Voriconazole (VRCZ) was used for a long period to prevent recurrence of the IPA. Afterwards, infiltrates in the bilateral upper lung fields were detected on a chest CT scan, and a diagnosis of pulmonary mucormycosis was made following detection of Mucor circinelloides from the patient's sputum culture. He then began receiving AMPH-B but died of massive hemoptysis. Mucormycosis usually occurs in immunocompromised hosts such as neutropenic patients with hematologic diseases and is a fatal fungal infection characterized by a rapid and progressive clinical course. Some overseas investigators have recently reported that VRCZ prophylaxis may result in breakthrough mucormycosis in hematopoietic stem cell transplant recipients. These findings suggest that it is very important to pay attention to mucormycosis in hematopoietic stem cell transplant recipients in this country.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Cord Blood Stem Cell Transplantation; Echinocandins; Fatal Outcome; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Mucormycosis; Peptides, Cyclic; Pyrimidines; Transplantation Conditioning; Triazoles; Voriconazole

A 63-year-old man was admitted to our hospital because he complained of fever and productive cough; this was associated with cavitary infiltrates on his chest X-ray. Although several antibiotics were given, his symptoms did not improve. Bronchofiberscope investigation yielded Aspergillus fumigatus; thus, he was diagnosed with chronic necrotizing pulmonary aspergillosis. Itraconazole, 200 mg/day, was given, and his symptoms and infiltrates on chest X-ray gradually improved. After 2 months of treatment, new infiltrates appeared on a chest X-ray. Antibacterial agents had also shown no effect, and voriconazole was substituted for itraconazole. However, the infiltrates progressed in spite of the voriconazole administration. We added micafungin to the voriconazole treatment. Both his symptoms and the infiltrates on chest X-rays improved. Because voriconazole is thought to be the most effective agent against Aspergillus spp., it is difficult to treat cases that are refractory to voriconazole. The treatment of this case provides invaluable information on how to treat pulmonary aspergillosis related to diseases other than hematologic malignancies.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Chronic Disease; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Necrosis; Pyrimidines; Radiography; Triazoles; Voriconazole

A 73-year-old man (height, 158.2 cm; weight, 49.8 kg) presented with upper abdominal tenderness after 3 weeks of treatment with 150 mg/d of micafungin (3 mg/kg . d) (Mycamine, Astellas Pharma US Inc., Deerfield, Illinois) intravenously for pulmonary aspergillosis accompanied by [DOSAGE ERROR CORRECTED] pulmonary Mycobacterium avium complex (MAC) infection. Pulmonary aspergillosis was noninvasively diagnosed by a fungus lump in a cavity in the right upper lung field with a high value of 1,3-beta-D-glucan and a positive result for aspergillosis antigen. The patient had a medical history of gastrectomy due to gastric cancer and idiopathic thrombocytopenic purpura (ITP). He had been prescribed 800 mg/d of clarithromycin, 400 mg/dL of rifampicin, and 750 mg/d of ethambutol hydrochloride for pulmonary MAC infection for 2 years and 5 mg/d of prednisolone for ITP for 7 years. No traditional or homeopathic medicine had been received/administered. Laboratory tests at the onset of abdominal pain revealed a white blood cell count of 4300/microL with 51% neutrophils. There was no eosinophilia. Platelet count was 15,100/muL, with normal coagulation. Immunoglobulin G and immunoglobulin M were 1720 and 154 mg/dL, respectively. The patient had no history of allergy, biliary tract disease, hyperlipidemia, or hypercalcemia. He did not report alcohol use. The laboratory findings, magnetic resonance imaging, and upper abdominal tenderness were consistent with acute pancreatitis. After cessation of all drugs, his symptoms improved with bowel rest and parenteral nutrition. His laboratory measurements normalized thereafter. All drugs, except micafungin, were readministered for pulmonary MAC infection and ITP, and itraconazole was administered for pulmonary aspergillosis after the recovery from pancreatitis. During 16 months of follow-up, the pancreatitis did not recur.. We performed a literature search of all available English-language articles published on MEDLINE between January 1966 and January 2007 using the key terms micafungin (text and indexed terms) and pancreatitis (text and indexed terms). Based on the search of MEDLINE, there have been no reports of acute pancreatitis associated with micafungin. The Naranjo adverse drug reaction (ADR) probability scale was used to assess the probability of micafungin-associated acute pancreatitis. A score of 6 was obtained, indicating a probable ADR from micafungin treatment.. We report a case of acute pancreatitis probably associated with micafungin use in an elderly patient.

Topics: Acute Disease; Aged; Antifungal Agents; Aspergillosis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Mycobacterium avium-intracellulare Infection; Pancreatitis; Peptides, Cyclic

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent life-threatening bacterial and fungal infections. We characterized the effects of single and combination antifungal therapy on survival, histopathology, and laboratory markers of fungal burden in experimental aspergillosis in the p47phox-/- knockout mouse model of CGD. CGD mice were highly susceptible to intratracheal Aspergillus fumigatus challenge, whereas wild-type mice were resistant. CGD mice were challenged intratracheally with a lethal inoculum (1.25 x 10(4) CFU/mouse) of A. fumigatus and received one of the following regimens daily from day 0 to 4 after challenge (n = 19 to 20 per treatment group): (i) vehicle, (ii) amphotericin B (intraperitoneal; 1 mg/kg of body weight), (iii) micafungin (intravenous; 10 mg/kg), or (iv) amphotericin B plus micafungin. The rank order of therapeutic efficacy based on prolonged survival, from highest to lowest, was as follows: amphotericin B plus micafungin, amphotericin B alone, micafungin alone, and the vehicle. Lung histology showed pyogranulomatous lesions and invasive hyphae, but without hyphal angioinvasion or coagulative necrosis. Treatment with micafungin alone or combined with amphotericin B produced swelling of invasive hyphae that was not present in mice treated with the vehicle or amphotericin B alone. Assessment of lung fungal burden by quantitative PCR showed no significant difference between treatment groups. Serum galactomannan levels were at background despite documentation of invasive aspergillosis by histology. Our findings showed the superior efficacy of the amphotericin B and micafungin combination compared to either agent alone after A. fumigatus challenge and also demonstrated unique features of CGD mice as a model for experimental aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Drug Therapy, Combination; Echinocandins; Granulomatous Disease, Chronic; Lipopeptides; Lipoproteins; Lung; Micafungin; Mice; NADPH Oxidases; Peptides, Cyclic; Phosphoproteins

Visceral fungal infections are difficult to manage in patients with collagen diseases and immunocompromised hosts. In particular aspergillosis can be a life-threatening complication in these patients. Here we report that combined use of two antifungal agents (micafangin and itraconazole) was effective against severe aspergillosis of the bilateral pleural cavities in a 48-year old male patient diagnosed with Wegener's granulomatosis. Immunosuppressive therapy with corticosteroids and cyclophosphamides improved his nasal and pulmonary symptoms, but inflammation of the bilateral pleural cavities caused bronchial fistulas. Aspergillus fumigatus then infected the bilateral pulmonary cavities through these fistulas. This patient was treated with combined therapy of ITCZ and MCFG was given to this patient because of the risk of renal dysfunction associated with AMPH-B. After 5 weeks of treatment his clinical findings had improved and the fungus was suppressed.

Topics: Adult; Antifungal Agents; Aspergillosis; Drug Administration Schedule; Drug Therapy, Combination; Echinocandins; Granulomatosis with Polyangiitis; Humans; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Peptides, Cyclic; Pleural Cavity

We report a case of invasive sinus aspergillosis that extended to the orbital cavity and cavernous sinus and was improved by treatment with micafungin and itraconazole.. A 83-year-old woman was referred to our hospital because of headache and impaired of eye movement on the right side. Physical examination revealed impaired function of cranial nerves, II, II, IV, and VI on the right side. MRI showed evidence of inflammation of the right sphenoid sinus and ethmoidal sinus and an enhancing mass in the right cavernous sinus and orbit. Because a culture of a specimen from the right sphenoid sinus extracted during endoscopic sinus surgery, yielede Aspergillus fumigatus, a diagnosed of invasive sinus aspergillosis complicated by cavernous sinus symdrome and orbital apex symdrome was made. It was difficult to completely remove the mass in the sinuses surgically and drug therapy with micafungin was started and then itraconazole was added. The clinical manifestations and the impaired function of cranial nerves II, III, IV, and VI improved, and MRI showed regression of the mass in the sinuses temporary in response to drug therapy.. Invasive sinus aspergillosis often progresses rapidly in the absence of surgery. Our case is valuable, because invasive sinus aspergillosis was improved by drug therapy alone, and combined treatment with micafungin and itraconazole was effective.

Topics: Aged, 80 and over; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cavernous Sinus; Combined Modality Therapy; Echinocandins; Ethmoid Sinusitis; Female; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Orbit; Peptides, Cyclic; Sinusitis; Sphenoid Sinusitis

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Debridement; DNA, Fungal; Drug Therapy, Combination; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Itraconazole; Lipopeptides; Lipoproteins; Lymphoma, Non-Hodgkin; Male; Maxillary Diseases; Maxillary Sinus; Micafungin; Middle Aged; Opportunistic Infections; Peptides, Cyclic; Renal Insufficiency; Sinusitis; Treatment Outcome

Mortality from invasive pulmonary aspergillosis approaches 80% with few useful therapeutic options available. In these studies, we examined the efficacy of micafungin (MICA) alone or in combination with other antifungals in a model of pulmonary aspergillosis in immunosuppressed DBA/2 mice infected intranasally with conidia of Aspergillus fumigatus 10AF. In the initial study, groups of mice were given saline, or 1, 3 or 10 mg kg(-1) of MICA b.i.d., s.c. All saline controls, and 90% of untreated mice succumbed to infection. The efficacy of MICA was difficult to assess because of an apparent toxicity at 10 mg kg(-1). MICA given at 1 mg/kg significantly prolonged survival over the saline controls (P = 0.008). MICA at 3 or 10 mg kg(-1) versus the saline controls approached significance. No treatment regimen differed in efficacy. The efficacy of combination therapy was assessed, with mice given either no treatment, MICA at 1 mg/kg/dose, 0.8 mg kg(-1) of intravenous amphotericin B (AMB), 100 mg kg(-1) of oral itraconazole (ICZ), or 100 mg/kg/dose of twice-daily subcutaneous nikkomycin Z (NIK). AMB alone and MICA + AMB or MICA +NIK significantly prolonged survival (P < 0.05 - 0.02) over that of the controls. ICZ alone, ICZ+MICA and NIK alone did not significantly prolong survival. MICA alone at 1 mg/kg approached significance in prolonging survival. The combination of MICA and ICZ appeared to be potentially antagonistic. Although AMB+MICA was efficacious, no synergistic activity was noted for any of the regimens. Overall, these results indicate that MICA has moderate activity against pulmonary aspergillosis and might be useful in combination with conventional AMB.

Topics: Aminoglycosides; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Drug Antagonism; Drug Therapy, Combination; Echinocandins; Female; Immunosuppression Therapy; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Mice; Mice, Inbred DBA; Peptides, Cyclic; Survival Analysis

We describe a 55-year-old man with acute myelogenous leukemia who developed breakthrough Trichosporon asahii fungemia during 5 days of micafungin treatment. Although the patient's clinical condition improved considerably after the start of voriconazole treatment, blood culture results remained positive for T. asahii for 3 days, and fever persisted for 7 days thereafter. The patient achieved complete hematological remission, and he received successful consolidation chemotherapy without developing Trichosporon infection with the prophylactic use of voriconazole therapy. This case report illustrates that voriconazole may be useful in the treatment of disseminated T. asahii infection in neutropenic patients.

Topics: Acute Disease; Antifungal Agents; Aspergillosis; Echinocandins; Fungemia; Humans; Leukemia, Myeloid; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Mycoses; Peptides, Cyclic; Pyrimidines; Triazoles; Trichosporon; Voriconazole

The patient was a 42-year-old man who visited a physician with fever, and was diagnosed with pulmonary abscess. Antibiotic therapy was ineffective, and he was referred to our hospital. Chest CT scanning revealed a lesion with cavity formation with an infiltrative shadow in the right upper lobe, and another infiltrative shadow in the left upper lobe. Chronic necrotizing pulmonary aspergillosis (CNPA) was diagnosed on the basis of positive culture of bronchial lavage specimens and positive serological test results for Aspergillus, in addition to the clinical and radiographic features. Intravenous administration of micafungin (MCFG) was initiated with combination therapy of percutaneous cavity drainage, inhaled amphotericin B and oral itraconazole. Clinical symptoms and findings gradually improved, and he was discharged after 40 days of MCFG therapy. MCFG was safe and effective therapy in this case, and may be considered a new therapeutic option for CNPA.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Chronic Disease; Drug Therapy, Combination; Echinocandins; Humans; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Necrosis; Peptides, Cyclic

We previously reported that a 150 mg or higher daily dose is necessary for treatment of pulmonary aspergillosis with micafungin (MCFG) alone in patients with blood diseases. Since a delay in the treatment of pulmonary aspergillosis has a major influence on patient survival, clarification of the effective blood concentration of MCFG enables rapid treatment. Establishment of an appropriate dose is also useful for reducing the risk of adverse effects, such as MCFG-induced impairment of liver function. Aiming for the rapid and safe treatment of pulmonary aspergillosis, we established new clinical diagnostic criteria of mycosis and MCFG therapeutic effect judgment criteria, and investigated the effective blood concentration of MCFG for mycosis. The blood trough level of MCFG in patients with blood diseases at each clinical improvement rating of pulmonary aspergillosis was 5.23+/-2.44 microg/ml in markedly improved cases, 4.08+/-2.63 microg/ml in improved cases, and 3.45+/-1.63 microg/ml in successfully prevented cases, showing no significant difference among the 3 groups. Based on this finding, it is advisable to target a 5 microg/ml or higher blood trough level of MCFG in establishing the dose for aspergillosis in patients with blood diseases.

Topics: Adult; Aged; Antifungal Agents; Aspergillosis; Echinocandins; Female; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic

A 52-year-old man with a 6-month history of bloody sputum was admitted to our hospital. Chest X-ray on admission showed a pulmonary cavity with liquid content in the left upper field and consolidation at the circumference of the lesion. Chest computed tomography (CT) on the 13th hospital day revealed a typical fungus ball in the cavity, which we diagnosed as pulmonary aspergilloma. We administered him micafungin sodium for 1 month. Voriconazole was administered subsequently, but side effects developed. Therefore, itraconazole was administered as a substitute. Chest high-resolution CT (HRCT) clearly showed a reduction in size of the aspergilloma, thus confirming the effectiveness of antifungal agent administration in this case. However, since hemoptysis occurred for the case, left upper lobectomy was performed and postoperative course was excellent.

Topics: Administration, Oral; Antifungal Agents; Aspergillosis; Combined Modality Therapy; Echinocandins; Humans; Infusions, Intravenous; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic; Pneumonectomy; Treatment Outcome

Micafungin, the first candin antifungal drug developed in Japan, has a significant therapeutic effect against deep-seated mycoses caused by Candida or Aspergillus. Little is known, however, about the optimal dosage or disposition of micafungin in patients with severe hepatic impairment. Nine liver transplant recipients (5 males and 4 females) were enrolled in this study. In 1 recipient with a markedly small-for-size graft (ratio of graft volume to standard liver volume at the time of transplantation: 25.9%), the areas under the plasma concentration-time curves up to 12 hours postdose (AUC(0-12 h)) at doses of 50 and 100 mg/d were 79.38 and 601.17 mug.h/mL, respectively. The corresponding elimination half-life (T(1/2)) values were 16.01 and 75.75 hours, and saturated elimination was observed only at the dose of 100 mg/d. The mean urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) in the small-for-size graft recipient was significantly (P < .05) lower than that in the other recipients. In conclusion, graft size was an important factor affecting disposition of micafungin. For liver transplant recipients with markedly small-for-size grafts, the optimal dosage of micafungin to reach and maintain therapeutic plasma levels is estimated to be 50 mg/d.

Topics: Antifungal Agents; Area Under Curve; Aspergillosis; Candidiasis; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Echinocandins; Female; Humans; Lipopeptides; Lipoproteins; Liver; Liver Transplantation; Male; Micafungin; Organ Size; Peptides, Cyclic; Postoperative Complications; Postoperative Period

The patient was a 73-year-old female who visited a physician with a chief complaint of fever, and was diagnosed with pneumonia. Ampicillin/sulbactam was administered, but ineffective, and the patient was referred to our hospital. In addition to severe inflammatory findings, cavity lesions were observed in the right upper lobe on plain chest X-ray and thoracic CT. Since Aspergillus fumigatus was cultured in bronchoalveolar lavage, a definite diagnosis of pulmonary aspergillosis was made. Intravenous administration of micafungin was initiated, but severe inflammatory findings persisted, and infiltrative shadows rapidly expanded. Oral itraconazole was concomitantly administered, and clinical symptoms and findings slowly improved. The plasma trough levels of micafungin, itraconazole, and hydroxyitraconazole were higher than the minimal inhibitory concentrations for the etiologic fungus, A. fumigatus, throughout the treatment period. No adverse events of the concomitant treatment were observed. Combination of the two antifungal agents may be effective for intractable pulmonary aspergillosis.

Topics: Administration, Oral; Aged; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Diagnosis, Differential; Drug Therapy, Combination; Echinocandins; Female; Humans; Infusions, Intravenous; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Peptides, Cyclic; Treatment Outcome

A 55-year-old man, who had diabetes from age 46 years old had been treated for a lung abscess in the right upper lobe at age 51. He underwent an operation for stomach cancer at age 52. When he was 55 years old, a cavity lesion appeared in his right upper lobe at the site of the treated lung abscess. Pulmonary aspergillosis was diagnosed by bronchial biopsy. In this case, we controlled his diabetes and used micafungin which has a mechanism unlike other conventional antifungal agents. The shadow decreased and examination of the resected specimen showed that the fungus had disappeard. Pulmonary aspergillosis is an important mycosis profunda and micafungin seems to be an effective antifungal agent against it.

Topics: Antifungal Agents; Aspergillosis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Lung Abscess; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic

This study was conducted to evaluate the effectiveness of a new antifungal drug, micafungin, and standard antifungal drugs against endophthalmitis induced in a rabbit by intravitreal injection of Aspergillus fumigatus, an important fungal pathogen. Effectiveness was evaluated by the preservation of b-wave amplitude at 72 h after injection of the fungus relative to the b-wave amplitude at baseline before any intravitreal injections. A 0.06 ml inoculum of 10(6) conidia of A. fumigatus was injected into the vitreous of the right eye of all rabbits; and, 12 h later, a 0.06 ml solution containing one of 3 antifungal drugs or saline was injected into the vitreous of both eyes. All three antifungal drugs produced significant b-wave preservation at 72 h in infected eyes compared to that in infected eyes receiving saline injections. There was no statistically significant difference between the effects of micafungin and amphotericin B in the right eyes with fungal endophthalmitis, and both produced significantly more preservation of b-wave amplitude than voriconazole. Amphotericin B, but neither micafungin nor voriconazole produced significant reduction of the b-wave amplitude in the left eyes.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Echinocandins; Electroretinography; Endophthalmitis; Eye Infections, Fungal; Follow-Up Studies; Lipopeptides; Lipoproteins; Micafungin; Ophthalmoscopy; Peptides, Cyclic; Pyrimidines; Rabbits; Retina; Triazoles; Vitreous Body; Voriconazole

Central nervous system (CNS) aspergillosis is a severe disease that responds poorly to current therapies. The current studies examined the efficacies of several antifungal agents alone or in combination with a murine model of CNS aspergillosis. Immunosuppressed mice were infected intracerebrally with Aspergillus fumigatus and treated with an amphotericin B preparation, an echinocandin, or voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that micafungin (MICA), caspofungin (CAS), VCZ, conventional amphotericin B (AMB), Abelcet (ABLC) (a lipid-carried AMB formulation; Enzon Pharmaceuticals, Inc.), and AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of body weight showed reduced efficacy. Neither MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS aspergillosis; combinations of AmBi and MICA or CAS were not antagonistic and may have a slight benefit.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Caspofungin; Central Nervous System Fungal Infections; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Echinocandins; Lipopeptides; Lipoproteins; Liposomes; Micafungin; Mice; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

We report 2 cases of pulmonary aspergillosis treated successfully by combining micafungin and traconazole. Case 1: A 51-year-old man with hemoptysis and dyspnea on effort treated for pulmonary tuberculosis and aspergillosis was found on chest CT on admission to have a fungus ball in the left upper lobe and increasing consolidation around the cavity of both lung fields. Bronchoscopy proved positive for aspergillus PCR in bronchial lavage. He was diagnosed with chronic necrotizing pulmonary aspergillosis, based on clinical and radiological findings and the positive reaction for aspergillus PCR. He was treated with micafungin alone at first, this proved ineffective, so itraconazole was added, resulting in improvement. Case 2: A 24-year-old woman with stabilized Hodgkin's disease (mixed). She had suffered from a cough and back pain, and chest CT showed increasing consolidation inside and around a giant bulla. She was diagnosed with chronic necrotizing pulmonary aspergillosis, based on isolation for Aspergillus sp. in sputum culture and a positive reaction for Aspergillus antigen in bronchial lavage and Aspergillus antibody in serum. She was treated with the combined micafungin and itraconazole, which rapidly improved symptoms and radiological findings. Pulmonary aspergillosis therapy is often difficult, because delivery of the drug to the infection site is limited and drug tolerance is poor. We found that combination micafungin and itraconazole therapy is tolerable and effective in these cases.

Topics: Adult; Antifungal Agents; Aspergillosis; Bronchoalveolar Lavage; Drug Administration Schedule; Drug Therapy, Combination; Echinocandins; Female; Humans; Itraconazole; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic; Tomography, X-Ray Computed

Invasive aspergillosis is an important factor in the morbidity and mortality of patients suffering from hematologic disorders treated with chemotherapy. Treatment with amphotericin B is often limited because of toxicity, particularly nephrotoxicity. We describe a case of invasive pulmonary Aspergillus fumigatus infection in acute myeloid leukemia with renal failure due to amphotericin B therapy, which responded to treatment with a new antifungal agent, micafungin. Micafungin appears to be an effective and safe therapy for Aspergillus infections with renal failure due to amphotericin B.

Topics: Amphotericin B; Aspergillosis; Echinocandins; Humans; Leukemia, Monocytic, Acute; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Peptides, Cyclic; Renal Insufficiency; Treatment Outcome

Micafungin, a new echinocandin, inhibits fungal cell wall beta-glucan synthesis. We postulated micafungin and host phagocytic cells could act together in damaging fungi. Using the metabolic XTT assay, micafungin alone (0.01 and 0.10 microg/ml) inhibited Aspergillus fumigatus germlings by 48% and 61%, respectively. Polymorphonuclear neutrophils (PMNs) inhibited germlings by 53%. Micafungin at 0.01 or 0.10 microg/ml and PMNs resulted in additive inhibition, 82% and 99%, respectively. Monocyte-derived macrophage (MDM) monolayers inhibited germling growth by 66%; micafungin (0.01 or 0.10 microg/ml) alone inhibited by 32% and 42%, respectively. MDMs and micafungin (0.01 or 0.10 microg/ml) caused an additive inhibition of growth, 85% and 95%, respectively. Hyphae were generated by incubation of conidia for 24 h with or without micafungin. PMNs alone, added to hyphae, inhibited growth by 19% in the subsequent 20 h. Hyphae generated in the presence of micafungin (0.10 microg/ml) and subsequently cultured with micafungin for 24 h inhibited growth by 64%. PMNs plus micafungin resulted in 82% inhibition. Monocytes alone inhibited hyphal growth by only 5%. Hyphae produced in the presence of micafungin (0.01 microg/ml) and incubated again with micafungin for 24 h inhibited growth by 47%; combination with monocytes resulted in 62% inhibition. These data indicate that micafungin inhibits growth of tissue forms of A. fumigatus, and phagocytes and micafungin together have an additive effect. These findings support the thesis that the greater efficacy of micafungin in vivo compared with in vitro could be due to combined effect of phagocytic cells and micafungin.

Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Echinocandins; Humans; Hyphae; Lipopeptides; Lipoproteins; Macrophages; Micafungin; Microbial Sensitivity Tests; Monocytes; Neutrophils; Peptides, Cyclic; Phagocytes; Tetrazolium Salts

We treated a 52-year-old woman with acute lymphoblastic leukemia (ALL) who developed invasive pulmonary aspergillosis (IPA) as a result of neutropenia following remission-induction chemotherapy. Although serological test results, such as those for platelia and pastrex, were all negative and the serum level of beta-D-glucan was low, Aspergillus DNA was detected in blood by the polymerase chain reaction method. A clinically documented diagnosis of IPA was made on the basis of chest x-rays, computed tomography scan findings, and the detection of Aspergillus DNA. Micafungin (FK463), a candin class antifungal agent, was administered at a dose of 75 to 150 mg/day, because other antifungal agents were not effective. The increase in serum concentration of micafungin was dose-dependent and was accompanied by improvement of symptoms and objective findings. Micafungin was effective for the treatment of IPA in this patient with ALL.

Topics: Antineoplastic Agents; Aspergillosis; Clinical Trials, Phase II as Topic; Echinocandins; Female; Humans; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Middle Aged; Neutropenia; Opportunistic Infections; Peptides, Cyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

The efficacy of voriconazole in combination with amphotericin B or micafungin was studied in a transiently neutropenic guinea-pig model of invasive pulmonary aspergillosis. Guinea-pigs treated with the antifungal drugs, alone or in two-drug combinations, had an improved survival rate and reduced fungal burden in the lungs compared to untreated control animals. The efficacy of monotherapy and combination therapy was similar; activity was neither enhanced nor reduced with the two-drug combinations. Further studies of efficacy, dosing and optimal regimens for antifungal combinations are warranted.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Female; Guinea Pigs; Lipopeptides; Lipoproteins; Lung; Lung Diseases, Fungal; Micafungin; Peptides, Cyclic; Pyrimidines; Survival Analysis; Triazoles; Voriconazole

We tested the efficacy of micafungin (FK) alone or in combination with other antifungals against systemic murine aspergillosis. FK alone at 10 mg/kg of body weight/dose prolonged survival (P = 0.01) and reduced CFU in the brain and kidney. Combination therapy that used suboptimal FK with amphotericin B or itraconazole prolonged survival. Although no survivors were free of infection, no antagonism was seen. Nikkomycin Z with FK showed significantly greater potency (P < 0.01) than either alone.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Drug Therapy, Combination; Echinocandins; Female; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic

We compared the activity of four doses of micafungin (FK463) with that of amphotericin B, liposomal amphotericin B and itraconazole in a murine model of disseminated aspergillosis. Temporarily neutropenic mice were infected with a lethal dose of either an itraconazole-resistant Aspergillus fumigatus isolate or Aspergillus terreus, a species that is less susceptible to amphotericin B. Treatment was started 24 h after infection and lasted for 7 days. Mice were treated with either amphotericin B (0.5 or 5 mg/kg), liposomal amphotericin (5 or 25 mg/kg), itraconazole (25 or 75 mg/kg) or FK463 (either 1, 2, 5 or 10 mg/kg). Treatment of the A. fumigatus model with either amphotericin B, liposomal amphotericin or FK463 prolonged survival. Doses of FK463 5 and 10 mg/kg had a 100% survival. Treatment of A. terreus infection with either itraconazole or FK463, but not amphotericin B, also prolonged survival. Doses of liposomal amphotericin of 5 and 25 mg/kg were ineffective against A. terreus infection. No treatment regime was able to totally clear the liver or kidneys in either model. The data indicate that FK463 may have a clinical role in the treatment of life-threatening invasive aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Colony Count, Microbial; Drug Resistance, Fungal; Echinocandins; Immunosuppressive Agents; Itraconazole; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia; Peptides, Cyclic

Invasive pulmonary aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Simultaneous inhibition of fungal cell-wall and cell-membrane biosynthesis may result in synergistic interaction against Aspergillus fumigatus. We studied the antifungal activity of micafungin, a new echinocandin, in combination with ravuconazole, a second-generation triazole, against experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. This combination led to significant reductions in mortality (P

Topics: Animals; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Female; Lipopeptides; Lipoproteins; Lung; Lung Diseases, Fungal; Micafungin; Organ Size; Peptides, Cyclic; Rabbits; Thiazoles; Triazoles

AmBisome and micafungin were used alone and in combination in a series of studies designed to identify any additive or antagonistic effects of combination antifungal therapy.. Immune-suppressed mice were infected either intravenously or intranasally with Aspergillus fumigatus. Micafungin, liposomal amphotericin B or both drugs together were administered for 7 days. Parameters of efficacy included survival and tissue burden of A. fumigatus.. Whilst each drug was effective in murine aspergillosis, additive effects were observed only in reduction of tissue burden in limited experimental conditions. No antagonism was seen.. The present studies neither encourage nor discourage clinical use of combination therapy. Clinical trials are suggested before combined therapy is routinely adopted.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Lipoproteins; Liposomes; Male; Micafungin; Mice; Mice, Inbred ICR; Peptides, Cyclic

Micafungin sodium (MCFG) is a new lipopeptide antifungal agent of the echinocandin class. MCFG inhibits 1,3-beta-glucan synthesis in C. albicans and A. fumigatus in a non-competitive manner and has antifungal activity against both Aspergillus and Candida species. In neutropenic mouse models of disseminated candidiasis and pulmonary aspergillosis, the efficacy of MCFG was superior to that of fluconazole and itroconazole, but comparable to that of amphotericin B. The efficacy and safety of MCFG were investigated in 70 patients with deep-seated mycosis caused by Candida and Aspergillus species. The overall clinical response rates were 57.1% in aspergillosis and 78.6% in candidiasis. The incidence of adverse events related to micafungin was 17.9 %, and there was no dose-related occurrence of any adverse events. The results from this study indicated that micafungin was effective against aspergillosis and candidiasis, with no tolerability problems.

Topics: Adult; Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Mice; Peptides, Cyclic

The echinocandins comprise a major development in systemic antifungal therapy. They rapidly and irreversibly inhibit glucan synthesis in the fungal cell wall, a distinct target from azole antifungals, flucytosine and polyenes. As such, the echinocandins appear effective against triazole and amphotericin B resistant fungi. The spectrum is still not fully understood because of problems with susceptibility testing, and because of limited studies in animal models. The primary target species for clinical studies include Candida and Aspergillus, but the class is likely to have broader use. Lack of nephrotoxicity and few drug interactions make this class attractive. The major limitations at present appear to be the lack of oral formulation and uncertainty regarding the extent of the spectrum. These drugs have the potential of being significant additions to the management of mycoses in the critically ill patient.

Topics: Anidulafungin; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Candidiasis; Caspofungin; Cell Wall; Echinocandins; Fungi; Glucans; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides; Peptides, Cyclic; Randomized Controlled Trials as Topic

The efficacy of intravenous injection of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of disseminated candidiasis and aspergillosis and was compared with those of fluconazole (FLCZ) and amphotericin B (AMPH-B). In the candidiasis model, FK463 significantly prolonged the survival of intravenously infected mice at doses of 0.125 mg/kg of body weight or higher. In disseminated candidiasis caused by Candida species, including FLCZ-resistant Candida albicans, FK463 exhibited an efficacy 1.4 to 18 times inferior to that of AMPH-B, with 50% effective doses (ED(50)s) ranging from 0.21 to 1.00 mg/kg and 0.06 to 0.26 mg/kg, respectively, and was much more active than FLCZ. The protective effect of FK463 was not obviously influenced by the fungal inoculum size, the starting time of the treatment, or the immunosuppressed status of the host. The reduction in efficacy was less than that observed with FLCZ or AMPH-B. The efficacy of FK463 was also evaluated in the disseminated candidiasis target organ assay and was compared with those of FLCZ and AMPH-B. Efficacies were evaluated on the basis of a comparison between the mean log(10) CFU in kidneys in the groups treated with antifungal agents and that in control group. A single dose of FK463 at 0.5 mg/kg or higher significantly reduced the viable counts in kidneys compared with the numbers of yeast cells before treatment, and its efficacy was comparable to that of AMPH-B, while FLCZ at 4 mg/kg showed only a suppressive effect on the growth of C. albicans in the kidneys. In the disseminated aspergillosis model, FK463 given at doses of 0.5 mg/kg or higher significantly prolonged the survival of mice infected intravenously with Aspergillus fumigatus conidia. The efficacy of FK463 was about 2 times inferior to that of AMPH-B, with ED(50)s ranging from 0.25 to 0.50 mg/kg and 0.11 to 0.29 mg/kg, respectively. These results indicate that FK463 may be a potent parenterally administered therapeutic agent for disseminated candidiasis and aspergillosis.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candida albicans; Candidiasis; Echinocandins; Immunosuppression Therapy; Kidney; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Mice, Inbred ICR; Peptides, Cyclic

The efficacy of FK463, a novel water-soluble lipopeptide, was evaluated in mouse models of pulmonary aspergillosis and was compared with that of amphotericin B (AMPH-B). In the pulmonary aspergillosis models induced by intranasal inoculation, FK463 exhibited good efficacy, with 50% effective doses in the range of 0. 26 to 0.51 mg/kg of body weight; these values were comparable to those of AMPH-B. In an Aspergillus target organ assay with immunosuppressed mice, under conditions of constant plasma levels of FK463, using a subcutaneously implanted osmotic pressure pump, a significant reduction in viable fungal cells was observed at plasma FK463 levels of 0.55 to 0.80 microgram/ml or higher. We conclude that FK463 is highly effective in the treatment of pulmonary aspergillosis in this animal model. These results indicate that FK463 may be a potent parenterally administered antifungal agent for pulmonary aspergillosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Echinocandins; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Peptides, Cyclic; Treatment Outcome