micafungin and Candidiasis

Micafungin is characterized as one of the most active available drugs for candidemia treatment; however, their use is also associated in prophylaxis protocols in cases of invasive fungal infections. The use of this drug is widely appreciated in the medical field due to be the most active echinocandin available for invasive fungal infections. In order to provide important parameters related to the chemical, physical, biological and therapeutic characteristics, this review article gathers important research results that demonstrate the biological potential of this drug, as well as to present analytical methods that can be used to determine the antifungal potential and a monitoring of administered dosages. Important studies about the methods most commonly used in biological activity evaluation and determination/quantification by analytical methods are provided in this review article. With the data provided, the scientific community will have the possibility to choose the analytical methods and biological that can be employed in clinical and scientific research to provide greater safety and reliability of the results to be found.

Topics: Antifungal Agents; Aspergillus fumigatus; Candida; Candidiasis; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Electrophoresis, Capillary; Humans; Micafungin; Solubility; Tandem Mass Spectrometry; Treatment Outcome

Candida auris is a new pathogen called "superbug fungus" which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic review and meta-analysis was undertaken to determine the epidemic situation, drug resistance patterns and mortality of C. auris.. We systematically searched studies on the clinical report of Candida auris in Pubmed, Embase and Cochrane databases until October 6, 2019. A standardized form was used for data collection, and then statics was performed with STATA11.0.. It showed that more than 4733 cases of C. auris were reported in over 33 countries, with more cases in South Africa, United States of America, India, Spain, United Kingdom, South Korea, Colombia and Pakistan. C. auirs exhibited a decrease in case count after 2016. Clade I and III were the most prevalent clades with more cases reported and wider geographical distribution. Blood stream infection was observed in 32% of the cases, which varied depending on the clades. Resistance to fluconazole, amphotericin B, caspofungin, micafungin and anidulafungin in C. auris were 91, 12, 12.1, 0.8 and 1.1%. The overall mortality of C. auris infection was 39%. Furthermore, subgroup analyses showed that mortality was higher in bloodstream infections (45%), and lower in Europe (20%).. Over 4000 cases of C. auris were reported in at least 33 countries, which showed high resistance to fluconazole, moderate resistance to amphotericin B and caspofungin, high sensitivity to micafungin and anidulafungin. The crude mortality for BSI of C. auris was 45% which was similar to some drug-resistant bacteria previously reported. In conclusion, C. auris displayed similar characteristics to some drug resistance organisms. This study depicts several issues of C. auris that are most concerned, and is of great significance for the clinical management.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Fluconazole; Humans; Micafungin; Prevalence

Candida resistance to antifungals impaired invasive candidiasis outcome. In a context of echinocandin resistance development, we aimed to evaluate the association between phenotypic resistance to micafungin and fks mutations of Candida glabrata. For this systematic review and meta-analysis, we searched MEDLINE, Scopus and Web of Science for reports published up to December 2017. Studies of C glabrata candidiasis with minimum inhibitory concentrations (MIC) determination of micafungin and fks genotyping were included. Reviews, studies not using reference methods, non-glabrata Candida, experimental isolates and undetailed mutations were excluded. Two authors independently assessed the eligibility of articles and extracted data. The main outcome was the diagnostic accuracy of fks mutations compared to micafungin MIC for C glabrata, measured as fixed-effect odd ratio. Heterogeneity was calculated with the I

Topics: Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Fungal Proteins; Genotype; Humans; Micafungin; Microbial Sensitivity Tests; Mutation

Treatment of symptomatic candiduria is notoriously challenging because of the limited repository of antifungals that achieve adequate urinary concentrations. Fluconazole, amphotericin B-based products, and flucytosine are established treatment options for most Candida species. Candida krusei exhibits intrinsic resistance to fluconazole and decreased susceptibility to amphotericin B and flucytosine. In transplant patients, both amphotericin B-based products and flucytosine are less desirable because of their toxicities. Other triazole antifungals are unappealing because they do not achieve adequate urinary concentrations, have multiple toxicities, and interact with transplant-related immunosuppressive medications. Echinocandins are well-tolerated but have been traditionally deferred in the treatment of symptomatic funguria because of their poor urinary concentrations but there is a small but emerging body of literature supporting their use. Here, we present a case of successful eradication of chronic symptomatic C krusei urinary tract infection with micafungin 150 milligrams daily in a liver and kidney transplant recipient, and we review the literature on treatment of symptomatic candiduria.

Topics: Antifungal Agents; Candida; Candidiasis; Humans; Kidney Transplantation; Liver Transplantation; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Transplant Recipients; Treatment Outcome; Urinary Tract Infections

Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15-8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40-80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4-10 mg/kg in premature neonates and 2-4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.

Topics: Adult; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Child; Critical Illness; Dose-Response Relationship, Drug; Esophagitis; Humans; Infant; Infant, Newborn; Micafungin

Intravenous micafungin (Mycamine

Topics: Antifungal Agents; Candida; Candidiasis; Child; Clinical Trials as Topic; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin

The echinocandins-caspofungin, anidulafungin and micafungin-are semi-synthetic cyclic hexapeptide antimicrobial agents with modified N-linked acyl lipid side chains which anchor the compounds to the phospholipid bilayer of the fungal cell membrane, thereby inhibiting synthesis of fungal cell wall glucan. Over the last 10 years, echinocandins have become the first-line antifungal treatment of candidaemia and other forms of invasive candidiasis (IC). Echinocandins are generally well tolerated, but their use is limited by their requirement for daily intravenous dosing, lack of oral formulation and limited spectrum. In critically ill patients, it is also recognised that achievement of their pharmacokinetic/pharmacodynamic targets shows large inter-individual variability. As a drug class, they are safe to use and are associated with few adverse reactions and few drug-drug interactions of significance. Recent discovery of their ability to prevent and treat Candida biofilm formation particularly in the presence of invasive medical devices and also their ability to penetrate into mucosal surfaces such as vulvovaginal candidiasis has opened up new opportunities for research into their drug delivery. New dosing intervals are being explored to allow less frequent intravenous dosing in the ambulatory setting, and a new long-acting echinocandin, CD101, is being developed for weekly and topical administration.

Topics: Administration, Intravenous; Anidulafungin; Animals; Antifungal Agents; Biofilms; Candidiasis; Caspofungin; Drug Administration Schedule; Drug Interactions; Echinocandins; Humans; Lipopeptides; Micafungin

In the Asia-Pacific region, Candida albicans is the predominant Candida species causing invasive candidiasis/candidemia in Australia, Japan, Korea, Hong Kong, Malaysia, Singapore and Thailand whereas C. tropicalis is the most frequently encountered Candida species in Pakistan and India. Invasive isolates of C. albicans, C. parapsilosis complex and C. tropicalis remain highly susceptible to fluconazole (>90% susceptible). Fluconazole resistance (6.8-15%), isolates with the non-wild-type phenotype for itraconazole susceptibility (3.9-10%) and voriconazole (5-17.8%), and echinocandin resistance (2.1-2.2% in anidulafungin and 2.2% in micafungin) among invasive C. glabrata complex isolates are increasing in prevalence. Moreover, not all isolates of C. tropicalis have been shown to be susceptible to fluconazole (nonsusceptible rate, 5.7-11.6% in China) or voriconazole (nonsusceptible rate, 5.7-9.6% in China).

Topics: Anidulafungin; Antifungal Agents; Asia; Azoles; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidemia; Candidiasis; Candidiasis, Invasive; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Incidence; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Phenotype; Prevalence; Voriconazole

Infection of implanted cardiac devices has a low rate of occurrence. Fungal infections of such devices represent an atypical phenomenon, associated with high mortality. Both medical and surgical therapies are recommended for a successful outcome. A 60-year-old woman with past medical history of heart failure with reduced ejection fraction, implantable cardioverter-defibrillator (ICD) placement, sarcoidosis and diabetes presented with fevers and atypical pleuritic chest pain. Transthoracic echocardiogram revealed a highly mobile 2.09 cm by 4.49 cm mass associated with the ICD wire. Blood cultures were positive for Candida albicans. The patient underwent sternotomy for removal. The vegetation was 4 cm by 2 cm by 2 cm in size, attached to the right ventricle without interference with the tricuspid valve. The patient was treated with micafungin for 2 weeks and then fluconazole for 6 weeks. In this case report, we describe the rare infection of an ICD lead with C. albicans, in the form of a fungal ball. This is the 18th reported case of Candida device-related endocarditis and the first reported in a woman. Prior case reports have occurred primarily in pacemaker rather than ICD leads. The vegetation size is also one of the largest that has been reported, measuring 4 cm at its greatest length. As Candida device-related endocarditis is so rare, and as fatality occurs in half of cases, clinical management can only be derived from sporadic case reports. Therefore, the course of this patient's disease care will be a useful adjunct to the current literature for determining treatment and prognosis in similar cases.

Topics: Antifungal Agents; Candida albicans; Candidiasis; Defibrillators, Implantable; Echinocandins; Echocardiography; Endocarditis; Female; Fluconazole; Humans; Lipopeptides; Micafungin; Middle Aged; Prosthesis-Related Infections

The invasive fungal infections (IFIs) have increased in critically ill patients in recent years and are a serious complication that determine the evolution and prognosis of critically ill patients, especially invasive candidiasis (IC)and candidemia. Fortunately, treatment options for these infections have increased and there is a large arsenal of antifungal agents. This review of the literature, using PubMed and Cochrane databases, assesses the situation of the IFIs in critically ill patients and discusses the role of micafungin in this context. The broader spectrum of this candin, which gets the antifungal effect with lower MICs and that translates into greater clinical efficacy with a lower rate of adverse effects and easier to use, with proven cost-effectiveness compared with other antifungal, position micafungin as a useful therapeutic option for the management of invasive candidiasis / candidemia in critically ill patients.

Topics: Antifungal Agents; Candidiasis; Critical Illness; Echinocandins; Fungi; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mycoses; Prognosis

Intravenous micafungin (Mycamine®; Fungard®), an echinocandin, is approved in the EU for the treatment of adult (aged ≥ 16 years) and paediatric patients with invasive candidiasis and for the treatment of adult patients with oesophageal candidiasis. It is also approved in the EU as prophylactic treatment to prevent Candida infections in adult and paediatric patients undergoing haematopoietic stem cell transplant (HSCT) or patients who are expected to have neutropenia for ≥ 10 days. This article reviews the therapeutic use of micafungin for the treatment and prophylaxis of Candida infections in adult and paediatric patients, focusing on approved indications in Europe, and briefly discusses the pharmacology of the drug. Micafungin shows very good in vitro activity against clinically relevant isolates of Candida spp., with a low propensity to be associated with the emergence of resistant isolates. The drug has a convenient once-daily dosage regimen and is associated with relatively few drug-drug interactions. In large, multinational trials in adult and/or paediatric patients with invasive candidiasis, micafungin was noninferior to intravenous caspofungin or liposomal amphotericin B. In similarly designed trials in adult patients with oesophageal candidiasis, treatment with micafungin was noninferior to that with intravenous fluconazole or caspofungin. As prophylactic treatment in adult and paediatric patients who had undergone HSCT, micafungin was superior to fluconazole therapy and noninferior to oral itraconazole in large, multicentre trials. Micafungin was generally well tolerated by participants in these clinical trials, given the severe morbidity of the underlying conditions of patients, with a similar tolerability profile to caspofungin and, in general, to fluconazole. It was better tolerated than liposomal amphotericin B or oral itraconazole. Thus, micafungin is a valuable first-line or alternative option to other antifungal agents for the management of candidaemia and invasive candidiasis in adult and paediatric patients, including neonates, and as prophylaxis against fungal infections in patients undergoing HSCT.

Topics: Antifungal Agents; Candida; Candidiasis; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Randomized Controlled Trials as Topic; Treatment Outcome

The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC ≤ 2 mcg/ml; non-S: MIC > 2 mcg/ml) was applied to all echinocandins and species. More data now allow reassessment of these CBPs. We examined cases of echinocandin failure where both MICs and fks mutations were assessed; wild type (WT) MICs and epidemiological cutoff values (ECVs) for a large Candida collection; molecular analysis of fks hotspots for Candida with known MICs; and pharmacokinetic and pharmacodynamic (PK/PD) data. We applied these findings to propose new species-specific CBPs for echinocandins and Candida. Of 18 candidiasis cases refractory to echinocandins and with fks mutations, 28% (CSF), 58% (ANF) and 66% (MCF) had MICs in the S category using CBP of ≤ 2 mcg/ml, while 0-8% would be S using CBP of ≤ 0.25 mcg/ml. WT MIC distributions revealed ECV ranges of 0.03-0.25 mcg/ml for all major species except C. parapsilosis (1-4 mcg/ml) and C. guilliermondii (4-16 mcg/ml). Among Candida tested for fks mutations, only 15.7-45.1% of 51 mutants were detected using the CBP for NS of >2 mcg/ml. In contrast, a cutoff of >0.25 mcg/ml for C. albicans, C. tropicalis, C. krusei, and C. dubliniensis detected 85.6% (MCF) to 95.2% (CSF) of 21 mutant strains. Likewise, a cutoff of >0.12 mcg/ml for ANF and CSF and of >0.06 mcg/ml for MCF detected 93% (ANF) to 97% (CSF, MCF) of 30 mutant strains of C. glabrata. These data, combined with PK/PD considerations, support CBPs of ≤ 0.25 mcg/ml (S), 0.5 mcg/ml (I), ≥ 1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C. krusei and ≤ 2 mcg/ml (S), 4 mcg/ml (I), and ≥ 8 mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C. glabrata are ≤ 0.12 mcg/ml (S), 0.25 mcg/ml (I), and ≥ 0.5 mcg/ml (R), whereas those for MCF are ≤ 0.06 mcg/ml (S), 0.12 mcg/ml (I), and ≥ 0.25 mcg/ml (R). New, species-specific CBPs for Candida and the echinocandins are more sensitive to detect emerging resistance associated with fks mutations, and better able to predict risk for clinical failure.

Topics: Anidulafungin; Antifungal Agents; beta-Glucans; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fluconazole; Glucosyltransferases; Humans; Inhibitory Concentration 50; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation; Proteoglycans; Randomized Controlled Trials as Topic; Species Specificity; Treatment Outcome

The echinocandins anidulafungin, caspofungin, and micafungin have a broad and similar spectrum of in vitro and in vivo activity against most Candida spp. Minimal inhibitory concentrations (MICs) for Candida spp. are usually below 1 μg/mL for most isolates. The exceptions are Candidaparapsilosis and C. guilliermondii. Species-specific clinical breakpoints (CBPs) and epidemiologic cutoff values (ECVs) have been proposed by the Clinical and Laboratory Standards Institute (CLSI) for the eight most common Candida spp. versus each echinocandin; these values are useful to detect in vitro antifungal resistance (CBPs) and to identify isolates harboring fks mutations or having reduced susceptibility (ECVs). This paper presents a review of the literature (2006-2010) regarding the in vitro activity similarities or differences among the three echinocandins against Candida spp.; different parameters or measurements of in vitro potency were evaluated. The focus of the review is the non-Candida albicans species.

Topics: Anidulafungin; Candida; Candidiasis; Caspofungin; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Drug Resistance, Multiple, Fungal; Echinocandins; Fluconazole; Fungal Proteins; Glucosyltransferases; Humans; In Vitro Techniques; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Species Specificity; Therapeutic Equivalency

Topics: Antifungal Agents; Candidiasis; Catheters; Contraindications; Cross Infection; Disease Susceptibility; Echinocandins; Fluconazole; Humans; Immunocompromised Host; Immunosuppressive Agents; Lipopeptides; Micafungin; Risk Factors; Transplantation

The burden of neonatal invasive Candida infection (ICI) has been increasing recently and identification of effective preventative and treatment strategies is a priority. In this view, the echinocandin class of antifungal agents has emerged as a suitable and promising option for treatment. These agents have overall characteristics that suitably meet the needs of neonatal patients, such as coverage against biofilms and against fluconazole-resistant strains of Candida spp, which is an issue in an epoch of increasing prophylactic use of fluconazole in the nursery. Micafungin is the only echinocandin authorized for neonatal use by the EMA, based on efficacy and PK data from neonatal populations. Although the kinetics and appropriate dosing of this agent in premature and term infants have been described in the recent years, through either neonatal studies or extrapolation form adult data, further studies are needed to better address this area. These studies should be properly designed for neonatal populations, and must better address long-term safety and the clinical outcomes related to echinocandin use in neonates.

Topics: Adult; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Echinocandins; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Micafungin

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

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

Most recalcitrant infections are associated to colonization and microbial biofilm development. These biofilms are difficult to eliminate by the immune response mechanisms and the current antimicrobial therapy.. To describe the antifungal of micafungin against fungal biofilms based in the scientific and medical literature of recent years.. We have done a bibliographic retrieval using the scientific terms "micafungin", "activity", "biofilm", "Candida", "Aspergillus", "fungi", "mycos"*, susceptibility, in PubMed/Medline from the National Library of Medicine from 2006 to 2009.. Most current antifungal agents (amphotericin B and fluconazole) and the new azole antifungals have no activity against fungal biofilms. However, micafungin and the rest of echinocandins are very active against Candida albicans, Candida dubliniensis, Candida glabrata, and Candida krusei biofilms but their activities are variable and less strong against Candida tropicalis and Candida parapsilosis biofilms. Moreover, they have not activities against the biofilms of Cryptococcus y Trichosporon.. The activity of micafungin against Candida biofilms gives more strength to its therapeutic indication for candidaemia and invasive candidiasis associated to catheter, prosthesis and other biomedical devices.

Topics: Antifungal Agents; Aspergillus; Biofilms; Candida; Candidiasis; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Mycoses; Prosthesis-Related Infections; Species Specificity

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

In neonatal intensive care units, deep fungal disease due to Candida spp. are an important clinical problem, partly due to the increasing prevalence of Candida disease and also to the high associated and constant morbimortality; both factors are independently maintained though there has been a significant improvement in the management of neonatal patients.. To define the therapeutic use of micafungin for the treatment of neonatal invasive candidiasis.. We use a review of biomedic data bases namely Medline and EMBASE.. Micafungin is the latest introduced echinocandin. It has a wide spectrum of activity and covers Candida albicans and non-albicans Candida species. It has scarce drugs interactions and is devoid of toxicity, being an attractive approach for the treatment of invasive candidiasis (without meningitis, endocarditis and endophthalmitis). Althought the European Medicines Agency approved in 2008 the use of Micafungin for the treatment of invasive candidiasis in children, the available clinical experience is limited and currently more clinical studies are warranted to define its efficacy and safety in neonates.

Topics: Adolescent; Adult; Age Factors; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Clinical Trials as Topic; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Male; Meta-Analysis as Topic; Micafungin; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies

Over the last 30 years a significant increase of Candida spp. invasive disease has been observed in non-neutropenic critical ill patients. Both fluconazole and amphotericin B have been considered first line treatment for invasive (proven and probable) Candida spp. disease, although the mortality rate is still high.. To review the current data on the use of micafungin for the treatment of Candida invasive disease in critical ill patients.. The pharmacologic, mycological and clinical properties of micafungin are reviewed based on current published data. The use and efficacy of micafungin for the treatment of Candida invasive disease in critical ill patients is discussed.. To reduce the rate of mortality more effective antifungals and pre-emptive treatment strategies are currently warranted. Candins achieve better results for the treatment of invasive Candida disease in non-neutropenic critical ill patients. Micafungin has a good safety profile (similar to fluconazole). Micafungin is a first line drug for the treatment of invasive Candida disease and may be used as a pre- emptive approach followed by a de-escalating strategy with azoles.

Topics: Antifungal Agents; Candidiasis; Caspofungin; Clinical Trials as Topic; Critical Care; Critical Illness; Drug Therapy, Combination; Echinocandins; Fungemia; Humans; Incidence; Leukocyte Count; Lipopeptides; Micafungin; Neutrophils; Randomized Controlled Trials as Topic

Micafungin is an echinocandin approved for the prevention of Candida spp. infection in hematopoietic stem cell transplantation and therapy of oesophageal candidiasis, disseminated candidiasis and candidemia in adults, children and neonates.. To evaluate the role of micafungin for candidiasis therapy in solid organ transplant recipients.. A medical literature review according to micafungin role for candidiasis therapy in transplant patients is performed.. Micafungin has shown fungicide activity against Candida species, including strains resistant or poorly susceptible to fluconazole. No dose adjustment is required when micafungin is administered in combination with other drugs used in transplant patients, excluding sirolimus, nifedipine and itraconazol. With these drugs, a minimal dose reduction is recommended. The results observed in transplant patients included in clinical trials are favourable and similar to results obtained in other kind of patients.. The clinical results, its safety profile and the low grade of medical interactions permit micafungin to be considered for therapy in specific groups of transplant patients.

Topics: Adult; Antifungal Agents; Candidiasis; Child; Clinical Trials as Topic; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Fungemia; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant, Newborn; Lipopeptides; Micafungin; Organ Transplantation; Postoperative Complications

Invasive candidiasis is a severe infection among onco-hematological patients, with an attributable mortality around 40%. Micafungin has shown efficacy in antifungal prophylaxis among hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis.. To assess the role of micafungin in the treatment of invasive candidiasis among onco-hematological patients.. Literature review.. In a study on 126 patients with candidemia treated with micafungin, an overall response rate of 83% was reported. A double-blind study of 531 patients with invasive candidiasis comparing micafungin (100mg/day) versus liposomal amphotericin B (3mg/kg/day) reported success in 90% of patients in both arms, with a more favorable safety profile with micafungin. Other double blind randomized, phase III study compared two doses of micafungin (100mg/day and 150mg/day) with standard doses of caspofungin (70mg loading dose, then 50mg/day) in adults with invasive candidiasis. Overall success rate was 74% for micafungin 100mg/day, 70% for micafungin 150mg/day, and 71% for caspofungin. A double blind randomized study compared micafungin (2mg/kg/day) to liposomal amphotericin B (3mg/kg/day) in the treatment of invasive candidiasis in children with a predominance of infections with non-albicans Candida spp. Overall success rate was similar (73% for micafungin and 76% for liposomal amphotericin B).. Comparative phase III studies have demonstrated non-inferiority of micafungin compared to standard antifungal agents for invasive candidiasis. Micafungin is safe and effective in the treatment of children and adults with invasive candidiasis. Effectivity in invasive infections caused by non-albicans Candida spp is especially relevant in onco-hematological patients receiving fluconazole prophylaxis.

Topics: Adult; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Candidiasis; Caspofungin; Child; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Double-Blind Method; Echinocandins; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lipopeptides; Micafungin; Postoperative Complications; Prosthesis-Related Infections; Randomized Controlled Trials as Topic

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

Intravenous micafungin (Mycamine; Funguard) is an echinocandin indicated in Japan and the EU for the treatment of pediatric patients (including neonates) with invasive candidiasis and as prophylaxis against Candida infection in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the EU, micafungin is also indicated in pediatric patients who are expected to have neutropenia for >/=10 days. In Japan, children may also receive micafungin for the treatment of, or as prophylaxis against, invasive Aspergillus infection. Micafungin is not currently approved for use in pediatric patients in the US. Micafungin has very good antifungal activity against a wide range of Candida spp. in vitro. It has a favorable pharmacokinetic profile allowing for once-daily administration, has few drug-drug interactions, and reports of resistance are rare. The results of pediatric substudies indicate that intravenous micafungin is effective in a majority of patients for the treatment of candidemia and other types of invasive candidiasis, and provides effective prophylaxis against invasive fungal infections in pediatric patients undergoing HSCT. The tolerability profile of micafungin in pediatric patients was generally acceptable. In the EU, micafungin is indicated for use when other antifungal medications are not appropriate. Therefore, micafungin provides an alternative to other antifungal agents used in the management of candidemia and invasive candidiasis in pediatric patients, or as prophylaxis against fungal infections in pediatric patients undergoing HSCT.

Topics: Antifungal Agents; Candidiasis; Child; Echinocandins; Humans; Lipopeptides; Micafungin

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

Micafungin is one of three currently FDA-approved echinocandins. It has potent in vitro activity against Candida species including non-albicans Candida and azole-resistant Candida species and has also demonstrated clinical efficacy against deep-seated Candida infections. Additional in vitro data and preliminary clinical efficacy studies suggest that it also has utility for the treatment of infections caused by Aspergillus species. However, its approved indications remain for the treatment of both invasive and esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. is generally well tolerated with few significant adverse effects.

Topics: Animals; Antifungal Agents; Candidiasis; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Interactions; Echinocandins; Humans; Lipopeptides; Micafungin

To compare available antifungal treatments for invasive candidiasis, a leading cause of nosocomial bloodstream infections.. We performed a systematic review and meta-analysis of randomized controlled trials that compared different antifungal agents for the treatment of candidemia and other forms of invasive candidiasis. Two reviewers independently appraised the quality of trials and extracted data. The primary outcome was all-cause mortality, and secondary outcomes were microbiological failure, treatment failure, and adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled.. Of the 15 included trials, 9 compared fluconazole with other drugs (amphotericin B, itraconazole, or a combination of fluconazole and amphotericin B), 4 compared echinocandins with other drugs (fluconazole, amphotericin B, liposomal amphotericin B), 1 compared micafungin and caspofungin, and 1 compared amphotericin B plus fluconazole and voriconazole. No difference in mortality was observed with fluconazole vs amphotericin B (RR, 0.92; 95% CI, 0.72-1.17); however, the rate of microbiological failure increased in the fluconazole arm (RR, 1.52; 95% CI, 1.12-2.07). Anidulafungin decreased the rate of microbiological failure compared with fluconazole (RR, 0.50; 95% CI, 0.29-0.86) with fewer adverse events. Caspofungin was comparable to amphotericin B in mortality and efficacy, with fewer adverse events requiring discontinuation (RR, 0.11; 95% CI, 0.04-0.36). Micafungin was comparable to liposomal amphotericin B in mortality.. All assessed antifungal agents showed similar efficacy, but the rate of microbiological failure increased with fluconazole vs amphotericin B or anidulafungin. Amphotericin B is associated with a higher rate of adverse events than fluconazole and echinocandins.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Caspofungin; Confidence Intervals; Drug Therapy, Combination; Echinocandins; Fluconazole; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Odds Ratio; Pyrimidines; Treatment Outcome; Triazoles; Voriconazole

Intravenous micafungin (Mycamine; Fungard), an echinocandin, inhibits the synthesis of 1,3-beta-D-glucan, an essential cell wall component in many fungi. It is approved in adults (focus of this review) and in neonates and paediatric patients (Pediatric Drugs [in press]) in the EU and elsewhere for the treatment of invasive candidiasis and oesophageal candidiasis, and as prophylactic treatment to prevent Candida infections in haematopoietic stem cell transplant (HSCT) recipients.Intravenous micafungin shows very good activity against clinically relevant isolates of Candida spp. Furthermore, the pharmacokinetic profile of micafungin permits once-daily treatment and means that it is associated with relatively few drug-drug interactions. However, like all of the echinocandins and all formulations of amphotericin B, micafungin must be given intravenously. In large, well designed clinical trials in adult patients (>or=16 years of age) with invasive candidiasis, intravenous micafungin was shown to be noninferior to intravenous caspofungin or liposomal amphotericin B. In similarly designed trials in adult patients with oesophageal candidiasis, intravenous micafungin was shown to be noninferior to fluconazole or caspofungin treatment. As prophylactic treatment in adult and paediatric patients who had undergone HSCT, micafungin was superior to fluconazole therapy in a large, well designed trial. Micafungin was generally well tolerated by participants in these clinical trials. Furthermore, it was as well tolerated as caspofungin and fluconazole, and better tolerated than liposomal amphotericin B. The position of micafungin relative to newer antifungal therapies, such as anidulafungin, voriconazole and posaconazole, remains to be fully determined. Thus, micafungin is an emerging option for the treatment of adult patients with invasive or oesophageal candidiasis, and as prophylaxis against Candida infections in HSCT recipients.

Topics: Antifungal Agents; Candida; Candidiasis; Drug Interactions; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Esophageal Diseases; HIV Infections; Humans; Lipopeptides; Micafungin

Diabetes mellitus (DM) has been considered to predispose to candidiasis. While poor glycemic control increases the risk of superficial candidiasis (especially oral candidiasis), invasive candidiasis is not related to DM. Invasive candidiasis is diagnosed by combination of clinical manifestation, laboratory findings and isolation of Candida spp. Strategy of treatment for invasive candidiasis is consist of prophylactic, empiric and targeted therapy. MCFG, FLCZ and AMPH-B are recommended as first line drugs for invasive candidiasis, and L-AMB, VRCZ, ITCZ are considered as alternative drugs in Japanese guideline.

Topics: Amphotericin B; Antifungal Agents; Antigens, Fungal; beta-Glucans; Biomarkers; Candida; Candidiasis; Diabetes Complications; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Proteoglycans

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

Topics: Antifungal Agents; Candidiasis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin

The echinocandins represent the newest class of antifungals to combat infections caused by Candida sp. Micafungin is an echinocandin recently approved by the United States Food and Drug Administration. It is indicated in adults for esophageal candidiasis and prophylaxis against candidal infections in hematopoietic stem cell transplant recipients. Micafungin exhibits in vitro fungicidal activity against Candida sp, including fluconazole-resistant isolates. Its in vivo efficacy is comparable to that of fluconazole in the treatment of esophageal candidiasis and superior to that of fluconazole for prophylaxis of invasive candidal infections. Because it is not significantly metabolized by the cytochrome P450 3A system, micafungin is associated with few drug interactions. Micafungin does not require adjustment in patients with renal and/or hepatic impairment, and it has been shown to be well tolerated in both adult and pediatric patients. Its efficacy against Candida sp, coupled with its overall safety and drug interaction profiles, makes it an attractive option in the treatment against esophageal candidiasis and prophylaxis against invasive candidal infections.

Topics: Animals; Antifungal Agents; Candidiasis; Drug Interactions; Echinocandins; Esophageal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Lipopeptides; Lipoproteins; Micafungin; Peptides, Cyclic; Treatment Outcome

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

Topics: Anidulafungin; Antifungal Agents; beta-Glucans; Candida; Candidiasis; Caspofungin; Cross Infection; Echinocandins; Fungemia; Humans; Infusions, Intravenous; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Peptides, Cyclic; Practice Guidelines as Topic

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

Caspofungin, micafungin and anidulafungin are three drugs of the echinocandin class of antifungals available for intravenous treatment of invasive candidiasis and aspergillosis. They exhibit high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In various clinical studies investigating candidemia and invasive candidiasis, Candida esophagitis, and fever in neutropenia, the clinical efficacy of the echinocandin tested was similar to that of established antifungals. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that echinocandins can be used as salvage therapy in life-threatening fungal infections. There is no cross-resistance to other antifungals. Excellent safety and tolerability of treatment with caspofungin has been documented over a total of 4.3 million patient days. Echinocandins are poor substrates of the cytochrome P450 enzyme family and can be safely co-administered with most drugs without the need for dosage adaptation. No dose reduction is required in renal impairment. A reduction in the daily maintenance dose has been recommended for caspofungin, but not for micafungin and anidulafungin in patients presenting with mild to moderate hepatic failure.

Topics: Actins; Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Area Under Curve; Candidiasis; Caspofungin; Drug Resistance, Microbial; Echinocandins; Humans; Lipopeptides; Lipoproteins; Liver; Liver Failure; Micafungin; Models, Chemical; Peptides, Cyclic; Rats

The clinical effects and tolerability of micafungin sodium in daily practice for the treatment of fungal infection in critically ill patients were evaluated in an open-labeled, non-comparative, observational study. All patients admitted to intensive care units (ICUs) of 3 hospitals in Chiba prefecture between June 2003 and March 2005, who were treated with micafungin because of known or suspected fungal infection, were included in the study. A total of 34 patients received micafungin and 29 cases of them were subjected to analysis. Fungal infections were classified as "proven" in 3 patients (10.3%) and "possible" in 26 (89.7%). Candida was detected in 16 patients, most of them were Candida albicans and 4 cases were non-albicans Candida. Clinical effects of micafungin were "cured" and "improved" in 20 patients (77%), "failure" in 6 (23%), and "undetermined" in 3 cases. Adverse events were reported in 10 patients, but there was no significant event. In conclusion, micafungin was effective in 77% of proven or suspected fungal infections in critically ill patients admitted to the ICU. The drug was well tolerated and discontinuation of its treatment due to adverse events was not experienced during the study period.

Topics: Antifungal Agents; Candidiasis; Critical Care; Drug Tolerance; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic

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

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

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: Antifungal Agents; beta-Glucans; Biomarkers; Candidiasis; Diagnosis, Differential; Echinocandins; Fluconazole; Glucans; Humans; Lipopeptides; Lipoproteins; Micafungin; Molecular Diagnostic Techniques; Peptides, Cyclic; Prognosis; Serologic Tests

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

Neutropenia is linked to the development of invasive candidiasis/candidaemia, for which micafungin has demonstrated efficacy, but evidence in patients with neutropenia is limited. The aim of this study was to evaluate the efficacy of micafungin for the treatment of invasive candidiasis/candidaemia in patients with neutropenia (<500 neutrophils/μL) and without neutropenia. This pooled, post hoc analysis of 2 Phase 3 trials compared micafungin 100 mg/d (adults) and 2 mg/kg/d (paediatrics) with L-AmB 3 mg/kg/d (NCT00106288) and micafungin 100 mg/d and 150 mg/d with caspofungin 70 mg/d followed by 50 mg/d (adults) (NCT00105144); treatment duration 2-4 weeks (≤8 weeks for chronic disseminated candidiasis). Effects of neutropenia duration and Candida spp. on efficacy outcomes (treatment success, clinical and mycological response) were examined. Of 685 patients, 77 had neutropenia. The most common infection in patients with/without neutropenia was due to C. tropicalis (31/77) and C. albicans (295/608) respectively. Overall success was numerically lower in patients with vs without neutropenia (63.6% vs 72.9%). Clinical and mycological response was similar between groups. Neutropenia duration or Candida spp. did not impact micafungin's overall success rate. This analysis supports evidence that micafungin is effective against invasive candidiasis/candidaemia in patients with neutropenia, irrespective of neutropenia duration or Candida spp., although overall success may be lower than in patients without neutropenia.

Topics: Adolescent; Adult; Antifungal Agents; Candida; Candida albicans; Candida tropicalis; Candidemia; Candidiasis; Candidiasis, Invasive; Caspofungin; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Neutropenia; Treatment Outcome; Young Adult

The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis.. Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg. Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h. Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

Topics: Age Factors; Animals; Antifungal Agents; Area Under Curve; Candidiasis; Female; Fluconazole; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Micafungin; Mice; Prospective Studies

Although frequently used in treating intensive care unit (ICU) patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome.. To determine whether empirical micafungin reduces invasive fungal infection (IFI)-free survival at day 28.. Multicenter double-blind placebo-controlled study of 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between July 2012 and February 2015 in 19 French ICUs.. Empirical treatment with micafungin (100 mg, once daily, for 14 days) (n = 131) vs placebo (n = 129).. The primary end point was survival without proven IFI 28 days after randomization. Key secondary end points included new proven fungal infections, survival at day 28 and day 90, organ failure, serum (1-3)-β-D-glucan level evolution, and incidence of ventilator-associated bacterial pneumonia.. Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-β-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and IFI free (hazard ratio [HR], 1.35 [95% CI, 0.87-2.08]). Results were similar among patients with a (1-3)-β-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85-2.33]). Day-28 IFI-free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96-2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008).. Among nonneutropenic critically ill patients with ICU-acquired sepsis, Candida species colonization at multiple sites, and multiple organ failure, empirical treatment with micafungin, compared with placebo, did not increase fungal infection-free survival at day 28.. clinicaltrials.gov Idenitfier: NCT01773876.

Topics: Aged; Anti-Bacterial Agents; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Critical Illness; Cross Infection; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Multiple Organ Failure; Time Factors

The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and <17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg·h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to <17 years.

Topics: Adolescent; Antifungal Agents; Candidiasis; Candidiasis, Invasive; Child; Child, Preschool; Echinocandins; Female; Humans; Infant; Lipopeptides; Male; Micafungin

Echinocandins exhibit concentration-dependent effects on Candida species, and preclinical studies support the administration of large, infrequent doses. The current report examines the pharmacokinetics/pharmacodynamics of two multicenter, randomized trials of micafungin dosing regimens that differed in both dose level and dosing interval. Analysis demonstrates the clinical relevance of the dose level and area under the concentration-time curve (AUC). Better, although not statistically significant (P = 0.056), outcomes were seen with higher maximum concentrations of drug in serum (Cmax) and large, infrequent doses. The results support further clinical investigation of novel micafungin dosing regimens with large doses but less than daily administration. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00666185 and NCT00665639.).

Topics: Antifungal Agents; Area Under Curve; Candida; Candidiasis; Dose-Response Relationship, Drug; Drug Administration Schedule; Echinocandins; Esophagus; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Treatment Outcome

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

Esophageal candidiasis (EC) is a common and serious complication in patients infected with the human immunodeficiency virus (HIV). Micafungin has been shown to have dose-related efficacy and to be well tolerated in patients with HIV and EC. This analysis of data from a randomized, double-blind study examined pharmacokinetic parameters of micafungin (dosed at 50, 100, and 150 mg/day) and its metabolites in a subset of patients with HIV and EC. Micafungin exhibited linear, predictable pharmacokinetics, similar to the previous observations in healthy control subjects. Micafungin peak plasma concentration and exposure were increased with dose, while half-life and clearance remained consistent with increasing dose. Plasma concentrations of the metabolites M-1, M-2, and M-5 remained low throughout the study (24 h exposure ≤14% relative to micafungin at end of therapy for each). No differences in micafungin pharmacokinetic parameters were observed according to the sex or race of the patients. The high systemic exposures associated with micafungin 100 and 150 mg/day relative to micafungin 50 mg/day were found to directly correlate with endoscopic clearance. These data provide evidence that the pharmacokinetics of micafungin underlie the dose-related efficacy in patients with HIV and EC.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Double-Blind Method; Echinocandins; Esophageal Diseases; Esophagoscopy; Female; Half-Life; HIV Infections; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Young Adult

Infection with Candida glabrata and Candida krusei represents a major challenge. We sought to describe outcomes for patients with candidaemia/invasive candidiasis (C/IC) due to these pathogens who were treated with micafungin.. We pooled two randomized trials of micafungin versus comparator. We identified patients infected with either C. glabrata or C. krusei. One trial compared micafungin (100 mg/day with option for dose escalation) with liposomal amphotericin B, while the other compared micafungin (either 100 or 150 mg/day) and caspofungin (NCT00106288 and NCT00105144). Clinical cure was our primary endpoint while 28 day mortality represented a secondary endpoint.. Among 1070 subjects with C/IC, 183 were infected with either C. glabrata (n = 144) or C. krusei (n = 39). One hundred and seventeen received micafungin. Clinical cure rates in those receiving micafungin were similar to those randomized to comparator [73.5% (86/117) versus 62.1% (41/66), P = not significant]. Mortality at 28 days was also similar [29.1% (34/117) with micafungin versus 34.8% (23/66) with comparator, P = not significant]. In logistic regression, treatment agent correlated with neither cure nor mortality. Factors independently linked with lower cure rates included: IC neutropenia; higher severity of illness; and medical admission. Higher severity of illness and failure to remove a central venous catheter were associated with 28 day mortality. Crude and adjusted outcomes were comparable irrespective of micafungin dose administered.. Micafungin results in similar outcomes to comparators for C/IC due to C. glabrata and C. krusei. The 100 mg/day dose represents an acceptable option in this setting. Patient characteristics and catheter management appear to be more important factors affecting clinical outcomes.

Topics: Adult; Aged; Antifungal Agents; Candida; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Treatment Outcome

The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (≤7.7%) vs. no malignancy (≤8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candidiasis; Caspofungin; Child; Child, Preschool; Double-Blind Method; Echinocandins; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Middle Aged; Neoplasms; Treatment Outcome; Young Adult

Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).

Topics: Adult; Antifungal Agents; Area Under Curve; Bayes Theorem; Candidiasis; Echinocandins; Humans; Infant, Newborn; Infant, Premature; Lipopeptides; Meningoencephalitis; Metabolic Clearance Rate; Micafungin; Models, Biological; Monte Carlo Method; Syndrome

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N = 1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to 30 versus or=70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define non-antifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; APACHE; Candidiasis; Catheterization; Echinocandins; Female; Fungemia; Humans; Lipopeptides; Male; Micafungin; Middle Aged; North America; Prospective Studies; Racial Groups; Survival Analysis; Treatment Outcome; Young Adult

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

Invasive candidiasis and candidemia are life-threatening nosocomial infections in intensive care patients.. A post hoc analysis of a phase 3 trial assessing micafungin (100 mg/day for subjects > 40 kg; 2 mg/kg/day for subjects

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Candidiasis; Cross Infection; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Multivariate Analysis

Invasive candidiasis is increasingly prevalent in premature infants and seriously ill children, and pediatric data on available antifungal therapies are lacking.. We conducted a pediatric substudy as part of a double-blind, randomized, multinational trial to compare micafungin (2 mg/kg) with liposomal amphotericin B (3 mg/kg) as first-line treatment of invasive candidiasis. Treatment success was defined as clinical and mycologic response at the end of therapy. Statistical analyses were descriptive, as the sample size meant that the study was not powered for hypothesis testing.. One hundred six patients were included in the intent-to-treat population; and 98 patients-48 patients in the micafungin group and 50 patients in the liposomal amphotericin B group-in the modified intent-to-treat population. Baseline characteristics were balanced between treatment groups. Overall, 57 patients were <2 years old including 19 patients who were premature at birth; and 41 patients were 2 to <16 years old. Most patients (91/98, 92.9%) had candidemia, and 7/98 (7.1%) patients had other forms of invasive candidiasis. Treatment success was observed for 35/48 (72.9%) patients treated with micafungin and 38/50 (76.0%) patients treated with liposomal amphotericin B. The difference in proportions adjusted for neutropenic status was -2.4% [95% CI: (-20.1 to 15.3)]. Efficacy findings were consistent, independent of the neutropenic status, the age of the patient, and whether the patient was premature at birth. Both treatments were well tolerated, but with a lower incidence of adverse events that led to discontinuation in the micafungin group (2/52, 3.8%) compared with the liposomal amphotericin B group (9/54, 16.7%) (P = 0.05, Fisher exact test).. Micafungin seems to be similarly effective and as safe as liposomal amphotericin B for the treatment of invasive candidiasis in pediatric patients. (ClinicalTrials.gov number, NCT00106288).

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis; Child; Child, Preschool; Double-Blind Method; Echinocandins; Humans; Infant; Infant, Newborn; Infant, Premature; Lipopeptides; Lipoproteins; Micafungin; Treatment Outcome

Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis.. We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288.. 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B.. Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; APACHE; Candidiasis; Double-Blind Method; Echinocandins; Female; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Peptides, Cyclic; Treatment Outcome

Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis.. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy.. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms.. Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidiasis; Caspofungin; Dose-Response Relationship, Drug; Double-Blind Method; Echinocandins; Female; Fungemia; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic; Treatment Outcome

: Candidal fungal infection rates in neonates are increasing and are a significant cause of mortality, especially in low birth weight infants. Micafungin is an echinocandin that works by inhibiting 1,3-beta-D-glucan synthase, an enzyme responsible for fungal cell wall synthesis. The objective of this study was to determine the safety and pharmacokinetics of micafungin in premature infants.. : This was a phase I, single-dose, multicenter, open-label, sequential-dose trial of intravenous micafungin investigating 3 doses (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg) in 18 premature infants weighing >1000 g (n = 6 in each dosage group). A further 5 infants (500-1000 g) were enrolled in the 0.75 mg/kg dosage group only.. : The mean +/- standard deviation gestational age in the >1000 g dosage group was 26.4 +/- 2.4 weeks and, on entry, patients had one or more of a variety of underlying conditions, including sepsis, pneumonia and other infections caused by Candida or other species. Micafungin pharmacokinetics in preterm infants appears linear. However, premature infants >1000 g on average displayed a shorter half-life (8 hours) and a more rapid rate of clearance (approximately 39 mL/h per kg) compared with published data in older children and adults. All doses of micafungin were well tolerated and no serious drug-related adverse events were observed.. : Single doses of micafungin, ranging up to 3.0 mg/kg, appear well tolerated in premature infants weighing >1000 g. The drug's elimination half-life and total plasma clearance in preterm infants appear dissimilar to published values for these parameters in older children and adults. The reason(s) for this apparent difference remain to be investigated.

Topics: Antifungal Agents; Candidiasis; Echinocandins; Female; Half-Life; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intravenous; Lipopeptides; Lipoproteins; Male; Metabolic Clearance Rate; Micafungin; Peptides, Cyclic; Pneumonia; Sepsis

Topics: Antifungal Agents; Candidiasis; Drug Therapy, Combination; Echinocandins; Humans; Immunosuppressive Agents; Lipopeptides; Lipoproteins; Micafungin; Organ Transplantation; Peptides, Cyclic; Stem Cell Transplantation

To determine efficacy and safety of intravenous micafungin vs. intravenous fluconazole in the treatment of oesophageal candidiasis.. A total of 523 patients > or =16 years with documented oesophageal candidiasis were randomized (1:1) in this controlled, non-inferiority study to receive either micafungin (150 mg/day) or fluconazole (200 mg/day). Response was evaluated clinically and endoscopically. Post-treatment assessments were performed at 2 and 4 weeks after discontinuation of therapy.. Median duration of therapy was 14 days. For the primary end-point of endoscopic cure, treatment difference was -0.3% (micafungin 87.7%, fluconazole 88.0%). Documented persistent invasive disease at the end of therapy was reported in 2.7% and 3.9% of patients, respectively. Both 84.8% of micafungin and 88.7% of fluconazole patients remained recurrence free at 4-weeks post-treatment. The overall therapeutic response rate was 87.3% for micafungin and 87.2% for fluconazole. The incidence of drug-related adverse events was 27.7% for micafungin and 21.3% for fluconazole. Six (2.3%) micafungin- and two (0.8%) fluconazole-treated patients discontinued therapy; rash was the most common event leading to discontinuation.. Intravenous micafungin (150 mg daily) is well tolerated and as efficacious as intravenous fluconazole (200 mg daily) in the primary treatment of oesophageal candidiasis, achieving high rates of clinical and endoscopic cure.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Candidiasis; Double-Blind Method; Echinocandins; Esophageal Diseases; Female; Fluconazole; Humans; Infusions, Intravenous; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic; Treatment Outcome

Candida spp. are the fourth leading cause of bloodstream infections, and non-albicans species are increasing in importance. Micafungin is a new echinocandin antifungal agent with excellent in vitro activity against Candida spp. Pediatric, neonatal, and adult patients with new or refractory candidemia were enrolled into this open-label, noncomparative, international study. The initial dose of micafungin was 50 mg/d (1 mg/kg for patients <40 kg) for infections due to C. albicans and 100 mg/d (2 mg/kg for patients <40 kg) for infections due to other species. Dose escalation was allowed. Maximum length of therapy was 42 days. A total of 126 patients were evaluable (received at least five doses of micafungin). Success (complete or partial response) was seen in 83.3% patients overall. Success rates for treatment of infections caused by the most common Candida spp. were as follows: C. albicans 85.1%, C. glabrata 93.8%, C. parapsilosis 86.4%, and C. tropicalis 83.3%. Serious adverse events related to micafungin were uncommon. Micafungin shows promise as a safe and effective agent for the treatment of newly diagnosed and refractory cases of candidemia. Large-scale, randomized, controlled trials are warranted.

Topics: Adolescent; Adult; Antifungal Agents; Candida; Candidiasis; Child; Child, Preschool; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Internationality; Lipopeptides; Lipoproteins; Male; Micafungin; Peptides, Cyclic; Prospective Studies; Treatment Outcome

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

To determine the minimum effective dose and safety of micafungin in the treatment of HIV-related oesophageal candidiasis.. A total of 120 patients were enrolled in this open label study of the effects of daily 1 h infusions of micafungin on endoscopically proven fungal oesophagitis. Patients were randomly assigned to receive 12.5, 25, 50, 75 and 100 mg of micafungin daily. Response was evaluated clinically and endoscopically.. The protocol defined minimum effective dose of micafungin was 12.5 mg. The percentage of patients experiencing clearing of physical signs and symptoms showed a dose-response relationship and reached 94.7% in the 100 mg dose group. All patients in the 50, 75 and 100 mg dose groups achieved an endoscopically verified improvement in oesophagitis. Adverse effects of micafungin were generally mild and not dose-related. No serious renal, hepatic or drug-related infusion reactions were encountered.. Micafungin was found to be effective, well-tolerated and safe. The minimum effective dose was found to be 12.5 mg and a significant linear trend in the successful treatment of oesophageal candidiasis was observed across the doses used with 75 and 100 mg dose levels achieving high rates of clinical and endoscopic cure.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Echinocandins; Esophageal Diseases; Female; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Peptides, Cyclic; Treatment Outcome

Severely immunocompromised individuals are highly susceptible to Candida infection of the esophagus. This randomized, double-blind study assessed the dose-response relationship of the new echinocandin antifungal, micafungin, compared with that of standard fluconazole treatment.. A total of 245 patients (age, > or =18 years) with a prior diagnosis of acquired immunodeficiency syndrome/human immunodeficiency virus (HIV) infection and esophageal candidiasis, confirmed by endoscopy and culture, were randomized to receive micafungin (50, 100, or 150 mg per day) or fluconazole (200 mg per day). Both agents were administered once per day by a 1-h intravenous infusion for 14-21 days. The primary efficacy end point was endoscopic cure rate, defined as endoscopy grade of 0 at the end of therapy.. The endoscopic cure rate (grade 0) was dose-dependent with 50, 100, and 150 mg of micafungin per day at 68.8%, 77.4%, and 89.8%, respectively. Symptoms improved or resolved rapidly (3-7 days of treatment in the majority of patients). The endoscopic cure rate for 100 and 150 mg of micafungin per day (83.5%) was comparable to that for 200 mg of fluconazole per day (86.7%; 95% confidence interval for the difference in endoscopic cure rate, -14.0% to 7.7%). The overall safety and tolerability was acceptable, with no important differences between micafungin (all doses) and fluconazole.. The dose-response findings demonstrate a greater efficacy with micafungin at 100 and 150 mg per day than at 50 mg per day. This study also indicates that the efficacy of micafungin (at dosages of 100 and 150 mg per day) was comparable to that of fluconazole, suggesting that micafungin represents a valuable new treatment option for esophageal candidiasis in HIV-positive patients.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Antifungal Agents; Candidiasis; Double-Blind Method; Echinocandins; Esophageal Diseases; Female; Fluconazole; HIV Infections; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic

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

Candida (Clavispora) lusitaniae is a rare, emerging non-

Topics: Antifungal Agents; Candida; Candidiasis; Drug Resistance, Fungal; Drug Resistance, Multiple; Echinocandins; Fluconazole; Humans; Micafungin; Microbial Sensitivity Tests

Candida auris is an emerging fungal pathogen that is feared to spread of infection because of its propensity for multidrug resistance and high mortality rate. This pathogenic yeast is classified into four major clades by phylogenetic analyses, which are referred to the South Asia clade (clade I), East Asia clade (clade II), South Africa clade (clade III), and South America clade (clade IV), based on the location of the initial isolate. In this study, we evaluated the virulence of C. auris strains belonging to four major clades and the therapeutic effects of micafungin in a silkworm infection model. The highest mortality rate at 21 h after C. auris inoculation was observed for strains from clade IV (80% or more). In contrast, it was 20% or less in those from other clades. Antifungal susceptibility tests indicated resistance to fluconazole and sensitivity to echinocandins in the blood-derived strains. Micafungin prolonged the survival of blood-derived C. auris infected silkworms. These results suggest that the silkworm infection model is useful for evaluating the virulence of C. auris and determining its therapeutic effects.. Candida auris is an emerging fungal pathogen that has spread worldwide because of its multidrug resistance. We developed a silkworm infection model with C. auris to evaluate the virulence of clinical isolates. An evaluation system using silkworms is useful for determining C. auris virulence.

Topics: Animals; Antifungal Agents; Bombyx; Candida; Candida auris; Candidiasis; Micafungin; Microbial Sensitivity Tests; Phylogeny; Virulence

Candida urinary tract infections (UTIs) are common nosocomial infections among critically ill patients hospitalized in pediatric intensive care Units (PICU). We aimed to report outcomes of critically ill pediatric patients who received micafungin for hospital acquired Candida UTIs. We analyzed treatment success rates and success rates among different Candida species.. This retrospective cohort study included patients who received micafungin for Candida UTI as first choice in our PICU between January 2017 and July 2018. Data, including demographic and clinical features, were retrospectively collected from medical files of the patients. Treatment efficacy was defined as resolution of clinical symptoms and a negative culture for Candida at day 14 after initiation of micafungin treatment.. Twenty-four pediatric patients (median age 5.72 years, range, 2 months-16 years) were included in the present study. Fourteen (58.3%) patients had urinary catheters at the time of Candida isolation. Resolution of symptoms and a negative culture at day 3 of micafungin treatment were achieved in 17 (70.8%) and 14 (58.3%) patients, respectively. Moreover, 19 (79.2%) patients had a normal urine analysis and negative culture 14 days after initiation of micafungin treatment. Treatment responses did not statistically differ between Candida species.. Micafungin is safe and efficacious in critically ill pediatric patients with Candida UTIs. Its efficacy in our pediatric population was as comparable to that observed in adult studies, therefore, it should be considered as an effective therapeutic option in Candida UTIs of critically ill pediatric patients.

Topics: Adolescent; Antifungal Agents; Candida; Candidiasis; Child; Child, Preschool; Humans; Infant; Micafungin; Retrospective Studies; Urinary Tract Infections

Invasive fungal infection, particularly intraabdominal candidiasis, exerts a negative impact on the outcome of pancreas transplant recipients (PTRs). Optimal antifungal prophylaxis in this context remains unclear.. We performed a single-centre retrospective study to compare the incidence of invasive candidiasis during the first 6 post-transplant months in a cohort of 218 PTRs over two periods in which different agents for antifungal prophylaxis were used: fluconazole (Fluco-Px) from March 1995 to June 2012, and micafungin followed by fluconazole (Mica-Px) from July 2012 to December 2018.. A total of 152 and 66 PTRs received Fluco-Px and Mica-Px. Mean age was 39.7 ± 7.8 years, 56.4% (123/218) were males, and 85.3% (186/218) underwent simultaneous pancreas-kidney transplantation. Invasive candidiasis occurred in 21.7% (33/152) of PTRs under Fluco-Px compared to 24.2% (16/66) of those under Mica-Px (p-value = .681). Median time from transplantation to infection was 8 days (interquartile range [IQR]: 6-16) under Fluco-Px versus 6.5 (IQR: 3.3-15.8) under Mica-Px (p-value = .623). Non-albicans Candida species comprised 27.5% (11/40) and 25.0% (4/16) of episodes under Fluco-Px and Mica-Px respectively (p-value = .849). Surgical site infection was the most common form in both groups (82.5% [33/40] and 87.5% [14/16]; p-value = .954). Multivariable analysis identified cold ischaemia time of the pancreas and kidney grafts, surgical reintervention and insulin requirement after transplantation as risks factor for invasive candidiasis.. This retrospective study did not reveal a significant benefit from the initial use of micafungin-based antifungal prophylaxis over fluconazole among PTRs in terms of invasive candidiasis.

Topics: Adult; Antifungal Agents; Candida; Candidiasis; Candidiasis, Invasive; Female; Fluconazole; Humans; Male; Micafungin; Middle Aged; Pancreas; Pancreas Transplantation; Retrospective Studies; Transplant Recipients

We aimed to detect possible changes in Candida species distribution over time and to know the antifungal susceptibility profile of isolates obtained from patients with bloodstream infection (BSI) due to this pathogen. Risk factors associated with 30-day mortality were also assessed. We conducted a retrospective cohort study of patients diagnosed with Candida BSI at a Japanese university hospital from 2013 to 2021. The change in the distribution pattern of the Candida spp. isolated was examined by considering three successive sub-periods of 3 years each. Risk factors for 30-day mortality were determined using Cox regression analysis. In the entire study period, Candida albicans was the most frequent species (46.7%), followed by Candida glabrata (21.5%) and Candida parapsilosis (18.7%). There was no change in Candida species distribution comparing the three sub-periods analyzed. All isolates were susceptible to micafungin, and most were susceptible to fluconazole, except for C. glabrata. No isolates were resistant to amphotericin B or voriconazole. The overall 30-day mortality was 40.2%. Univariate analysis revealed an association between 30-day mortality and central venous catheter (CVC) removal at any time, high Pitt bacteremia score (PBS), and high Charlson comorbidity index (CCI). Multivariate Cox analysis found that high PBS was the only independent predictor of 30-day mortality; subsequent multivariate Cox regression demonstrated that early CVC removal significantly reduced 30-day mortality. Candida species distribution and antifungal susceptibility profile in our hospital remained similar from 2013 to 2021. Early CVC removal may improve candidemia outcomes.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida glabrata; Candidemia; Candidiasis; Drug Resistance, Fungal; Fluconazole; Hospitals, University; Humans; Japan; Longitudinal Studies; Micafungin; Microbial Sensitivity Tests; Retrospective Studies; Voriconazole

This study aimed to identify parameters that influence micafungin pharmacokinetics in Chinese patients with sepsis in the intensive care unit and optimize micafungin dosage by determining the probability of reaching pharmacodynamic targets.. Blood samples were collected from 32 Chinese patients with sepsis who were treated with micafungin. The samples were analyzed and used to build a population pharmacokinetic model. Monte Carlo simulations were performed to estimate the probability of achieving adequate plasma levels of micafungin against Candida species.. Alanine aminotransferase and sequential organ failure assessment score were found to significantly influence the clearance and peripheral distribution volume of micafungin, respectively. Monte Carlo simulations based on area under the plasma concentration-time curve over 24 h showed that patients must be administered at least 200 and 250 mg micafungin daily to reach minimum inhibitory concentration breakpoints of 0.032 and 0.064 mg/L for Candida glabrata and Candida tropicalis, respectively. Additionally, a probability of target attainment of ≥ 90% could not be achieved for Candida krusei or Candida parapsilosis with a 300 mg daily dose.. The recommended daily dose of micafungin (100 mg) may produce low clinical success ratios in non-Candida albicans infections; therefore, higher doses should be administered to improve clinical outcomes.

Topics: Adult; Aged; Aged, 80 and over; Biological Variation, Population; Candida; Candidiasis; China; Dose-Response Relationship, Drug; Female; Humans; Intensive Care Units; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Prospective Studies; Sepsis; Young Adult

C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Female; Fluconazole; Fungal Proteins; Gene Expression; Gene Expression Regulation, Fungal; Humans; Hyphae; Larva; Lepidoptera; Membrane Glycoproteins; Membrane Transport Proteins; Micafungin; Microbial Sensitivity Tests; Phenotype; Virulence

Damage to gut mucosa following conditioning regimens may favour bacterial infections that can trigger graft versus host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Rifaximin, an oral and non-absorbable antibiotic, has been recently proposed as effective prophylaxis to reduce bacterial infections in the gut and consequently acute GvHD in this setting. The present study evaluated safety and outcomes of HSCT patients that were treated with rifaximin prophylaxis at Perugia University Hospital. Rifaximin prophylaxis was introduced as standard of care in HSCT patients in May 2018. We retrieved data from 118 consecutive transplants, and we compared the outcomes of rifaximin-treated patients with historical controls that did not receive antibiotic prophylaxis. While incidences of neutropenic fever, documented bacterial infections, and aGvHD were similar in the two groups, we found an increased frequency of invasive candidiasis and clinically relevant Candida spp. infections in rifaximin-treated patients (5 patients vs 1 patient, 25% [± 0.99%] vs 1% [± 0.01%], p < .0001). Three rifaximin-treated patients experienced life-threating candidemia (2 C. krusei, 1 C. orthopsilosis). Rifaximin was the only factor that increased the risk of Candida spp. infections. Rifaximin could have contributed to microbiome disruption which favoured an outbreak of life-threatening Candida infections. This important complication forced us to halt its use. Larger, prospective studies are needed to assess the impact of rifaximin prophylaxis on incidence of bacterial infections, aGvHD, and survival of HSCT patients.

Topics: Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis; Drug Resistance, Fungal; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Micafungin; Middle Aged; Retrospective Studies; Rifaximin; Risk Factors; Transplantation, Homologous

An echinocandin, such as micafungin, is recommended as first-line treatment for invasive Candida infections in immunocompromised patients. This multicenter, observational, prospective, non- interventional study evaluated the real-world use of micafungin in clinical practice in Slovenia and Romania, as this remains unexplored.. The primary endpoint was evaluation of micafungin use, including rationale for prescription, treatment duration, and daily dose. Secondary endpoints included recordings of patient baseline characteristics and evaluations of efficacy and safety. Across 11 centers in two countries, 118 patients (18 children [< 16 years] and 100 adults [≥ 16 years]) received micafungin for the first time according to their clinic's standard practice.. Micafungin was prescribed for treatment in 57.6% of patients and for prophylaxis in 40.7% of patients. The median (range) treatment duration was 9.0 (0 - 54) days and 13.0 (2 - 6)] days, respectively. The median dose of micafungin was higher than recommended for children receiving prophylaxis or treatment for invasive candidiasis and for adults receiving prophylaxis. Fever was the most commonly observed clinical sign at baseline (16 children [88.9%] and 31 adults [31%]) and hematologic malignancy was the most frequent primary diagnosis at admission (11 children [61.1%] and 40 adults [40%]). Candida species were the most commonly identified causal agents of invasive fungal infections (2 children [11.1%] and 48 adults [48%]).. The efficacy and safety profiles of micafungin use in Slovenia and Romania based on clinician's own experiences in local clinical practice were consistent with those reported in other real-world studies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidiasis; Child; Child, Preschool; Female; Humans; Immunocompromised Host; Infant; Infant, Newborn; Male; Micafungin; Middle Aged; Practice Patterns, Physicians'; Prospective Studies; Romania; Slovenia; Young Adult

Candida auris, a multidrug-resistant species, has the propensity of nosocomial transmission despite normal decontamination procedures. Here, we describe the isolation of C auris from patients in various hospitals in Kuwait during 2014-2018. Susceptibility to antifungal drugs and molecular basis of resistance to fluconazole, voriconazole and micafungin were also studied.. Candida auris (n = 314) obtained from 126 patients in eight hospitals were studied. All isolates were identified by PCR amplification and/or PCR-sequencing of ribosomal DNA (rDNA). Antifungal susceptibility was determined by Etest. Molecular basis of resistance to fluconazole and micafungin was studied by PCR-sequencing of ERG11 and FKS1 genes, respectively.. Bloodstream (n = 58), urine (n = 124), respiratory (n = 98) and other (n = 34) specimens yielded 314 C auris isolates. The proportion of bloodstream C auris among all yeast isolates was higher (42 of 307, 13.7%) in 2018 as compared to 2014-2017 (16 of 964, 1.7%) (P = .001). More bloodstream isolates (42 of 139) were cultured in 2018 than during 2014-2017 (16 of 175) (P = .001). Resistance to amphotericin B, fluconazole, voriconazole and micafungin was detected in 27.1%, 100%, 41.1% and 1.7% isolates, respectively. Fluconazole-resistant isolates contained either Y132F or K143R mutation in ERG11. Isolates with K143R mutation were additionally resistant to voriconazole. Micafungin-resistant isolates contained S639F mutation in hot spot 1 of FKS1.. Our study highlights spreading of C auris in major hospitals across Kuwait and its increasing role as a bloodstream pathogen in 2018. Cross-resistance to voriconazole was also seen in isolates with K143R mutation in ERG11, while micafungin-resistant isolates harboured S639F mutation in hot spot 1 of FKS1.

Topics: Antifungal Agents; Candida; Candidemia; Candidiasis; Cross Infection; Drug Resistance, Fungal; Fluconazole; Genes, Fungal; Humans; Kuwait; Micafungin; Microbial Sensitivity Tests; Pathology, Molecular; Voriconazole

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

Antifungal combination is an interesting approach for the treatment of several fungal infections but there is currently little evidence to support combined therapy in Candida auris infections. The antibacterial colistin has recently been shown to interact synergistically with antifungals against Candida spp., including azole-resistant isolates. The current study evaluated the in vitro interaction between colistin and either caspofungin or micafungin against 15 C. auris isolates by a checkerboard methodology based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method. Results were analysed by two approaches: calculation of the fractional inhibitory concentration index (FICI) and response surface analysis based on the Bliss model. The minimum inhibitory concentration (MIC) range (geometric mean [Gmean]) of caspofungin and micafungin was 0.25 to 1 µg/mL (0.691 µg/mL) and 0.03 to 0.125 µg/mL (0.114 µg/mL), respectively. No activity was observed for colistin alone with MIC of >64 µg/mL for all the isolates. When colistin was combined with caspofungin, synergistic interactions were observed for all strains with FICI values of 0.08 to 0.14. In contrast, indifferent interactions were observed for the combination of colistin with micafungin with FICI values of 0.51 to 1.01. Synergy was also demonstrated using the Bliss model against all isolates for the colistin-caspofungin combination and in 60% of isolates for the colistin-micafungin combination. Antagonism was not observed for any combination.

Topics: Anti-Bacterial Agents; Antifungal Agents; Candida; Candidiasis; Caspofungin; Colistin; Drug Synergism; Echinocandins; Humans; Micafungin

The spectrum of yeasts and their antifungal susceptibility profile are poorly known and treatment of fungal disease has remained empirical. The aim of this study is to determine the spectrum and antifungal susceptibility profile of yeasts particularly of Candida species.. A descriptive study on the composition of Candida species and antifungal susceptibility profile were conducted from January 2018 to September 2018. Clinical samples collected from different sites were cultured on Sabouraud dextrose agar and incubated for an appropriate time. Identification of yeast isolates and their antifungal susceptibility profile were determined by the VITEK 2 compact system. Descriptive statistics such as frequency and percentage of Candida species were calculated using SPSS version 20.. Of 209 yeasts recovered, 104(49.8%), 90 (43.1%), 15(7.2%) were C. albicans, non albicans Candida species, and other yeasts, respectively. Among non albicans Candida species, Candida krusei was the commonest isolate. Of other yeast groups, 66.7% was represented by Cryptococcus laurentii. Regardless of Candida species identified, 85.6, 3.9, and 10.5% of the isolates were susceptible, intermediate, and resistant to fluconazole, respectively. C krusei was 100% resistant to the drug. Voriconazole demonstrated the greatest antifungal activity against Candida isolates in which 99.4% of Candida isolates were susceptible. The susceptibility and the resistance rate of Candida isolate to both caspofungin and micafungin were the same being 96 and 4% respectively. However, micafungin was more potent than caspofungin. The susceptibility, resistant, and intermediate rates of yeasts against flucytosine were, 86.2, 6.6, and 7.2%, respectively.. The present study demonstrated the distribution of Candida species in different clinical specimens where the isolation rate of non-albicans Candida species was comparable to Candida albicans. The high resistance rate of C. krusei to fluconazole and flucytosine may demonstrate that the treatment of candidiasis empirically is questionable.

Topics: Antifungal Agents; Candida; Candida albicans; Candidiasis; Caspofungin; Drug Resistance, Fungal; Ethiopia; Humans; Micafungin; Microbial Sensitivity Tests

Candida sp. osteoarticular infection is rare and most often due to hematogenous seeding during an episode of candidemia in immunocompromised patients. However, the diagnosis can be delayed in patients with subtle symptoms and signs of joint infection without a concurrent episode of candidemia.. A 75-year-old woman presented with a three-year history of pain and swelling of the left knee. Candida pelliculosa was detected from the intraoperative tissue when the patient had undergone left total knee arthroplasty 32 months ago, but no antifungal treatment was performed. One year after the total knee arthroplasty, C. pelliculosa was repeatedly isolated from the left knee synovial fluid and antifungal treatment comprising amphotericin B deoxycholate and fluconazole was administered. However, joint infection had extended to the adjacent bone and led to progressive joint destruction. The patient underwent surgery for prosthesis removal and received prolonged antifungal treatment with micafungin and fluconazole.. This case shows that C. pelliculosa, an extremely rare non-Candida albicans sp., can cause fungal arthritis and lead to irreversible joint destruction owing to delayed diagnosis and treatment.

Topics: Aged; Amphotericin B; Antifungal Agents; Arthritis, Infectious; Arthroplasty, Replacement, Knee; Candida; Candidemia; Candidiasis; Deoxycholic Acid; Device Removal; Drug Combinations; Female; Fluconazole; Humans; Intraoperative Care; Joint Prosthesis; Knee; Micafungin; Osteomyelitis

To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens.. An HPLC-fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens.. A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains.. A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidiasis; Chromatography, High Pressure Liquid; Computer Simulation; Critical Illness; Drug Dosage Calculations; Drug Monitoring; Female; Fluorometry; Humans; Infusions, Intravenous; Intensive Care Units; Male; Micafungin; Middle Aged; Models, Biological; Predictive Value of Tests; Reproducibility of Results

A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid.. Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay.. The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.

Topics: Adult; Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Critical Illness; Echinocandins; Female; Humans; Male; Micafungin; Microbial Sensitivity Tests; Peritonitis; Prospective Studies

Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions.. We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention.. In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.

Topics: Aged; Anidulafungin; Antifungal Agents; Candida; Candidemia; Candidiasis; Humans; Immunocompromised Host; Induction Chemotherapy; Male; Micafungin; Spondylitis; Treatment Outcome; Voriconazole

Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known.. We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis.. In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively.. Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery.

Topics: Antifungal Agents; Candidiasis; Humans; Invasive Fungal Infections; Lung Transplantation; Micafungin

Candida spp. are ranked as one of the four major causative agents of fungal infections. The number of infections caused by Candida species resistant to fluconazole, which is applied as the first line drug in candidiasis treatment, increases every year. In such cases the application of echinocandin is necessary. Echinocandin susceptibility testing has become a routine laboratory practice in many countries due to the increasing frequency of clinical failures during treatment with these drugs.. We performed anidulafungin, micafungin and caspofungin susceptibility testing according to the microdilution broth method on 240 Candida isolates collected in Polish hospitals.. We identified 12 isolates resistant to all echinocandins within 240 examined isolates. Moreover, 6 of the examined samples were identified as rare Candida species and among them we observed very high echinocandin MIC values.. Our research proves that in Poland there is a problem of echinocandin resistance. Moreover, we identified two species of Candida which are rare causative agents of human infections, and there was no reported incidence of such infections in Poland until now.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Micafungin; Microbial Sensitivity Tests; Poland

We investigated covariates of pharmacokinetics of micafungin in critically ill patients. After application of micafungin, plasma samples were collected. Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. Using this model, the adequacy of a fixed 100 mg dosing regimen was evaluated in the study cohort. A two-compartment model with linear elimination was found to describe the obtained data. SOFA score was identified as a significant covariate on both clearance and central volume of distribution, respectively. Patients in highly critical condition, represented by a SOFA above 10 showed a 30.8% lower central volume of distribution than the less critically ill patients. For patients with bilirubin levels above 4 mg/dl, clearance was decreased by 21.1%. Renal replacement therapy (RRT) did not influence micafungin clearance or the volumes of distribution. In a posthoc evaluation of the modeled population, 100 mg micafungin was suitable when assessing the PKPD targets (AUC/MIC) for C. albicans and C. glabrata, with insufficient target attainment for C. parapsilosis. Micafungin pharmacokinetics appear not to be influenced by the status of RRT. A dose of 100 mg micafungin is suitable for infections with C. albicans and C. glabrata in critically ill patients.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida albicans; Candida glabrata; Candida parapsilosis; Candidiasis; Critical Illness; Drug Monitoring; Female; Humans; Male; Micafungin; Middle Aged; Young Adult

Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. We used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death or failure of microbiologic clearance.

Topics: Antifungal Agents; Candidiasis; Electronic Health Records; Female; Hospitalization; Humans; Infant; Male; Micafungin

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

Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in

Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Candidiasis, Invasive; Caspofungin; Drug Resistance, Fungal; Fungal Proteins; Gene Expression; Genetic Loci; Glucosyltransferases; Humans; Micafungin; Microbial Sensitivity Tests; Mutation Rate

Fungal endocarditis is a relatively rare occurrence with high morbidity and mortality. Patients may have an indolent and non-specific course requiring a high index of suspicion to make a diagnosis. Here, we present the case of a 33-year-old patient who presented with fevers and acute lower limb ischemia requiring a 4-compartment fasciotomy caused by septic emboli from Candida albicans endocarditis. The patient had a large vegetation in the ascending aorta associated with a mycotic aneurysm, which is an exceedingly rare location for a vegetation. We also review the literature and summarize the typical echocardiographic appearance and vegetation locations in fungal endocarditis.

Topics: Adult; Aneurysm, Infected; Antifungal Agents; Aortic Valve; Candida albicans; Candidiasis; Diagnosis, Differential; Echocardiography; Endarteritis; Heart Valve Diseases; Heart Valve Prosthesis; Humans; Male; Micafungin; Prosthesis-Related Infections

Invasive candidiasis is a common and serious infection in premature newborns. Preventing and treating fungal infections is very important to improve the prognosis of premature infants. Fluconazole and amphotericin B are used as the first choice in the treatment of invasive fungal infections of the newborns. In some cases, fluconazole and amphotericin B cannot be used due to nephrotoxicity, hepatotoxicity or resistant strains. Micafungin, which is among recently developed echinocandins, is the drug of choice in these cases. The use of micafungin in newborns is new and there is a limited experience about the effect of high dose usage in the central nervous system. The aim of this study was to evaluate the electronic files of patients who used micafungin for the treatment of culture-proven or possible invasive fungal infection during their hospital stay in the neonatal intensive care unit during a 24-month period (2016-2017) in the third-level intensive care unit. A total of 15 patients (10 premature and 5 term babies) were included in the study. The mean birth weight of the patients was 1732 ± 999 g and the mean gestational age was 32.2 ± 5.8 weeks. All patients had long-term intensive care and increased risk of invasive candidiasis infection. Central venous catheterization and multiple antibiotics usage were the most common risk factors in these patients. The other risk factors included intubation, total parenteral nutritional use and surgical procedure application. Candida species were isolated from the cultures of four patients. Candida species isolated from patients were Candida albicans, Candida glabrata, Candida catenulata, Candida parapsilosis. The mean time for onset of micafungin was 29.9 ± 16.6 days. Mean duration of micafungin therapy was 22.4 ± 11.2 days. Eight patients received amphotericin B, three patients received fluconazole therapy and four patients did not receive any antifungal therapy before the onset of micafungin. None of these patients had an abnormal kidney or liver function tests due to micafungin use. As a conclusion, high dose (10 mg/kg/day) micafungin is a safe and effective treatment choice both in the treatment of neonatal culture proven or probable invasive candida infections that were caused by refractory Candida strains, and in the case of nephrotoxicity and hepatotoxicity.

Topics: Antifungal Agents; Candida; Candidiasis; Fluconazole; Humans; Infant, Newborn; Infant, Premature; Micafungin; Retrospective Studies; Treatment Outcome

Overall, fungi are estimated to cause approximately 1% of prosthetic joint infections, Candida glabrata account for less than 10% of these cases. No well-defined treatment strategy is available.. A 71-year-old Caucasian man with non-insulin-dependent diabetes was admitted for hip prosthesis revision. For the past 17 years he suffered from recurrent infection of a perianal fistula, the last episode being 1 week before admission, and was prescribed amoxicillin/clavulanate 1 g twice a day. At surgery, the synovial fluid tested positive for infection with the Synovasure® Alpha Defensin Test, and the orthopedic surgeon reported intraoperative evidence of infection. While the synovial fluid failed to grow microorganisms, seven different samples including periprosthetic tissue and the prosthesis grew Candida glabrata. Imipenem 2 g and teicoplanin 600 mg daily were administered during surgery. Also an antibiotic loaded spacer was positioned. A week later micafungin 100 mg a day was added, and after another week imipenem was replaced with ertapenem 1 g once a day. The combination of antibiotics and antifungal was administered for a total of 7 weeks, while he also underwent treatment of the perianal fistula. The reimplantation was performed after an 8-week antibiotic-free interval. Before reimplantation, his erythrocyte sedimentation rate and C-reactive protein level were normal. At reimplant surgery, several samples were collected for microbiology, before administering ertapenem 1 g, teicoplanin 600 mg and micafungin 100 mg once a day. This antimicrobial combination was continued for 15 days until the microbiologic investigations, including culture and molecular testing after sonication technique of the spacer, were reported negative for bacteria and fungi. In this patient, systemic antifungal and extensive debridement allowed for clinical and microbiologic cure.. Although Candida glabrata prosthetic joint infection is a rare event, the incidence could increase in the future, and there is need for more definitive treatment protocols. Diagnosis depends on culture. Fungal etiology must always be included in the differential diagnosis of prosthetic joint infection.

Topics: Aged; Anti-Bacterial Agents; Antifungal Agents; Arthroplasty, Replacement, Hip; Candida glabrata; Candidiasis; Hip Prosthesis; Humans; Male; Micafungin; Prosthesis-Related Infections; Rectal Fistula; Teicoplanin; Treatment Outcome

We previously reported that Candida albicans responded to mild heat stress in a range of temperature elevations simulating fever, and concluded that mild heat stress increases susceptibility to antifungal drugs. In this study, we show that mild heat stress causes a morphological change in hyphae during the process of biofilm formation. We found that mild heat stress extended the period of hyphal stage maintenance in C. albicans biofilm. Although the rate of hyphal change from yeast form to hyphal form reached the maximum within 3 hr, later, almost every cell quickly reverted to the yeast growth phase within 6 hr at 37°C but not at 39°C, or under mild heat stress. Electron microscopy using a smart specimen preparation technique revealed that mild heat stress significantly increased the thickness of the inner cell wall accompanied by a decrease in density of the outer cell wall in the hyphae of C. albicans biofilm. To identify the gene responsible for the morphological changes associated with mild heat stress, we performed microarray gene expression analysis. Eleven genes were upregulated and 17 genes were downregulated under mild heat stress in biofilm cells. The increased PHR1 gene expression in response to mild heat stress was confirmed in quantitative RT-PCR analysis. The mutant upregulated PHR1 expression showed the same sensitivity against antifungal drug micafungin as dependent on mild heat stress. Our findings point to possible therapeutic effects of hyperthermia as well as to the effect of fever during infections.

Topics: Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Cell Wall; Down-Regulation; Drug Resistance, Fungal; Fever; Fungal Proteins; Gene Expression; Gene Expression Regulation, Fungal; Hot Temperature; Hyphae; Membrane Glycoproteins; Micafungin; Microscopy, Electron; Stress, Physiological; Time Factors

Topics: Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Echinocandins; Endocarditis; Fluconazole; Heart Valve Prosthesis; Humans; Male; Micafungin; Prosthesis-Related Infections; Recurrence

Topics: Amphotericin B; Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Fungal Proteins; Glucosyltransferases; Humans; Micafungin; Microbial Sensitivity Tests; Reactive Oxygen Species; Sequence Deletion; Trehalose

Candida spp. is able to form a biofilm, which is considered resistant to the majority of antifungals used in medicine. The aim of this study was to evaluate the in vitro activity of micafungin against Candida spp. biofilms at different stages of their maturation (2, 6, and 24 h). We assessed the inhibitory effect of micafungin against 78 clinical isolates of Candida spp., growing as planktonic or sessile cells, by widely recommended broth microdilution method. The in vitro effect on sessile cells viability was evaluated by colorimetric reduction assay. All examined strains were susceptible or intermediate to micafungin when growing as planktonic cells. At the early stages of biofilm maturation, from 11 (39.3%) to 20 (100%), tested strains, depending on the species, exhibited sessile minimal inhibitory concentrations (SMICs) of micafungin at ≤ 2 mg/L. For 24-h-old Candida spp. biofilms, from 3 (10.7%) to 20 (100%) of the tested strains displayed SMICs of micafungin at ≤ 2 mg/L. Our findings confirm that micafungin exhibits high potential anti-Candida-biofilm activity. However, this effect does not comprise all Candida species and strains. All strains were susceptible or intermediate to micafungin when growing as planktonic cells, but for biofilms, micafungin displays species- and strain-specific activity. Paradoxical growth of C. albicans and C. parapsilosis was observed. Antifungal susceptibility testing of Candida spp. biofilms would be the best solution, but to date, no reference method is available. The strongest antibiofilm activity of micafungin is observed at early stages of biofilm formation. Possibly, micafungin could be considered as an effective agent for prevention of biofilm-associated candidiasis, especially catheter-related candidaemia.

Topics: Antifungal Agents; Biofilms; Candida albicans; Candida glabrata; Candida parapsilosis; Candidiasis; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Little is known about the side effects of micafungin in extremely low birth weight infants. In a retrospective single-center study, 19 extremely low birth weight infants were analyzed for micafungin efficacy and safety. At a mean±standard deviation daily dosage of 7.5 ± 2.0 mg/kg, no clinically relevant side effects were observed. A significant increase of liver enzymes was reversible after treatment.

Topics: Antifungal Agents; Candidiasis; Electronic Health Records; Female; Humans; Infant; Infant, Extremely Low Birth Weight; Liver; Male; Micafungin; Retrospective Studies; Tertiary Care Centers

Topics: Adult; Antifungal Agents; Candida tropicalis; Candidiasis; Combined Modality Therapy; Endophthalmitis; Eye Infections, Fungal; Humans; Male; Micafungin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retinal Neoplasms; Vitrectomy

We studied the ability of five echinocandin-susceptible C. glabrata isolates to acquire in vitro resistance to anidulafungin and micafungin. All isolates became phenotypically resistant after 2-4 days of exposure to low and constant micafungin concentrations (P < .05). Mutations in the HS1 region of the FKS2 gene were found in all isolates. The acquisition of resistance was not related to the previous use of antifungal treatment in the patients or the presence of mutations at MSH2 gene. We found differences (P < .0001) in the median survival of Galleria mellonella larvae infected with FKS2 mutant isolates (5 days) and wild-type isolates (3 days).

Topics: Anidulafungin; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Disease Models, Animal; DNA Mutational Analysis; Drug Resistance, Fungal; Glucosyltransferases; Lepidoptera; Micafungin; Mutation; Survival Analysis

Topics: Antifungal Agents; Candida albicans; Candidiasis; Debridement; Humans; Lower Extremity; Lupus Erythematosus, Systemic; Male; Micafungin; Middle Aged; Musculoskeletal Pain; Pyomyositis; Risk Factors; Tomography Scanners, X-Ray Computed; Treatment Outcome

To identify the frequency of micafungin resistance among clinically significant isolates of Candida stored at our institution from 2005 to 2015. Chart review of patients with resistant isolates then informed the clinical setting and outcomes associated with these infections.. Clinical Candida isolates had been stored at -80°C in Brucella broth with 20% glycerol from 2005. Isolates were tested using broth microdilution to determine micafungin MICs. All Candida glabrata isolates and all isolates demonstrating decreased susceptibility to micafungin were screened for FKS mutations using a Luminex assay.. In total, 3876 Candida isolates were tested for micafungin resistance, including 832 C. glabrata isolates. Of those, 33 isolates from 31 patients were found to have either decreased susceptibility to micafungin and/or an FKS mutation. C. glabrata accounted for the majority of these isolates. While bloodstream infections were found to have a very high mortality rate, isolates from other sites were uncommonly associated with 30-day mortality. Overall resistance rates were very low.. Echinocandin resistance in C. glabrata has been increasingly reported but rates at our institution remain very low. We hypothesize that a focus on antifungal stewardship may have led to these observations. Knowledge of local resistance patterns is key to appropriate empirical treatment strategies.

Topics: Academic Medical Centers; Adult; Antifungal Agents; Candida; Candida glabrata; Candidemia; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Male; Micafungin; Microbial Sensitivity Tests; Mutation

A total of 46 clinical isolates of

Topics: Aged; Aged, 80 and over; Animals; Antifungal Agents; Candida; Candidiasis; Echinocandins; Female; Humans; Hydrogen Peroxide; Male; Micafungin; Mice; Microbial Sensitivity Tests; Middle Aged

Multiple cases of Candida auris infection have been reported with high mortality rates owing to its MDR nature. Rezafungin (previously CD101) is a novel echinocandin with enhanced stability and pharmacokinetics that achieves high plasma drug exposure and allows for once weekly dose administration.. Evaluate the efficacy of rezafungin in the treatment of disseminated C. auris infection using a mouse model of disseminated candidiasis.. Mice were immunosuppressed 3 days prior to infection and 1 day post-infection. On the day of infection, mice were inoculated with 3 × 107C. auris blastospores via the tail vein. Mice were randomized into four groups (n = 20): rezafungin at 20 mg/kg, amphotericin B at 0.3 mg/kg, micafungin at 5 mg/kg and a vehicle control. Treatments were administered 2 h post-infection. Rezafungin was given additionally on days 3 and 6 for a total of three doses, while the remaining groups were treated every day for a total of seven doses. Five mice from each group were sacrificed on days 1, 4, 7 and 10 of the study. Kidneys were removed from each mouse to determine the number of cfu for each respective day.. Rezafungin had significantly lower average log10 cfu/g of tissue compared with amphotericin B- and vehicle-treated mice on all days when kidneys were harvested. Additionally, rezafungin-treated mice had significantly lower average log10 cfu/g of tissue compared with micafungin-treated mice on day 10.. Our findings show that rezafungin possesses potent antifungal activity against C. auris in a disseminated model of candidiasis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidiasis; Echinocandins; Female; Immunocompromised Host; Micafungin; Mice; Random Allocation

Here we sought to describe the real-life usage of micafungin in a UK tertiary referral hospital.. A prospective, non-interventional, observational surveillance study was performed.. Micafungin was commenced in 174 courses involving 148 patients to treat invasive candidiasis and candidaemia (132 courses) and aspergillosis in situations where alternatives such as voriconazole or liposomal amphotericin B could not be used (42 courses). Fungal infection was defined as proven as per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines in 84 courses (48.3%). Micafungin was well tolerated; 10 patients (6.8%) developed a rise in alanine aminotransferase (ALT) and only 1 patient stopped therapy due to this. Therapy was rationalised to fluconazole in 77 courses (44.3%). There were no differences in intensive care unit admission or deaths when comparing all 174 courses where patients received micafungin for Aspergillus and Candida infection, respectively [49% vs. 42% (P=0.82) and 24% vs. 15% (P=0.186)]. One patient developed disseminated mucormycosis and four patients had recurrent candidaemia (attributed to poor source control) while receiving micafungin.. Micafungin was clinically effective for the treatment of invasive Candida and Aspergillus infections, and usage did not increase the risk of liver dysfunction even in patients with abnormal ALT at baseline.

Topics: Adolescent; Adult; Aged; Candidiasis; Child; Female; Fungi; Humans; Male; Micafungin; Middle Aged; Prospective Studies; Tertiary Care Centers; United Kingdom; Young Adult

There have been over 80 documented cases of swallow syncope-a rare form of reflex or neurally mediated syncope-with most cases associated with an underlying esophageal disorder. Here, we describe the first reported case of swallow syncope or presyncope caused by an infectious esophagitis. Our 65-year-old patient initially developed dysphagia, odynophagia, and presyncope with swallowing. This lead to nutrition and medication avoidance behavior, which was followed by the development of diabetic ketoacidosis. The diagnosis of swallow presyncope was confirmed with a provocative swallow study demonstrating 8 s sinus arrest, and an underlying cause of Candida esophagitis was found by upper endoscopy. Symptoms completely resolved after treatment with micafungin.

Topics: Aged; Antifungal Agents; Candida; Candidiasis; Deglutition Disorders; Diabetic Ketoacidosis; Esophagitis; Female; Humans; Micafungin; Syncope

Topics: Acute Coronary Syndrome; Antifungal Agents; Aortic Valve Insufficiency; Blood Culture; Candida glabrata; Candidiasis; Coronary Angiography; Diagnosis, Differential; Echinocandins; Echocardiography; Electrocardiography; Endocarditis; Female; Heart Valve Prosthesis Implantation; Humans; Lipopeptides; Micafungin; Middle Aged; Myocardial Infarction; Thrombectomy

Topics: Anidulafungin; Antifungal Agents; Austria; Candida; Candidiasis; Caspofungin; Disk Diffusion Antimicrobial Tests; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin

Intra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents; however, their clinical effectiveness is highly variable, with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption ionization mass spectrometry imaging technology, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model. Drug accumulation within lesions was observed with both drugs at their humanized therapeutic doses. CD101, but not micafungin, accumulated in lesions at levels above the mutant prevention concentration of the infecting strain. These findings indicate that current echinocandin drugs are limited by penetration at the site of infection and have implications for clinical outcomes and emergence of resistance in patients with IAC.

Topics: Abdominal Abscess; Animals; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins; Female; Lipopeptides; Micafungin; Mice; Microbial Sensitivity Tests; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

We evaluated the

Topics: Aminoglycosides; Anidulafungin; Animals; Antifungal Agents; Candida albicans; Candidiasis; Chitin Synthase; Drug Combinations; Drug Resistance, Fungal; Drug Synergism; Echinocandins; Glucosyltransferases; Humans; Lipopeptides; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests

We report data on the frequency of the paradoxical effect of echinocandins against Candida spp. (n = 602 incident isolates) using the EUCAST definitive document EDef 7.2 procedure. The paradoxical effect for one or more echinocandins was observed in 16% of the isolates. However, differences between species were found, and the paradoxical effect was more common in Candida tropicalis (P < 0.001). Caspofungin was the drug in which the paradoxical effect was most common, followed by anidulafungin and micafungin (P < 0.001).

Topics: Anidulafungin; Antifungal Agents; Candida; Candida tropicalis; Candidemia; Candidiasis; Caspofungin; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests

We assessed the in vitro susceptibility of five echinocandin-susceptible Candida glabrata isolates after exposure to micafungin. The direct exposure to plates at different micafungin concentrations resulted in the inhibition of growth at 0.062 μg/ml. The progressive exposure was performed on plates using 0.031 μg/ml of micafungin and sequential propagation on plates containing the next 2-fold concentration; the MICs of micafungin and anidulafungin increased sequentially, and all the isolates became echinocandin resistant, showing fks2 mutations.

Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation

Echinocandins are an important class of antifungal agents in the treatment of invasive candidiasis. However, little is known about the metabolomic effects of echinocandins on Candida . We therefore performed LC-high-resolution MS (LC-HRMS)-based metabolomics profiling of the response of Candida albicans cells to increasing concentrations of micafungin to determine the metabolic response of Candida to micafungin subinhibitory injury.. Isolates of C. albicans were cultured on nitrocellulose filters to mid-logarithmic phase of growth and micafungin (0-0.25 mg/L) was added. At mid-logarithmic phase, replicates were metabolically quenched. Intracellular metabolites were analysed by LC-HRMS. Changes in pool sizes of individual metabolites were analysed by Student's t -test adjusted for multiple hypothesis testing by Benjamini-Hochberg correction. Metabolites were ascribed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database.. Among 3446 detected metabolites, 204 were identified by comparison against pure standard or comparison against a library of mass-retention-time pairs. Fifty had significantly altered abundances in response to increasing micafungin concentrations. Pool sizes of amino acids, nucleic acids and polyamine metabolism were significantly increased at subinhibitory concentrations, while exposure to inhibitory concentrations resulted in a precipitous decrease consistent with fungicidal activity.. Micafungin induces a re-routing of metabolic pathways inhibiting protein synthesis and cell replication. These results shed light on new mechanisms of action of echinocandins.

Topics: Amino Acids; Antifungal Agents; Candida albicans; Candidiasis; Candidiasis, Invasive; Carbon; Chromatography, Liquid; Echinocandins; Lipopeptides; Mass Spectrometry; Metabolic Networks and Pathways; Metabolomics; Micafungin; Microbial Sensitivity Tests; Nucleic Acids

Currently, echinocandins are first-line drugs for treatment of invasive candidiasis. However, data on how serum influences killing activity of echinocandins against uncommon Candida species are limited. Therefore, the killing activity of micafungin in RPMI-1640 and in 50% serum was compared against Candida guilliermondii, Candida lusitaniae, and Candida kefyr. Minimum inhibitory concentration (MIC) ranges in RPMI-1640 were 0.5-1, 0.12-0.25, and 0.06-0.12 mg/L, respectively. In 50% serum, MICs increased 32- to 256-fold. In RPMI-1640 ≥ 0.25, ≥4, and 32 mg/L micafungin was fungicidal against all four C. kefyr (≤4.04 hours), two of three C. lusitaniae (≤16.10 hours), and two of three C. guilliermondii (≤12.30 hours), respectively. In 50% serum, all three species grew at ≤4 mg/L. Micafungin at 16-32 mg/L was fungicidal against all C. kefyr isolates (≤3.03 hours) and at 32 mg/L was fungistatic against one of three C. lusitaniae isolates. Two C. lusitaniae isolates and all three C. guilliermondii grew at all tested concentrations. Adding human serum to susceptibility test media drew attention to loss of fungicidal or fungistatic activity of micafungin in the presence of serum proteins, which is not predicted by MICs in case of C. kefyr and C. lusitaniae in RPMI-1640. Our results strongly suggest that micafungin and probably other echinocandins should be used with caution against rare Candida species.

Topics: Antifungal Agents; Blood Proteins; Candida; Candidiasis; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Serum

To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies.. Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations.. The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida; Candida parapsilosis; Candidiasis; Cohort Studies; Drug Delivery Systems; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Prospective Studies; Young Adult

We studied the antifungal activity of SCY-078 (an orally bioavailable 1,3-β -d- glucan synthesis inhibitor), micafungin and fluconazole against the planktonic and sessile forms of 178 Candida and non- Candida isolates causing fungaemia in patients recently admitted to a large European hospital.. The in vitro activity of SCY-078, micafungin and fluconazole against the planktonic form of the isolates was assessed using EUCAST EDef 7.3 and CLSI M27-A3. Antibiofilm activity was assessed using the XTT reduction assay.. SCY-078 and micafungin showed potent in vitro activity against Candida and non- Candida isolates. The in vitro activity of both drugs was similar, but SYC-078 displayed significantly lower MIC values than micafungin against Candida parapsilosis and non- Candida isolates, whereas micafungin displayed significantly lower MIC values for the remaining species ( P  <0.001). In contrast, SCY-078 and micafungin showed essentially the same activity against the biofilms with the exception of Candida glabrata , in which the micafungin sessile MIC values were significantly lower ( P  <0.001). These observations were confirmed by assessing biofilm structure by scanning electron microscopy after antifungal treatment.. Our study showed that the high in vitro activity of SCY-078 against invasive Candida isolates in both sessile and planktonic forms is comparable to that of micafungin.

Topics: Antifungal Agents; Biofilms; Candida; Candida albicans; Candida glabrata; Candidiasis; Candidiasis, Invasive; Echinocandins; Glucosyltransferases; Glycosides; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Triterpenes

The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the echinocandins favor infrequent administration of large doses. The in vivo investigation reported here tested the utility of a range of humanized dose levels of micafungin using a variety of prolonged dosing intervals for the prevention and therapy of established disseminated candidiasis. Humanized doses of 600 mg administered every 6 days prevented fungal growth in prophylaxis. Humanized doses of 300 to 1,000 mg administered every 6 days demonstrated efficacy for established infections.

Topics: Animals; Antifungal Agents; Candida; Candidiasis; Disease Models, Animal; Drug Administration Schedule; Echinocandins; Humans; Lipopeptides; Micafungin; Mice; Microbial Sensitivity Tests; Treatment Outcome

The echinocandins and liposomal amphotericin B are active against biofilm produced by echinocandin-susceptible Candida strains. However, few data have been reported on the production of biofilm by echinocandin-resistant isolates and their antifungal susceptibility. We studied the production of biofilm by fks mutant Candida strains and intrinsically echinocandin-resistant non-Candida isolates and the susceptibility of both entities to liposomal amphotericin B and echinocandins. We analyzed the production of biofilm by isolates from patients with fungemia (fks mutant Candida, n = 5; intrinsically echinocandin-resistant non-Candida, n = 12; and Candida wild type, n = 10). Biofilm formation was measured to classify strains according to biomass (crystal violet assay) and metabolic activity (XTT reduction assay). Preformed biofilms were tested against liposomal amphotericin B, caspofungin, micafungin, and anidulafungin. The sessile MIC was defined as the antifungal concentration yielding a 50% or 80% reduction in the metabolic activity of the biofilm compared to that of the growth control (SMIC50 and SMIC80, respectively). fks mutant Candida isolates formed biofilms in a fashion similar to that of Candida wild-type strains. The echinocandins had the highest activity against biofilms formed by wild-type Candida isolates, followed by fks mutant Candida isolates and non-Candida isolates. Liposomal amphotericin B had the highest activity against fks mutant Candida biofilms. The formation of biofilm by echinocandin-resistant strains was similar to that of wild-type strains, although resistance to echinocandins remained high.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Biofilms; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Glucosyltransferases; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK).. To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial. Infants on ECMO either received intravenous micafungin 4 mg/kg every 24 h for invasive candidiasis prophylaxis or 8 mg/kg every 24 h when a fungal infection was suspected or confirmed. We collected plasma samples after single and multiple micafungin doses. We defined the therapeutic target as the adult exposure associated with efficacy in phase III trials and the prophylactic target as one-half of the therapeutic target.. We enrolled 12 infants (124 samples) with a median age of 59 days. Using a 1-compartment model, median weight-normalized volume of distribution and clearance were 0.64 L/kg and 0.041 L/kg/h, respectively. Dose-exposure simulations revealed that doses of 2.5 and 5 mg/kg every 24 h matched exposure targets for prophylaxis and treatment of invasive candidiasis, respectively. We did not observe any drug-related adverse events.. In infants on ECMO, micafungin volume of distribution was higher and clearance was in the upper range of previously published values for infants not on ECMO. Based on these data, we recommend dosing of 2.5 and 5 mg/kg every 24 h for prophylaxis and treatment of invasive candidiasis, respectively, to match adult exposure proven effective against Candida spp.

Topics: Antibiotic Prophylaxis; Antifungal Agents; Area Under Curve; Candidiasis; Echinocandins; Extracorporeal Membrane Oxygenation; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Prospective Studies

Six cases of patients diagnosed with urinary tract infection (UTI) successfully treated with micafungin are reported. Four were infected with fluconazole-resistant Candida spp. and two (with hepatic injury) were infected with fluconazole-sensitive Candida spp. Traditionally, echinocandins have not been considered for the treatment of UTIs. However, despite its low urinary excretion rate, therapeutic drug monitoring of micafungin urinary levels could be helpful in order to achieve optimal pharmacokinetic/pharmacodynamic (PK/PD) indices for treating UTIs caused by Candida spp. resistant to fluconazole.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Candida; Candidiasis; Drug Monitoring; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Urinary Tract Infections; Urine

To compare the efficacy and safety of micafungin with caspofungin for the empirical treatment of severe intra-abdominal infections in surgical intensive care patients.. This was a retrospective cohort study.From May 1 st 2012 to April 30 2015, 47 patients with severe intra-abdominal infection complicated with specific risk of Intra-abdominal invasive candidiasis (IAC) receiving empirical treatment of echinocandins were enrolled in Department of Critical Care Medicine, Peking University First Hospital. Micafungin and caspofungin substituted each other every six months. The baseline information, risk factors of IAC, characteristics of intra-abdominal infections, antifungal treatment and other intra-abdominal infections(IAI) related treatment information, clinical outcome were collected and compared between the micafungin and caspofungin groups.. Forty-seven patients met inclusion/exclusion criteria. The average score of APACHE Ⅱ was (19.0±7.7), the incidence of IAC was 23.4%. The patients were divided into the micafungin group (n=26) and the caspofungin group (n=21). The average therapeutic course was 10 (5, 13) days.There were no significant differences in the baseline information, risk factors of IAC, characteristics of intra-abdominal infections and other IAI related treatment informations between the two groups. SOFA score, body temperature, persistence of extra-gastrointestinal fungal colonization significantly improved from the baseline in both groups. The leukocyte count decrease was different between the micafungin group and the caspofungin group respectively[(12.5±5.4)10(9)/L vs (9.8±4.3) 10(9)/L, P=0.013; (12.9±5.4) 10(9)/L vs (10.4±4.7) 10(9)/L, P=0.134]. There were no significantly differences in the recovery of GI function, the incidence of breakthrough IC, the incidence of newly developed organ failure, the 30-day mortality, the length of ICU stay and hospitalization period or the incidence of alternative antifungal therapy between the micafungin group and the caspofungin group. No drug-related adverse event requiring echinocandins discontinuation occurred.. The empirical treatment of echinocandins for patients with severe intra-abdominal infection and specific risk factors of IAC may be effective. The empirical treatment of micafungin and caspofungin were equally effective and safe.

Topics: Antifungal Agents; Candidiasis; Caspofungin; Critical Care; Echinocandins; Humans; Incidence; Intraabdominal Infections; Intraoperative Care; Lipopeptides; Micafungin; Retrospective Studies; Risk Factors

In high-risk patients, candiduria may be associated with the development of urinary tract infections (UTI) and invasive candidiasis. The triazole antifungals achieve good urine concentrations, but their use is limited by the emergence of non-albicans Candida spp. with low-triazole susceptibility. The echinocandins remain fungicidal against many azole-resistant Candida spp., but low urine concentrations limit their use. We examined the rates of candiduria elimination in micafungin-treated patients.. This retrospective analysis evaluated consecutive patients with candiduria (1/2008-4/2011) who were treated with micafungin (100 mg/day) and had post-micafungin urine cultures. Patients were deemed to have either candiduria or UTI and were assessed for short-term (within 2 weeks post-micafungin) and long-term (>1 month post-micafungin) urine sterilization.. Thirty-three patients meeting our inclusion criteria were identified. Of these, 16 (48 %) were diagnosed with a Candida UTI. A total of 25 patients (76 %) had Foley catheters, which were replaced in 11 (44 %) cases. The majority of patients had Candida albicans (39 %), but Candida krusei and Candida glabrata (33 %) were also isolated. Eight patients (24 %) were immunocompromised, and 29 (88 %) received broad-spectrum antibiotics. Rates of urine sterilization during micafungin treatment, 2 weeks after micafungin, and >1 month after micafungin were 81, 78, and 75 %, respectively.. Among hospitalized patients with candiduria, micafungin administration was frequently associated with both short- and long-term urine sterilization. This was observed among patients with or without Foley removal and among those with Candida albicans, as well as non-albicans Candida spp.

Topics: Adult; Aged; Antifungal Agents; Candida; Candidiasis; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome; Urinary Tract Infections; Urine

High doses of micafungin are advocated in neonates with systemic candidiasis, but limited pharmacokinetic (PK) and safety data are available to support their use. Eighteen preterm neonates and infants with systemic candidiasis, three of whom had meningitis, were treated for at least 14 days with 8 to 15 mg/kg of body weight/day of intravenous micafungin. Plasma micafungin concentrations (four measurements for each patient) were determined after the third dose, and the cerebrospinal fluid (CSF) micafungin concentrations in three patients were also obtained. Population PK analyses were used to identify the optimal model, and the model was further validated using external data (n = 5). The safety of micafungin was assessed by measurement of the levels of liver and kidney function biomarkers. The mean age and weight at the initiation of treatment were 2.33 months (standard deviation [SD], 1.98 months) and 3.24 kg (SD, 1.61 kg), respectively. The optimal PK model was one that scaled plasma clearance to weight and the transaminase concentration ratio. The CSF of three patients was sampled, and the observed concentrations were between 0.80 and 1.80 mg/liter. The model-predicted mean micafungin area under the concentration-time curve over 24 h was 336 mg · h/liter (SD, 165 mg · h/liter) with the 10-mg/kg/day dosage. Eighteen of the 23 subjects (78.2%) had clinical resolution of their infection, but 5 had neurologic impairments. Among the transaminases, alkaline phosphatase measurements were significantly higher posttreatment, with a geometric mean ratio of 1.17 (90% confidence interval, 1.01, 1.37). Furthermore, marked elevations in the gamma-glutamyltransferase (GGT) level were observed in three patients treated with 10- to 15-mg/kg/day doses, and improvement of the GGT level was noted after a dose reduction. Higher weight-based doses of micafungin were generally well tolerated in neonates and infants and achieved pharmacokinetic profiles predictive of an effect.

Topics: Antifungal Agents; Candidiasis; Central Nervous System Diseases; Dose-Response Relationship, Drug; Echinocandins; Female; gamma-Glutamyltransferase; Humans; Infant; Infant, Newborn; Kidney; Lipopeptides; Liver; Male; Meningitis, Fungal; Micafungin

Micafungin and caspofungin, which are both echinocandins, elicit their antifungal effects by suppressing the synthesis of β-D-glucan, an essential component of fungal cell walls. If micafungin is not effective against a fungal infection, is it unreasonable to switch to caspofungin?. An 80-year-old Asian man presented to our hospital with brain and lung abscesses. Klebsiella pneumonia and Escherichia coli were identified by sputa culture and Streptococcus mitis was identified in the brain abscess culture obtained by drainage surgery. He was treated with antibiotics and both abscesses shrank after the treatment. But he continued to have a high fever and Candida glabrata was identified by blood culture. The origin of the infection was not clarified and micafungin was administered intravenously. The fungus showed poor susceptibility to micafungin; we then switched the antifungal from micafungin to caspofungin. After caspofungin treatment, his body temperature remained below 37 °C and his β-D-glucan levels decreased remarkably.. In vitro, micafungin is considered more effective against C. glabrata because its minimum inhibitory concentration against C. glabrata is lower than that of caspofungin. However, in vivo, there is no significantly different effect between the two drugs. When micafungin is not effective against candidiasis, a switch to caspofungin might be applicable because the pharmacokinetics in each echinocandin is slightly different.

Topics: Aged, 80 and over; Antifungal Agents; Brain Abscess; Candida glabrata; Candidiasis; Caspofungin; Echinocandins; Fever; Humans; Lipopeptides; Lung Abscess; Male; Micafungin; Treatment Outcome

The rising rates of invasive fungal infections caused by non-albicans Candida and the increasing emergence of antifungal resistance complicate the management of invasive candidiasis. Accurate and timely antifungal susceptibility testing is critical to targeting antifungal therapy. The purpose of this study was to compare commercially available susceptibility testing methods using prospectively collected Candida isolates. Susceptibility testing was performed on 74 Candida isolates collected from July 2014 to March 2015 using broth microdilution according to the Clinical and Laboratory Standards Institute method, Etest, Vitek 2 (YS-05) and Sensititre. Essential agreement and categorical agreement (CA) were assessed using the reference method. Of the 34 total blood isolates collected, Candida albicans comprised only 38 % (13) of the Candida spp. with Candidaglabrata being nearly as prevalent (29 %, 10). CA using Etest was 86 % for fluconazole, 72 % for caspofungin, 98 % for micafungin and 97 % for anidulafungin. Vitek 2 CA was 90 % for fluconazole and 98 % for caspofungin. Sensititre CA was 93 % for fluconazole, 98 % for caspofungin, 98 % for micafungin and 100 % for anidulafungin. Although our study tested a small population of Candida isolates, our results were variable by method. When implementing antifungal susceptibility testing, clinicians should be aware of the strengths and limitations of each testing method.

Topics: Anidulafungin; Antifungal Agents; Candida; Candida albicans; Candidiasis; Candidiasis, Invasive; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Respiratory System; Urine

Echinocandins are not active against basidiomycetous yeasts, such as Cryptococcus neoformans, Trichosporon, and Rhodotorula species, and zygomycosis. We present a patient with renal failure and candidemia, who developed a breakthrough fungal infection with cryptococcemia and cryptococcuria while receiving micafungin therapy.

Topics: Aged; Antifungal Agents; Candidiasis; Cryptococcosis; Cryptococcus neoformans; Echinocandins; Fungemia; Humans; Lipopeptides; Male; Micafungin; Renal Insufficiency

Mould-active antifungal prophylaxis is increasingly used in patients at risk for invasive fungal disease. Between June 2011 and June 2012, one hundred patients with various haematological malignancies at risk for invasive fungal disease received primary antifungal prophylaxis with intravenous micafungin at a daily dosage of 50 mg during neutropenia. The median number of days on micafungin prophylaxis was 14 (range, 6-48 d). The incidence of proven and probable breakthrough invasive fungal diseases (bIFDs) was 6% and 3%, respectively. There were two bloodstream infections caused by yeasts or yeast-like fungi (Candida krusei, Trichosporon asahii) in two patients during the neutropenic phase after allogeneic haematopoietic stem cell transplantation. Four proven bIFDs caused by non-Aspergillus moulds and three cases of probable pulmonary bIFDs were documented during the neutropenic phase after induction/consolidation chemotherapy for acute leukaemia. Colonisation with Candida spp. was documented in 51% of the patients with none of the isolates being in vitro micafungin resistant. Compared to a historical control, receiving primary prophylaxis with posaconazole micafungin is at least as effective in preventing IFD. In both cohorts, bIFDs were exclusively caused by emerging pathogens with a highly preserved in vitro sensitivity to amphotericin B.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Administration Schedule; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies; Transplantation, Homologous; Triazoles; Trichosporon; Trichosporonosis

Topics: Adolescent; Adult; Aged; Antifungal Agents; Bone Marrow Transplantation; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Hematologic Neoplasms; Humans; Lipopeptides; Male; Micafungin; Middle Aged

There are 2.1 billion people worldwide who are overweight or obese. However, most current doses of drugs were derived for normal weight patients. For several drugs, the relationship between clearance and patient weight follows fractal geometry rules. Clearance directly determines the area under the concentration time curve (AUC) after i.v. infusion. For micafungin, AUC-to-minimum inhibitory concentration (AUC/MIC) ratios have a close deterministic relationship with efficacy in candidiasis; an AUC/MIC ≥3,000 is associated with 98% efficacy. We performed computer-aided clinical trial simulations of 100,000 patients with candidiasis to identify the lowest micafungin dose able to achieve AUC/MIC ≥3,000 in patients weighing up to 200 kg. We used the cumulative fraction of response to derive the formula "Dose (mg) = patient weight + 42" for use by the clinician at the bedside to individualize micafungin doses for overweight and obese patients. This paradigm for dose individualization could be used to optimize efficacy for many classes of anti-infective agents in obese patients.

Topics: Antifungal Agents; Candidiasis; Clinical Trials as Topic; Computer Simulation; Drug Dosage Calculations; Echinocandins; Fractals; Humans; Lipopeptides; Micafungin; Obesity; Overweight; Patient-Specific Modeling

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

The echinocandins are recommended as first-line therapy for Candida species infections, but drug resistance, especially among Candida glabrata, is becoming more frequent. We investigated the antifungal susceptibility of anidulafungin, caspofungin, and micafungin against 584 isolates of Candida spp. (bloodstream, other sterile sites) collected from patients admitted to an Italian university hospital between 2000 and 2013. The susceptibility was evaluated using the broth microdilution method according to both the European Committee for Antimicrobial Susceptibility Testing (EUCAST EDef 7.2) and the Clinical Laboratory Standards Institute (CLSI M27-A3). The echinocandin susceptibilities were assessed on the basis of the species-specific clinical breakpoints proposed by the EUCAST version 6.1 and CLSI M27-S4 documents. The two methods were comparable by assessing essential agreement (EA), categorical agreement (CA), and Spearman's correlation analysis (rho, r).. The modal minimum inhibitory concentrations (MICs; μg ⋅ mL (-1)) values by both methods (EUCAST/CLSI) for anidulafungin, caspofungin, and micafungin for each species were, respectively, as follows: C. albicans, 0.03/0.12, 0.016/0.5, and 0.016/0.008; C. parapsilosis complex, 2/1, 2/2, and 2/1; C. tropicalis, 0.06/0.12, 0.06/0.12, and 0.06/0.12; C. glabrata complex, 0.03/0.25, 0.06/0.12, and 0.03/0.06; C. guilliermondii, 2/1, 2/2, and 2/2; and C. krusei, 0.06/0.12, 0.12/0.5, and 0.06/0.12. The overall resistance rates for EUCAST/CLSI were as follows: anidulafungin, 2.5/0.9%; caspofungin, breakpoint not available/3.8%; micafungin, 2.7/1.5%. Candida glabrata complex was the least susceptible to all three echinocandins, and the percentages of resistant isolates by EUCAST/CLSI were as follows: anidulafungin, 13.5/2.7%; caspofungin, breakpoint not available/16.2%; micafungin, 18.9/13.5%. The overall EA was 93 % for micafungin, 92% for anidulafungin, and 90% for caspofungin. The CA was >90% for all organism-drug combinations with the exception of C. glabrata and anidulafungin (89%). Spearman's rho for EUCAST/CLSI was 0.89 (p < 0.001) for caspofungin, 0.85 (p < 0.001) for anidulafungin, and 0.83 for micafungin (p < 0.001).. Independent of the procedure applied, no alarming resistance to the tested agents was found, although a reduced susceptibility was detected for C. glabrata complex. The EUCAST and CLSI methods produce similar MICs, indicating that using one method or the other should not result in susceptibilities different enough to affect treatment decisions.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Hospitals, University; Humans; Italy; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Colonization of patients occurs before development into invasive candidiasis. There is a need to determine the incidences of Candida colonization and infection in SICU patients, and evaluate the usefulness of beta-D-glucan (BDG) assay in diagnosing invasive candidiasis when patients are colonized.. Clinical data and fungal surveillance cultures in 28 patients were recorded from November 2010, and January to February 2011. Susceptibilities of Candida isolates to fluconazole, voriconazole, amphotericin B, micafungin, caspofungin and anidulafungin were tested via Etest. The utilities of BDG, Candida score and colonization index for candidiasis diagnosis were compared via ROC.. 30 BDG assays were performed in 28 patients. Four assay cases had concurrent colonization and infection; 23 had concurrent colonization and no infection; three had no concurrent colonization and infection. Of 136 surveillance swabs, 52 (38.24 %) were positive for Candida spp, with C. albicans being the commonest. Azole resistance was detected in C. albicans (7 %). C. glabrata and C. tropicalis were, respectively, 100 and 7 % SDD to fluconazole. All 3 tests showed high sensitivity of 75-100 % but poor specificity ranging 15.38-38.46 %. BDG performed the best (AUC of 0.89).. Despite that positive BDG is common in surgical patients with Candida spp colonization, BDG performed the best when compared to CI and CS.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Anidulafungin; Antifungal Agents; beta-Glucans; Candida; Candida albicans; Candida glabrata; Candidiasis; Candidiasis, Invasive; Carrier State; Caspofungin; Critical Care; Echinocandins; Female; Fluconazole; Humans; Incidence; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Sensitivity and Specificity; Singapore; Tertiary Care Centers; Voriconazole

Limited information about the pharmacokinetics of micafungin in the peritoneal cavity is available. The aim of this study was to explore the pharmacokinetics/pharmacodynamics of micafungin in plasma and peritoneal fluid in post-surgical critically ill patients with proven or suspected intra-abdominal fungal infection.. Patients were administered 100 mg/day micafungin. Serial blood and peritoneal fluid samples were collected on day 1 and day 3 (steady-state) of treatment. Concentrations were determined by validated chromatography and were subject to a population pharmacokinetic analysis with Pmetrics(®). Monte Carlo simulations were performed for AUC0-24/MIC ratios in plasma. The PTA was calculated using AUC0-24/MIC cut-offs: 285 for Candida parapsilosis and 3000 for non-parapsilosis Candida spp.. Ten patients were included; six were male. The median (range) age, APACHE II score and Mannheim peritonitis index were 72 (43-85) years, 15 (11-36) and 26 (8-37), respectively. On day 1, median (SD) penetration of micafungin into the peritoneal cavity was 30% (30%-40%). A three-compartment model adequately described the data. The mean (SD) estimates for clearance and volume of distribution of the central compartment were 1.27 (0.75) L/h and 9.26 (1.11) L, respectively. In most patients, the PTA in plasma was ≥ 90% for MICs of 0.008-0.016 mg/L for Candida spp. and 0.125-0.25 mg/L for C. parapsilosis.. After the first dose, micafungin at 100 mg/day achieves pharmacokinetic/pharmacodynamic targets in plasma for Candida spp. and C. parapsilosis MICs of 0.008-0.016 and 0.125-0.25 mg/L, respectively.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Ascitic Fluid; Candidiasis; Critical Illness; Drug Monitoring; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Peritonitis; Plasma; Postoperative Complications; Prospective Studies; Time Factors

Precise FKS mutation rates among Candida species are undefined because studies have not systematically screened consecutive, disease-causing isolates. The Sensititre YeastOne (SYO) assay measures echinocandin MICs against Candida with less variability than reference broth microdilution methods. However, clinical breakpoint MICs may overstate caspofungin nonsusceptibility compared to other agents. Our objectives were to determine Candida FKS mutation rates by studying consecutive bloodstream isolates and to determine if discrepant susceptibility results were associated with FKS mutations. FKS hot spots were sequenced in echinocandin-intermediate and -resistant isolates and those from patients with breakthrough candidemia or ≥ 3 days of prior echinocandin exposure. Overall, 453 isolates from 384 patients underwent susceptibility testing; 16% were echinocandin intermediate or resistant. Intermediate susceptibility rates were higher for Candida glabrata than for other species (P < 0.0001) and higher for caspofungin than for other agents (P < 0.0001). Resistance rates were similar between agents. FKS mutations were detected in 5% of sequenced isolates and 2% of isolates overall. Corresponding rates among C. glabrata isolates were 8% and 4%, respectively. Among Candida albicans isolates, rates were 5% and <1%, respectively. Mutations occurred exclusively with prior echinocandin exposure and were not detected in other species. Isolates with discrepant susceptibility results did not harbor FKS mutations. Mutation rates among isolates resistant to ≥ 2, 1, and 0 agents were 75%, 13%, and 0%, respectively. In conclusion, FKS mutations were uncommon among non-C. glabrata species, even with prior echinocandin exposure. Discrepancies in echinocandin susceptibility by SYO testing were not driven by mutations and likely reflect imprecise caspofungin clinical breakpoints.

Topics: Antifungal Agents; Candida; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation Rate

Echinocandins are N-acyl-substituted cyclic hexapeptides with potent in vitro and in vivo activity against Candida species that are used for primary treatment and prevention of candidemia and invasive candidiasis. Recent progress in the translational research of echinocandins has led to new approaches for treatment of central venous catheter Candida biofilms. Other studies have laid the experimental and clinical foundation for use of extended dosing intervals for administration of echinocandins in treatment and prevention of candidemia and invasive candidiasis.

Topics: Antifungal Agents; Biofilms; Candida; Candidemia; Candidiasis; Candidiasis, Invasive; Caspofungin; Catheter-Related Infections; Echinocandins; Humans; Lipopeptides; Micafungin; Translational Research, Biomedical

Candida biofilm-associated infections of central venous catheters are a challenging therapeutic problem. Recent in vitro and in vivo studies of the structure, formation, pathogenesis, and treatment establish a rationale for new approaches to management of these tenacious infections.

Topics: Anidulafungin; Animals; Antifungal Agents; Biofilms; Candida; Candidiasis; Caspofungin; Catheter-Related Infections; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Vascular Access Devices

Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.

Topics: Anidulafungin; Antifungal Agents; Azoles; Candida; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Echinocandins; Glucosyltransferases; Humans; Intraabdominal Infections; Lipopeptides; Micafungin; Mutation

The current standard of treatment of invasive candidiasis with echinocandins requires once-daily therapy. To improve quality of life, reduce costs, and improve outcome, we studied the pharmacokinetics (PK), efficacy, and safety of alternate dosing regimens of micafungin (MFG) for the treatment of experimental subacute disseminated candidiasis.. MFG was administered for 12 days starting 24 hours after intravenous inoculation of 1 × 10(3) Candida albicans blastoconidia. Study groups consisted of MFG at 1 mg/kg every 24 hours (MFG1), 2 mg/kg every 48 hours (MFG2), and 3 mg/kg every 72 hours (MFG3), and untreated controls. PK of MFG were determined on day 7 by high-performance liquid chromatography and modeled using nonparametric adaptive grid program. A 2-compartment PK model with volume of the central compartment (Vc), clearance (SCL), and the intercompartmental rate constants Kcp and Kpc was used. The fungal burden in 7 tissues was determined 312 hours after the initiation of therapy.. PK of MFG were linear and the parameter means ± SD were Vc = 0.41 ± 0.18 L, Kcp = 2.80 ± 1.55/hour, Kpc = 1.71 ± 0.93/hour, and SCL = 0.16 ± 0.003 L/hour (r(2) = 0.99). The area under the plasma drug concentration - time curve for MFG1, MFG2, and MFG3 was 198.7 ± 19.8, 166.3 ± 36.7, and 192.8 ± 46.2 mg × hour/L, respectively (P = .24). All treatment groups showed significant and comparable resolution of (1→3)-β-D-glucan levels and clearance of C. albicans from liver, spleen, kidney, brain, lung, vitreous humor, and vena cava in comparison to untreated controls (P ≤ .05). There were no differences in hepatic or renal function among study groups.. Less fractionated MFG regimens of every 48 and 72 hours are safe and as effective in experimental disseminated candidiasis as once-daily therapy in neutropenic hosts.

Topics: Animals; Antifungal Agents; beta-Glucans; Candida albicans; Candidiasis; Candidiasis, Invasive; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Echinocandins; Female; Lipopeptides; Micafungin; Neutropenia; Proteoglycans; Rabbits

We present the rare case of a 76-year-old female with infective endocarditis (IE) caused by Candida glabrata. Immediately before developing the present infection, she developed IE with vegetation on the mitral annular calcification, which was caused by Streptococcus mitis and successfully treated with penicillin-G and gentamicin. However, her fever recurred, and she developed disseminated intravascular coagulation. Blood culture revealed C. glabrata, and echocardiography revealed new vegetation on the mitral valve. After 4 weeks of treatment with micafungin, prosthetic valve replacement was performed, followed by additional administration of micafungin for 4 weeks (total of 8 weeks). No relapse at 9 months after surgery has been observed. C. glabrata endocarditis is extremely rare and difficult to manage. Our case and review of past reported cases suggest that early diagnosis and initiation of treatment contribute to good prognosis of C. glabrata endocarditis.

Topics: Aged; Anti-Bacterial Agents; Antifungal Agents; Candida glabrata; Candidiasis; Early Diagnosis; Echinocandins; Echocardiography; Endocarditis, Subacute Bacterial; Female; Gentamicins; Heart Valve Prosthesis; Humans; Lipopeptides; Micafungin; Penicillin G; Streptococcus mitis

Since epidemiological cutoff values (ECVs) using CLSI MICs from multiple laboratories are not available for Candida spp. and the echinocandins, we established ECVs for anidulafungin and micafungin on the basis of wild-type (WT) MIC distributions (for organisms in a species-drug combination with no detectable acquired resistance mechanisms) for 8,210 Candida albicans, 3,102 C. glabrata, 3,976 C. parapsilosis, 2,042 C. tropicalis, 617 C. krusei, 258 C. lusitaniae, 234 C. guilliermondii, and 131 C. dubliniensis isolates. CLSI broth microdilution MIC data gathered from 15 different laboratories in Canada, Europe, Mexico, Peru, and the United States were aggregated to statistically define ECVs. ECVs encompassing 97.5% of the statistically modeled population for anidulafungin and micafungin were, respectively, 0.12 and 0.03 μg/ml for C. albicans, 0.12 and 0.03 μg/ml for C. glabrata, 8 and 4 μg/ml for C. parapsilosis, 0.12 and 0.06 μg/ml for C. tropicalis, 0.25 and 0.25 μg/ml for C. krusei, 1 and 0.5 μg/ml for C. lusitaniae, 8 and 2 μg/ml for C. guilliermondii, and 0.12 and 0.12 μg/ml for C. dubliniensis. Previously reported single and multicenter ECVs defined in the present study were quite similar or within 1 2-fold dilution of each other. For a collection of 230 WT isolates (no fks mutations) and 51 isolates with fks mutations, the species-specific ECVs for anidulafungin and micafungin correctly classified 47 (92.2%) and 51 (100%) of the fks mutants, respectively, as non-WT strains. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin and micafungin due to fks mutations.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Echinocandins; Europe; Fungal Proteins; Gene Expression; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation; North America; South America

Micafungin (MCF) is an antifungal agent of the echinocandin class approved in Europe both in adults and in children for the treatment of invasive candidiasis. Few analytical methods for therapeutic drug monitoring (TDM) of this drug have been described so far. In this paper, we describe a rapid and validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the measurement of MCF in plasma. MCF was analyzed in 100-μL plasma samples over a wide range of concentrations (0.1-20 μg/mL) by LC-MS/MS after protein precipitation. The suitability of the assay for TDM was evaluated by using plasma samples from pediatric patients who received MCF for the treatment of invasive candidiasis. The overall turnaround time for the assay was 20 min. The lower limit of quantification of the method was 0.1 ng/mL. No ion suppression due to matrix effects was found with different pre-analytical conditions, such as hemolysis, lipemia, and hyperuricemia. A simple and rapid LC-MS/MS method which provides high specificity, precision, and accuracy for quantification of MCF in plasma has been developed and validated.

Topics: Antifungal Agents; Candidiasis; Child; Chromatography, Liquid; Drug Monitoring; Echinocandins; Humans; Limit of Detection; Lipopeptides; Micafungin; Reproducibility of Results; Tandem Mass Spectrometry; Time Factors

Candida tropicalis, a species closely related to Candida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. Like C. albicans and Candida dubliniensis, C. tropicalis is able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear in C. tropicalis. Recently, echinocandin- and azole-resistant C. tropicalis isolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of the C. tropicalis genes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis in C. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions in C. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance in C. tropicalis.

Topics: Animals; Antifungal Agents; Calcineurin; Candida tropicalis; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Hyphae; Lipopeptides; Micafungin; Mice; Transcription Factors; Virulence

Echinocandin-resistant clinical isolates of Candida albicans have been reported, and key-hot spot mutations in the FKS1 gene, which encodes a major glucan synthase subunit, have been identified in these (caspofungin-resistant [CAS-R]) strains. Although these mutations result in phenotypic resistance to echinocandins in planktonic cells, there is little data on antifungal susceptibilities of CAS-R C. albicans strains within biofilms. Thus, we analyzed biofilms formed by 12 C. albicans CAS-R clinical strains in which we previously identified FKS1 hot-spot mutations and compared the sessile antifungal and paradoxical activity of anidulafungin (ANID), caspofungin (CAS), and micafungin (MICA). Biofilms were formed in a 96-well static microplate model and assayed using both tetrazolium-salt reduction and crystal violet assays, as well as examination by scanning electron microscopy. We first sought to assess biofilm formation and structure in these fks1 mutants and found that the biofilm mass and metabolic activities were reduced in most of the fks1 mutants as compared with reference strain SC5314. Structural analyses revealed that the fks1 mutant biofilms were generally less dense and had a clear predominance of yeast and pseudohyphae, with unusual "pit"-like cell surface structures. We also noted that sessile minimum inhibitory concentrations (MICs) to ANID, CAS, and MICA were higher than planktonic MICs of all but one strain. The majority of strains demonstrated a paradoxical effect (PE) to particular echinocandins, in either planktonic or sessile forms. Overall, biofilms formed by echinocandin-resistant clinical isolates demonstrated varied PEs to echinocandins and were structurally characterized by a preponderance of yeast, pseudohyphae, and pit-like structures.

Topics: Anidulafungin; Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Caspofungin; Echinocandins; Glucosyltransferases; Humans; Lipopeptides; Membrane Proteins; Micafungin; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron; Mutant Proteins; Staining and Labeling

To report a case of a woman in whom alopecia appeared after several months of treatment with anidulafungin.. A 34-year-old woman with chronic femoral osteomyelitis with the presence of persistent suppuration, developed a Candida albicans infection, isolated in the fistula exudate cultures. After initial failures of single therapy with azoles, it was decided to administer fluconazole and anidulafungin 100 mg/d. One month after starting the treatment, the patient mentioned a greater hair loss than usual. At 3 months, the patient stopped taking the drug on noting the loss and easy falling out of her hair, with alopecia plaques 1 to 2 cm in size. At 2 months after stopping the anidulafungin, it was decided to restart combined antifungal treatment using micafungin and fluconazole; there was no mention of new or greater loss of hair. It was decided to change micafungin to anidulafungin again 90 days after starting treatment. In the first month of treatment, there appeared to be a reactivation in hair loss that later stabilized and improved.. Drug-induced hair loss is an adverse reaction that has been identified during different hair growth phases. It has been described for the azoles group and has not been associated with candins until now. Results of the causality analysis, using the probability scale established by Naranjo, found the relationship as probable.. Anidulafungin could be associated with hair loss. Physicians must be aware of this adverse effect in order to approach it properly and to detect possible nonadherence to treatment.

Topics: Adult; Alopecia; Anidulafungin; Antifungal Agents; Candidiasis; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Humans; Lipopeptides; Micafungin

The response rate among 58 patients with cancer and candidemia or deep-seated candidiasis treated with micafungin monotherapy was 81%. Intensive care unit (ICU) stay, concomitant nonfungal infections, and acute kidney injury were significantly associated with the 30-day crude mortality rate. Severe neutropenia was an independent predictor of micafungin failure. The efficacy and safety of micafungin in cancer patients with invasive candidiasis were comparable to those reported for patients without malignancy and for cancer patients treated with caspofungin.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidemia; Candidiasis; Candidiasis, Invasive; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Neoplasms; Neutropenia; Young Adult

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

Echinocandins are recommended for Candia glabrata candidemia. Mutations in the FKS1 and FKS2 genes are associated with echinocandin resistance. Few studies have assessed risk factors for FKS mutant isolates and outcomes in patients receiving micafungin treatment.. Patients with C. glabrata bloodstream infection admitted to a large, tertiary care hospital between 2009 and 2012 were included in this study. For each isolate, FKS1 and FKS2 genes were sequenced to identify mutations. Risk factors for FKS mutations and treatment outcomes in patients receiving an echinocandin were assessed using multivariate logistic regression.. Seventy-two patients were included in the study of which 13 (18%) had an FKS mutant isolate. The only significant predictor for FKS mutations was prior echinocandin exposure (odds ratio [OR], 19.9; 95% confidence interval [CI], 4.7-84.7; P ≤ .01). Treatment failure occurred in 17 (30%) of 57 patients who received an echinocandin and was more common in patients with FKS mutants (6 of 10; 60%) compared with non-FKS mutants (11 of 47; 23%). Underlying gastrointestinal disorder (OR, 4.7; 95% CI, 1.1-20.9; P = .04) and prior echinocandin exposure (OR, 8.3; 95% CI, 1.7-40.4; P ≤ .01) were independent predictors of echinocandin treatment failure. Treatment response and echinocandin minimum inhibitory concentrations varied among specific FKS mutations.. FKS mutations were identified in 18% of 72 patients with C. glabrata candidemia. Common risk factors for FKS mutant isolates included previous echinocandin exposure, which also influenced response rates.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidemia; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Mutation; Patient Outcome Assessment; Prognosis; Risk Factors; Treatment Failure; Treatment Outcome; Young Adult

Currently available therapies for candidiasis are based on antifungal drugs belonging to azole and echinocandin families that interfere with different aspects of fungal metabolism. These drugs, beyond their specific effects, elicit also a cellular stress including an unbalance of redox state that is counteracted not only utilizing antioxidant species but also increasing the outcome export by transporters to detoxify the internal environment. These cellular actions are both based on the cytosolic concentration of reduced glutathione (GSH). In this paper we investigated the effects of two antifungal drugs fluconazole and micafungin on the redox state of the cell in C. albicans to understand if the resistance to these drugs is accompanied by variation of glutathione metabolism. Analyses of resistant strains showed a marked difference in glutathione contents in strains resistant to fluconazole (CO23RFLC) or micafungin (CO23RFK). In CO23RFLC, the total amount of glutathione was more than doubled with respect to CO23RFK thanks to the increased activity of γ-glutamilcysteine synthetase, the key enzyme involved in GSH synthesis. We demonstrated that the GSH increase in CO23RFLC conferred to this strain a clear advantage in counteracting oxidative toxic agents while assignment of other roles, such as a more efficient elimination of the drug from the cell, should be considered more speculative. As far as MCFG resistance is concerned, from our data a role of glutathione metabolism in supporting this condition is not evident. Overall our data indicate that glutathione metabolism is differently affected in the two resistant strains and that glutathione system may play an important role in the global organization of C.albicans cells for resistance to fluconazole. Such scenario may pave the way to hypothesize the use of oxidant drugs or inhibitors able to deplete reduced glutathione level as a novel approach, for counteracting the resistance to this specific antifungal drug.

Topics: Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Glutathione; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Oxidation-Reduction

We report the case of a 31-week gestational age neonate with Candida albicans sepsis and a hepatic abscess. Diagnosis relied on clinical and radiological signs of sepsis, liver function impairment and culture isolation of Candida spp. from sterile sites. Liver ultrasound documented the presence of a multiloculated abscess. Treatment with micafungin (3 mg/kg/day) resulted in normalization of liver function and inflammatory laboratory values and improvement of clinical condition. After 30 days of treatment, the liver abscess resolved and at the 8-month follow up the infant is doing well. Prompt diagnosis and antifungal treatment avoided surgical drainage and liver surgery in this high-risk neonate.

Topics: Antifungal Agents; Candidiasis; Echinocandins; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Liver; Liver Abscess; Male; Micafungin; Treatment Outcome; Ultrasonography

Endocarditis caused by Candida dubliniensis is a rare event and limited to few case reports. In this report, the authors present a patient with a history of intravenous drug use and hepatitis C and endocarditis involving a prosthetic aortic valve. Also reviewed are the treatment guidelines for Candida sp. endocarditis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Echinocandins; Endocarditis; Fluconazole; Humans; Lipopeptides; Male; Micafungin; Middle Aged

We compared the ability of the EUCAST EDef 7.2 and the Etest to detect the susceptibility to micafungin of 160 Candida and non-Candida clinical isolates. Agreement was higher when Etest MICs were obtained after 24 h of incubation; essential agreement was 90%, and categorical agreement was >90%. False susceptibility was seen only for Candida krusei (10%), and false resistance was observed in 6% of the isolates, ranging from 2.6% (C. glabrata) to 13% (C. albicans).

Topics: Antifungal Agents; Artifacts; Candida; Candidiasis; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified.. The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article.. In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY.. De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.

Topics: Antifungal Agents; Candidiasis; Cost-Benefit Analysis; Decision Support Techniques; Echinocandins; Fluconazole; Health Services; Humans; Life Expectancy; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Quality-Adjusted Life Years

Although Clinical and Laboratory Standards Institute (CLSI) clinical breakpoints (CBPs) are available for interpreting echinocandin MICs for Candida spp., epidemiologic cutoff values (ECVs) based on collective MIC data from multiple laboratories have not been defined. While collating CLSI caspofungin MICs for 145 to 11,550 Candida isolates from 17 laboratories (Brazil, Canada, Europe, Mexico, Peru, and the United States), we observed an extraordinary amount of modal variability (wide ranges) among laboratories as well as truncated and bimodal MIC distributions. The species-specific modes across different laboratories ranged from 0.016 to 0.5 μg/ml for C. albicans and C. tropicalis, 0.031 to 0.5 μg/ml for C. glabrata, and 0.063 to 1 μg/ml for C. krusei. Variability was also similar among MIC distributions for C. dubliniensis and C. lusitaniae. The exceptions were C. parapsilosis and C. guilliermondii MIC distributions, where most modes were within one 2-fold dilution of each other. These findings were consistent with available data from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (403 to 2,556 MICs) for C. albicans, C. glabrata, C. krusei, and C. tropicalis. Although many factors (caspofungin powder source, stock solution solvent, powder storage time length and temperature, and MIC determination testing parameters) were examined as a potential cause of such unprecedented variability, a single specific cause was not identified. Therefore, it seems highly likely that the use of the CLSI species-specific caspofungin CBPs could lead to reporting an excessive number of wild-type (WT) isolates (e.g., C. glabrata and C. krusei) as either non-WT or resistant isolates. Until this problem is resolved, routine testing or reporting of CLSI caspofungin MICs for Candida is not recommended; micafungin or anidulafungin data could be used instead.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Europe; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; North America; Observer Variation; South America; Species Specificity

By CLSI interpretive criteria, anidulafungin and micafungin MICs determined by various methods were sensitive (60 to 70%) and highly specific (94 to 100%) for identifying FKS mutations among 120 Candida glabrata isolates. Anidulafungin and micafungin breakpoints were more specific than CLSI's caspofungin breakpoint in identifying FKS mutant strains and patients with invasive candidiasis who were likely to fail echinocandin treatment (P ≤ 0.0001 for both). Echinocandin MICs were most useful clinically when interpreted in the context of prior echinocandin exposure.

Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Echinocandins are commonly used as initial empiric therapy in cases of moderate to severe invasive candidiasis. The authors demonstrate that caution should be exercised in applying this approach in certain clinical situations. A case of Candida glabrata fungemia and associated chorioretinitis that was clinically resistant to therapy with micafungin but appeared to resolve with amphotericin B is presented. The authors then briefly review current issues regarding the diagnosis and treatment of C glabrata chorioretinitis.

Topics: Aged; Antifungal Agents; Candida glabrata; Candidiasis; Chorioretinitis; Drug Resistance, Fungal; Echinocandins; Female; Humans; Lipopeptides; Micafungin; Treatment Failure

Topics: Aged; Antifungal Agents; Arthritis, Rheumatoid; Candida albicans; Candidiasis; Diabetes Complications; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Humans; Immunosuppressive Agents; Joint Prosthesis; Lipopeptides; Micafungin; Prosthesis-Related Infections; Shoulder Joint

The aim of this study was to compare the in vitro and in vivo activities of micafungin, caspofungin, and anidulafungin against Candida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against a C. glabrata-susceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains of C. glabrata were selected: C. glabrata 30, a laboratory strain harboring the mutation Fks2p-P667T, and C. glabrata 51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs. In vivo studies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached.

Topics: Anidulafungin; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins; Female; Humans; Lipopeptides; Micafungin; Mice; Microbial Sensitivity Tests; Mutation

We recently observed that the micafungin MICs for some Candida glabrata fks hot spot mutant isolates are less elevated than those for the other echinocandins, suggesting that the efficacy of micafungin may be differentially dependent on such mutations. Three clinical C. glabrata isolates with or without (S3) fks hot spot mutations R83 (Fks2p-S663F) and RR24 (Fks1p-S629P) and low, medium, and high echinocandin MICs, respectively, were evaluated to assess the in vivo efficacy in an immunocompetent mouse model using three doses of each echinocandin. Drug concentrations were determined in plasma and kidneys by high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic mathematical model was used to define the area under the concentration-time curve (AUC) that produced half- and near-maximal activity. Micafungin was equally efficacious against the S3 and R83 isolates. The estimates for the AUCs of each echinocandin that induced half-maximal effect (E(50)s) were 194.2 and 53.99 mg · h/liter, respectively. In contrast, the maximum effect (E(max)) for caspofungin was higher against S3 than R83, but the estimates for E(50) were similar (187.1 and 203.5 mg · h/liter, respectively). Anidulafungin failed to induce a ≥1-log reduction for any of the isolates (AUC range, 139 to 557 mg · h/liter). None of the echinocandins were efficacious in mice challenged with the RR24 isolate despite lower virulence (reduced maximal growth, prolonged lag phase, and lower kidney burden). The AUC associated with half-maximal effect was higher than the average human exposure for all drug-dose-bug combinations except micafungin and the R83 isolate. In conclusion, differences in micafungin MICs are associated with differential antifungal activities in the animal model. This study may have implications for clinical practice and echinocandin breakpoint determination, and further studies are warranted.

Topics: Anidulafungin; Animals; Antifungal Agents; Area Under Curve; Biological Availability; Candida glabrata; Candidiasis; Caspofungin; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Resistance, Fungal; Echinocandins; Genes, Fungal; Glucosyltransferases; Humans; Kidney; Lipopeptides; Micafungin; Mice; Microbial Sensitivity Tests; Mutation

We report findings for a 74-year-old woman with Candida tropicalis endophthalmitis for whom an increase in b-D-glucan level and worsening of endophthalmitis were observed after intravenous injection of micafungin, an echinocandin antifungal agent. Endogenous endophthalmitis caused by C. tropicalis developed in both eyes. On the basis of her surgical history, laboratory data,and lesions, tentative diagnosis of fungal endophthalmitis was made. She was then treated with fluconazole and itraconazole, but the b-D-glucan level did not decrease, and there was no improvement of the endophthalmitis. The fluconazole was discontinued and replaced by micafungin.Unexpectedly, the level of b-D-glucan increased and endophthalmitis did not improve. The micafungin was immediately stopped and replaced by intravenous fluconazole with amphotericin B syrup, but the itraconazole was continued. Marked resolution of the vitreous inflammation was observed in both eyes, and the serum b-D-glucan level was reduced. Because active macular infiltrates were observed in the right eye, vitrectomy was performed. The micafungin minimum inhibitory concentration against the C. tropicalis strain isolated from our patient was 0.03 lg/ml. This paradoxical effect of micafungin should be remembered, and b-D-glucan level should be frequently monitored after intravenous injection of micafungin.

Topics: Aged; Antifungal Agents; beta-Glucans; Candida tropicalis; Candidiasis; Echinocandins; Endophthalmitis; Female; Fundus Oculi; Humans; Itraconazole; Lipopeptides; Micafungin

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

To investigate the correlation between in vitro killing activity and in vivo efficacy of micafungin (MCFG) and liposomal amphotericin B (L-AMB) against Candida tropicalis in a neutropenic murine lethal infection model.. Candida albicans (one strain) and C. tropicalis (three strains) were tested in time-kill studies. Cyclophosphamide-treated mice were inoculated intravenously with each strain. One day after inoculation, antifungals were administered intravenously once daily for 1 or 3 days.. MCFG exhibited fungicidal activity against C. albicans ATCC 90029 and C. tropicalis SP-20142, and fungistatic activity against C. tropicalis ATCC 42678 and SP-20047. The ED(50)s (dosage that results in 50% survival) of MCFG for C. tropicalis ATCC 42678 and SP-20047 (4.1-50 mg/kg) were higher than those for other strains (1.6-12 mg/kg). A 1-day course of MCFG was not effective against C. tropicalis ATCC 42678 and SP-20047 at the clinical dose (5 mg/kg), which achieved an AUC level almost equal to that of 100 mg in humans, whereas a 3-day course of 5 mg/kg MCFG was efficacious against all strains. In contrast, L-AMB showed fungicidal activity against all strains tested and the ED(50)s of L-AMB were 0.08-0.65 mg/kg. In both treatment regimens, the minimum effective doses of L-AMB (≤0.5 mg/kg) were less than the clinical dosage (≤5 mg/kg).. The in vivo efficacy of MCFG and L-AMB showed a correlation with the in vitro killing activity. At the clinical dose, L-AMB exerted anti-C. tropicalis activity within a shorter treatment period than MCFG.

Topics: Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Candida tropicalis; Candidiasis; Disease Models, Animal; Echinocandins; Lipopeptides; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia

The results of a 3-year experience with voriconasole in oncologic practice are presented. Rational schemes for the use of caspofungin and mycofungin in the treatment of oncologic inpatients and the criteria of their use in the therapy of fungal nosocomial infections were developmed. Good clinical and microbiological efficacy of caspofungin and mycofungin against Candida non-albicans was shown.

Topics: Aged; Antifungal Agents; Candida; Candidiasis; Caspofungin; Cross Infection; Drug Resistance, Fungal; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Neoplasms

We evaluated species distribution and antifungal susceptibility of Candida isolates during 2002-2008. Of 177 Candida isolates from blood, species distribution was 90 (51%) Candida albicans, 30 (17%) C. parapsilosis, 22 (12%) C. glabrata, 6 (3%) C. tropicalis and 29 (16%) other Candida spp.. Of 162 Candida isolates from vascular catheter, species distribution was 87 (54%) C. albicans, 14 (9%) C. parapsilosis, 36 (22%) C. glabrata, 5 (3%), C. tropicalis, 2 (1%) C. krusei and 18 (11%) other Candida spp.. Of 1889 Candida isolates from urine, species distribution was 1165 (62%) C. albicans, 22 (1%) C. parapsilosis, 484 (26%) C. glabrata, 83 (4%) C. tropicalis, 26 (1%) C. krusei and 109 (6%) other Candida spp.. Of 782 Candida isolates from stool, species distribution was 425 (54%) C. albicans, 3 (1%) C. parapsilosis, 103 (13%) C. glabrata, 28 (4%) C. tropicalis, 5 (1%), C. krusei and 218 (28%) other Candida spp. Both C. albicans and non-Candida spp. isolated from urine increased slightly over the past 7 years. Flucytosine, fluconazole, itraconazole and micafungin still have strong activity against Candida isolates.

Topics: Antifungal Agents; Candida; Candidiasis; Diagnosis, Differential; Echinocandins; Feces; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Vascular Access Devices

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

To compare and evaluate the efficacy of topical 0.1% micafungin (MCFG) and topical 0.2% fluconazole (FCZ) in the treatment of Candida fungal keratitis.. Twenty-nine eyes of 29 patients who were diagnosed as having Candida fungal keratitis, proven by corneal culture isolates, were investigated in this prospective study. Patients were divided into a MCFG treatment group (12 eyes) and an FCZ treatment group (17 eyes). Age, gender, initial status of ulcer (ulcer size and degree of injection), initial and final best-corrected visual acuity (BCVA), healing periods, final status of cornea and recurrences in each group were studied and compared.. There were no significant differences in relation to age, gender, ulcer size and degree of injection before treatment between the two groups. There were also no significant differences in the healing periods until complete epithelialisation (MCFG treatment group (41.3 ± 38.0 days); FCZ treatment group (34.4 ± 37.7 days)), change in BCVA, corneal clarity/opacification, perforation and recurrence status at the final examination between the two groups.. The efficacy of 0.1% MCFG eye-drops appears to be comparable with that of 0.2% FCZ eye-drops in the treatment of Candida fungal keratitis.

Topics: Administration, Topical; Aged; Antifungal Agents; Candida; Candidiasis; Cornea; Corneal Ulcer; Echinocandins; Eye Infections, Fungal; Female; Fluconazole; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Ophthalmic Solutions; Prospective Studies; Treatment Outcome; Visual Acuity

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

The CLSI clinical breakpoint (CBP) for echinocandin susceptibility (S; MICs of ≤ 2 μg/ml) may classify isolates with acquired resistance (R) mutations as susceptible. Epidemiological cutoff values (ECVs) have been established to distinguish wild-type (WT) Candida strains from those that may exhibit R mutations. The CLSI-developed ECVs for anidulafungin, caspofungin, and micafungin were applied to 15,269 isolates of Candida spp. collected from over 100 centers worldwide between 2001 and 2009 to determine the frequency of non-WT strains of each species. The collection included 8,378 isolates of Candida albicans, 2,352 isolates of C. glabrata, 2,195 isolates of C. parapsilosis, 1,841 isolates of C. tropicalis, and 503 isolates of C. krusei. The mean percentages of non-WT isolates per year for anidulafungin, caspofungin, and micafungin, respectively, were as follows: for C. albicans, 0.3, 0.1, and 2.1; for C. glabrata, 0.8, 1.3, and 1.6; for C. parapsilosis, 0.0, 1.5, and 0.5; for C. tropicalis, 0.9, 0.7, and 0.9; and for C. krusei, 0.5, 6.4, and 3.5. We noted increases in the percentage of non-WT isolates, from 0.5% (2001) to 3.1% (2009) for caspofungin and C. parapsilosis, from 0.4% (2004) to 1.8% (2009) for anidulafungin and C. glabrata, from 2.4% (2004) to 5.7% (2009) for micafungin and C. krusei, and from 0.0% (2004) to 3.1% (2009) for micafungin and C. parapsilosis. No trends were noted for any species and drug when we used the CBP. Echinocandin CBPs are insensitive for detecting emerging R. Although uncommon, decreased S among Candida isolates was observed for each of the echinocandins and varied by species. Using ECVs is important in determining R trends among echinocandins and Candida.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Topics: Antifungal Agents; Candidemia; Candidiasis; Clinical Trials, Phase III as Topic; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Randomized Controlled Trials as Topic

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

The clinical utility of the echinocandins is potentially compromised by the emergence of drug resistance. We investigated whether Candida albicans with amino acid substitutions at position Ser645 in Fks1 can be treated with either a conventional or an elevated dosage of micafungin. We studied Candida albicans (wild-type SC5314; MIC, 0.06 mg/liter) and four fks1 mutants (one FKS1/fks1 heterozygote mutant [MIC, 0.5 mg/liter] and three fks1/fks1 homozygous mutants [MICs for all, 2 mg/liter]) with a variety of amino acid substitutions at Ser645. The pharmacokinetic and pharmacodynamic relationships were characterized in a persistently neutropenic murine model of disseminated candidiasis. A mathematical model was fitted to all pharmacokinetic and pharmacodynamic data. This mathematical model was then used to "humanize" the murine pharmacokinetics, and the predicted antifungal effect was determined. The estimated maximal rate of growth and ultimate fungal densities in the kidney for each of the strains were similar. The administration of micafungin at 1 mg/kg of body weight to the wild type resulted in moderate antifungal activity, whereas the administration of 5 and 20 mg/kg resulted in rapid fungicidal activity. In contrast, the FKS1/fks heterozygote was killed only with 20 mg/kg, and the homozygous fks1 mutants failed to respond to any dosage. The bridging study revealed that human dosages of 100 and 400 mg/day were active only against the wild type, with no activity against either the heterozygote or the homozygote mutants. Ser645 Fks1 Candida albicans mutants cannot be treated with either conventional or elevated dosages of micafungin and should be deemed resistant.

Topics: Amino Acid Substitution; Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Genotype; Humans; Lipopeptides; Male; Micafungin; Mice; Microbial Sensitivity Tests

The susceptibilities of Candida isolates to the echinocandins anidulafungin, caspofungin, and micafungin were determined by using the recently revised CLSI breakpoints and Etest on 238 clinical bloodstream Candida isolates collected between September 2005 and August 2006. The isolates represent approximately 95% of all non-albicans Candida bloodstream infections and one-third of Candida albicans bloodstream infections during this 1-year period in Sweden. The collection included 81 C. albicans, 81 C. glabrata, 36 C. parapsilosis, 14 C. dubliniensis, 8 C. tropicalis, 8 C. lusitaniae, 5 C. krusei, 2 C. guilliermondii and 2 C. inconspicua isolates as well as 1 C. pelliculosa isolate. The MICs were largely consistent with the global epidemiology of bloodstream Candida isolates. All C. albicans and C. glabrata isolates were susceptible to all 3 echinocandins (MIC ≤ 0.016 μg/ml in all instances). Resistance (MIC ≥ 8 μg/ml) to anidulafungin alone was observed for 4 (11.1%) C. parapsilosis isolates and for 1/2 C. guilliermondii isolates. Intermediate susceptibility to caspofungin alone was observed for 2/5 C. krusei isolates. One of the eight C. tropicalis isolates was classified as being intermediately susceptible to micafungin (MIC, 0.5 μg/ml) and as being resistant to anidulafungin and caspofungin (MIC ≥ 1 μg/ml). This isolate harbored a heterozygous FKS1 hot spot mutation (S80P) known to confer echinocandin resistance. This first study to apply the revised CLSI breakpoints for Etest endpoints showed that the breakpoints worked successfully in detecting an isolate with a hot spot mutation. Acquired echinocandin resistance is rare in Sweden. Echinocandin MICs against C. parapsilosis and C. guilliermondii were lowest for micafungin.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Fungal Proteins; Fungemia; Glucosyltransferases; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation, Missense; Sweden

To investigate the penetration of micafungin, a new class of echinocandin antifungal agent, into the aqueous humor and vitreous after an intravenous administration.. Endogenous endophthalmitis caused by Candida albicans developed bilaterally in a 67-year-old man. Three hours before vitrectomy, the patient received an intravenous injection of 300 mg micafungin. Samples of aqueous and vitreous were collected during the vitrectomy approximately 60 min after the intravenous injection. The concentration of micafungin in both bodies was determined by high-performance liquid chromatography.. The concentration of micafungin was 25.36 μg/mL in the serum, 0.026 μg/mL in the aqueous, and 0.043 μg/mL in the vitreous. The micafungin minimum inhibitory concentration (MIC) against the C. albicans strain isolated from our patient was 0.03 μg/mL. Thus, the micafungin reached the MIC in the vitreous.. We suggest that intravenous micafungin should be considered in mild cases of endogenous fungal endophthalmitis, or be given in combination with other intravitreal antifungal agents with vitrectomy in more severe cases.

Topics: Aged; Antifungal Agents; Aqueous Humor; Candida albicans; Candidiasis; Chromatography, High Pressure Liquid; Echinocandins; Endophthalmitis; Eye Infections, Fungal; Humans; Injections, Intravenous; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Vitrectomy; Vitreous Body

Candida glabrata is a leading cause of disseminated candidiasis. The echinocandins are increasingly used as first-line agents for the treatment of patients with this syndrome, although the optimal regimen for the treatment of invasive Candida glabrata infections in neutropenic patients is not known. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin, anidulafungin, and caspofungin in a neutropenic murine model of disseminated Candida glabrata infection to gain further insight into optimal therapeutic options for patients with this syndrome. A mathematical model was fitted to the data and used to bridge the experimental results to humans. The intravenous inoculation of Candida glabrata in mice was followed by logarithmic growth throughout the experimental period (101 h). A dose-dependent decline in fungal burden was observed following the administration of 0.1 to 20 mg/kg of body weight every 24 h for all three agents. The exposure-response relationships for each drug partitioned into distinct fungistatic and fungicidal components of activity. Surprisingly, the average human drug exposures following currently licensed regimens were predicted to result in a fungistatic antifungal effect. Higher human dosages of all three echinocandins are required to induce fungicidal effects in neutropenic hosts.

Topics: Anidulafungin; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Dose-Response Relationship, Drug; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia

Topics: Adult; Antifungal Agents; Candida glabrata; Candidiasis; Critical Illness; Echinocandins; Female; Humans; Lipopeptides; Micafungin; Obesity, Morbid

We report the attainment of micafungin concentrations from brain tissue and pancreatic pseudocyst fluid from two patients with invasive candidiasis. Micafungin was present in low levels at both body sites, indicating limited penetration into central nervous system (CNS) tissue and pancreatic fluid. Further studies are needed to fully characterize its pharmacokinetics at these locations, as micafungin may potentially serve as an alternative antifungal therapy for CNS or pancreatic candidal infections for which the currently recommended first-line therapy fails.

Topics: Adult; Aged; Antifungal Agents; Brain; Candidiasis; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Pancreatic Pseudocyst

A Candida glabrata calcineurin mutant exhibited increased susceptibility to both azole antifungal and cell wall-damaging agents and was also attenuated in virulence. Although a mutant lacking the downstream transcription factor Crz1 displayed a cell wall-associated phenotype intermediate to that of the calcineurin mutant and was modestly attenuated in virulence, it did not show increased azole susceptibility. These results suggest that calcineurin regulates both Crz1-dependent and -independent pathways depending on the type of stress.

Topics: Animals; Antifungal Agents; Base Sequence; Calcineurin; Candida glabrata; Candidiasis; DNA Primers; DNA, Fungal; Drug Resistance, Fungal; Female; Fungal Proteins; Genes, Fungal; Humans; In Vitro Techniques; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mutation; Opportunistic Infections; Transcription Factors; Virulence

We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.

Topics: Adult; Antifungal Agents; Candida glabrata; Candida tropicalis; Candidiasis; Drug Resistance, Fungal; Echinocandins; Female; Glucosyltransferases; Humans; Male; Middle Aged; Mutation

We evaluated the prevalence of fks1 hot spot (HS) 1 mutations among 133 Candida strains from six species displaying various caspofungin MIC values (from < or =0.008 to >8 microg/ml). Only 4 (2.9%) strains displayed FKS1 HS1 amino acid substitutions: 1 C. albicans (F641Y) among 32 isolates tested (3.1%), 1 C. glabrata (S645P) among 34 isolates tested (2.9%), and 2 C. tropicalis (F641S) among 12 isolates tested (16.7%). The 4 isolates displaying FKS1 HS1 alterations showed elevated caspofungin MIC results (1 to >8 microg/ml) but lower anidulafungin and micafungin MIC values (0.12 to 4 microg/ml and 0.25 to 4 microg/ml, respectively) in some instances within the wild-type MIC population, as determined using the epidemiologic cutoff values (ECV). Candida krusei, C. parapsilosis, and C. guilliermondii isolates tested showed no FKS1 HS1 alterations regardless of echinocandin MIC result. We additionally analyzed 8 C. albicans and 7 C. glabrata strains for mutations on other HS regions of fks1 and fks2. Three C. glabrata strains showed alterations on FKS2 HS1 (two S645P and one L644W). In general, strains displaying S645P alteration showed higher echinocandin MIC values than strains harboring other mutations. Overall, Candida spp. strains showing caspofungin MIC values within the ECV did not display fks HS mutations. In contrast, strains showing alterations in this region displayed anidulafungin and/or micafungin MIC values within the wild-type population, suggesting that caspofungin could be the most sensitive agent for detection of these resistance mutations. Furthermore, results from this large, geographically diverse Candida spp. collection demonstrated that fks1 HS1 mutations remain uncommon among isolates with various echinocandin MIC levels.

Topics: Amino Acid Sequence; Amino Acid Substitution; Antifungal Agents; Base Sequence; Candida; Candida albicans; Candida glabrata; Candidiasis; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Genes, Fungal; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Sequence Homology, Amino Acid; Species Specificity

Previous pharmacodynamic studies using in vivo candidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicans and were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosis strains with various MICs (anidulafungin, 0.015 to 4.0 microg/ml; caspofungin, 0.03 to 4.0 microg/ml; and micafungin, 0.008 to 1.0 microg/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosis required more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) were significantly lower than those for C. albicans (mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.

Topics: Anidulafungin; Animals; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candidiasis; Caspofungin; Echinocandins; Female; Kidney; Lipopeptides; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Protein Binding; Species Specificity

T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. In our preliminary studies, Candida glabrata exhibited significant trailing growth (partial inhibition of growth over an extended range of antifungal concentrations) in the presence of T-2307 when it was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines with 0.2% glucose and 48 h of incubation, making reading of the MIC difficult. In the present study, we attempted to attenuate trailing growth to avoid misreading of the MIC. On the basis of the hypothesis that T-2307 may inhibit the mitochondrial functions of cells, the carbon source or the glucose concentration in the medium was changed. The trailing growth of C. glabrata ATCC 90030 in the presence of T-2307 was attenuated as the concentration of glucose in the medium decreased to 0.1% or lower, and trailing growth was completely inhibited when glycerol was used. A susceptibility test using Alamar blue was performed to facilitate reading of the MIC without changing the composition of the medium and provided a clear MIC endpoint at 24 h. To investigate if T-2307 shows efficacy against trailing isolates in vivo, we evaluated the efficacy of T-2307 in a murine model of disseminated candidiasis caused by C. glabrata. T-2307 at 0.05 mg/kg of body weight/day significantly decreased the viable count in the kidneys compared to that for the control group (P < 0.05). It would be better to test the susceptibility of C. glabrata to T-2307 using modified media or Alamar blue to avoid misreading of the MIC due to the significant trailing growth.

Topics: Animals; Antifungal Agents; Candida glabrata; Candidiasis; Male; Mice; Microbial Sensitivity Tests; Molecular Structure

This study compared nine susceptibility testing methods and 12 endpoints for anidulafungin, caspofungin, and micafungin with the same collection of blinded FKS hot spot mutant (n = 29) and wild-type isolates (n = 94). The susceptibility tests included EUCAST Edef 7.1, agar dilution, Etest, and disk diffusion with RPMI-1640 plus 2% glucose (2G) and IsoSensitest-2G media and CLSI M27A-3. Microdilution plates were read after 24 and 48 h. The following test parameters were evaluated: fks hot spot mutants overlapping the wild-type distribution, distance between the two populations, number of very major errors (VMEs; fks mutants misclassified as susceptible), and major errors (MEs; wild-type isolates classified as resistant) using a wild-type-upper-limit value (WT-UL) (two twofold-dilutions higher than the MIC(50)) as the susceptibility breakpoint. The methods with the lowest number of errors (given as VMEs/MEs) across the three echinocandins were CLSI (12%/1%), agar dilution with RPMI-2G medium (14%/0%), and Etest with RPMI-2G medium (8%/3%). The fewest errors overall were observed for anidulafungin (4%/1% for EUCAST, 4%/3% for CLSI, and 3%/9% for Etest with RPMI-2G). For micafungin, VME rates of 10 to 71% were observed. For caspofungin, agar dilution with either medium was superior (VMEs/MEs of 0%/1%), while CLSI, EUCAST with IsoSensitest-2G medium, and Etest were less optimal (VMEs of 7%, 10%, and 10%, respectively). Applying the CLSI breakpoint (S

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Culture Media; Echinocandins; Indicator Dilution Techniques; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Reference Standards

In this study, we measured time-kills and post-antifungal effects (PAFEs) for micafungin against Candida albicans (n=4), Candida glabrata (n=3), Candida parapsilosis (n=3) and Candida krusei (n=2) isolates and further characterised the PAFEs. Minimum inhibitory concentrations (MICs) were 0.5-1.0 mg/L against C. parapsilosis and 0.008-0.125 mg/L against the other species. Micafungin caused kills >1 log at 1 x MIC, 4 x MIC (range 1.19-3.10 log) and 16 x MIC (2.27-3.68 log), achieving fungicidal levels (> or = 3 log) against nine isolates. One-hour drug exposure during PAFE experiments resulted in kills of 0.73-2.88 log and 1.72-3.55 log at 4 x and 16 x MIC, respectively, achieving fungicidal levels against five isolates. Isolates of each species collected 8 h after a 1-h exposure to micafungin (4 x and 16 x MIC) were hypersusceptible to sodium dodecyl sulphate (SDS) and Calcofluor White. Cells tested during the PAFE period demonstrated cell wall disturbances as evident on electron micrographs as well as significant reductions in adherence to epithelial cells. Phagocytosis by J774 macrophages was significantly enhanced for three PAFE isolates tested. Micafungin is fungicidal and exerts PAFEs that kill diverse Candida spp., disturb cell walls of viable organisms, reduce adherence and enhance susceptibility to phagocytosis.

Topics: Animals; Antifungal Agents; Benzenesulfonates; Candida; Candidiasis; Cell Adhesion; Cell Line; Cell Wall; Cells, Cultured; Echinocandins; Epithelial Cells; Humans; Lipopeptides; Macrophages; Micafungin; Mice; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron, Transmission; Phagocytosis; Sodium Dodecyl Sulfate; Time Factors

Given the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for the successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed the safety and pharmacokinetics (PK) of micafungin in 13 young infants (>48 h and <120 days of life) with suspected candidemia or invasive candidiasis. Infants of body weight > or =1,000 and <1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4-5 days. In the 7-mg/kg/day group, the mean baseline weight and gestational age were 2,101 g and 30 weeks, respectively; in the 10-mg/kg/day group, they were 688 g and 25 weeks, respectively. The median pharmacokinetic values for the 7- and 10-mg/kg/day groups, respectively, were as follows: area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 258.1 and 291.2 microg x h/ml; clearance at steady state adjusted for body weight, 0.45 and 0.57 ml/min/kg; maximum plasma concentration, 23.3 and 24.9 micro g/ml; and volume of distribution at steady state adjusted for body weight, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day are well tolerated and provide exposure levels that have been shown (in animal models) to be adequate for central nervous system coverage.

Topics: Age Factors; Candidiasis; Dose-Response Relationship, Drug; Drug Administration Schedule; Echinocandins; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin

We tested a global collection of Candida sp. strains against anidulafungin, caspofungin, and micafungin, using CLSI M27-A3 broth microdilution (BMD) methods, in order to define wild-type (WT) populations and epidemiological cutoff values (ECVs). From 2003 to 2007, 8,271 isolates of Candida spp. (4,283 C. albicans, 1,236 C. glabrata, 1,238 C. parapsilosis, 996 C. tropicalis, 270 C. krusei, 99 C. lusitaniae, 88 C. guilliermondii, and 61 C. kefyr isolates) were obtained from over 100 centers worldwide. The modal MICs (in microg/ml) for anidulafungin, caspofungin, and micafungin, respectively, for each species were as follows: C. albicans, 0.03, 0.03, 0.015; C. glabrata, 0.06, 0.03, 0.015; C. tropicalis, 0.03, 0.03, 0.015; C. kefyr, 0.06, 0.015, 0.06; C. krusei, 0.03, 0.06, 0.06; C. lusitaniae, 0.05, 0.25, 0.12; C. parapsilosis, 2, 0.25, 1; and C. guilliermondii, 2, 0.5. 05. The ECVs, expressed in microg/ml (percentage of isolates that had MICs that were less than or equal to the ECV is shown in parentheses) for anidulafungin, caspofungin, and micafungin, respectively, were as follows: 0.12 (99.7%), 0.12 (99.8%), and 0.03 (97.7%) for C. albicans; 0.25 (99.4%), 0.12 (98.5%), and 0.03 (98.2%) for C. glabrata; 0.12 (98.9%), 0.12 (99.4%), and 0.12 (99.1%) for C. tropicalis; 0.25(100%), 0.03 (100%), and 0.12 (100%) for C. kefyr; 0.12 (99.3%), 0.25 (96.3%), and 0.12 (97.8%) for C. krusei; 2 (100%), 0.5 (98.0%), and 0.5 (99.0%) for C. lusitaniae; 4 (100%), 1 (98.6%), and 4 (100%) for C. parapsilosis; 16 (100%), 4 (95.5%), and 4 (98.9%) for C. guilliermondii. These WT MIC distributions and ECVs will be useful in surveillance for emerging reduced echinocandin susceptibility among Candida spp. and for determining the importance of various FKS1 or other mutations.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

We report an uncommon but emerging fungal pathogen, Candida kefyr, as a causative agent of infective endocarditis in a patient with a known history of hypertrophic obstructive cardiomyopathy. A 74-year-old woman with diabetes type II, hypertrophic obstructive cardiomyopathy, presented with gross hematuria and abdominal pain. Computed tomography scan revealed a hemorrhagic mass in the superior pole of the right kidney, with a thrombus extending from the ureter to the bladder. She underwent cryotherapy of the renal mass, together with retrograde ureteral stent placement, developed hypotension and respiratory distress, spiked high-grade fever, and had a new pansystolic murmur over the mitral and aortic areas. Urine and blood culture grew C. kefyr. Transthoracic echocardiogram revealed large mitral valve vegetation with moderate regurgitation. Micafungin was started, patient responded, and fungemia cleared. Repeat echocardiogram showed small vegetation, preserved leaflet mobility and mild regurgitation. Patient received 10 days of micafungin, followed by 6 weeks of fluconazole.

Topics: Aged; Antifungal Agents; Candidiasis; Cardiomyopathy, Hypertrophic; Echinocandins; Endocarditis; Female; Fluconazole; Humans; Kidney Neoplasms; Lipopeptides; Micafungin

Topics: Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Candida tropicalis; Candidiasis; Drug Therapy, Combination; Echinocandins; Follow-Up Studies; Fungemia; Humans; Infant; Lipopeptides; Male; Micafungin; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pulmonary Aspergillosis; Pyrimidines; Tomography, X-Ray Computed; Triazoles; Voriconazole

The antifungal broth microdilution (BMD) method of the European Committee on Antibiotic Susceptibility Testing (EUCAST) and the Etest agar diffusion method were compared with the Clinical and Laboratory Standards Institute (CLSI) BMD method M27-A3 for anidulafungin, caspofungin, and micafungin susceptibility testing of 133 clinical isolates of Candida species. The isolates were characterized for the presence or absence of fks1 and/or fks2 gene mutations and included 34 isolates of C. glabrata (4 mutant strains), 32 of C. albicans (1 mutant strain), 25 of C. parapsilosis, 19 of C. guilliermondii, 12 of C. tropicalis (2 mutant strains), and 11 of C. krusei. Excellent essential agreement (EA; within 2 dilutions) between the CLSI and EUCAST and CLSI and Etest MIC results was observed. The overall EA between the EUCAST and CLSI results ranged from 89.5% (caspofungin) to 99.2% (micafungin), whereas the EA between the Etest and CLSI results ranged from 90.2% (caspofungin) to 93.2% (anidulafungin). The categorical agreement (CA) between methods for each antifungal agent was assessed using previously determined epidemiological cutoff values (ECVs). Excellent CA (>90%) was observed for all comparisons between the EUCAST and CLSI results with the exceptions of C. glabrata and caspofungin (85.3%) and C. krusei and caspofungin (54.5%). The CA between the Etest and CLSI results was also excellent for all comparisons, with the exception of C. krusei and caspofungin (81.8%). All three methods were able to differentiate wild-type (WT) strains from those with fks mutations. With anidulafungin as the test reagent, the CLSI method identified 5 of 7 mutant strains, whereas the EUCAST method and the Etest identified 6 of 7 mutant strains. With either caspofungin or micafungin as the test reagent, the CLSI method identified all 7 mutant strains and the EUCAST method identified 6 of 7 mutant strains. The Etest identified all 7 mutant strains using caspofungin as the reagent. All three test methods showed a high level of agreement and of ability to distinguish fks mutant strains of Candida species from WT strains using each of the echinocandins.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests

For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >or=3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 microg/ml, but all demonstrated caspofungin MICs of >2 microg/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 microg/ml, but 4/5 had micafungin MICs of >2 microg/ml. The remaining isolates retained echinocandin MICs of 2 microg/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.

Topics: Adolescent; Adult; Aged; Antifungal Agents; Candida; Candidiasis; Drug Resistance, Fungal; Echinocandins; Female; Fungal Proteins; Glucosyltransferases; Humans; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged

Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations.

Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Echinocandins; Fungal Proteins; Glucosyltransferases; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mutation; Polymerase Chain Reaction

Diagnosis and treatment of Candida albicans endocarditis can be difficult. We report a case of this rare condition in which a patient on oral fluconazole presented with septic pulmonary emboli without initial echocardiographic evidence of vegetation. Rapid attainment of a tissue diagnosis, along with combined medical surgical treatment proved to be effective for this patient.

Topics: Adolescent; Antifungal Agents; Biopsy; Candidiasis; Cardiovascular Surgical Procedures; Combined Modality Therapy; Echinocandins; Endocarditis; Female; Humans; Lipopeptides; Micafungin; Pulmonary Artery; Pulmonary Embolism; Treatment Outcome; Tricuspid Valve

This study retrospectively reviews the susceptibility of 135 baseline ICU candidemia isolates (from 1997 to 2007) to nine antifungals as determined by the AFST-EUCAST microdilution method and identifies the most frequent causative agents of confirmed point-source candidemia outbreaks in local intensive care units. A minority of common and rare Candida species displayed decreased susceptibility to all antifungals.

Topics: Antifungal Agents; Candida; Candidiasis; Data Collection; Disease Susceptibility; Greece; Humans; Intensive Care Units; Microbial Sensitivity Tests; Retrospective Studies

Candida dubliniensis commonly shows paradoxical or trailing growth effects in vitro in the presence of echinocandins. We tested the in vitro activities of anidulafungin, caspofungin, and micafungin against clinical isolates of C. dubliniensis and evaluated the efficacy of these drugs in two murine models of systemic infection. The three echinocandins were similarly effective in the treatment of experimental disseminated infections with C. dubliniensis strains showing or not showing abnormal growth in vitro.

Topics: Anidulafungin; Animals; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Lipopeptides; Male; Micafungin; Mice

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

Recent studies suggest that differences in antifungal activity among echinocandins may exist. In this study, the activities of three echinocandins (anidulafungin, caspofungin, and micafungin) against Candida parapsilosis isolates from burn unit patients, healthcare workers and the hospital environment were determined. Additionally, the effect of these echinocandins on the cell morphology of caspofungin-susceptible and caspofungin-non-susceptible isolates was assessed using scanning electron microscopy (SEM). The C. parapsilosis isolates obtained from patients were susceptible to anidulafungin, but were less so to caspofungin and micafungin. Isolates obtained from healthcare workers or environmental sources were susceptible to all antifungals. SEM data demonstrated that although anidulafungin and caspofungin were equally active against a caspofungin-susceptible C. parapsilosis strain, they differed in their ability to damage a caspofungin-non-susceptible strain, for which lower concentrations of anidulafungin (1 mg/L) than of caspofungin (16 mg/L) were needed to induce cellular damage and distortion of the cellular morphology. To determine whether the difference in the antifungal susceptibility of C. parapsilosis isolates to anidulafungin as compared to the other two echinocandins could be due to different mutations in the FKS1 gene, the sequences of the 493-bp region of this gene associated with echinocandin resistance were compared. No differences in the corresponding amino acid sequences were observed, indicating that differences in activity between anidulafungin and the other echinocandins are not related to mutations in this region. The results of this study provide evidence that differences exist between the activities of anidulafungin and the other echinocandins.

Topics: Anidulafungin; Antifungal Agents; Burn Units; Burns; Candida; Candidiasis; Carrier State; Caspofungin; Echinocandins; Environmental Microbiology; Fungal Proteins; Genotype; Glucosyltransferases; Health Personnel; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Sequence Analysis, DNA

To describe the use of micafungin and fluconazole in the management of a fungal prosthetic joint infection caused by Candida albicans.. A 55-year-old female who had undergone total left knee arthroplasty due to rheumatoid arthritis presented with symptoms of a left knee infection. Intravenous vancomycin 1 g every 12 hours and intravenous ampicillin/sulbactam 1.5 g every 6 hours were initiated. Arthrocentesis produced cloudy synovial fluid with a white blood cell (WBC) count of 5.995 x 10(3)/microL. C-reactive protein (CRP) was 19.8 mg/dL and erythrocyte sediment rate (ESR) was greater than 120 mm/h. Gram stain was negative, but intraoperative cultures grew C. albicans. Four days later the patient's condition worsened and repeat arthrocentesis showed WBC count of 16.8 x 10(3)/microL with budding yeast in the synovial fluid. Antibiotics were stopped and liposomal amphotericin B 5 mg/kg once daily was started but was stopped after a few doses due to renal failure. Intravenous micafungin 100 mg daily was initiated; intravenous fluconazole 400 mg daily was added 2 days later and subsequently changed to oral fluconazole after 2 days of therapy. The patient received combination micafungin/fluconazole therapy for 8 weeks. After approximately 8 weeks of therapy, the CRP level and ESR had decreased from 19.8 to 7.1 mg/dL and greater than 120 to 81 mm/h, respectively. The patient's pain and range of motion in her knee had returned to baseline levels at last follow-up after the total knee arthroplasty. After 8 weeks of combination therapy, micafungin was discontinued but oral fluconazole was continued; approximately 8 weeks later the patient relapsed, requiring removal of the prosthetic knee hardware.. Fungal prosthetic joint infections are rare, but definitive data regarding appropriate treatment are lacking. Echinocandins are an attractive treatment option due to their enhanced biofilm penetration. In our patient, treatment with micafungin plus fluconazole for 8 weeks followed by fluconazole monotherapy was associated with an initial good outcome in the treatment of a C. albicans prosthetic knee infection with retained hardware. This was, to our knowledge, the first case using micafungin in a prosthetic joint infection.. Although micafungin plus fluconazole showed positive results in our patient, more data are needed regarding combination therapy for fungal prosthetic joint infections.

Topics: Antifungal Agents; Arthroplasty, Replacement, Knee; Biofilms; Candidiasis; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Humans; Knee Prosthesis; Lipopeptides; Micafungin; Middle Aged; Prosthesis-Related Infections

Topics: Aged, 80 and over; Antifungal Agents; Bile; Candidiasis; Cholecystitis; Echinocandins; Esophageal Neoplasms; Humans; Itraconazole; Lipopeptides; Male; Micafungin

Micafungin (MCFG) is an echinocandin antifungal agent that exhibits potent activity against most species of Candida and Aspergillus. We investigated the in vitro antifungal combination effects of MCFG with four other antifungal agents - fluconazole (FLCZ), voriconazole (VRCZ), amphotericin B, and flucytosine - against clinical isolates of 54 Candida spp. by checkerboard analysis. The synergistic antifungal effects of MCFG-FLCZ and MCFG-VRCZ were 11% and 15%, respectively, and the latter displayed a synergistic activity of 63% against Candida glabrata. Antagonism was not observed in any of the combinations tested.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Drug Synergism; Echinocandins; Fluconazole; Flucytosine; Humans; Lipopeptides; Micafungin; Pyrimidines; Triazoles; Voriconazole

Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/d) dose of micafungin.. A repeated dose, open-label pharmacokinetic, and safety trial of intravenous micafungin in 12 preterm neonates >48 hours of life with suspected systemic infections. Neonates received 15 mg/kg/d of micafungin for 5 days. Blood samples were drawn relative to either the fourth or fifth dose. Systemic exposure was assessed by examination of the plasma area under the curve.. The median birth weight and gestational age of the neonates were 775 g and 27 weeks, respectively. No adverse events related to micafungin were detected. The mean area under the curve and clearance for the cohort was 437.5 microg'h/mL and 0.575 mL/min/kg, respectively. The calculated clearance and volume of distribution for neonates was greater than that observed in older children and adults.. These data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5 mg/kg in adults. No adverse events related to micafungin were observed.

Topics: Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Echinocandins; Humans; Infant, Newborn; Infant, Premature; Lipopeptides; Micafungin

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients.

Topics: AIDS-Related Opportunistic Infections; Alanine Transaminase; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Liver Function Tests; Micafungin

Although clinical experience in neonates with candidiasis exists for amphotericin B and fluconazole, these standard treatments are often hindered by drug-associated toxicity or development of resistant strains. The aim of the present study was therefore to investigate the efficacy and tolerability of a new antifungal agent, micafungin (MCFG), for treating Candida infections in premature infants.. This was a retrospective cohort study. Premature infants diagnosed with Candida infections from October 2003 to July 2004 were brought to the neonatal intensive care unit at the Center of Perinatal Medicine, Nara Medical University Hospital. Four newborns were given 0.5-1.0 mg/kg per day micafungin.. Four premature infants (mean +/- SD gestational age, 24.1 +/- 0.9 weeks; mean +/- SD birthweight, 579.3 +/- 80.5 g) experienced complications from Candida infection; two cases of the fungal infection were caused by Candida glabrata and two cases were caused by Candida albicans. MCFG was administered at 0.5 or 1.0 mg/kg per day (mean dosage days, 9.8 +/- 3.1 days) and it decreased beta-D-glucan levels while improving clinical symptoms in all cases. Additionally, there were no apparent side-effects.. MCFG is both effective and tolerable for use in premature infants suffering from Candida infections.

Topics: Antifungal Agents; beta-Glucans; Candidiasis; Echinocandins; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lipopeptides; Male; Micafungin; Retrospective Studies; Treatment Outcome

Topics: Adult; Antifungal Agents; Candidiasis; Child; Echinocandins; Humans; Lipopeptides; Micafungin; Mycoses

Recent epidemiologic literature indicates that candidal species resistant to azoles are becoming more prevalent in the face of increasing incidence of hospitalizations with candidemia. Echinocandins, a new class of antifungal agents, are effective against resistant candidal species. As delaying appropriate antifungal coverage leads to increased mortality, we evaluated the cost-effectiveness of 100 mg daily empiric micafungin (MIC) vs. 400 mg daily fluconazole (FLU) for suspected intensive care unit-acquired candidemia (ICU-AC) among septic patients.. We designed a decision model with inputs from the literature in a hypothetical 1000-patient cohort with suspected ICU-AC treated empirically with either MIC or FLU or no treatment accompanied by a watchful waiting strategy. We examined the differences in the number of survivors, acquisition costs of antifungals, and lifetime costs among survivors in the cohort under each scenario, and calculated cost per quality adjusted life year (QALY). We conducted Monte Carlo simulations and sensitivity analyses to determine the stability of our estimates.. In the base case analysis, assuming ICU-AC attributable mortality of 0.40 and a 52% relative risk reduction in mortality with appropriate timely therapy, compared with FLU (total deaths 31), treatment with MIC (total deaths 27) would result in four fewer deaths at an incremental cost/death averted of $61,446. Similarly, in reference case, incremental cost-effectiveness of MIC over FLU was $34,734 (95% confidence interval $26,312 to $49,209) per QALY. The estimates were most sensitive to the QALY adjustment factor and the risk of candidemia among septic patients.. Given the increasing likelihood of azole resistance among candidal isolates, empiric treatment of ICU-AC with 100 mg daily MIC is a cost-effective alternative to FLU.

Topics: Antifungal Agents; Candidiasis; Cost-Benefit Analysis; Cross Infection; Decision Trees; Drug Costs; Drug Resistance, Fungal; Echinocandins; Fluconazole; Fungemia; Humans; Incidence; Intensive Care Units; Lipopeptides; Micafungin; Models, Econometric; Monte Carlo Method; Quality-Adjusted Life Years

To evaluate the cost-effectiveness of micafungin compared to caspofungin in the treatment of systemic Candida infections (SCIs) in the UK, including invasive candidiasis and candidaemia.. Cost-effectiveness of both echinocandin antifungal drugs was estimated using decision analysis. Response to treatment, resource utilisation, and costs in the model were derived from a phase 3, head-to-head comparative trial. The model includes only data directly related to the treatment of the systemic Candida infection over the study duration (a maximum period of 14 weeks). Transition probabilities were calculated based on the efficacy results from the clinical trial.. The model's effectiveness outcome is surviving patients who are successfully treated, based on the absence of signs and symptoms, radiographic abnormalities, and culture/histologic evidence associated with the fungal infection. In addition, subgroup analyses were performed to identify cost-effectiveness in several specific patient groups.. The total medical treatment costs for the micafungin group were pound 29,095, which is similar to the total costs for the caspofungin group (pound 29,953). In the micafungin arm 60% of the patients and in the caspofungin arm 58% of the patients were successfully treated and alive. Cost-effectiveness ratio of micafungin was pound 48,771, and of caspofungin pound 52,066 per successfully treated patient. Because the costs are lower and the effectiveness is higher for micafungin in comparison with caspofungin, micafungin is more cost-effective than caspofungin. However, probabilistic sensitivity and subgroup analysis show that the differences cannot be considered significant due to a large variance although micafungin remained the most cost-effective option throughout all but one of the sensitivity analyses.. Costs and effects of micafungin compare to those of caspofungin in the treatment of systemic Candida infections in the UK. The results indicate that micafungin is cost-effective compared to caspofungin, although the difference was not found to be significant.

Topics: Adolescent; Adult; Antifungal Agents; Candidiasis; Caspofungin; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Echinocandins; Economics, Pharmaceutical; Health Care Costs; Humans; Lipopeptides; Micafungin; Middle Aged; Models, Economic; United Kingdom; Young Adult

A 72-year-old man was admitted to our hospital because of a low grade fever and malaise. He had received a middle to lower esophagectomy and proximal gastrectomy with reconstruction of a gastric conduit for esophageal cancer 12 years previously. Chest X-ray and CT scan revealed massive pleural effusion and consolidations on the right side. Candida glabrata was isolated 4 times from pleural fluid specimens. Candida antigen was negative in both serum and pleural effusion. However, while serum beta-D-glucan was negative, the level of beta-D-glucan in pleural effusion was extremely elevated. Thus, the patient was diagnosed as having C. glabrata empyema. He was treated with insertion of a thoracostomy tube followed by intrapleural instillation of amphotericin B and intravenous administration of micafungin. Pleural effusion was reduced and the repeated culture of the pleural effusion became negative after 27 days of treatment. Empyema with C. glabrata is rare and the present case is the second report of the disease in the Japanese literature.

Topics: Aged; Amphotericin B; Antifungal Agents; Candida glabrata; Candidiasis; Echinocandins; Empyema; Humans; Lipopeptides; Male; Micafungin; Thoracostomy

Candida albicans is the leading fungal pathogen of humans, causing life-threatening disease in immunocompromised individuals. Treatment of candidiasis is hampered by the limited number of antifungal drugs whose efficacy is compromised by host toxicity, fungistatic activity, and the emergence of drug resistance. We previously established that the molecular chaperone Hsp90, which regulates the form and function of diverse client proteins, potentiates resistance to the azoles in C. albicans and in the model yeast Saccharomyces cerevisiae. Genetic studies in S. cerevisiae revealed that Hsp90's role in azole resistance is to enable crucial cellular responses to the membrane stress exerted by azoles via the client protein calcineurin. Here, we demonstrate that Hsp90 governs cellular circuitry required for resistance to the only new class of antifungals to reach the clinic in decades, the echinocandins, which inhibit biosynthesis of a critical component of the fungal cell wall. Pharmacological or genetic impairment of Hsp90 function reduced tolerance of C. albicans laboratory strains and resistance of clinical isolates to the echinocandins and created a fungicidal combination. Compromising calcineurin function phenocopied compromising Hsp90 function. We established that calcineurin is an Hsp90 client protein in C. albicans: reciprocal co-immunoprecipitation validated physical interaction; Hsp90 inhibition blocked calcineurin activation; and calcineurin levels were depleted upon genetic reduction of Hsp90. The downstream effector of calcineurin, Crz1, played a partial role in mediating calcineurin-dependent stress responses activated by echinocandins. Hsp90's role in echinocandin resistance has therapeutic potential given that genetic compromise of C. albicans HSP90 expression enhanced the efficacy of an echinocandin in a murine model of disseminated candidiasis. Our results identify the first Hsp90 client protein in C. albicans, establish an entirely new role for Hsp90 in mediating resistance to echinocandins, and demonstrate that targeting Hsp90 provides a promising therapeutic strategy for the treatment of life-threatening fungal disease.

Topics: Analysis of Variance; Animals; Antifungal Agents; Azoles; Calcineurin; Candida albicans; Candidiasis; Disease Models, Animal; DNA-Binding Proteins; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; HSP90 Heat-Shock Proteins; Lipopeptides; Male; Micafungin; Mice; Stress, Physiological; Transcription Factors

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

Prior analyses suggest that empiric fluconazole for ICU patients with sepsis is cost-effective. Using updated estimates of efficacy and cost, Zilberberg and colleagues compare the use of micafungin with that of fluconazole. The authors conclude that micafungin is an attractive alternative to fluconazole. This conclusion is driven by recent reduction in micafungin's cost and by better activity of micafungin against azole-resistant Candida species. Their results are limited by inflated estimates of efficacy, life expectancy and risk of Candida sepsis. This commentary explores the rationale for early anti-Candida strategies in the ICU and highlights the contribution and limitations of the article by Zilberberg and colleagues.

Topics: Antifungal Agents; Candida; Candidiasis; Clinical Protocols; Echinocandins; Fluconazole; Humans; Intensive Care Units; Lipopeptides; Micafungin; Sepsis

Topics: Antifungal Agents; Candidiasis; Double-Blind Method; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Europe; Humans; Lipopeptides; Liver Failure; Micafungin; Randomized Controlled Trials as Topic

Preterm neonates with candidemia frequently have persistently positive blood cultures, despite the use of conventional antifungal therapy. Our institutional treatment protocol for invasive candidiasis incorporates lipid complex amphotericin B as initial therapy with the sequential addition of fluconazole and high-dose micafungin (10 mg kg(-1)) every 48 to 72 h, if cultures from a sterile site remain positive. Our study objectives were to compare the clinical profiles and outcomes of preterm neonates with candidemia that responded to or were refractory to conventional antifungals. We further evaluate the clinical efficacy of high-dose micafungin pharmacotherapy of refractory candidemia.. A chart review was performed on preterm infants (n=29) with invasive candidiasis and demographic, microbiologic and outcome data abstracted. Proportions and continuous variables were compared between the groups using Fisher's exact two-tailed test and t-test.. The refractory (n=19) candidemia and early responder (n=10) groups had comparable mean (+/-s.d.) gestation, 27(+/-3.1) vs 27.8 (+/-2.7) weeks. The refractory group was administered antibiotics for a longer duration, 14.5 (+/-10.3) vs 7.1 (+/-5) days, had a preponderance of non-albicans infections, 11 (57.9%) vs 1 (10%) and were on enteral feeds > 20 ml kg(-1) day(-1) significantly less often (21 vs 70%). Mortality was significantly higher (53 vs 20%) and fungal clearance rates lower (63.1 vs 90%), with a longer duration to clearance in the group with refractory candidemia. Mean aspartate aminotransferase (AST) showed a statistically significant increase following micafungin treatment, although clinical significance remains unclear.. Candidemia refractory to conventional antifungals is associated with prolonged antibiotic use, lack of enteral nutritive feeds and non-albicans infection. Despite high-dose micafungin pharmacotherapy in combination with conventional antifungals, infants with refractory candidemia had high mortality and poor fungal clearance.

Topics: Anti-Bacterial Agents; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Cohort Studies; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Enteral Nutrition; Female; Fungemia; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Long-Term Care; Male; Micafungin; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome

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

We describe the prevalences and susceptibility profiles of two recently described species, Candida metapsilosis and Candida orthopsilosis, related to Candida parapsilosis in candidemia. The prevalences of these species (1.7% for C. metapsilosis and 1.4% for C. orthopsilosis) are significant. Differences observed in their susceptibility profiles could have therapeutic importance.

Topics: Antifungal Agents; Candida; Candidiasis; Fungemia; Humans; Microbial Sensitivity Tests; Population Surveillance; Prevalence; Spain; Species Specificity

We describe a case of recurring Candida glabrata infection in a 68-year-old African-American female on caspofungin therapy. The initial isolate was susceptible, but isolates recovered during following relapses were not. All isolates were clonal, and high-MIC strains contained a mutation in the highly conserved hot spot 1 region of Fks1p.

Topics: Aged; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fatal Outcome; Female; Fungal Proteins; Fungemia; Glucosyltransferases; Humans; Lipopeptides; Membrane Proteins; Microbial Sensitivity Tests; Mutation

Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

Topics: Amino Acid Sequence; Amino Acid Substitution; Antifungal Agents; Base Sequence; Candida; Candidiasis; DNA Primers; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Enzyme Inhibitors; Fungal Proteins; Gene Expression; Genes, Fungal; Glucosyltransferases; Humans; Membrane Proteins; Molecular Sequence Data; Mutagenesis, Site-Directed; Saccharomyces cerevisiae Proteins; Sequence Homology, Amino Acid; Species Specificity

This study assessed the tissue distribution of anidulafungin in rats. Anidulafungin rapidly distributed into tissues, achieving peak concentrations within 30 min, and maintained levels above MICs for common pathogens over 72 h. In tissues susceptible to fungal infection (liver, lung, spleen, kidney), exposure was 9- to 12-fold higher than in plasma.

Topics: Anidulafungin; Animals; Antifungal Agents; Autoradiography; Candidiasis; Carbon Radioisotopes; Echinocandins; Humans; Infusions, Intravenous; Kidney; Liver; Lung; Male; Rats; Rats, Inbred F344; Spleen; Tissue Distribution

Previous studies using in vivo candidiasis models have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum/MIC and 24-h area under the curve (AUC)/MIC, are associated with echinocandin treatment efficacy. The current investigations used a neutropenic murine model of disseminated Candida albicans and C. glabrata infection to identify the 24-h AUC/MIC index target associated with a stasis and killing endpoint for the echinocandin, micafungin. The kinetics after intraperitoneal micafungin dosing were determined in neutropenic infected mice. Peak levels and AUC values were linear over the 16-fold dose range studied. The serum drug elimination half-life ranged from 7.5 to 16 h. Treatment studies were conducted with 4 C. albicans and 10 C. glabrata isolates with micafungin MICs varying from 0.008 to 0.25 microg/ml to determine whether similar 24-h AUC/MIC ratios were associated with efficacy. The free drug AUC/MICs associated with stasis and killing (1-log) endpoints were near 10 and 20, respectively. The micafungin exposures associated with efficacy were similar for the two Candida species. Furthermore, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those recently reported for another echinocandin, anidulafungin, against the identical Candida isolates in this model.

Topics: Animals; Antifungal Agents; Candida albicans; Candida glabrata; Candidiasis; Colony Count, Microbial; Disease Models, Animal; Echinocandins; Female; Lipopeptides; Micafungin; Mice; Mice, Inbred ICR; Neutropenia

We report a case of Candida glabrata invasive candidiasis that developed reduced susceptibility to caspofungin during prolonged therapy. Pre- and posttreatment isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed an F659V substitution within the FKS2 region of the glucan synthase complex.

Topics: Adult; Amino Acid Substitution; Antifungal Agents; Base Sequence; Candida glabrata; Candidiasis; Caspofungin; DNA Primers; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Genes, Fungal; Glucosyltransferases; Humans; Lipopeptides

Pyrosequencing was compared to Sanger dideoxy sequencing to detect mutations in FKS1 responsible for reduced echinocandin susceptibility in Candida albicans. These methods were in complete agreement for 10 of 12 clinical isolates with elevated echinocandin MICs, supporting the potential feasibility of pyrosequencing to detect mutations within diploid fungi.

Topics: Anidulafungin; Antifungal Agents; Base Sequence; Candida albicans; Candidiasis; Caspofungin; DNA Mutational Analysis; DNA, Fungal; Drug Resistance, Fungal; Echinocandins; Genes, Fungal; Glucosyltransferases; Humans; Lipopeptides; Micafungin; Point Mutation

We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Candida tropicalis; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fungemia; Hematologic Neoplasms; Humans; Lipopeptides; Male; Middle Aged

The CLSI Antifungal Subcommittee followed the M23-A2 "blueprint" to develop interpretive MIC breakpoints for anidulafungin, caspofungin, and micafungin against Candida species. MICs of < or = 2 microg/ml for all three echinocandins encompass 98.8 to 100% of all clinical isolates of Candida spp. without bisecting any species group and represent a concentration that is easily maintained throughout the dosing period. Data from phase III clinical trials demonstrate that the standard dosing regimens for each of these agents may be used to treat infections due to Candida spp. for which MICs are as high as 2 microg/ml. An MIC predictive of resistance to these agents cannot be defined based on the data from clinical trials due to the paucity of isolates for which MICs exceed 2 microg/ml. The clinical data set included only three isolates from patients treated with an echinocandin (caspofungin) for which the MICs were > 2 microg/ml (two C. parapsilosis isolates at 4 microg/ml and one C. rugosa isolate at 8 microg/ml). Based on these data, the CLSI subcommittee has decided to recommend a "susceptible only" breakpoint MIC of < or = 2 microg/ml due to the lack of echinocandin resistance in the population of Candida isolates thus far. Isolates for which MICs exceed 2 microg/ml should be designated "nonsusceptible" (NS). For strains yielding results suggestive of an NS category, the organism identification and antimicrobial-susceptibility test results should be confirmed. Subsequently, the isolates should be submitted to a reference laboratory that will confirm the results by using a CLSI reference dilution method.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Clinical Trials as Topic; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Statistics as Topic; Treatment Outcome

In vitro susceptibility assays of antifungal activity do not always accurately predict in vivo efficacy. As well as having a clear clinical importance, the ability to predict efficacy is also essential for effective screening of novel drug compounds. Initial screening of novel compounds must often be based on in vitro data. The present report describes the use of serum-MIC, an in vitro test of antifungal susceptibility, to accurately predict in vivo efficacy of echinocandin drugs in a mouse model of disseminated candidiasis. The basis of the serum-MIC method was to measure the inhibitory activity of a test compound against Candida albicans hyphal growth in the presence of pooled mouse serum. For 13 previously uncharacterized echinocandin compounds, as well as for the known echinocandin drugs, micafungin and caspofungin, serum-MIC determinations were shown to give better correlation to efficacy in the animal model than conventional, CLSI standard, in vitro antifungal susceptibility tests. The most accurate prediction of efficacy was obtained when the serum-MIC was adjusted in relation to the serum concentration at 30 min post-treatment. Furthermore, when the efficacy of micafungin was determined by measuring C. albicans kidney burden in the mouse model of infection, the adjusted serum-MIC consistently reflected the effective serum concentrations. Our data indicate that determination of serum-MIC values will facilitate prediction of the in vivo potency of new antifungal compounds such as novel echinocandins.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Echinocandins; Hyphae; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Predictive Value of Tests; Serum; Treatment Outcome

The treatment, diagnosis and therapeutic monitoring of hematogenous Candida meningoencephalitis (HCME) are not well understood. We therefore studied the expression of (1-->3)-beta-D-glucan (beta-glucan) in cerebrospinal fluid (CSF) and plasma in a nonneutropenic rabbit model of experimental HCME treated with micafungin and amphotericin B. Groups studied consisted of micafungin (0.5 to 32 mg/kg) and amphotericin B (1 mg/kg) treatment groups and the untreated controls (UC). Despite well-established infection in the cerebrum, cerebellum, choroid, vitreous humor (10(2) to 10(3) CFU/ml), spinal cord, and meninges (10 to 10(2) CFU/g), only 8.1% of UC CSF cultures were positive. By comparison, all 25 UC CSF samples tested for beta-glucan were positive (755 to 7,750 pg/ml) (P < 0.001). The therapeutic response in CNS tissue was site dependent, with significant decreases of the fungal burden in the cerebrum and cerebellum starting at 8 mg/kg, in the meninges at 2 mg/kg, and in the vitreous humor at 4 mg/kg. A dosage of 24 mg/kg was required to achieve a significant effect in the spinal cord and choroid. Clearance of Candida albicans from blood cultures was not predictive of eradication of organisms from the CNS; conversely, beta-glucan levels in CSF were predictive of the therapeutic response. A significant decrease of beta-glucan concentrations in CSF, in comparison to that for UC, started at 0.5 mg/kg (P < 0.001). Levels of plasma beta-glucan were lower than levels in simultaneously obtained CSF (P < 0.05). CSF beta-glucan levels correlated in a dose-dependent pattern with therapeutic responses and with Candida infection in cerebral tissue (r = 0.842). Micafungin demonstrated dose-dependent and site-dependent activity against HCME. CSF beta-glucan may be a useful biomarker for detection and monitoring of therapeutic response in HCME.

Topics: Amphotericin B; Animals; Antifungal Agents; beta-Glucans; Biomarkers; Candidiasis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Monitoring; Echinocandins; Female; Lipopeptides; Meningitis, Fungal; Meningoencephalitis; Micafungin; Rabbits

The echinocandins are being used increasingly as therapy for invasive candidiasis. Prospective sentinel surveillance for the emergence of in vitro resistance to the echinocandins among invasive Candida sp. isolates is indicated. We determined the in vitro activities of anidulafungin, caspofungin, and micafungin against 5,346 invasive (bloodstream or sterile-site) isolates of Candida spp. collected from over 90 medical centers worldwide from 1 January 2001 to 31 December 2006. We performed susceptibility testing according to the CLSI M27-A2 method and used RPMI 1640 broth, 24-h incubation, and a prominent inhibition endpoint for determination of the MICs. Of 5,346 invasive Candida sp. isolates, species distribution was 54% C. albicans, 14% C. parapsilosis, 14% C. glabrata, 12% C. tropicalis, 3% C. krusei, 1% C. guilliermondii, and 2% other Candida spp. Overall, all three echinocandins were very active against Candida: anidulafungin (MIC50, 0.06 microg/ml; MIC90, 2 microg/ml), caspofungin (MIC50, 0.03 microg/ml; MIC90, 0.25 microg/ml), micafungin (MIC50, 0.015 microg/ml; MIC90, 1 microg/ml). More than 99% of isolates were inhibited by < or = 2 microg/ml of all three agents. Results by species (expressed as the percentages of isolates inhibited by < or = 2 microg/ml of anidulafungin, caspofungin, and micafungin, respectively) were as follows: for C. albicans, 99.6%, 100%, and 100%; for C. parapsilosis, 92.5%, 99.9%, and 100%; for C. glabrata, 99.9%, 99.9%, and 100%; for C. tropicalis, 100%, 99.8%, and 100%; for C. krusei, 100%, 100%, and 100%; and for C. guilliermondii, 90.2%, 95.1%, and 100%. There was no significant change in the activities of the three echinocandins over the 6-year study period and no difference in activity by geographic region. All three echinocandins have excellent in vitro activities against invasive strains of Candida isolated from centers worldwide. Our prospective sentinel surveillance reveals no evidence of emerging echinocandin resistance among invasive clinical isolates of Candida spp.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests

Hematogenous Candida meningoencephalitis (HCME) is a relatively frequent manifestation of disseminated candidiasis in neonates and is associated with significant mortality and neurodevelopmental abnormalities. The outcome after antifungal therapy is often suboptimal, with few therapeutic options. Limited clinical data suggest that echinocandins may have role to play in the treatment of HCME.. We studied the pharmacokinetics and pharmacodynamics of micafungin in a rabbit model of neonatal HCME and bridged the results to neonates by use of population pharmacokinetics and Monte Carlo simulation.. Micafungin exhibited linear plasma pharmacokinetics in the range of 0.25-16 mg/kg. Micafungin penetrated most compartments of the central nervous system (CNS), but only with doses >2 mg/kg. Micafungin was not reliably found in cerebrospinal fluid. With few exceptions, drug penetration into the various CNS subcompartments was not statistically different between infected and noninfected rabbits. A dose-microbiological response relationship was apparent in the brain, and near-maximal effect was apparent with doses of 8 mg/kg. Monte Carlo simulations revealed that near-maximal antifungal effect was attained at human neonatal doses of 12-15 mg/kg.. These results provide a foundation for clinical trials of micafungin in neonates with HCME and a model for antimicrobial bridging studies from bench to bedside in pediatric patients.

Topics: Animals; Antifungal Agents; Candidiasis; Disease Models, Animal; Dose-Response Relationship, Drug; Echinocandins; Female; Humans; Infant, Newborn; Lipopeptides; Lipoproteins; Meningoencephalitis; Micafungin; Microbial Sensitivity Tests; Monte Carlo Method; Rabbits

There is concern about the rise of antifungal drug resistance, but little is known about comparative biological properties and pathogenicity of drug-resistant strains. We generated fluconazole (FLC; CO23 RFLC)- or micafungin (FK; CO23 RFK)-resistant strains of Candida albicans by treating a FLC- and FK-susceptible strain of this fungus (CO23 S) with stepwise-increasing concentrations of either drug. Molecular analyses showed that CO23 RFLC had acquired markedly increased expression of the drug-resistance efflux pump encoded by the MDR1 gene, whereas CO23 RFK had a homozygous mutation in the FSK1 gene. These genetic modifications did not alter to any extent the growth capacity of the drug-resistant strains in vitro, either at 28 degrees C or at 37 degrees C, but markedly increased their experimental pathogenicity in a systemic mouse infection model, as assessed by the overall mortality and target organ invasion. Interestingly, no apparent increase in the vaginopathic potential of the strains was observed with an estrogen-dependent rat vaginal infection. The increased pathogenicity of drug-resistant strains for systemic infection was associated with a number of biochemical and physiological changes, including (i) marked cellular alterations associated with a different expression and content of major cell wall polysaccharides, (ii) more rapid and extensive hypha formation in both liquid and solid media, and (iii) increased adherence to plastic and a propensity for biofilm formation. Overall, our data demonstrate that experimentally induced resistance to antifungal drugs, irrespective of drug family, can substantially divert C. albicans biology, affecting in particular biological properties of potential relevance for deep-seated candidiasis.

Topics: Animals; Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Candidiasis, Vulvovaginal; Cell Adhesion; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Fungal Proteins; Host-Pathogen Interactions; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Phenotype; Rats; Rats, Wistar; Virulence

We have reported previously that Candida albicans is involved in the pathogenesis of peptic ulcer perforation; it was shown that C. albicans aggravated the severity of duodenal ulceration and increased the rate of perforation. We considered it incumbent upon us to ascertain whether C. albicans is a virulence factor involved in peptic ulcer perforation. In the present study, we administered an antifungal drug (micafungin) intravenously to rats that had received intragastric (i.g.) administration of C. albicans and cysteamine, in order to examine that micafungin could counteract the C. albicans-aggravation of duodenal ulcers.. Cysteamine was administered thrice on day 1 to male Wistar rats. C. albicans was administered to the animals 1 h before, and 12 and 24 h after the first administration of cysteamine. Micafungin (n = 22) or saline (n = 24) was administered 12, 24, and 48 h after the administration of cysteamine.. The area of the duodenal ulcers was also significantly smaller in the micafungin group (P < 0.05). In addition, the survival rate of the rats was significantly higher in the micafungin group (P < 0.05). While in the control group, the ulcer base was found to be colonized by C. albicans, there was no evidence of the presence of C. albicans in the micafungin group.. It was shown that intravenous injection of micafungin counteracted the aggravation by C. albicans of cysteamine-induced duodenal ulcers in rats. This finding supports the concept that C. albicans is an aggravating factor for peptic ulcers.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Cysteamine; Duodenal Ulcer; Echinocandins; Injections, Intravenous; Lipopeptides; Lipoproteins; Male; Micafungin; Rats; Rats, Wistar; Severity of Illness Index; Treatment Outcome

Topics: Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin

Candida guilliermondii (C. guilliermondii) are uncommon, representing approximately 1% of all Candida infections, but have been reported to show a higher rate of drug-resistance and mortality rate than C. albicans. Current guidelines for treatment of non-albicans candidemia in neutropenic patients now recommend the use of amphotericin B or voriconazole (VRCZ). We describe here the successful treatment for a 58-year-old male with azole-refractory C. guilliermondii fungemia by combination with liposomal (L-AmB) and micafungin (MCFG) therapy. He was diagnosed as having mantle cell lymphoma, and treatment with HyperCVAD (Rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) was started. Despite prophylactic treatment with fluconazole, he developed fungemia due to C. guilliermondii 41 days after the start of chemotherapy. Positive blood culture and high levels of (1-->3)-beta-D-glucan persisted despite changing the treatment from fluconazole to voriconazole. Although L-AmB was also added to VRCZ, the clinical symptoms worsened. When MCFG was combined with L-AmB, the symptoms and data dramatically improved. Thus, combination therapy consisting of MCFG and L-AmB might be more effective against candidemia that is refractory to azole than combination therapy with VRCZ and L-AmB.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Azoles; Candidiasis; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Fungemia; Humans; Immunocompromised Host; Lipopeptides; Lipoproteins; Lymphoma, Mantle-Cell; Male; Micafungin; Middle Aged; Treatment Outcome; Vincristine

Caspofungin and micafungin belong to the echinocandins; the mechanism of action of echinocandins is based on the inhibition of (1,3)-beta-D-glucan synthase. The aim of this study was to investigate in vitro the optimal antifungal lock treatment details against a Candida albicans biofilm.. An in vitro model of a C. albicans (ATCC 3153 or ATCC 66396) biofilm associated with 100% silicone catheters was used. The effectiveness of the antifungal treatment was assayed against biofilms aged 12 h or 5 days, after exposure to caspofungin (2 mg/L) or micafungin (5 mg/L) for 12 h. The durability of the reduction in the biofilm metabolic activity was investigated (1-3 days after echinocandin treatment). The efficacy of caspofungin and micafungin was determined by evaluating a significant decrease (P < 0.0001) in the metabolic activity of biofilm yeasts.. The results showed that the tested antifungal agents used as lock solution significantly (P < 0.0001) reduced the metabolic activity of C. albicans, whatever the biofilm maturation stage (12 h or 5 days old biofilms). The reduction in the metabolic activity of biofilm yeasts was maintained, even after 48 h.. These data suggest that caspofungin (2 mg/L) and micafungin (5 mg/L) could represent good candidates for the reduction or control of fungal biofilms associated with silicone medical devices, as part of an antifungal lock. They were able to induce a significant and persistent reduction in the yeast metabolic activity of intermediate and mature biofilms, 12 h and 5 days old, respectively, when used as catheter lock solutions.

Topics: Antifungal Agents; Biofilms; Candida albicans; Candidiasis; Caspofungin; Catheterization; Echinocandins; Equipment and Supplies; Humans; Lipopeptides; Lipoproteins; Micafungin; Silicones; Time Factors

In vitro pharmacodynamic model (PDM) simulation of serum antifungal concentrations may predict the value of combination antifungal regimens against Candida sp. endocarditis. We investigated the effects of combinations of flucytosine (5FC), micafungin (Mica), and voriconazole (Vor) against Candida-infected human platelet-fibrin clots, used as simulated endocardial vegetations (SEVs). Single clinical bloodstream isolates of Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis were used. All four isolates were susceptible to 5FC, while C. glabrata was resistant to Vor and C. tropicalis had a paradoxical resistance phenotype to Mica. The SEVs were prepared with an initial inoculum of 1 x 10(6) CFU/g of SEV and added to a PDM, which utilized yeast nitrogen broth-2% glucose and incubation at 35 degrees C and simulated antifungal pharmacokinetic profiles. Fungal densities in the SEVs were determined in quadruplicate over 72 h. Scanning electron microscopy (SEM) was used to evaluate treatment and control SEVs. Vor was the least active single agent against all Candida spp. except for C. parapsilosis, where it was comparable to Mica. In contrast, 5FC was the most active against all Candida spp. except for C. tropicalis, where it was comparable to Mica. The combination of 5FC plus Vor was superior to either agent alone against C. parapsilosis. The combination of Vor plus Mica was inferior to the use of Mica alone against C. tropicalis. The triple combination of 5FC plus Vor plus Mica was no better than single or dual agents against any of the Candida spp. The ultrastructural features of infected SEVs were unique for each Candida sp., with C. parapsilosis in particular manifesting friable biofilm clusters. In general, 5FC and Mica were superior in their rates and extents of fungal burden reduction compared to Vor against Candida-infected SEVs. Evaluation of 5FC and Mica in animal models of Candida endocarditis is warranted.

Topics: Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candida tropicalis; Candidiasis; Drug Resistance, Fungal; Drug Therapy, Combination; Echinocandins; Endocarditis; Flucytosine; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Models, Biological; Pyrimidines; Triazoles; Voriconazole

The purpose of this study was to investigate whether mechanisms of azole resistance in Candida albicans contribute to reduced micafungin activity in vitro.. MICs were determined for a collection of strains with well-characterized mechanisms of azole resistance obtained from systemic, oral and vaginal infections. This collection of strains includes those with resistance-associated phenotypes. All known molecular mechanisms of azole resistance are included in this set of isolates (alone or in combination). Micafungin activity was further investigated for a subset of isolates by agar dilution.. There was no correlation between any of the azole resistance mechanisms or resistance phenotypes and micafungin activity as determined by MIC, even in isolates with cross-resistance to multiple azole drugs. Overexpression of the ABC transporter CDR2 has been suggested to contribute to reduced echinocandin activity in agar dilution studies. By broth microdilution, there was no difference in MIC between the pump overexpressors and the collection as a whole. However, azole-resistant isolates from matched strains exhibited a small increase in their micafungin MICs relative to their susceptible controls. By agar dilution analysis, multiple CDR2-overexpressing strains exhibited reduced growth in the presence of micafungin relative to the laboratory strain SC5314.. Azole resistance mechanisms do not contribute to increased micafungin MIC as determined by broth microdilution. However, within sets of matched isolates, strains overexpressing CDR2 had a slight increase in micafungin MIC. Changes in micafungin susceptibility are associated with CDR2 overexpression in agar dilution tests.

Topics: Antifungal Agents; ATP-Binding Cassette Transporters; Azoles; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Gene Dosage; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests

A commercially prepared, dried colorimetric microdilution panel (Sensititre YeastOne Trek Diagnostic Systems, Cleveland, OH) was compared in three different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference microdilution method by testing 2 quality control strains, 25 reproducibility strains, and 404 isolates of Candida spp. against anidulafungin, caspofungin, and micafungin. Reference MIC endpoints and YeastOne colorimetric endpoints were read after 24 h of incubation. YeastOne endpoints were determined to be the lowest concentration at which the color in the well changed from red (positive, indicating growth) to blue (negative, indicating no growth). Excellent essential agreement (within 2 dilutions) between the reference and colorimetric MICs was observed. Overall agreement was 100% for all three agents. Categorical agreement ranged from 99.3% (anidulafungin) to 100% (caspofungin, micafungin) and interlaboratory reproducibility was 99%. The YeastOne colorimetric method appears to be comparable to the CLSI reference method for testing the susceptibility of Candida spp. to the echinocandins anidulafungin, caspofungin, and micafungin.

Topics: Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Reference Standards; Reproducibility of Results; Sensitivity and Specificity

To investigate the economic impact of micafungin (MICA) for treatment of invasive candidiasis and candidaemia (systemic Candida infections), a health economic analysis was conducted comparing MICA with liposomal amphotericin B (L-AMB).. The model was based on a phase III, randomised, double-blind, clinical trial which compared MICA with L-AMB. The model entailed a period of 14-20 weeks starting from initiation of treatment and was analysed from a German hospital perspective.. The main outcome measures were defined as the percentage of patients achieving clinical and mycological response after initial treatment and who were alive at the end of the study (EOS), and the total treatment-associated costs over the study period.. The health economic analysis shows that with MICA, 52.9% of patients are successfully treated and were alive at EOS compared to 49.1% for L-AMB. In addition, MICA has, on average, lower treatment-associated costs than L-AMB with euro43 243 and euro49 216 per patient, respectively. Because the costs are lower and the effectiveness is higher for MICA in comparison with L-AMB, MICA is more cost-effective than L-AMB. However, the results of the probabilistic sensitivity analysis show that the differences cannot be considered significant due to a large variance, although MICA remained the most cost-effective option throughout the one-way sensitivity analyses.. The lower costs and higher effectiveness reported for MICA versus L-AMB in this analysis indicate that MICA may be a more cost-effective therapy in the treatment of invasive candidiasis and candidaemia when compared with L-AMB.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Cost-Benefit Analysis; Double-Blind Method; Echinocandins; Germany; Humans; Lipopeptides; Lipoproteins; Micafungin; Models, Economic; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic

The effect of micafungin dose scheduling on the treatment of candidemia is unknown. Neutropenic mice with disseminated Candida glabrata infection were treated with single intraperitoneal micafungin doses of 0 to 100 mg/kg of body weight and sacrificed 7 days later. The maximal decline in kidney fungal burden was 5.8 log(10) CFU/g. A 1-week pharmacokinetic-pharmacodynamic study revealed a micafungin serum half-life of 6.13 h. In mice treated with > or =50 mg/kg, there was maximal fungal decline without regrowth during the 1-week dosing interval. Next, doses associated with 34% (34% effective dose [ED(34)]) and 50% (ED(50)) of maximal kill were administered at one of three dose schedules: a single dose at t = 0, two equal doses at t = 0 and t = 3.5 days, and 7 equal doses daily. Some mice received a single dose of 100 mg/kg. Fungal burden was examined on days 1, 5, and 7. In mice treated with the ED(34), microbial kill with the daily therapy initially lagged behind the intermittent doses but exceeded it by day 7. In mice treated with the ED(50), daily and intermittent doses had equivalent day 7 effects. In mice treated with 100 mg/kg, there was no regrowth. The relative likelihoods that the area under the concentration-time curve/MIC ratio was linked to microbial kill versus peak concentration/MIC ratio or time above the MIC was 10.3 and 10,161.2, respectively. In all the experiments, no paradoxical increase in fungal burden was observed with high micafungin doses. However, only a single Candida isolate was tested. Regimens that simulated micafungin concentration-time profiles in patients treated with a single micafungin dose of 1,400 mg once a week demonstrated maximal fungal decline. Once-weekly micafungin therapy is as efficacious as daily therapy in a murine model of disseminated candidiasis.

Topics: Animals; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Echinocandins; Kidney; Lipopeptides; Lipoproteins; Micafungin; Mice; Microbial Sensitivity Tests; Models, Statistical; Neutropenia; Peptides, Cyclic

Paradoxical growth of some Candida isolates occurs at concentrations above the MIC for echinocandins. In 60 Candida bloodstream isolates from cancer patients (20 C. albicans isolates and 10 isolates each of C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata), paradoxical growth was more frequent with caspofungin than micafungin or anidulafungin, was unrelated to MIC, and was strikingly absent in C. glabrata isolates.

Topics: Antifungal Agents; Candida; Candidiasis; Culture Media; Fungemia; Humans; Microbial Sensitivity Tests; Neoplasms; Peptides, Cyclic; Species Specificity

Disseminated candidiasis is associated with a high rate of morbidity and mortality. The presence of neutrophils and the timely administration of antifungal agents are likely to be critical factors for a favorable therapeutic outcome of this syndrome. The effect of neutropenia on the temporal profile of the burden of Candida albicans in untreated mice and those treated with amphotericin B was determined using a pharmacodynamic model of disseminated candidiasis. A mathematical model was developed to describe the rate and extent of the C. albicans killing attributable to neutrophils and to amphotericin B. The consequences of a delay in the administration of amphotericin B, flucytosine, or micafungin were studied by defining dose-response relationships. Neutrophils caused a logarithmic decline in fungal burden in treated and untreated mice. The combination of amphotericin B and neutrophils resulted in a high rate of Candida killing and a sustained anti-C. albicans effect. In neutropenic mice, 5 mg/kg of body weight of amphotericin B was required to prevent progressive logarithmic growth. An increased delay in drug administration resulted in a reduction in the maximum effect to a point at which no drug effect could be observed. Neutrophils and the timely initiation of antifungal agents are critical determinants in the treatment of experimental disseminated candidiasis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Dose-Response Relationship, Drug; Echinocandins; Flucytosine; Kidney; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Microbial Sensitivity Tests; Neutropenia; Neutrophils; Peptides, Cyclic; Time Factors

An excellent correlation between micafungin MICs were demonstrated against Candida bloodstream isolates (n = 200) by the Sensititre YeastOne and National Committee for Clinical Laboratory Standards M27-A2 methods. Use of antibiotic medium 3 (2%) dextrose improved micafungin activity and was not associated with paradoxical growth as noted with 3 Candida isolates tested using RPMI (2%) dextrose.

Topics: Antifungal Agents; Blood; Candida; Candidiasis; Culture Media; Echinocandins; Fungemia; Glucose; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

To evaluate the efficacy of subconjunctival injection of micafungin in the treatment of experimental Candida albicans keratitis in rabbits compared with fluconazole.. In 1 eye of 24 New Zealand white rabbits, C. albicans (5 x 10 yeast cells) was inoculated in the corneal stroma. The animals were randomly assigned to 3 groups and received subconjunctival injection of 0.5 mL of 0.1% micafungin, 0.2% fluconazole, or physiologic saline once a day for 3 weeks. The eyes were examined slit-lamp biomicroscopically and histopathologically. The clinical course of fungal keratitis was compared among the 3 groups. In another 36 rabbits, a microbiological examination was performed using a quantitative isolate recovery technique, and the numbers of colony-forming units were compared among groups.. The clinical scores were significantly lower in the micafungin group than in the other 2 groups throughout the study period (P < 0.0001 approximately P = 0.0027, Bonferroni multiple comparison). The fluconazole group showed significantly lower clinical scores than the saline group on day 18 (P = 0.0343). At the end of the study period, there were significant differences between the saline and micafungin groups (P < 0.0001), the saline and fluconazole groups (P = 0.0072), and the fluconazole and micafungin groups (P = 0.0013). Histopathologically, similar results were obtained. Moreover, the results of the microbiological examination nearly matched the clinical and histopathologic findings.. Subconjunctival administration of micafungin was effective in the treatment of experimental Candida keratitis. Local application of micafungin to the eye would be a feasible treatment option for clinical fungal keratitis.

Topics: Animals; Antifungal Agents; Candidiasis; Conjunctiva; Disease Models, Animal; Echinocandins; Eye Infections, Fungal; Fluconazole; Injections; Keratitis; Lipopeptides; Lipoproteins; Male; Micafungin; Peptides, Cyclic; Rabbits

A patient with Candida albicans thrush and oesophagitis was treated with high doses of caspofungin but treatment eventually failed. Four C. albicans isolates were serially recovered before and after caspofungin treatment. A microbiological study was performed to characterize these four isolates.. In vitro antifungal susceptibility testing was performed by the EUCAST reference method in RPMI and AM3 and by Etest. Molecular typing of the four isolates was done by sizing three polymorphic microsatellite markers. To look for specific mutations, sequencing of a region of the gene encoding the 1-3-beta-D-glucan synthase was performed for the four isolates.. In vitro antifungal susceptibility testing showed an increase in both caspofungin and micafungin MICs for the two isolates recovered after caspofungin treatment failure. The best discrimination between the pre-treatment and post-treatment isolates was obtained with Etest. Molecular typing of the four isolates showed that the post-treatment isolates with reduced susceptibility were identical to a susceptible pre-treatment isolate, suggesting the acquisition of caspofungin resistance. Sequencing of the gene encoding the 1-3-beta-D-glucan synthase showed a mutation responsible for an amino acid change at Phe-641 that could confer reduced susceptibility to both echinocandins.. Our results indicate that is it useful to perform in vitro susceptibility testing in the cases of clinical failure during caspofungin therapy.

Topics: Adult; Amino Acid Sequence; Amino Acid Substitution; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis; Caspofungin; Drug Resistance, Fungal; Echinocandins; Fluconazole; Genotype; HIV Infections; HIV-1; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Molecular Sequence Data; Peptides, Cyclic; Pyrimidines; Treatment Failure; Triazoles; Voriconazole

Topics: Antifungal Agents; Candida; Candidiasis; Drug Synergism; Echinocandins; Fluconazole; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

Micafungin, the first licensed echinocandin in Japan, has shown excellent in vitro and in vivo activity against all Candida species. However, the appropriate dose for the initial treatment of candidemia remains to be determined. In this study, we retrospectively examined the relationship between the clinical outcome of candidemia and the initial dose of micafungin. Patients were divided into two groups according to the initial dose of micafungin administered: group I (<2.25 mg/kg/day) and group II (>or=2.25 mg/kg/day). Micafungin produced an excellent 30-day clinical response in patients with candidemia, including Candida parapsilosis; the overall 30-day clinical response was 86%. The administration of higher doses of micafungin accelerated the clinical response and duration until the clinical response in group II was significantly shorter than that in group I (P = 0.021). However, no significant differences were observed in the 30-day mortality attributable to the fungal infection between the two groups. Considering these results, we recommend the administration of 2.25 mg/kg/day or more of micafungin in the initial treatment of patients with candidemia.

Topics: Aged; Aged, 80 and over; Antifungal Agents; Candidiasis; Dose-Response Relationship, Drug; Echinocandins; Female; Fungemia; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Retrospective Studies; Survival Analysis

Micafungin is a new echinocandin exhibiting broad-spectrum activity against Candida spp. The activity of the echinocandins against Candida species known to express intrinsic or acquired resistance to fluconazole is of interest. We determined the MICs of micafungin and caspofungin against 315 invasive clinical (bloodstream and other sterile-site) isolates of fluconazole-resistant Candida species obtained from geographically diverse medical centers between 2001 and 2004. MICs were determined using broth microdilution according to the CLSI reference method M27-A2. RPMI 1640 was used as the test medium, and we used the MIC endpoint of prominent growth reduction at 24 h. Among the 315 fluconazole-resistant Candida isolates, 146 (46%) were C. krusei, 110 (35%) were C. glabrata, 41 (13%) were C. albicans, and 18 (6%) were less frequently isolated species. Micafungin had good in vitro activity against all fluconazole-resistant Candida spp. tested; the MICs at which 50% (MIC(50)) and 90% (MIC(90)) of isolates were inhibited were 0.03 microg/ml and 0.06 microg/ml, respectively. All the fluconazole-resistant Candida spp. were inhibited at a micafungin MIC that was

Topics: Antifungal Agents; Candida; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

To illustrate the progressive loss of cross-echinocandin activity on Candida albicans isolates with strong clonal homology from a patient with advanced HIV infection and chronic oesophagitis progressively resistant to uninterrupted micafungin treatment.. Antifungal susceptibility profiles for different antifungal agents were determined against serial C. albicans isolates retrieved before and during therapy. Multilocus sequencing typing (MLST) was performed on each of the isolates. FKS1 mutations conferring reduced susceptibility to echinocandin drugs were determined by DNA sequence analysis.. Four C. albicans isolates showing identical allelic homology were retrieved from the patient at the initiation and during therapy with micafungin. The progressive lack of clinical response to micafungin therapy was associated with increased MICs of all three echinocandin drugs (caspofungin, micafungin and anidulafungin) in association with the acquisition of mutations in the FKS1 gene.. This report documents for the first time a progressive loss of activity of all three echinocandin drugs against clonally related C. albicans isolates following long-term clinical exposure to this new class of antifungal agents.

Topics: Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Esophagitis; Fatal Outcome; Glucosyltransferases; HIV Infections; Humans; Lipopeptides; Lipoproteins; Male; Membrane Proteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic; Saccharomyces cerevisiae Proteins

This is the first report to investigate the antifungal susceptibility of 21 clinical isolates of seven Candida species to epigallocatechin 3-O-gallate (EGCg) and to compare with six antifungal agents, amphotericin B (AMPH), fluconazole (FLCZ), flucytosin (5FC), itraconazole (ITCZ), micafungin (MCFG), and miconazole (MCZ), using a method following the National Committee for Clinical Laboratory Standards (NCCLS) M27-A guidelines. Among the tested species, Candida glabrata exhibited the highest susceptibility to EGCg (MIC50, 0.5-1 microg/ml and MIC90, 1-2 microg/ml) compared favorably with FLCZ, although they were slightly less susceptible than to AMPH, 5FC, MCFG, ITCZ, and MCZ. Candida guilliemondii and Candida parapsilosis (MIC50, 1-4 microg/ml and MIC90, 2-16 microg/ml) were also susceptible to EGCg, although they appear to be slightly less susceptible to EGCg than C. glabrata and the other antifungal agents tested. Moreover, the susceptibility of Candida krusei strains (MIC50, 2 microg/ml and MIC90, 4-8 microg/ml) to EGCg was approximately 2- to 8-fold higher than those of 5FC and FLCZ. Our data indicate that EGCg can inhibit clinically pathogenic Candida species, although the concentrations of EGCg for antifungal susceptibility were slightly higher than those of tested antifungal agents on the whole. Based on these results, we suggest that EGCg may be effectively used as a possible agent or adjuvant for antifungal therapy in Candidiasis.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Catechin; Dose-Response Relationship, Drug; Echinocandins; Fluconazole; Flucytosine; Humans; Itraconazole; Lipopeptides; Lipoproteins; Micafungin; Miconazole; Microbial Sensitivity Tests; Peptides, Cyclic; Species Specificity

Amphotericin B (AMB), micafungin, and caspofungin MICs, minimal fungicidal concentrations, and time-killing curves were determined in the presence and absence of 10% inactivated serum. AMB was the only agent with consistent killing activity (time required to achieve 99.9% of growth reduction was 2.1 to 3.2 h). The presence of serum enhanced caspofungin activity but lowered those of micafungin and AMB.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Caspofungin; Echinocandins; Kinetics; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic

To develop proper treatments for patients who do not respond to current antifungal treatments, we tested new combinations of antifungal drugs for treating disseminated infections by Candida glabrata in a murine model.. Mice were rendered neutropenic by intraperitoneal cyclophosphamide and intravenous 5-fluorouracil administration. The animals were infected intravenously with 2 x 10(8) cfu of C. glabrata. The efficacies of micafungin combined with amphotericin B, fluconazole or flucytosine, and of amphotericin B combined with fluconazole were evaluated by survival and tissue burden reduction.. Micafungin plus amphotericin B was the most effective combination at reducing tissue burden. Micafungin at 10 mg/kg combined with amphotericin B at 0.75, 1.5 or 3 mg/kg prolonged survival with respect to the monotherapies, but only the second combination showed a synergistic effect in reducing fungal load in spleen and kidney. Amphotericin B at 1.5 mg/kg combined with micafungin at 5, 10 or 20 mg/kg reduced tissue burden with respect to the monotherapies, but the effects of the three combinations were very similar. These results suggest that amphotericin B in combination with micafungin is promising for the treatment of disseminated C. glabrata infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Echinocandins; Fluconazole; Flucytosine; Immunocompromised Host; Kidney; Lipopeptides; Lipoproteins; Micafungin; Mice; Peptides, Cyclic; Spleen; Survival Analysis

Long-term inserted and surgically implanted catheters can be colonised by Candida spp. Candida biofilms in vitro are often resistant to antifungal agents. The aim of this study was to investigate the in vitro activity of micafungin (MFG) against six Candida spp. biofilms on polystyrene (PS) and central venous catheter (CVC) sections. Safranin staining and differential interference contrast microscopy were used to demonstrate biofilm production. MFG activity was determined by the reduction in metabolic activity (%RMA) by tetrazolium reduction assay on both substrates. In vitro, Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, Candida dubliniensis and Candida kefyr produced mature biofilms on PS and CVC sections. MFG was active against C. kefyr (0.5 microg/mL) and C. glabrata (<0.5 microg/mL) on PS. However, MFG displayed resistance (>16 microg/mL) against C. albicans, C. dubliniensis,C. tropicalis and C. parapsilosis. On CVC disks, MFG was active against C. glabrata (1 microg/mL) as well as C. parapsilosis and C. albicans (<0.5 microg/mL). MFG was resistant (>16 microg/mL) against C. dubliniensis, C. tropicalis and C. kefyr. MFG was active in vitro against all six Candida spp. on both substrates. However, MFG could not reduce the metabolic activity completely even at the highest concentration.

Topics: Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Biofilms; Candida; Candidiasis; Catheterization, Central Venous; Catheters, Indwelling; Child; Echinocandins; Humans; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Microscopy, Interference; Peptides, Cyclic; Phenazines; Polystyrenes; Staining and Labeling; Tetrazolium Salts

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

We investigated the effects of fluconazole and micafungin for the therapy of deep-seated candidiasis in a cyclophosphamide-induced immunosuppressed mouse model.. We used the experimental model of intraperitoneal fungal abscess caused by Candida albicans, as described previously.. Micafungin efficacy was equal to that of fluconazole in one-tenth dosage even in peritonitis. We also assessed the short-term (24 h) and long-term (8 days) therapeutic effects after the end of therapy. Although the therapeutic effect of fluconazole was similar to that of micafungin at 24 h after the end of therapy, the effect of micafungin was superior to that of fluconazole at 8 days after the end of therapy.

Topics: Animals; Antifungal Agents; Candidiasis; Cyclophosphamide; Dose-Response Relationship, Drug; Echinocandins; Female; Fluconazole; Immunocompromised Host; Immunosuppressive Agents; Lipopeptides; Lipoproteins; Micafungin; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Peptides, Cyclic; Specific Pathogen-Free Organisms

A new intravenous drug for prophylaxis and treatment of Candida infections.

Topics: Adult; Antifungal Agents; Candidiasis; Child; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Fungal; Echinocandins; Esophageal Diseases; Humans; Injections, Intravenous; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Peptides, Cyclic

A 49 year-old woman with chronic renal failure (CRF) on continuous ambulatory peritoneal dialysis (CAPD) because of Goodpasture Syndrome was admitted to our hospital since she had a high fever and severe abdominal pain. A diagnosis of peritonitis was made from the physical examination and laboratory findings. The peritonitis was refractory to conventional antibiotics therapy. Candida parapsilosis was detected from dialysite. The peritonitis was aggravated although the antibiotic was changed to an antifungal agent (fluconazole 400mg/day). Fluconazole was replaced to micafungin (MCFG) and the catheter for CAPD was removed. The fungal peritonitis improved dramatically and beta-D glucan was decreased from 104 to 12.6 (pg/ml). No adverse effect was observed after using MCFG. It has been known that fungal peritonitis of CRF patients is refractory to treatment and the mortality rate is high. To our best knowledge, there is no report that MCFG was used for CRF patients with fungal peritonitis. However, we used MCFG safely and effectively for CRF patients. Therefore, it is suggested that MCFG is a new effective and safe antifungal agent for Candida parapsilosis peritonitis with CRF.

Topics: Antifungal Agents; Candida; Candidiasis; Echinocandins; Female; Humans; Kidney Failure, Chronic; Lipopeptides; Lipoproteins; Micafungin; Middle Aged; Peptides, Cyclic; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis

A 63-year-old woman was admitted to our hospital with fever and cough. Candidemia was diagnosed by blood culture and culture of IVH catheter. Although, the patient was treated with fluconazole, clinical symptoms and chest radiographic findings worsened. After micafungin was replaced with fluconazole, her symptoms, chest radiographic findings improved and stabilized. It is suggested that micafungin is useful for the treatment of candidemia associated with Candida parapsilosis.

Topics: Antifungal Agents; Candidiasis; Catheterization, Peripheral; Echinocandins; Equipment Contamination; Female; Fungemia; Humans; Lipopeptides; Lipoproteins; Micafungin; Middle Aged; Parenteral Nutrition, Total; Peptides, Cyclic; Pneumonia

To report the efficacy of topical application of a new antifungal agent, micafungin (MCFG), in the treatment of yeast-related corneal ulcers.. Noncomparative interventional case reports.. Three patients with yeast-related corneal ulcer after keratoplasty recalcitrant to conventional antifungal treatment for 4 weeks were recruited in this study.. Topical 0.1% antifungal MCFG eye drops were applied in 3 patients with yeast-related corneal ulcer every hour while awake until epithelialization. After epithelialization, the frequency of eye drops was reduced to 5 times a day. MCFG eye drops were discontinued 1 month after the disappearance of stromal infiltration in each case. The patients underwent best corrected visual acuity (BCVA) measurements, slit-lamp examination, fluorescein-dye staining, and anterior segment photography. Corneal scrapings and cultures of surgical materials were also performed.. Changes in ulcer size, stromal infiltration, fluorescein dye staining, and BCVA were looked for.. All corneal ulcers epithelialized within 14 days after commencement of application of 0.1% MCFG eye drops. Yeasts were detected from corneal smears in all eyes. Two cases revealed positive culture isolates for Candida albicans and Candida parapsilosis. No recurrence of fungal keratitis was observed in any of the cases throughout the follow-up periods.. Topical 0.1% MCFG eye drops seem to be an effective and a promising option in the treatment of refractory yeast-related corneal ulcers.

Topics: Administration, Topical; Aged; Antifungal Agents; Candida albicans; Candidiasis; Corneal Ulcer; Echinocandins; Eye Infections, Fungal; Female; Humans; Keratoplasty, Penetrating; Lipopeptides; Lipoproteins; Micafungin; Middle Aged; Ophthalmic Solutions; Peptides, Cyclic; Surgical Wound Infection; Treatment Outcome

Topics: Adolescent; Adult; Antifungal Agents; Candida; Candidiasis; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Internationality; Lipopeptides; Lipoproteins; Male; Micafungin; Peptides, Cyclic; Treatment Outcome

We compared the efficacies of amphotericin B, fluconazole, flucytosine, and micafungin in a systemic murine infection by three isolates of Candida glabrata. Amphotericin B showed the best results, although none of the drugs dramatically reduced mortality or tissue burden in liver or spleen.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Echinocandins; Fluconazole; Flucytosine; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Microbial Sensitivity Tests; Peptides, Cyclic

While Candida albicans remains the most common Candida isolate, Candida glabrata accounts for approximately 15 to 20% of all Candida infections in the United States. In this study we used immunosuppressed mice infected with C. glabrata to investigate the efficacy of liposomal amphotericin B alone or in combination with the echinocandin caspofungin or micafungin. For monotherapy, mice were given six daily doses of liposomal amphotericin B (3 to 20 mg/kg of body weight), caspofungin (1 to 5 mg/kg), or micafungin (2.5 to 10 mg/kg). With concomitant therapy, mice received liposomal amphotericin B (7.5 mg/kg) in addition to caspofungin (2.5 mg/kg) or micafungin (2.5 mg/kg) for 6 days. For sequential therapy, liposomal amphotericin B was administered on days 1 to 3 and caspofungin or micafungin was given on days 4 to 6; conversely, caspofungin or micafungin was administered on days 1 to 3 and liposomal amphotericin B was given on days 4 to 6. Efficacy was based on the number of CFU per gram of kidney 21 days postchallenge. Monotherapy with liposomal amphotericin B (7.5 to 20 mg/kg) was significantly more effective than no drug treatment (control group) (P < 0.05) and demonstrated a dose-dependent response, with 20 mg/kg lowering the CFU/g from 6.3 to 4.2 (significantly different from the value for the control group [P < 0.001]). Monotherapy with all echinocandin doses lowered the CFU/g from 6.0 to 6.4 to 2.7 to 3.3 (significantly different from the value for the control group [P < 0.001]) with no dose-dependent response. Complete clearance of infection could be achieved only when liposomal amphotericin B was given either concomitantly with caspofungin or micafungin or if liposomal amphotericin B was given sequentially with caspofungin. In conclusion, the combination of liposomal amphotericin B with an echinocandin markedly improved the therapeutic outcome in murine C. glabrata systemic infection.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candidiasis; Caspofungin; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Immunocompromised Host; Lipopeptides; Lipoproteins; Liposomes; Micafungin; Mice; Peptides, Cyclic

The aim of this study was to evaluate species distribution and antifungal susceptibility of Candida blood isolates in Japan.. In a 1 year surveillance programme, 535 Candida blood isolates were collected. Identification of species was followed by examination with the broth microdilution method, as described in NCCLS M27-A2, of antifungal susceptibility to six agents, including voriconazole and micafungin, with readings after 24 and 48 h of incubation.. The overall species distribution was: 41% Candida albicans, 23% Candida parapsilosis, 18% Candida glabrata, 12% Candida tropicalis and 2% Candida krusei. The concentrations of fluconazole necessary to inhibit 90% of the isolates (MIC(90)) at 24/48 h were 0.25/1 mg/L for C. albicans, 0.5/2 mg/L for C. parapsilosis, 4/32 mg/L for C. glabrata and 4/>128 mg/L for C. tropicalis. Percentages of fluconazole resistance were 1.8% for C. albicans, 0.8% for C. parapsilosis, 5.2% for C. glabrata and 3.2% for C. tropicalis, taking the tendency of trailing growth of C. tropicalis into account. MIC(90) of voriconazole was 0.5 mg/L, although 35% of isolates less susceptible (>/=16 mg/L) to fluconazole showed resistance (>/=2 mg/L). Micafungin was very active against all species (MIC(90), 0.03 mg/L) except for C. parapsilosis (MIC(90), 2 mg/L).. These data suggest that, in Japan, the species distribution of Candida bloodstream infections and the fluconazole resistance rate are similar to those reported previously in North America and Europe. Voriconazole and micafungin appear to have strong in vitro activity against Candida blood isolates, although continuing surveillance and further clinical research are needed.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Echinocandins; Flucytosine; Humans; Itraconazole; Japan; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

This study presents the efficiency of the experimental antifungal agents 6-amino-2-n-pentylthiobenzothiazole (APB) and the echinocandin micafungin, and amphotericin B against fluconazole-resistant Candida albicans and Candida dubliniensis (MIC95 for fluconazole > 64 mg/l). The benzothiazole APB was less active against C. albicans and C. dubliniensis (MIC80 = 8 - 32 mg/l, MIC95 = 16 - 64 mg/l) than amphotericin B, which was efficient in a concentration range from 0.125 to 2 mg/l. However, the efficiency of micafungin was very high with MIC80, and MIC100 < or = 0.031 mg/l.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic; Thiazoles

Major problems in the management of keratomycosis stem from the difficulty of its diagnosis and limited choice of antifungal agents. In the present paper we propose a new method of detecting (1,3)-beta-D-glucan, one of the major components of fungal cell wall, in tears from an animal model of keratomycosis. In addition, we investigated the efficacy of topical application of micafungin, a new antifungal agent that inhibits the activity of (1,3)-beta-D-glucan synthase in this animal model.. Candida albicans (5 x 10(5) organisms) was inoculated into the corneal stroma of 20 New Zealand White rabbits. The animals were randomly assigned to two groups and treated with subconjunctival injection of 0.5 mL of saline or 0.1% micafungin every day for 3 weeks. The clinical course of keratomycosis in both groups was compared. Before and 3 weeks after the injection of saline or micafungin, 5 microL of tears in each eye were collected by capillary tube. The concentration of (1,3)-beta-D-glucan was quantitatively measured by modified Limulus test.. The concentration of (1,3)-beta-D-glucan was significantly higher in keratomycosis model animals than in controls (mean +/- SD, 17.4 +/- 9.4 pg/mL and 2.8 +/- 1.8 pg/mL, respectively) at 21 days after treatment. Subconjunctival injection of micafungin had no significant effect on ocular lesions of keratomycosis until 9 days, after which ocular lesions significantly improved. Subconjunctival application of micafungin decreased the concentration of (1,3)-beta-D-glucan in tears to 4.9 +/- 3.0 pg/mL at 21 days after treatment.. Increased levels of (1,3)-beta-D-glucan in tears were detected in this model of keratomycosis. Measuring the concentration of (1,3)-beta-D-glucan in tears may be a reliable noninvasive method for the diagnosis of keratomycosis. Topical application of micafungin was effective in the treatment of keratomycosis.

Topics: Animals; beta-Glucans; Candidiasis; Corneal Diseases; Echinocandins; Eye Infections, Fungal; Glucosyltransferases; Limulus Test; Lipopeptides; Lipoproteins; Male; Micafungin; Peptides, Cyclic; Rabbits; Tears

Topics: Anidulafungin; Antifungal Agents; Candidiasis; Caspofungin; Echinocandins; Esophageal Diseases; Fungal Proteins; Humans; Lipopeptides; Lipoproteins; Micafungin; 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

We report a case of candidemia due to Candida krusei after subarachinoid hemorrhage. A 51 year-old male patient consulted us for high fever and increase of CRP 10 days post operation against subarachinoid hemorrhage. There was a temporary decrease in the CRP after administration of ceftazidime (CAZ) but it again when treatment with CAZ was stopped. Because of detected Candida sp. by blood culture, fluconazole was administered i.v. for 5 days, but C. krusei was positive during the treatment. Therefore, fluconazole was replaced with micafungin. The patient became better after the administration with micafungin for 14 days without side effect. Micafungin is effective against candidemia due to C. krusei.

Topics: Antifungal Agents; Candidiasis; Echinocandins; Fungemia; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Peptides, Cyclic

Micafungin is a new echinocandin with broad-spectrum in vitro and in vivo antifungal activity against both Aspergillus and Candida species. We compared the activity of micafungin with that of amphotericin B and fluconazole in a persistently immunocompromised murine model of disseminated candidiasis against a strain of Candida tropicalis that was resistant to amphotericin B and fluconazole in vitro. Mice were rendered persistently neutropenic with multiple doses of cyclophosphamide and infected intravenously with C. tropicalis. Mice were treated with either intraperitoneal amphotericin B (0.5-5 mg/kg per dose), oral fluconazole (50 mg/kg twice a day), intravenous micafungin (1-10 mg/kg per dose) or solvent control for 7 days. Mice were killed at 11 days post-infection and kidneys, lungs, brain and liver removed for quantitative culture. Overall mortality in the model was low, with rates varying between 10% and 25% in treatment groups. Micafungin at doses between 2 and 10 mg/kg were the only regimes able to reduce cfu below the level of detection of tissues infected with C. tropicalis. Micafungin was well tolerated by the mice and was much more effective than amphotericin B or fluconazole against an amphotericin B- and fluconazole-resistant C. tropicalis.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida tropicalis; Candidiasis; Disease Models, Animal; Echinocandins; Lipopeptides; Lipoproteins; Male; Micafungin; Mice; Neutropenia; Peptides, Cyclic

Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

Topics: Animals; Antifungal Agents; Aspergillosis, Allergic Bronchopulmonary; Candidiasis; Echinocandins; Galactose; Lipopeptides; Lipoproteins; Lung; Mannans; Micafungin; Neutropenia; Organ Size; Peptides, Cyclic; Rabbits

The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres. The MIC(50) results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively. The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole. These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.

Topics: Antifungal Agents; Blood; Candida; Candidiasis; Echinocandins; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Neoplasms; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole

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 new (1,3)-beta-D-glucan synthase inhibitor, against azole-resistant Candida albicans strains has been studied. The MIC of FK463 was lower than those of azoles and amphotericin B against CDR1-expressing C26 and CaMDR-expressing C40 strains. All mice treated with FK463 (1 mg/kg) survived disseminated murine candidiasis. The fungal burden in the kidney after 6 days was markedly reduced after therapy with FK463 and amphotericin B sodium deoxycholate, and plasma (1,3)-beta-D-glucan concentration was found to be lower in FK463-treated mice. In our study, FK463 was found to be a potent antifungal agent against disseminated infection with azole-resistant C. albicans.

Topics: Animals; Antifungal Agents; Azoles; Candida albicans; Candidiasis; Drug Resistance, Microbial; Echinocandins; Lipopeptides; Lipoproteins; Micafungin; Mice; Peptides, Cyclic

The antifungal activity of FK463 against 72 recent clinical isolates of Candida albicans (24), Candida glabrata (17), Candida tropicalis (11), Candida krusei (8) and Candida parapsilosis (12) was compared with those of amphotericin B, fluconazole and itraconazole by means of a broth microdilution method specified by the National Committee for Clinical Laboratory Standards (NCCLS) document M27-A. The lowest drug concentration at which 90% of the population was inhibited (MIC(90)) of FK463 against C. albicans, C. glabrata, C. tropicalis, C. krusei and C. parapsilosis was 0.0156, 0. 0156, 0.0313, 0.125 and 1 mg/L, respectively. FK463 exhibited broad-spectrum activity against clinically important Candida spp. (MIC range < or =0.0039-2 mg/L), and its MICs for such fungi were lower than those of other antifungal agents tested. The minimum fungicidal concentrations for Candida spp. did not differ by more than two-fold from the MICs. Results from pre-clinical evaluations performed to date indicate that FK463 should be a potent parenteral antifungal agent.

Topics: Antifungal Agents; Candida; Candidiasis; Echinocandins; Humans; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Peptides, Cyclic