echinocandin-b and Candidiasis

Anidulafungin, a new echinocandin, has recently been approved for the treatment of esophageal candidiasis, candidemia and other forms of invasive candidiasis, such as peritonitis and intra-abdominal abscesses in non-neutropenic patients. It is fungicidal against Candida spp. including those that are azole- and polyene-resistant and fungistatic against Aspergillus spp. Owing to its poor oral bioavailability it can only be administered intravenously. Its pharmacokinetics allow for once-daily dosing and a steady state concentration is easily achieved on day 2 following a loading dose of double the maintenance dose on day 1. It does not need adjustment for hepatic or renal insufficiency; there are no known drug interactions and it has a favorable tolerability profile. Its mechanism of action, which differs from other classes of antifungals, should prevent cross-resistance with azoles and polyenes.

Topics: Anidulafungin; Animals; Candidiasis; Drugs, Investigational; Echinocandins; Fungal Proteins; Humans; Peptides, Cyclic

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

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

A panel of infectious disease specialists, clinical microbiologists and hospital epidemiologists of the five Swiss university hospitals reviewed the current literature on the treatment of invasive fungal infections in adults and formulated guidelines for the management of patients in Switzerland. For empirical therapy of Candida bloodstream infection, fluconazole is the drug of choice in non-neutropenic patients with no severe sepsis or septic shock or recent exposure to azoles. Amphotericin B deoxycholate or caspofungin would be the treatment option for patients with previous azole exposure. In neutropenic patients, empirical therapy with amphotericin B deoxycholate is considered first choice. In patients with severe sepsis and septic shock, caspofungin is the drug of first choice. For therapy of microbiologically-documented Candida infection, fluconazole is the drug of choice for infections due to C. albicans, C. tropicalis or C. parapsilosis. When infections are caused by C. glabrata or by C. krusei, caspofungin or amphotericin B deoxycholate are first line therapies. Treatment guidelines for invasive aspergillosis (IA) were stratified into primary therapy, salvage therapy and combination therapy in critically ill patients. Voriconazole is recommended for primary (ie upfront) therapy. Caspofungin, voriconazole (if not used for primary therapy) or liposomal amphotericin B are recommended for salvage therapy for refractory disease. Combination therapy with caspofungin plus voriconazole or liposomal amphotericin B should be considered in critically ill patients. Amphotericin B deoxycholate is recommended as initial therapy for the empirical therapy in patients with neutropenia and persistent fever with close monitoring of adverse events.

Topics: Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Clinical Trials as Topic; Drug Therapy, Combination; Echinocandins; Fungal Proteins; Humans; Peptides, Cyclic; Polyenes; Switzerland

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

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability. Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy. Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B. In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. F

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Clinical Trials as Topic; Drug Therapy, Combination; Echinocandins; Fluconazole; Flucytosine; Fungal Proteins; Humans; Infant, Newborn; Peptides; Peptides, Cyclic

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

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

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

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

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 is a leading cause of late onset infection (> 3 days of age) in the premature infant. Therefore, decisions about the diagnosis and management of infections caused by Candida are commonplace in the neonatal intensive care unit. Despite this fact, there are few comparative trials about treatment of neonatal Candida infections to guide the practitioner. New antifungals have been developed in the past decade and some clinical experience has been reported that can be used to guide the treatment of infants with serious Candida infections. This article reviews recent pertinent data with regard to dosing guidelines, efficacy, and toxicities of available systemic antifungal agents in the newborn.

Topics: Amphotericin B; Antifungal Agents; Candidiasis; Caspofungin; Cross Infection; Echinocandins; Fluconazole; Flucytosine; Fungal Proteins; Fungemia; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Ketoconazole; Lipopeptides; Peptides; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

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

Echinocandin B (ECB) is a key precursor of antifungal agent Anidulafungin, which has demonstrated clinical efficacy in patients with invasive candidiasis. In this study, the effects of microparticle-enhanced cultivation and methyl oleate on echinocandin B fermentation titer were investigated. The results showed that the titer was significantly influenced by the morphological type of mycelium, and mycelium pellet was beneficial to improve the titer of this secondary metabolism. First, different carbon sources were chosen for the fermentation, and methyl oleate achieved the highest echinocandin B titer of 2133 ± 50 mg/L, which was two times higher than that of the mannitol. The study further investigated the metabolic process of the fermentation, and the results showed that L-threonine concentration inside the cell could reach 275 mg/L at 168 h with methyl oleate, about 2.5 times higher than that of the mannitol. Therefore, L-threonine may be a key precursor of echinocandin B. In the end, a new method of adding microparticles for improving the mycelial morphology was used, and the addition of talcum powder (20 g/L, diameter of 45 µm) could make the maximum titer of echinocandin B reach 3148 ± 100 mg/L.

Topics: Aspergillus nidulans; Candidiasis; Carbon; Culture Media; Echinocandins; Fermentation; Fungal Proteins; Mannitol; Microspheres; Mycelium; Oleic Acids; Talc; Threonine; Viscosity

The echinocandin susceptibilities of bloodstream Candida isolates growing in a biofilm was investigated. Within the therapeutic range of concentrations of each drug, caspofungin and micafungin were active against biofilms formed by Candida albicans or C. glabrata but not those formed by C. tropicalis or C. parapsilosis.

Topics: Antifungal Agents; Biofilms; Blood; Candida; Candidiasis; Echinocandins; Fungal Proteins; Microbial Sensitivity Tests; Peptides, Cyclic; Species Specificity

To develop a rapid flow-cytometric antifungal susceptibility test and to compare results with the standard methods.. Reference and laboratory strains of Candida were tested for susceptibility to fluconazole and echinocandin by fluorescent flow cytometry using Acridine Orange as indicator of viability. Flow cytometry results were compared with MICs as determined by macrodilution and/or Etest.. Seventy Candida strains were tested for susceptibility to fluconazole, and 74 strains for susceptibility to echinocandin. Minimal concentration of fluconazole causing 40% cell damage, as determined by flow cytometry, showed excellent association with MIC, as determined by other methods. The flow method, completed within 5 h, had excellent sensitivity and specificity to distinguish between sensitive, susceptible dose-dependent and resistant strains. The flow cytometry method for echinocandin was completed within 3 h, and minimal concentration causing 50% cell damage was associated with MIC as determined by macrodilution.. Antifungal susceptibility testing by FACS is a reliable, rapid method for determining susceptibility of Candida to fluconazole and echinocandin. The method allows same-day results, assisting in the selection of appropriate antifungal therapy.

Topics: Antifungal Agents; Candida; Candidiasis; Echinocandins; Flow Cytometry; Fluconazole; Fungal Proteins; Humans; Microbial Sensitivity Tests; Peptides, Cyclic; Reproducibility of Results; Sensitivity and Specificity; Time Factors

Resistance problems with caspofungin, an echinocandin inhibitor of fungal cell wall glucan synthesis, have been rare. We noted paradoxical turbid growth of Candida albicans isolates in broth in some high (supra-MIC) concentrations. Among isolates submitted for susceptibility testing and screened at drug concentrations up to 12.5 microg/ml, the frequency was 16%. Analysis of the turbid growth indicated slowing of growth in the presence of drug but with numbers of CFU up to 72% those of drug-free controls. Clearing of growth again by the highest drug concentrations produced a quadriphasic pattern in a tube dilution series. Cells growing at high drug concentrations were not resistant on retesting but showed the paradoxical effect of the parent. Among a selected series of isolates tested at concentrations up to 50 microg/ml, an additional 53% showed a "mini-paradoxical effect": no turbid growth but incomplete killing at high concentrations (supra-minimum fungicidal concentration). These effects were reproducible; medium dependent in extent; noted in macro- and microdilution, in the presence or absence of serum, and on agar containing drug (but not when drug concentrations were not constant, as in agar diffusion); not seen with other echinocandins and less commonly in other Candida species; and not due to destruction of drug in tubes showing the effect. Cooperative enhancement of inhibition by a second drug could eradicate the effect. We postulate that high drug concentrations derepress or activate resistance mechanisms. The abilities of subpopulations to survive at high drug concentrations could have in vivo consequences.

Topics: Antifungal Agents; Candida albicans; Candidiasis; Caspofungin; Colony Count, Microbial; Culture Media; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Echinocandins; Endpoint Determination; Fungal Proteins; Humans; Lipopeptides; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic; Phenotype

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

The synthesis and biological properties of a novel water-soluble echinocandin-like lipopeptide, FR131535, are described. This compound displayed potent in vitro and in vivo antifungal activities. The hemolytic activity of FR901379 was reduced by replacing the acyl side chain. This compound showed good water-solubility, comparable to the natural product FR901379.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bronchogenic Cyst; Candida albicans; Candidiasis; Disease Models, Animal; Echinocandins; Female; Fungal Proteins; Glucosyltransferases; Hemolysis; Membrane Proteins; Mice; Mice, Nude; Peptides; Peptides, Cyclic; Pneumonia, Pneumocystis; Schizosaccharomyces pombe Proteins; Solubility

In the course of screening for antifungal antibiotics, we have discovered a novel series of lipopeptide compounds structurally related to, but highly superior to, echinocandin B in terms of their water solubility due to the presence of a sulfate residue. These compounds, WF11899s, WF738s, WF14573s, WF16616 and WF22210, and their derivatives have diversity in their nuclear structures and acyl side chains. The producing strains were classified into two groups, the Coleomycetes group and the Hyphomycetes group. Compound FK463, a derivative of WF11899A, is currently in Phase 3 clinical development as a novel antifungal antibiotic.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Candidiasis; Disease Models, Animal; Echinocandins; Fungal Proteins; Fungi; Glucosyltransferases; Humans; Membrane Proteins; Mice; Microbial Sensitivity Tests; Mitosporic Fungi; Peptides; Peptides, Cyclic; Schizosaccharomyces pombe Proteins

The synthesis and biological activity of a series of N-alkylated derivatives of echinocandin B are described and compared with the N-acylated analogs. The linear, rigid geometry of the side chain that was essential to improve the antifungal potency of the N-acylated series gave similar in vitro results with the N-alkylated derivatives. However the slight structural variation forfeited all in vivo activity.

Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Candidiasis; Chromatography, High Pressure Liquid; Echinocandins; Fungal Proteins; Humans; Mass Spectrometry; Mice; Microbial Sensitivity Tests; Peptides; Peptides, Cyclic