Echinocandins - structure, mechanism of action and use in antifungal therapy.

With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of echinocandins is based on the inhibition of ß-(1,3)-d-glucan synthesis that builds the fungal cell wall. Caspofungin, micafungin, anidulafungin and rezafungin are semi-synthetic cyclic lipopeptides. Their specific chemical structure possess a potential to obtain novel derivatives with better pharmacological properties resulting in more effective treatment, especially in infections caused by Candida and Aspergillus species. In this review we summarise information about echinocandins with closer look on their chemical structure, mechanism of action, drug resistance and usage in clinical practice. We also introduce actual trends in modification of this antifungals as well as new methods of their administration, and additional use in viral and bacterial infections.

Successful eradication of chronic symptomatic Candida krusei urinary tract infection with increased dose micafungin in a liver and kidney transplant recipient: Case report and review of the literature.

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.

Micafungin Enhances the Human Macrophage Response to Candida albicans through ß-Glucan Exposure.

Micafungin belongs to the antifungal family of echinocandins, which act as noncompetitive inhibitors of the fungal cell wall ß-1,3-d-glucan synthase. Since Candida albicans is the most prevalent pathogenic fungus in humans, we study the involvement of micafungin in the modulation of the inflammatory response developed by human tissue macrophages against C. albicans The MIC for micafungin was 0.016 µg/ml on the C. albicans SC5314 standard strain. Micafungin induced a drastic reduction in the number of exponential SC5314 viable cells, with the fungicidal effect being dependent on the cellular metabolic activity. Notably, micafungin also caused a structural remodelling of the cell wall, leading to exposure of the ß-glucan and chitin content on the external surface. At the higher doses used (0.05 µg/ml), the antifungal also induced the blowing up of budding yeasts. In addition, preincubation with micafungin before exposure to human tissue macrophages enhanced the secretion of tumor necrosis factor alpha (TNF-α), interleukin-17A (IL-17A), and IL-10 cytokines. Our results strongly suggest that in C. albicans treatment with micafungin, in addition to having the expected toxic antifungal effect, it potentiates the immune response, improving the interaction and activation of human macrophages, probably through the unmasking of ß-glucans on the cell wall surface.

In vitro combination therapy with isavuconazole against Candida spp.

Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.

Breakthrough fungemia due to Candida fermentati with fks1p mutation under micafungin treatment in a cord blood transplant recipient.

The prophylactic use of antifungal drugs in allogeneic hematopoietic cell transplant recipients has revealed that the rate of non-albicans candidemia has increased. We herein report the case of a patient with adult T-cell leukemia who developed candidemia due to Candida fermentati during micafungin treatment after cord blood transplantation. The isolate was identified on day 47 by sequencing of the internal transcribed spacer region of the ribosomal RNA gene. The sequencing of the hot spot region of fks1p of isolate revealed naturally occurring amino acid substitutions, which conferred reduced echinocandin susceptibility. This case highlights that breakthrough candidemia due to C. fermentati occurred in a patient receiving micafungin treatment.

Echinocandins: The Expanding Antifungal Armamentarium.

The echinocandins are large lipopeptide molecules that, since their discovery approximately 41 years ago, have emerged as important additions to the expanding armamentarium against invasive fungal diseases. Echinocandins exert in vitro and in vivo fungicidal action against most Candida species and fungistatic action against Aspergillus species. However, the population of patients at risk for developing invasive fungal infections continues to increase. New therapeutic strategies using echinocandins are needed to improve clinical outcomes in patients with invasive fungal disease.

The Role of Echinocandins in Candida Biofilm-Related Vascular Catheter Infections: In Vitro and In Vivo Model Systems.

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.

Role of Echinocandins in Fungal Biofilm-Related Disease: Vascular Catheter-Related Infections, Immunomodulation, and Mucosal Surfaces.

Biofilm-related infections have become an increasingly important clinical problem. Many of these infections occur in patients with multiple comorbidities or with impaired immunity. Echinocandins (caspofungin, micafungin, and anidulafungin) exert their fungicidal activity by inhibition of the synthesis of the (1→3)-ß-d-glucan. They are active among in vitro and in vivo model systems against a number of Candida species and filamentous fungi in their planktonic and biofilm phenotype. Their superior activity against biofilms poses them in an advantageous position among the antifungal armamentarium. However, additional studies are warranted to expand our knowledge on the role of echinocandins against biofilm-related infections.

Single or 2-Dose Micafungin Regimen for Treatment of Invasive Candidiasis: Therapia Sterilisans Magna!

The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximum-tolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that the concentration will persist above minimum inhibitory concentrations of Candida species for several days. Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each other, is not only logical, but might even lead to faster clearance of Candida.

Impact of special patient populations on the pharmacokinetics of echinocandins.

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.

Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis.

BACKGROUND: The purpose of the current study was to prevent bloodstream infection and invasive fungal infection (IFI) by administering prophylactic antibiotic and antifungal agents during intensive chemotherapy in patients being treated for acute leukemia. METHODS: Prophylaxis treatment was administered during intensive chemotherapy in children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) from January 1, 2010 to December 31, 2012. Oral ciprofloxacin (at a dose of 300 mg/m(2) /12 hours) was administered after chemotherapy when a patient with AML or ALL became neutropenic and > 7 days of neutropenia was expected. Voriconazole (at a dose of 4 mg/kg/12 hours) was initiated at the onset of neutropenia in patients with AML and after 7 days of neutropenia in patients with ALL. Micafungin (at a dose of 2 mg/kg/day) was substituted for voriconazole when patients with ALL received vincristine. Prophylaxis treatment was discontinued when the absolute neutrophil count recovered to > 100/µL. All episodes of bloodstream infection, IFI, febrile neutropenia, and intensive care unit stays related to severe infection occurring between January 1, 2005 and December 31, 2012 were recorded. RESULTS: During the preprophylaxis period, 62 children with ALL and 24 children with AML experienced a total of 44 episodes of bloodstream infection and 22 episodes of IFI. Seven patients died of severe infection. In contrast, in the prophylaxis period, 10 episodes of bloodstream infection occurred and no IFIs were reported to occur in 51 patients with ALL and 14 patients with AML. Moreover, no patient died of severe infection. Episodes of febrile neutropenia and intensive care unit stay were significantly reduced during the prophylaxis period. CONCLUSIONS: Prophylaxis with ciprofloxacin and voriconazole or micafungin was found to reduce the rates of bloodstream infection and IFI in children with acute leukemia undergoing intensive chemotherapy.

The cell wall protein Rhd3/Pga29 is over-expressed in Candida albicans upon micafungin treatment.

Candida albicans cell wall constitutes a sensitive boundary that undergoes molecular changes upon environmental injuries. Antimycotics exert an intense action on cell wall eliciting both qualitative and quantitative changes of resident proteins. The emergence of drug resistance is marked by a modulation of cell wall proteomic profile. In this study, we monitored, at the proteome level through a two-dimensional gel electrophoresis-based approach, differences of cell wall proteins in sensitive and resistant strains of C. albicans, and variations occurring upon treatment of these strains with antifungal drugs. We identified Rhd3/Pga29, a glycophosphatidylinositol (GPI)-anchored protein, as the main over-expressed protein in micafungin resistant strain with respect to the sensitive control cells. A further increase of Rhd3/Pga29 took place when these resistant strains were treated with sub-lethal dose of micafungin. These results were also confirmed in other two clinical isolates resistant to caspofungin. Results were validated by Western blot analyses and RT-PCR and immunoelectron microscopy images confirmed the increase of the Rhd3/Pga29 on the cell wall as well as in the cytosolic compartment of the micafungin-treated resistant cells. Rhd3/Pga29 over-expression upon echinocandin treatment could represent a strategy of C. albicans to counteract the toxic action of this drug. A role of this protein has also been claimed in the virulence of the fungus, suggesting an involvement of Rhd3/Pga29 in the relationship between C. albicans and the host.