Combined Effect of Platelets and Anidulafungin against Aspergillus fumigatus Infections
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Invasive aspergillosis (IA) is one of the major causes of morbidity and mortality in severely immunocompromised patients. Despite the existence of antifungal treatment IA mortality rate remains extremely high and may reach up to 80%. Previous studies have suggested important role of platelets in antifungal host defence. In vitro data show that platelets are able to attenuate germination, hyphal elongation and viability of Aspergillus fumigatus. Interaction of platelets with Aspergillus fumigatus induces differential expressions of fungal genes associated with stress response regulation, cellular transport and metabolism. A new class of antifungals, echinocandins (caspofungin, micafungin and anidulafungin), have entered the market. Anidulafungin displays strong antifungal activity against Candida and Aspergillus species and has very few side effects due to its specific inhibiting effect on the fungal cell wall synthesis. Anidulafungin is currently licensed for the treatment of adult patients with invasive candidiasis. Clinical significance of anidulafungin for IA treatment has to be further evaluated. Recently published studies have shown that efficiency of antifungal substances can be enhanced when combined with platelets. In this review we discuss the literature on the potential combined effect of platelets and anidulafungin against Aspergillus fumigatus infections.Keywords:
Anidulafungin
Echinocandins
Echinocandins
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-β-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.
Echinocandins
Echinocandins
Anidulafungin
Esophageal candidiasis
Salvage therapy
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Echinocandins
Anidulafungin
Echinocandins
Candida parapsilosis
Azole
Candida glabrata
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The echinocandins are a new and unique class of antifungal agents that act on the fungal cell wall by way of noncompetitive inhibition of the synthesis of 1,3-beta-glucans. All agents of this class are of parenteral formulation, with no oral preparations available. Caspofungin (Cancidas) was the first approved echinocandin, followed recently by micafungin (Mycamine) and anidulafungin (Eraxis). The precise role of the echinocandins in the antifungal armamentarium is still unfolding. Caspofungin is approved for the treatment of candidal esophagitis and candidemia, salvage therapy of Aspergillus infections and for empirical therapy of febrile neutropenia. Micafungin is likewise approved for candidal esophagitis, in addition to antifungal prophylaxis for hematopoietic stem cell transplant recipients. Anidulafungin is also approved for treatment of candidal esophagitis, as well as therapy of candidemia. There has been anecdotal use of these agents to treat less common fungal pathogens, as well as limited use as a component of combination antifungal therapy. The echinocandins are an important addition to the antifungal armamentarium in the treatment of fungal infections in both immunocompromised patients and those with normal immunity.
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Echinocandins
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Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined by BMD method according to CLSI (M27 Ed4). Disconnected growth (PG plus TE) was most frequent with caspofungin (49.6%), followed by anidulafungin (33.7%), micafungin (25.7%), while it was least frequent with rezafungin (16.9%). PG was relatively common in the case of caspofungin (30.1%) but was rare in the case of rezafungin (3.0%). C. tropicalis, C. albicans, C. orthopsilosis and C. inconspicua exhibited PG most frequently with caspofungin, micafungin or anidulafungin. PG never occurred in the case of C. krusei isolates. Against C. tropicalis and C. albicans, echinocandins frequently showed PG after 24 h followed by TE after 48 h. All four echinocandins exhibited TE for the majority of C. auris and C. dubliniensis isolates. Disconnected growth was common among Candida species and was echinocandin- and species-dependent. In contrast to earlier echinocandins, PG was infrequently found with rezafungin.
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To identify and evaluate available data on pediatric echinocandin use.A PubMed search, limited to English-language articles, was conducted (1990-August 2009) using the search terms echinocandin, pediatric, child, pharmacokinetics, caspofungin, micafungin, and anidulafungin. Additional articles were retrieved from citations of selected references.Relevant information on the pharmacology, pharmacokinetics, efficacy, and safety of echinocandins in children was selected. Clinical trials, retrospective reviews, and case series were identified and evaluated. Data from these sources were included in this review.Caspofungin is the only echinocandin approved by the Food and Drug Administration for use in children. Pediatric pharmacokinetics has been evaluated with all 3 echinocandins but is limited with anidulafungin. Micafungin is the most well-studied agent in prospective clinical trials for antifungal prophylaxis in stem cell transplantation and treatment of invasive fungal infections. Caspofungin has been studied prospectively for febrile neutropenia and treatment of invasive fungal infections, but most published data are from retrospective reviews or case reports. One case report of anidulafungin for neonatal candidiasis has been published. The role of echinocandins in the management of invasive pediatric fungal infections has expanded. Micafungin and caspofungin are recommended as primary or alternative treatment of candidemia and esophageal or invasive candidiasis, and as salvage therapy for invasive aspergillosis. Micafungin is recommended for neutropenic prophylaxis in stem cell transplantation, while caspofungin may be used in febrile neutropenia as an alternative to azoles. Dosing has been well established for caspofungin only in children 3 months of age and above. Anidulafungin should be avoided in children until more pharmacokinetic and clinical data become available.Further comparative trials are needed to more clearly define the role of echinocandins, either as monotherapy or in combination for difficult-to-treat infections, in the pediatric population.
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Abstract: The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains of Candida , may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents. Keywords: echinocandins, caspofungin, anidulafungin, micafungin, pharmacokinetics, antifungals
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Esophageal candidiasis
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The echinocandins are a recently-developed class of antifungal agents that interfere with fungal cell wall synthesis through the inhibition of glucan synthesis. Although several intravenous preparations are in various stages of development, caspofungin is the only currently approved agent and no oral echinocandin derivatives are presently available. Caspofungin is approved for the treatment of invasive aspergillosis in patients who are refractory to, or intolerant of, other antifungal therapies. This agent has activity against most Candida species, and in a prospective randomized trial, was as effective as, and better tolerated than amphotericin B in the treatment of candidal esophagitis. Activity against the cyst form of Pneumocystis carinii has also been demonstrated. Caspofungin is administered in a daily intravenous dose, and is well tolerated. Concomitant use of this agent with cyclosporine is presently not recommended. Other echinocandin derivatives presently in phase II/III clinical development include micafungin and anidulafungin.
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Anidulafungin
Esophageal candidiasis
Refractory (planetary science)
Concomitant
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Echinocandins are an interesting group of antifungals that were originally discovered in the early 1970s. They are a group of lipopeptides produced by fungi which consists of a large number of structural analogs of echinocandin B, the first echinocandin to be structurally characterized. All clinically used echinocandins are produced semi-synthetically. The cyclic peptide nuclear core is retained while the acyl chain is replaced to minimize toxicity and expand their spectrum of activity. It was not until 2002 with the introduction of caspofungin (Cancidas) into the clinics that their true worth was realized. Since the introduction of caspofungin, two other echinocandins, micafungin (Mycamine) and anidulafungin (Eraxis) have been introduced. They all function by inhibiting an enzyme unique for fungal cell wall production, which presumably accounts for their minimal side-effects. In this review, topics pertaining to their production, structural diversity, and use in the clinic along with the recent patents are discussed.
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