Echinocandins are a class ofantifungal drugs[1] that inhibit the synthesis ofβ-glucan in the fungalcell wall vianoncompetitive inhibition of theenzyme1,3-β glucan synthase.[2][3] The class has been dubbed the "penicillin of antifungals,"[4] along with the relatedpapulacandins, as their mechanism of action resembles that of penicillin in bacteria.β-glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components, the fungal equivalent to bacterialpeptidoglycan.Caspofungin,micafungin, andanidulafungin aresemisynthetic echinocandin derivatives with limited clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.[5]
Drugs and drug candidates in this class are fungicidal against some yeasts (most species ofCandida, but notCryptococcus,Trichosporon, andRhodotorula). Echinocandins also have displayed activity againstCandida biofilms, especially in synergistic activity with amphotericin B and additive activity with fluconazole. Echinocandins are fungistatic against some molds (Aspergillus, but notFusarium andRhizopus), and modestly or minimally active against dimorphic fungi (Blastomyces andHistoplasma). They have some activity against the spores of the fungusPneumocystis jirovecii, formerly known asPneumocystis carinii. Caspofungin is used in the treatment of febrile neutropenia and as "salvage" therapy for the treatment of invasive aspergillosis.[6][clarification needed] Micafungin is used as prophylaxis againstCandida infections inhematopoietic stem cell transplantation patients.[6]
All three agents are well-tolerated, with the most common adverse effects being fever, rash, nausea, andphlebitis at the infusion site. They can also cause a histamine-like reaction (flushing) when infused too rapidly.[7] Toxicity is uncommon. Its use has been associated with elevated aminotransferases and alkaline phosphatase levels.[8]
The present-day clinically used echinocandins are semisynthetic pneumocandins, which are chemically lipopeptide in nature, consisting of large cyclic hexapeptoids. Caspofungin, micafungin, and anidulafungin are similar cyclic hexapeptide antibiotics linked to long modified N-linked acyl fatty acid chains. The chains serve as anchors on the fungal cell membrane to facilitate antifungal activity.[9] Due to their limited oral bioavailability, echinocandins are administered through intravenous infusion.[10]
Echinocandins noncompetitively inhibit beta-1,3-D-glucan synthase enzyme complex in susceptible fungi to disturb fungal cell glucan synthesis.[11]Beta-glucan destruction prevents resistance against osmotic forces, which leads to cell lysis.[12] They have fungistatic activity againstAspergillus species and fungicidal activity against mostCandida spp., including strains that are resistant to fluconazole.[6]In vitro and mouse models show echinocandins may also enhance host immune responses by exposing highly antigenic beta-glucanepitopes that can accelerate host cellular recognition and inflammatory responses.[13]
Echinocandinresistance is rare amongCandida spp. However, case studies have shown some resistance inC. albicans,C. glabrata,C. lusitaniae,C. tropicalis, andC. parapsilosis. Resistance patterns include alterations in the glucan synthase (Fks1-Fks2 complex), overexpression of efflux pumps, strengthening of cell wall by increased chitin production, upregulation of stress-response pathways,[14] and dysregulation of mismatch repair pathways. In addition a few species and strains ofCandida spp. andAspergillus spp. show a "paradoxic effect", i.e., they are susceptible to low concentrations but resistant to high concentrations in broth microdilution studies.[15]
Several non-candidal yeasts, e.g.,Cryptococcus,Trichosporon,Rhodotorula andBlastoschizomyces and filamentous fungi likeFusarium, zygomycetes andScedosporium are often resistant to echinocandins.[16] Echinocandins have weak in vitro activity (a high minimum inhibitory concentration) and very little clinical efficacy againstHistoplasma,Blastomyces, andCoccidioides, especially their yeast forms.[17]
Due to the large molecular weight of echinocandins, they have poor oral bioavailability and are administered by intravenous infusion. In addition, their large structures limit penetration into cerebrospinal fluid, urine, and eyes. In plasma, echinocandins have a high affinity to serum proteins. Echinocandins do not have primary interactions with CYP450 or P-glycoprotein pumps. Caspofungin has triphasic nonlinear pharmacokinetics, while micafungin (hepatically metabolized by arylsulfatase, catechol O-methyltransferase, and hydroxylation) and anidulafungin (degraded spontaneously in the system and excreted mostly as a metabolite in the urine) have linear elimination.[8][18][19] Younger patients exhibit a faster rate of elimination of micafungin and caspofungin.[20]
Caspofungin has some interference withciclosporin metabolism, and micafungin has some interference withsirolimus (rapamycin), but anidulafungin needs no dose adjustments when given with ciclosporin,tacrolimus, orvoriconazole.[21]
Advantages of echinocandins:[citation needed]
Disadvantages of echinocandins:
List of echinocandins:[23]
Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain ofPapularia sphaerosperma (Pers.), which were liposaccharide - i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase - and had action only onCandida spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity againstCandida spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first of these newer echinocandins to be approved by the U.S. Food and Drug Administration was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations have very low oral bioavailability, so they must be given intravenously to be useful. Echinocandins have become one of the first-line treatments forCandida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.[citation needed]
Media related toEchinocandins at Wikimedia Commons