Echinocandin


Echinocandins are a new class of antifungal drugs that inhibit the synthesis of β-glucan in the fungal cell wall via noncompetitive inhibition of the enzyme 1,3-β glucan synthase. The class has been termed the "penicillin of antifungals," along with the related papulacandins, 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, equivalent to bacterial peptidoglycan. Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.

Medical uses

Drugs and drug candidates in this class are fungicidal against some yeasts. Echinocandins also have displayed activity against Candida biofilms, especially in synergistic activity with amphotericin B and additive activity with fluconazole. Echinocandins are fungistatic against some molds, and modestly or minimally active against dimorphic fungi. These have some activity against the spores of the fungus Pneumocystis jirovecii, formerly known as Pneumocystis carinii. Caspofungin is used in the treatment of febrile neutropenia and as salvage therapy for the treatment of invasive aspergillosis. Micafungin is used as prophylaxis against Candida infections in hematopoietic stem cell transplantation patients.

Side effects

All three agents are well tolerated, with the most common adverse effects being fever, rash, nausea, and phlebitis at the infusion site. They can also cause a histamine-like reaction when infused too rapidly. Toxicity is uncommon. Its use has been associated with elevated aminotransferases and alkaline phosphatase levels.

Chemistry

The present-day clinically used echinocandins are semisynthetic pneumocandins, which are chemically lipopeptide in nature, consisting of large cyclic hexapeptoid. Caspofungin, micafungin, and anidulafungin are similar cyclic hexapeptide antibiotics linked to long modified N-linked acyl fatty acid chains. The chains act as anchors on the fungal cell membrane to help facilitate antifungal activity. Due to their limited oral bioavailability, echinocandins are administered through intravenous infusion.

Mechanism of action

Echinocandins noncompetitively inhibit beta-1,3-D-glucan synthase enzyme complex in susceptible fungi to disturb fungal cell glucan synthesis. Beta-glucan destruction prevents resistance against osmotic forces, which leads to cell lysis. They have fungistatic activity against Aspergillus species. and fungicidal activity against most Candida spp., including strains that are fluconazole-resistant. In vitro and mouse models show echinocandins may also enhance host immune responses by exposing highly antigenic beta-glucan epitopes that can accelerate host cellular recognition and inflammatory responses.

Resistance

Echinocandin resistance is rare among Candida. However, case studies have shown some resistance in C. albicans, C. glabrata, C. lusitaniae, C. tropicalis, and C. parapsilosis. Resistance patterns include alterations in the glucan synthase, overexpression of efflux pumps, strengthening of cell wall by increased chitin production, upregulation of stress-response pathways, and disregulation of mismatch repair pathways. In addition a few species/strains of Candida and Aspergillus show a "paradoxic effect" ie susceptible at lower dose but resistant at higher doses in broth microdilution studies.
Several non-candia yiests e.g. Cryptococcus, Trichosporon, rhodotorula and blastoschizomyces and filamentous fungi like fusarium, zygomyces and scedosporium are often resistant to Echinocandins. Very importantly Echinocandins show weak in vitro activity and very little clinical efficacy against Histoplasma, Blastomyces, and Coccidioides.

Pharmacokinetics

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 and anidulafungin have linear elimination. Younger patients exhibit a faster rate of elimination of micafungin and caspofungin.

Interference

Caspofungin has some interference with ciclosporin metabolism, and micafungin has some interference with sirolimus, but anidulafungin needs no dose adjustments when given with ciclosporin, tacrolimus, or voriconazole.

Advantages

Advantages of echinocandins:
Disadvantages of echinocandins:
List of echinocandins:
Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma, 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 on Candida spp.. 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 against Candida 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 approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.