Echinocandins

Approved and candidate drugs of this class have fungicidal properties against certain yeasts (most species of the genus Candida , but not against Cryptococcus , Trichosporon and Rhodotorula ). Echinocandins also show activity against candida biofilms, especially in synergistic activity with amphotericin B and in additive activity with fluconazole . Echinocandins are fungistatic against certain forms of Aspergillus (but not Fusarium and Rhizopus ), and are less active against dimorphic fungi ( Blastomyces and Histoplasma ). They have some activity against spores of Pneumocystis carinii fungi. Caspofungin is used in the treatment of febrile neutropenia and as a rescue therapy in the treatment of invasive aspergillosis ^[5] . Micafungin is used to prevent candida infection in patients with hematopoietic stem cell transplantation ^[5] .

Echinocandin toxicity is rare. Its manifestation was associated with increased levels of aminotransferases and alkaline phosphatase ^[6] .

At the present stage, the clinically used echinocandins are a semisynthetic product of pneumocandins, which are chemically lipopeptides in nature, consisting of large cyclic (hexa) peptoids. Caspofungin, micafungin and anidulafungin are similar to cyclic hexapeptide antibiotics associated with long modified N-linked chains of fatty acid residues. Chains act as anchors on the fungal cell membrane, facilitating the antifungal effect ^[7] . Due to the limited bioavailability of enteric (taken by mouth) forms of echinocandins, they are administered intravenously.

Echinocandins non-competitively inhibit the synthesis of 1,3-β-D-glucan, an important component of the fungal cell wall, which is absent in mammalian cells ^[8] . The destruction of beta-glucan suppresses resistance against osmotic forces , which leads to cell lysis ^[9] . They have fungistatic activity against aspergillus fungi and fungicidal activity against most representatives of the genus Candida , including fluconazole-resistant strains ^[5] . It has been shown in vitro and in mouse models that echinocandins can also enhance the immune response of the host organism by secreting very antigenic beta-glucan epitopes that can accelerate cell recognition and inflammatory responses ^[10] .

Resistance to echinocandins is rare. However, case studies have shown some resistance in C. albicans, C. glabrata, C. lusitaniae, C. tropicalis and C. parapsilosis . Their stability is due to changes in glucan synthase (Fks1-Fks2 complex), excessive expression of pumping pump proteins, as well as changes and / or excessive expression of Erg3 and Erg11 enzymes.

Due to their large molecular weight, echinocandins have poor oral bioavailability and are therefore administered via intravenous infusion. In addition, their large structures limit penetration into the cerebrospinal fluid , urine , and eyes . Echinocandins have a high affinity for serum proteins. They have no major interactions with P-glycoprotein or CYP450 pumps . Caspofungin has three-phase nonlinear pharmacokinetics, while micafungin (metabolized in the liver by arylsulfatase , catechol-o-methyltransferase , and hydroxylation) and anidulafungin (breaks down spontaneously and excreted mainly in the form of a metabolite in the urine) are linearly eliminated ^{[6] [11]} . Young patients show a higher rate of elimination of micafungin and caspofungin ^[12] .

Caspofungin affects cyclosporine metabolism; micafungin affects the metabolism of sirolimus (rapamycin); anidulafungin does not need dose adjustment in combination with cyclosporine, tacrolimus , or voriconazole ^{[13] [ specify ]} .

The benefits of echinocandins:

• a wide spectrum of action (especially against all types of Candida ), which allows them to be prescribed empirically for febrile neutropenia and during stem cell transplantation;
• can be used in case of fluconazole-resistant candidiasis or as a second line for refractory aspergillosis;
• long half-life (polyphase elimination: Alpha phase 1-2 hours + beta phase 9-11 hours + gamma phase 40-50 hours);
• low toxicity: isolated release of histamine (3%), fever (2.9%), nausea and vomiting (2.9%), phlebitis at the injection site (2.9%), very rarely allergies and anaphylaxis;
• it is not an inhibitor, nor an inducer, nor a substrate of the cytochrome P450 or p-glycoprotein system; therefore, it has minimal drug interactions;
• lack of contraindications for renal failure and hemodialysis;
• there is no need for dose adjustment depending on age, gender, race;
• better (or no less effective) than amphotericin B and fluconazole against thrush.

Disadvantages of echinocandins:

• embryotoxicity ^[3] (category C) - should be avoided during pregnancy;
• needs dose adjustment for liver diseases;
• poor penetration into the tissues of the eye for the treatment of fungal endophthalmitis ^[14] .

List of echinocandins:

• Pneumocandins (cyclic hexapeptides linked to a long chain fatty acid)
• Echinocandin B is not used due to the risk of hemolysis
• Zilofungin removed from testing due to solvent toxicity
• Caspofungin (trade name Cancidas, Merck )
• Micafungin (FK463) (trade name Mycamine, Astellas Pharma )
• Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, Pfizer)

The discovery of echinocandins results from studies of liposaccharides (derivatives of fatty acids and disaccharide) of papulocandins isolated from the strain Papularia sphaerosperma (Pers.) , Blocked 1,3-β-glucan synthase, and acted only on Candida spp. Screening for natural fungal fermentation products in the 1970s led to the discovery of echinocandins, a new group of antifungal drugs with a wide spectrum of activity against Candida spp . In 1974, echinocandin B was discovered as one of the first pneumocandin echinocandins, but it could not be used in clinical practice due to the high risk of hemolysis . Screening for the semi-synthetic echinocandin analogs led to the development of cyclofungin, the first echinofungin analog to be clinically tested, but in 1980 it was excluded from testing due to solvent toxicity required for systemic use. Later, semisynthetic analogues of echinocandins with the same antifungal activity, but less toxic, were found. Caspofungin was the first of the new echinocandins, and later micafungin and anidulafungin were approved. All these drugs have low bioavailability, therefore they are used only intravenously. Echinocandins have now become one of the first-line drugs for therapy against fungi of the genus Candida with an unknown pathogen, and even as antifungal prophylaxis during hematopoietic stem cell transplantation (bone marrow transplantation).