Echinocandins are a class of

antifungal drug An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as c ...

s that inhibit the synthesis of

β-glucan Beta-glucans, β-glucans comprise a group of β-D-glucose polysaccharides (glucans) naturally occurring in the cell walls of cereals, bacteria, and Fungus, fungi, with significantly differing Physical chemistry, physicochemical properties depen ...

in the fungal

cell wall A cell wall is a structural layer that surrounds some Cell type, cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, ...

via noncompetitive inhibition of the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

1,3-β glucan synthase. The class has been dubbed the "

penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...

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, the fungal equivalent to bacterial

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating ...

Caspofungin Caspofungin ( INN; brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc. It is a member of a class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby di ...

, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with limited 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 (most species of '' Candida'', but not '' Cryptococcus'', '' Trichosporon'', and ''

Rhodotorula ''Rhodotorula'' is a genus of fungi in the class (biology), class Microbotryomycetes. Most species are known in their yeast states which produce orange to red colony (biology), colonies when grown on Sabouraud agar, Sabouraud's dextrose agar (SD ...

''). 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 (''

Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...

'', but not ''

Fusarium ''Fusarium'' (; ) is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the s ...

'' and '' Rhizopus''), and modestly or minimally active against dimorphic fungi ('' Blastomyces'' and '' Histoplasma''). They 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 Phlebitis (or venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis (clotting inside blood vessels) and is then called thrombophlebitis or ...

at the infusion site. They can also cause a histamine-like reaction (flushing) when infused too rapidly. Toxicity is uncommon. Its use has been associated with elevated aminotransferases and alkaline phosphatase levels.Cancidas. Prescribing information-(caspofungin acetate) for injection. Merck & Co Inc, Whitehouse Station, NJ 2008.

Chemistry

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. 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 resistant to fluconazole. ''In vitro'' and mouse models show echinocandins may also enhance host immune responses by exposing highly antigenic beta-glucan

epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although e ...

s that can accelerate host cellular recognition and inflammatory responses.

Resistance

Echinocandin resistance is rare among ''Candida'' spp. 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 (Fks1-Fks2 complex), overexpression of efflux pumps, strengthening of cell wall by increased chitin production, upregulation of stress-response pathways, and dysregulation of mismatch repair pathways. In addition a few species and strains of ''Candida'' spp. and ''Aspergillus'' spp. show a "paradoxic effect", i.e., they are susceptible to low concentrations but resistant to high concentrations in broth microdilution studies. Several non-candidal yeasts, e.g., ''Cryptococcus'', ''Trichosporon'', ''Rhodotorula'' and ''Blastoschizomyces'' and filamentous fungi like ''Fusarium'', zygomycetes and ''Scedosporium'' are often resistant to echinocandins. Echinocandins have weak in vitro activity (a high minimum inhibitory concentration) and very little clinical efficacy against ''Histoplasma'', ''Blastomyces'', and ''Coccidioides'', especially their yeast forms.

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 (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. Younger patients exhibit a faster rate of elimination of micafungin and caspofungin.

Interference

Caspofungin has some interference with

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...

metabolism, and micafungin has some interference with sirolimus (rapamycin), but anidulafungin needs no dose adjustments when given with ciclosporin,

tacrolimus Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...

, or voriconazole.

Advantages

Advantages of echinocandins: * Broad range (especially against all ''Candida''), thus can be given empirically in febrile neutropenia and stem cell transplant * Can be used in case of azole-resistant ''Candida'' or use as a second-line agent for refractory aspergillosis * Long half-life (polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50 hours) * Low toxicity: only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis * Not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug interactions * Lack of interference from

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

and hemodialysis * No dose adjustment is necessary based on age, gender, race * Better (or no less effective) than amphotericin B and fluconazole against yeast (mainly Candida, NOT yeast form of dimorphic) infections

Disadvantages

Disadvantages of echinocandins: * ''Cryptococcus'', ''Trichosporon'', and zygomycetes are often resistant to echinocandins and they show weak activity against yeast forms of ''Histoplasma'', ''Blastomyces, and ''Coccidioides''. * Embryotoxic in animal studies (category C) thus should be avoided if possible in pregnancy * Some need adjustment of dosing for patients with liver disease. * Poor ocular penetration in fungal endophthalmitis

Examples

List of echinocandins: * Pneumocandins (cyclic hexapeptides linked to a long-chain fatty acid) * Echinocandin B not clinically used, risk of hemolysis * Cilofungin withdrawn from trials due to solvent toxicity *

(trade name Cancidas, by Merck) * Micafungin (FK463) (trade name Mycamine, by Astellas Pharma.) * Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer) * Rezafungin formerly CD101 IV, Rezafungin is considered to be safest echinocandins which also acts longest (weekly single dose). It is developed by Cidara Therapeutics. The STRIVE Trial (phase 2) showed weekly treatment with Rezafungin was safe and efficacious in the treatment of candidemia and/or invasive candidiasis.Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial , https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1380/5909460#.X2j03oyvxDQ.twitter

History

Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of ''Papularia 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 on ''Candida'' 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 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 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 for ''Candida'' before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

References

External links

* {{Antifungals Antifungals Embryotoxins Hexapeptides Cyclic peptides