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 crypto ...

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 fungi, with significantly differing physicochemical properties dependent on source. Typically, � ...

in the fungal

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering me ...

via noncompetitive inhibition of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

1,3-β glucan synthase 1,3-Beta-glucan synthase is a glucosyltransferase enzyme involved in the generation of beta-glucan in fungi. It serves as a pharmacological target for antifungal drugs such as caspofungin, anidulafungin, and micafungin, deemed 1,3-Beta-glucan ...

. The class has been termed the "

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum usin ...

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 peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most b ...

Caspofungin Caspofungin ( INN) (brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard. It is a member of a new class of antifungals termed the echinocandins. It work ...

micafungin Micafungin, sold under the brand name Mycamine, is an echinochandin antifungal medication used to treat and prevent invasive fungal infections including candidemia, abscesses, and esophageal candidiasis. It inhibits the production of beta-1,3-gl ...

, and

anidulafungin Anidulafungin ( INN) (trade names Eraxis, Ecalta) is a semisynthetic echinocandin used as an antifungal drug. It was previously known as LY303366. It may also have application in treating invasive ''Aspergillus'' infection when used in combinatio ...

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 ''Cryptococcus'' is a genus of fungi in the family Cryptococcaceae that includes both yeasts and filamentous species. The filamentous, sexual forms or teleomorphs were formerly classified in the genus ''Filobasidiella'', while ''Cryptococcus'' ...

'', ''

Trichosporon ''Trichosporon'' is a genus of anamorphic fungi in the family Trichosporonaceae. All species of ''Trichosporon'' are yeasts with no known teleomorphs (sexual states). Most are typically isolated from soil, but several species occur as a natural ...

'', and ''

Rhodotorula ''Rhodotorula'' is a genus of pigmented yeasts, part of the division Basidiomycota. It is readily identifiable by distinctive orange/red colonies when grown on Sabouraud's dextrose agar (SDA). This distinctive color is the result of pigments ...

''). 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, Mich ...

'', 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 soil mi ...

'' and ''

Rhizopus ''Rhizopus'' is a genus of common saprophytic fungi on plants and specialized parasites on animals. They are found in a wide variety of organic substances, including "mature fruits and vegetables", jellies, syrups, leather, bread, peanuts, and t ...

''), and modestly or minimally active against dimorphic fungi (''

Blastomyces ''Chrysosporium'' is a genus of hyaline hyphomycetes fungi in the family Onygenaceae. ''Chrysosporium'' colonies are moderately fast-growing, flat, white to tan to beige in color; they often have a powdery or granular surface texture. Hyaline, ...

'' and ''

Histoplasma ''Histoplasma'' is a genus of dimorphic fungi commonly found in bird and bat fecal material. ''Histoplasma'' contains a few species, including—''Histoplasma capsulatum''—the causative agent of histoplasmosis; and ''Histoplasma capsulatum va ...

''). They have some activity against the spores of the fungus ''

Pneumocystis jirovecii ''Pneumocystis jirovecii'' (previously ''P. carinii'') is a yeast-like fungus of the genus ''Pneumocystis''. The causative organism of ''Pneumocystis'' pneumonia, it is an important human pathogen, particularly among immunocompromised hosts. Pr ...

'', 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 (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 act 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 epitope is the specific piece of the antigen to which an antibody binds. The p ...

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 a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...

metabolism, and micafungin has some interference with

sirolimus Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis ...

(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 allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...

, or

voriconazole Voriconazole, sold under the brand name Vfend among others, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis, and infections by ' ...

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 end-stage kidney disease, 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 failure is classified as eit ...

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 Echinocandin B, a lipopeptide, is a naturally occurring cyclic hexapeptide with a linoleoyl side chain. It belongs to a class of antifungal agents called echinocandins, which inhibits the synthesis of glucan, a major component of the fungal cell ...

not clinically used, risk of hemolysis *

Cilofungin Cilofungin ( INN) is the first clinically applied member of the echinocandin family of antifungal drugs. It was derived from a fungus in the genus ''Aspergillus ' () is a genus consisting of several hundred mold species found in various climate ...

withdrawn from trials due to solvent toxicity *

(trade name Cancidas, by Merck) *

Micafungin Micafungin, sold under the brand name Mycamine, is an echinochandin antifungal medication used to treat and prevent invasive fungal infections including candidemia, abscesses, and esophageal candidiasis. It inhibits the production of beta-1,3-gl ...

(FK463) (trade name Mycamine, by Astellas Pharma.) *

Anidulafungin Anidulafungin ( INN) (trade names Eraxis, Ecalta) is a semisynthetic echinocandin used as an antifungal drug. It was previously known as LY303366. It may also have application in treating invasive ''Aspergillus'' infection when used in combinatio ...

(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