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Echinocandin B

Echinocandins are antifungal drugs that inhibit the synthesis of glucan in the cell wall, probably via noncompetetive inhibition of the enzyme 1,3-β glucan synthase[1][2] and are thus called penicillin of antifungals (a property shared with papulacandins, see history below).

Contents

Uses

It is used in candidiasis and aspergillosis.[3]

They are fungicidal against yeast eg most species of Candida (but not against Cryptococcus, Trichosporon & Rhodotorula) and fungistatic against mold eg Aspergillus (but not Fusarium & Rhizopus) modest or minimally active active against dimorphic fungi eg Blastomyces and Histoplasma. These have some activity against the spores of the fungus Pneumocystis carinii.

History

The present day clinically used echinocandins are semisynthetic pneumocandins which are chemically lipo-peptide in nature, consisting of large cyclic (hexa)peptides linked to a long chain fatty acid. Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were lipo-saccharide ie fatty acid derivatives of a disaccharide which also blocked the same target 1,3-β glucan synthase and had only anti-candida action (narrow spectrum). Screening of natural products of fungal fermentation in 1970's lead to the discovery to Echinocandins new group of antifungals with broad range activity against Candida species. One of the first Echinocandins of the pneumocandin type, discovered in 1974, Echynocandin B could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to Cilofungin, first echinofungin analog that entered clinical trials in 1980, which was later withdrawn for a toxicity presumably due to the solvent system needed for systemic administration. The semisysnthetic 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 and thus must be given intravenous 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.

Advantages

Advantages of echinocandins:

  • broad range (especially against all candida), thus can be given empirically in febrile neutropenia & 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 renal failure and hemodialysis.
  • no dose adjustment is necessary based on age, gender, race
  • better (or no less effective) than Amphotericin B and fluconazole against yeast infections

Disadvantages

Disadvantages of echinocandins:

  • Embryotoxic [4] (category C) thus cannot be used in pregnancy
  • Needs dose adjustment in liver disease

Interference

Caspofungin has some interference with ciclosporin metabolism and micafungin has some interference with sirolimus (rapamycin), but anidulafungin needs no dose adjustments when given with ciclosporin, tacrolimus or voriconazole [5].

Examples

List of echinocandins:

See also

  • papulacandins (fatty acid derivatives of a disaccharide)

References

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