Echinocandin

Echinocandins are a class of antifungals that prevent glucan synthesis pathways necessary for fungal cell wall formation. Echinocanins are antifungals that are widely used in clinical practice.
Three echinocandins are approved for clinical use – Caspofungin, Micafungin and Anidulafungin.
A fourth echinocandin – Rezafungin is being developed.

Some other antifungals (some in development) that act of fungal cell walls –

Glucan synthase inhibitors	Echinocandins	Caspofungin Micafungin Anidulafungin Rezafungin
Glucan synthase inhibitors	Triterpenoids (enfumafungin derivatives)	ibrexafungerp
Chitin synthase inhibitors	Nikkomycins	Nikkomycin Z
GPI anchor pathway inhibitors		manogepix/fosmanogepix

Source of Echinocandins

Caspofungin	Synthetically modified pneumocandin B0 of Glarea lozoyensis (Zalerion arboricola).
Micafungin	Synthetic modification of cyclic hexapeptide FR901370 derived from Coleophoma empetri
Anidulafungin	Synthetic modification of echinocandin B0, produced by Aspergillus nidulans

Mechanism of action

• Echinocandin is a noncompetitive inhibitor of the enzyme β-(1,3)-glucan synthase.
• β-(1,3)-glucan synthase is required for synthesis of β-( 1,3)-glucan from uridine diphosphate-glucose.
• β-(1,3)-glucan is a structural component of the fungal wall.
• Loss of β-(1,3)-glucan leads to the loss of cell wall integrity.
• The affected cells lyse due to osmotic pressure.

Echinocandins also exhibit immunomodulatory activity – it unmasks/releases glucans from the cell wall. This process enhances the phagocytic killing of fungus via dectin-1 receptor activation.

Mechanism of resistance:

• Mutation in the FKS gene: A part of the β-1-3-d-glucan synthase, the target of the echinocandins, is encoded by FKS gene.
• Low-level resistance has been associated with
  deletion of the GNSI gene and
  Overexpression of Sbe2p, a Golgi protein involved in cell wall formation.

Echinocandin resistance is associated with repeated/chronic exposure and inadequate source control.

Drug adaptation: Organisms like C glabrata exhibit a phenomenon called drug adaptation. On using echinocandin, almost all susceptible fungal cells die, leaving a very small number (1 in 10^4-5). These cells exhibit stress response – chitin synthesis and chromosomal rearrangements/repairs. These fungal cells are not resistant but show an adaptive response to the echinocandins.

Properties:

• Poorly absorbed from the GI tract, hence IV preparations are available.
  (Micafungin topical preparation has been used in candida keratitis).
• Long T1/2 (10-26 hrs) – once daily dose.
• Highly protein-bound (>95%)
• Caspofungin and micafungin undergo hepatic metabolism (dose adjustment in hepatic impairment, Child-Pugh >/=7)
• Excretion – degraded into an inactive product which is primarily excreted in faeces.
  Poor glomerular filtration and tubular secretion (unsuitable for fungal UTI).
• Pregnancy – Class C pregnancy risk agent (animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans).
• Distribution – Extensively distributed in tissues but limited distribution to CNS and eye
  (not used in CNS/eye infection).
  High concentration is achieved in liver, spleen and pulmonary alveolar space (but not in the pleural space).
• Synergy:
  Yeast – Echinocandin with amphotericin B, azoles – indifference/variable
  Aspergillus – Echinocandin with amphotericin B/azoles active against aspergillus – indifference or synergy can be seen.

Spectrum:

Candida:

• Most active class of antifungal agents against Candida biofilms (in vitro, animal model).
• Prolonged post-antifungal effects against Candida (in vitro).
• Eagle effect has been observed in vitro.
• Fungicidal activity against – C. albicans, C. dubliniensis, C. glabrata, C. krusei, C. tropicalis.
• Fungistatic activity against – C guilliermondii, C. lusitaniae, C parapsilosis family (usually resistant).
• C parapsilosis family carries Fks polymorphism resulting in high MIC and
  breakthrough infection (It is often considered inherently resistant).

Cryptococcus: Inactive ((1→6)-β-d-glucan is the major component of the cell wall)

Trichosporon: Inactive ((1→6)-β-d-glucan is the major component of the cell wall)

Aspergillus: Fungistatic. (In Aspergillus -Echinocandin affects the growing tip of Aspergillus. The effect is measured by MEC – minimum effective concentration – min concentration at which the organism produces small compact highly branched hyphae)

Endemic mycoses, Mucorales, Fusarium spp., Scedosporium spp:

• No significant activity.
• Low (1→3)-β-d-glucan in the cell wall.

Use:

• Candidemia and invasive candidiasis
• Mucosal candidiasis.
• Refractory aspergillosis – salvage therapy/2nd line/adjuvant.
• Prophylaxis of invasive fungal infection in hematopoietic stem cell transplant recipients (micafungin).
• Neutropenic fever and suspected fungal infection – empiric treatment.

Adverse effect:

• GI adverse effects
• Headache
• LFT derangement (aminotransferase)
• Infusion site reaction.