Amphotericin B

15.1.22

Amphotericin B is a polyene antibiotic discovered in 1953, from the bacteria Streptomyces nodosus, in the Orinoco basin in Venezuela.

Its name is derived from its amphoteric property, being able to react to both acid and base. It is insoluble at normal pH; hence it is available as a buffered colloidal solution, with sodium deoxycholate as the dispersing agent. This preparation is called amphotericin B deoxycholate.

The lipid formulations of this drug have been designed to reduce the toxicity associated with its use. There are three preparations available -

  • Amphotericin B deoxycholate (Fungizone) - Deoxycholate salt. Conventional amphotericin B.

  • Liposomal amphotericin B (AmBisome) - Amphotericin B within a liposome.

  • Amphotericin B lipid complex (Abelcet) - amphotericin B complexed with two phospholipids in a 1:1 drug-to-lipid molar ratio and forms large ribbon-like structures.

Properties

Limited oral bioavailability. It is also inactivated by gastric acid. Hence treatment for systemic fungal infection is used intravenously or other direct installation routes (intrathecal, intraperitoneal, intracavitary, nebulised etc).

Highly protein bound

Mainly excreted in bile, limited excretion in urine.

Mechanism of action

Amphotericin has two major mechanisms of action.

  1. Disruption of the cell membrane and

  2. Oxidative damage to the fungal cells.

The primary target of amphotericin B is the ergosterol. It disrupts the normal activity of the cell membrane like endocytosis. However, the major damage is caused by the formation of pores, which leaks the intracellular ion from the cells, leading to cell death. Only potassium ions are leaked at low amphotericin B concentrations, but as the concentration increases, the pores become multimeric – leaking calcium, magnesium, and other ions.

Amphotericin also can auto-oxidise itself generative an oxidative burst, which damages the fungal cells.

Amphotericin is also known to have immunomodulatory activity – it may generate a pro-inflammatory response by binding to the Toll-like receptors. It can also enhance the antifungal activity of the macrophage and other inflammatory cells.

Mechanism of resistance

Which fungi are inherently resistant to amphotericin B?

  • Amongst the Candida, Candida lusitaniae and Candida guilliermondii, tend to have variable MIC, however, they are often considered inherently resistant.

  • Aspergillus terreus, produces a catalase, which reduces the effectiveness of amphotericin B and it is considered inherently resistant.

  • Other inherently resistant fungus are – Scedosporium prolificans, Trichosporon asahii, some fusarium spp. and chromoblastomycosis.

Mechanism of acquired amphotericin resistance:

  • Alteration in the sterol content of the cell membrane. A mutation in the ERG gene could mediate this. The ergosterol biosynthesis is altered leading to a higher concentration of sterol intermediates like lanosterol in the cell membrane. These intermediates have less affinity for amphotericin B.

  • Production of catalase may confer resistance to amphotericin B by reducing the effect of the oxidative burst.

  • Biofilm formation may confer resistance to multiple antifungal classes.

  • Altered cell membrane composition like higher saturated fatty acid content, and altered cell wall content like increased glucan content and decreased chitin content.

Spectrum

Yeast

  • Candida, Cryptococcus, Malassezia spp., Saccharomyces cerevisiae and Rodotorulla are usually sensitive

  • Trichosporin asahii is resistant

(Some Candida spp. have higher MIC or are often resistant. They are – C. glabrata, C. Krusei, C. tropicalis, C. lusitaniae, C. guilliermondii, C. auris, C. haemulonii, and C. pseudohaemulonii.)

Mould

  • Aspergillus and Mucorales are usually susceptible

  • Pseudallescheria boydii/ Scedosporium apiospermum, sporothrix, dermatophytes and fusarium have variable resistance.

  • Scedosporium prolificans, chromoblastomycosis are resistant.

(Aspergillus terreus, Aspergillus alliaceus and some species of Fusarium are inherently resistant)

Dimorphic fungi

  • Usually susceptible, however Penicillium marneffei is often resistant.

Adverse effects

Some common adverse effects are

  • Acute reaction – Fever, chill, hypotension, myalgia, || nausea, vomiting, headache, || tachypnoea.

  • Renal adverse effects – renal failure, renal stone, renal tubular acidosis, azotemia, electrolyte imbalance.(two modes of toxicity – reduced blood flow to the kidney and direct renal tubular toxicity)

  • Hepatic abnormality (AmphotericinB should be discontinued).

  • Blood – anaemia, leucopenia, thrombocytopenia, agranulocytosis, and eosinophilia.

  • Skin reaction.

Indications

Liposomal amphotericin B (AmBisome)

  • Severe systemic or deep mycosis.

  • Febrile neutropenia not responding to the broad-spectrum antibiotics.

  • Aspergillosis.

  • Visceral leishmaniasis not responding to antimonial.

Amphotericin B deoxycholate (Fungizone)

  • Systemic fungal infection.

Amphotericin B lipid complex (Abelcet)

  • Severe invasive candidiasis.

  • Severe systemic fungal infections – Aspergillus, Cryptococcal infection – disseminated /meningitis.