Polyenes

crop_square Key points

  • check_circle Directly bind to ergosterol destabilising the fungal cell membrane
  • check_circle Amphotericin B is a potent drug against invasive fungal infections
  • check_circle Conventional amphotericin B is poorly tolerated, lipid formulation have less severe side effects

crop_square Background and biochemistry

Polyenes are a class of antifungal drugs isolated from Streptomyces bacteria. They have been in clinical use since the 1950s. Amphotericin B remains the most important drug for treating systemic fungal infections as well as some protozoal infections, mostly visceral leishmaniasis. Originally a poorly tolerated drug (used to be called “amphoterrible”), amphotericin B is now available as lipid formulations (e.g., AmBisome®) with a more favourable side effect profile albeit at a much higher price. All currently available polyenes are on the WHO’s list of essential medicines. Polyenes are a subgroup of macrolide antimicrobials. They are complex amphiphilic molecules with a multimembered macrocyclic lactone ring at their core.

crop_square Mechanism of action

Polyenes are fungicidal drugs which bind to ergosterol in the fungal cell membrane. Their mechanism of action is not fully understood. Ergosterol-bound polyenes may cause the formation of ion pores in the cell membrane leading to ion leakage and subsequent cell death. Polyenes are also hypothesised to absorb ergosterol from the cell membrane causing membrane destabilisation and disruption of essential cellular processes. In contrast to many other common antifungal drugs, polyenes do not target an enzyme, but the key component of fungal cell membranes. This may be one of the reasons why polyene resistance is still relatively rare after decades of clinical use. However, resistances to polyenes and in particular amphotericin B are emerging. These are most commonly mediated by mutations leading to alterations of the fungal cell wall composition, with ergosterol replaced by other sterols (e.g., lanosterol).

crop_square Drugs and spectrum of activity

  • Ampho­tericin B
  • Nys­tatin
  • Nata­mycin

crop_square Pharmacokinetics

Amphotericin B pharmacokinetics are complex and incompletely understood. They differ substantially between the older (conventional) amphotericin B deoxycholate and newer liposomal amphotericin B formulations. Conventional amphotericin B is highly bound to plasma lipoproteins and accumulates in the liver and other organs. It is not metabolised and primarily eliminated via faeces with an elimination half-life of around 15 days. Lipid encapsulation of amphotericin changes pharmacokinetic properties depending on the size of the lipid vesicles. Small liposomes of the commonly used liposomal amphotericin B 'AmBisome®' stay intact for longer than conventional amphotericin following intravenous administration. Drug concentrations are therefore higher after administration of liposomal amphotericin B compared to the conventional formulation. It is hypothesised that amphotericin B liposomes disintegrate upon contact with fungal cells releasing the drug at the site of infection. Amphotericin B liposomes are degraded by macrophages, primarily in the liver and spleen. Drug delivery to the kidneys is reduced lowering the risk for nephrotoxic side effects. Liposomal amphotericin B has an elimination half life comparable to the conventional drug, however, only a fraction of it is excreted via urine or faeces. A relevant proportion of liposomal amphotericin B may be sequestered by macrophages. Nystatin is not absorbed from the gastrointestinal tract and proved too toxic for systemic treatment.

crop_square Adverse drug effects

Conventional amphotericin B is a poorly tolerated and relatively toxic drug which limits its clinical use. Acute infusion reactions are thought to be caused by induction of proinflammatory cytokines and include fever, chills, and hypotension. They may be less severe if steroids are given simultaneously. Amphotericin B does not only bind to ergosterol of fungal cells but also to cholesterol of mammalian cell causing severe chronic side effects. Nephrotoxicity is frequently seen with electrolyte imbalances, azotaemia, and elevated creatinine levels. Lipid-based amphotericin B formulation show significantly lower rates of severe adverse effects. Nystatin oral suspension is generally well-tolerated but may cause gastrointestinal symptoms. It has been associated with Stephens-Johnson syndrome in rare cases.