Antifungals

Last updated 12th September 2019 - Tom Heaton

There are 3 main classes of antifungal medications:

1. Polyenes
   
2. Azoles
   
3. Echinocandins
   

Antifungal medications target components of the fungal membrane or wall that are unique to fungi.

Polyenes

Polyenes bind to the ergosterol in the cell membrane of the fungi.
This then results in the development of pores that lead to loss of osmotic control of the cell.
Examples include:

• Amphotericin B deoxycholate
  
• AmBisome (liposomal amphotericin B)
  
• Nystatin
  

Whilst the ergosterol is sufficiently different from human cholesterol to be able to use these agents, there is still some structural similarity, and this explains some of the toxicity of these agents when given systemically.

Amphotericin B

Initially isolated from the bacteria streptomyces nodosus.
It has a wide range of antifungal activity:

• Candida (most species)
  
• Cryptococcus
  
• Aspergillus (most species)
  
• Dimorphic fungi 
  

Resistance is pretty rare, although may be seen more in emerging pathogens.
It has significant toxicity though:

• Nephrotoxic
  
• Electrolyte derangement
  
  • Hypokalaemia
    
  • Hypomagnesaemia
    
• Infusion reactions
  
  • Nausea/vomiting
    
  • Chills/rigors
    
• Phlebitis
  
• Anaemia
  

It is usually used on in life threatening infections.
It has strong protein binding and so tissue penetration can be poor
The lipid formulations e.g. AmBisone are thought to reduce the toxicity of the drug by limiting its action to the site of the fungi.

Azoles

Azoles act by inhibiting the enzyme 14,alpha-demethylase.
This is a key enzyme in the synthesis of ergosterol.
There is subsequently reduced ability to reproduce, even if the result may not be death of the fungi.
It is important to note that this mechanism of action may actually impede the efficacy of polyenes.
Examples include:

• Fluconazole
  
• Itraconazole
  
• Voriconazole
  
• Clotrimazole
  

There is quite a variation in activity of the different azole against different fungal species.
A basic summary of indications:
Fluconazole

• First line for most candida
  
• Can be a step down for cryptococcus
  
• Mild-moderate coccidioidomycosis
  

Itraconazole

• Dimorphic fungi
  

Voriconazole

• Invasive aspergillus (may also add echinocandin)
  

Adverse effects include:

• Numerous drug interactions (warfarin, anticonvulsants)
  
• Hepatotoxicity 
  
• Alopecia - fluconazole
  
• Neurotoxicity - voriconazole
  
• Headaches
  
• Nausea/vomiting and abdominal pain
  
• Stevens-Johnson syndrome
  

Echinocandins

​Echinocandins inhibit the enzyme beta-1,3-glucan synthase, which is a key enzyme in the synthesis of  beta-1,3-glucan in the cell wall. 
Beta-1,3-glucan can be thought of as equivalent to the peptidoglycan of bacterial cell wells, and this echinocandins as the penicillin of antifungals. 
This can be fungicidal (e.g. in candida species) or simply fungistatic (e.g. in aspergillus).
Examples include:

• Caspofungin
  
• Anadulafungin
  
• Micafungin
  

These 3 drugs are all structurally similar, with poor oral bioavailability, necessitating IV use.
The indications are:

• Treatment of candida when azoles not suitable
  
• Second line for aspergillus disease
  

They have few drug interactions or side effects, but remain expensive.
Minor adverse effects include:

• Rash
  
• Diarrhoea
  
• Arthralgia
  

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Links & References

1. Strong Medicine. Antifungals (fungal infections - lesson 4). Youtube. 2015. https://www.youtube.com/watch?v=qkmF-kA0AR8
   
2. Beed, M. et al. Fungal infections and critically ill adults. CEACCP. 2014. 14(6). 262-267. https://academic.oup.com/bjaed/article/14/6/262/247636
   
3. Lockwood, G. Antimicrobial drugs. e-LFH. 2019. ​