Lecture 12 Echinocandins and Terbinafine Flashcards
Give 3 examples of enchinocandins
Caspofungin (oldest)
Micafungin
Anidulafungin (newest)
What is the mode of action of enchinocandins?
bind to the Fks1p subunit = blocks B1,3-D-glucan synthesis
In what form are enchinocandins given and why?
IV
Due to being a large molecule
Which species does enchinocandins work on?
candida
aspergillus
What are the licenced indication for caspofungin?
Invasive candidosis in adults
Aspergillosis as a refractory treatment i.e. must have tried another drug 1st
Empirical therapy for presumed fungai infection e.g. neutropenia, fever
What are the licenced indication for anidulafungin?
invasive candida in adults
What are the licenced indication for micafungin?
Invasive candidosis in children and adults
Oesophageal candidosis in adults
Prophylaxis against candidosis in adults or children e.g. for haematological diseases, bone marrow transplant etc.
Explain the licencing trial for caspofungin comparing caspofungin and amphotericin B
Compared caspofungin and amphotericin B in non neutropenic patients with candidaemia
No significant difference between drugs in successful outcomes
Significantly less renal toxitiy and hypokalaemia in amphotericin B patients
Explain the licencing trial for caspofungin in use for refractory invasive aspergillosis
83 patients
Favourable outcome: 37 Stable disease: 6
Failure of therapy: 40
Only 1 serious adverse event
Due to lack of comparison drug and small study size, 2nd line license given for this use
Explain the licencing trial for anidulafungin
Comparison between anidulafungin and fluconazole (standard treatment for candidosis at the time) in non neutropenic patients with invasive candidosis
No of patients: 235
Successful outcomes significantly higher for anidulafungin
Number of adverse events about the same
Explain the licencing trial for micafungin
Compared micafungin and ambisome in patients with invasive candidosis
494 patients - half on each drug
Successful outcome of both drugs similar
Less adverse effects with micafungin
Where are the majority of micafungins metabolised?
Caspofungin: >90% in blood and tissues
Anidulafungin: >90% in blood
Micafungin: hepatic metabolism
What are the toxicity risks associated with caspofungin?
Loss of potassium Fever Chills Mildly deranged liver functions Generally well tolerated
What are the toxicity risks associated with anidulafungin?
headache
nausea
mildly deranged liver functions
Generally well tolerated
What are the toxicity risks associated with micafungin?
Mildly deranged liver function
Headache
Generally well tolerated
What drugs does caspofungin interact with?
some immunosupressants
steroids - in children
some antivirals and abx
What drugs does anidulafungin interact with?
no known drug interactions
What drugs does micafungin interact with?
some immunosupressants
Which species are and are not resistant to echinocandins and how?
resistance is rare
candida albicans - resistance associated with murations in gene for FSK1 gene of B 1-3 glucan synthase complex, particularly codon 645 Ser
C. glabrata - mutations in FSK1 and 2 genes associated with echinocandins resistance
Cryptococcus spp not susceptible - may be due to glucan synthase target alteration, efflux pumps or degradation pathways present
Explain the paradoxical effect with echinocandins and how this occurs
Initially as the dose increases the growth of C. albicans decreases - very large doses sees an increase in growth
Effect is strain specific and dependent on growth medium - Also seen in Aspergillus fumigatus
Possible mechanism theories:
Upregulation of chitin biosynthesis to counteract the reduced glucan production
Upregulation of cell wall integrity pathway (protein kinase C)
Name the one drug in the allyamine class
Terbinafine
What is the mode of action of terbinafine?
Inhibition of squalene epoxidase - function is to catalyse a step in the ergosterol synthetic pathway
What form does terbinafine come in?
Tablets
gel
cream
spray
What is terbinafine indicated for?
Dermatophyte infections of the skin and nail
Cream for skin infections due to yeast
Explain the study proving the efficacy of terbinafine
Compared terbinafine and intraconazole pulse therapy (means it was given 1 week in every 4 weeks to reduce costs)
Terbinafine was statistically better are curing than intraconozole (includes clinical cure, mycological cure (inability to grow the fungus) and complete cure)
How much of terbinafine is protein bound?
> 90%
How is terbinafine metabolised?
extensively by CYP enzymes
What is the half life of terbinafine?
22h
What is the dosing of terbinafine?
1 daily
How is terbinafine eliminated?
80% in the urine
20% in the faeces
What are the adverse effects from terbinafine?
Occassionally liver dysfunction
Altered taste
Which drugs interact with terbinafine?
Lots due to CYP metabolism
Some other antifungals, antidepressants etc (similar to azoles)
Explain how affected terbinafine is by resistance and how this comes about?
resistance is rare
Trichophyton rubrum has a high minimum inhibitory concentration to terbinafine
Mutations occur via substitutions in the squalene epoxidase gene
