Ergosterol Synthesis Inhibitors
Ergosterol is one of the membrane sterols in fungi (analogous to cholesterol in humans). Blocking of sterol formation by azoles or allylamines leads to the accumulation of toxic sterols in the cell membrane, disrupting packing of membrane lipids.
Azoles
Azoles work by inhibiting 14α-sterol-demethylase, which is in the ergosterol biosynthesis pathway. Inhibition of this enzyme leads to accumulation of 14α methylsterols and disrupted packing of membrane lipids.
The two main types of azoles are the imidazoles and triazoles. Imidazoles, which include ketoconazole and clotrimazole, are quite toxic and are generally only used for more superficial mycoses. Triazoles, such as fluconazole (best against Candida but has no mould activity), itraconazole (better than fluconazole at dealing with moulds, but not as good at dealing with yeasts), voriconazole and posaconazole, are less toxic and target a broader spectrum of fungi. Even though triazoles are less toxic, that's not to say that they are non-toxic: they can still cause hepatotoxicity, and around 30% of patients taking voriconazole experience visual symptoms such as blurred vision and light sensitivity. Azoles also have a huge potential for drug-drug interactions, as they are metabolised by and inhibit cytochrome P450 enzymes.
Allylamines
Allylamines, such as terbinafine, inhibit squalene epoxidase, which is an earlier step in the ergosterol synthesis pathway. Inhibition of squalene epoxidase causes accumulation of squalene and deficiency of ergosterol, which again leads to interference with membrane function and fungal death.
Glucan Synthesis Inhibitors (Echinocandins)
Echinocandins, such as caspofungin, anidulafungin and micafungin inhibit glucan formation. As humans don't have glucan, echinocandins have limited toxic effects. They are used in severe Candida infections as they inhibit the growing ends and branches of fungal hyphae (remember, Candida can form true hyphae when it enters tissue). Unfortunately, echinocandins are very expensive, limiting their use.
Polyenes
Polyenes, such as amphotericin B (AMB) and nystatin, associate with ergosterol to form pores. Large amounts of ions can move through the pore, leading to cell death. Polyenes are broad-spectrum and can be quite useful, especially against invasive fungal infections such as invasive aspergillosis, disseminated candidiasis and cryptococcal meningitis.
Unfortunately, conventional AMB (c-AMB) can be very toxic to the kidneys. Liposomal preparations (L-AMB), which have lipid carriers that ensure uptake and transport by macrophages, have similar efficacy but less toxicity than c-AMB. Thus, L-AMBs, such as AmBisome and Abelcet, are the standard of care for patients with severe fungal infections.
Susceptibility testing
Unlike with bacteria, susceptibility testing is rarely performed on fungi as the results are not very reliable. In vitro resistance usually predicts failure, but in vitro sensitivity doesn't predict success. Also, fungi take a long time to grow as compared to bacteria.
Antifungal resistance
Unfortunately, fungi have already developed some resistance mechanisms to fungi. The main resistance mechanisms are alterations or defects in the ergosterol synthesis pathway, increase of efflux pumps, decrease of drug import and alterations to drug processing.
Treatments
There were a bunch of fungi mentioned throughout this lecture with treatments, but I thought it would be more coherent if I stuck them all at the end of this post, so here they are:
- Dermatophyte infections: First try topical therapy with ketoconazole, clotrimazole or terbinafine cream. Oral ketoconazole or terbinafine can be used if treatment is unsuccessful. Tinea capitis can be treated with oral terbinafine.
- Pityriasis versicolor (Malassezia): Treat with topical antifungal shampoos or with oral ketoconazole or itraconazole. Oral terbinafine is ineffective against pityriasis versicolor. (Malassezia itself isn't immune to terbinafine, but the location of the infection may play a role in its ineffectiveness in pityriasis versicolor.)
- Invasive candidasis: Intravenous azoles, such as itraconazole.
- Invasive aspergillosis: Voriconazole. Polyenes may still be used. Treatment should be started as soon as possible to reduce the risk of mortality.
- Cryptococcal meningitis: IV amphotericin plus flucytosine for two weeks, followed by high-dose fluconazole. Fluconazole may be continued to prevent reinfection.
- Penicillum marneffii: Amphotericin B, then high-dose itraconazole, then lifelong suppressive therapy.
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