Antifungals

Amphotericin B
Nystatin

They are inserted into fungal cell membranes, causing them to become leaky and die due to loss of ions and small molecules. 8 amphotericin B molecules link together to form a channel in the membrane

Polyene (amphotericin B)

They target ergosterol present in fungal cell membranes, while human cell membranes use cholesterol. However, the structure of ergosterol and cholesterol are very similar, so there is a lot of toxicity associated with them, used for life threatening infections

Used topically, too toxic for systemic use

Primarily kidney toxicity
Can be reduced with liposomal encapsulation formula, however it is very expensive and only used in high risk patients

Rare, sometimes happens through a decrease in ergosterol or an increase in chitin.

It is converted into ergosterol

A CYP450 that removes the 14a-methyl group from lanosterol which is one of the steps in the conversion to ergosterol

They inhibit 14a-demethylase which prevents the production of ergosterol. This then stops fungal cells from building their membranes and leads to inhibition of growth or death at high concentrations.

It inhibits 14a-demethylase, but also inhibits other CYP450 enzymes which leads to many DDIs

Azoles which have a 5 membered ring containing 2 nitrogens

Azoles which have a 5 membered ring containing 3 nitrogens

It is basic and binds to the heme iron of CYP450s, mainly 14a-demethylase, the rest of the azole determines selectivity

An imidazole (ketoconazole) (2 nitrogens)

Effective against candida, not effective against aspergillus
DDIs with CYP3A4

Triazole (fluconazole) (3 nitrogens)

Very water soluble, only drug with high penetration into the CSF, treat brain infections
Increased spectrum of activity, not effective against glabrata and krusei
DDIs with CYP2C9

Broad spectrum, effective against aspergillosis
CYP3A4 DDIs

2nd generation triazole, standard of care against aspergillosis
CYP2C19, 2C9, and 3A4 DDIs

Lessened CYP interactions, mostly only interacts with 3A4

Effective against aspergillosis and mucormycoses
Lessened CYP3A4 interactions

The gene that encodes for 14a-demethylase

mutations in Erg11 which cause 14a-demethylase to block azoles from binding with the heme iron. Grants resistance against all azoles

Efflux by ABC-1, most effective against fluconazole
Increased production of 14a-demethylase

Typically used topically

Non competitive inhibition of B-1,3-glucan synthase found in fungal cell membranes, which is used by fungal cells to create their cell wall, and is not found in human cells.

An echinocandin

anidulafungin
micafungin

Rare, can have mutations in FKS1 and FKS2 which which make the catalytic sites for B-1,3-glucan synthase, gives resistance to all echinocandins

A molecule up the pathway which is eventually converted into lanosterol and then ergosterol

An enzyme that converts squaline into 2,3 oxidosqualine which is then converted further into lanosterol

They inhibit squaline epoxidase, stopping the eventual conversion of squaline to ergosterol and preventing growth of the fungal cell membrane

naftifine
terbinafin

Limited spectrum, usually used against dermatophytes which cause topical nail bed infections, takes a long time to be effective
Few resistances, some resistance through efflux transporters

Allyl amine (naftifine)

It is converted to 5FU, which is highly toxic, but only by fungal cytosine deaminase, so it is only active and toxic if it becomes activated by a fungal cell
Some intestinal flora can also activate it which leads to toxicity

Flucytosine

Griseofulvin

It is highly incorperated into keratin in the nails, kills fungal cells present on the nails by tubulin binding

Infectious fungal species which rapidly spreads between people similar to a bacteria
High levels of resistance, naturally azole resistant