Trachte: Antifungals
Causes of fungal infections:
 Superinfection from using broad spectrum Abx
 Use of immunosuppressive agents, which body’s host-defense mechanisms
 Diseases that resistance to infection
Tx depends on:
 Immune status of patient
 Resistance considerations
 CNS involvement
 Systemic vs superficial
Basis for Selective Toxicity: ergosterol is the major membrane lipid in fungi (in mammals: cholesterol)

Severity of the infection
Antifungals: Used for systemic / deep or superficial mycoses?
Systemic / Deep
Superficial (mostly topical / sometimes systemic)
Amphotericin B, Flucytosine, Fluconazole, Itraconazole,
Voriconazole, Capsofungin
Nystatin, Amphotericin B, Terbinafine, Griseofulvin, Miconazole,
Ketoconazole, Clotrimazole
Drug
Amphotericin B
(Polyene)
Flucytosine
MOA
Alters sterol-containing
cell membranes: bind
sterol, form pores in
lipid bilayer
Ergosterol >
cholesterol
Selectivity:
Host cells don’t take
flucytosine
Host cells don’t
convert flucytosine to
5-fluorouracil
Spectrum
Systemic
CIDAL (in absence
of cell growth)
STATIC @dose
Toxicity
Nephro (80%)  GFR
(can be permenant w/dose.
w/new drugs that contain
lipids)
Resistance
-Acquired=less common
-Fungi with ability to synth
ergosterol
-Mutant fungi w/ quantities
of other sterols
Cardiotox: w/rapid
infusion (give slow)
< AmpB
Other: chills/fever, BP,
delirium, N/V,
thrombophlebitis
Reversible neutropenia and
occasional
thrombocytopenia
Nausea
Skin rashes, eosinophilia
Intolerable in AIDS pts
Combo of AmpB and Flucytosine: Resistance. Synergistic / Additive effect
 Amphotericin B activity may allow more uptake of flucytosine
 The dose of Amphotericin B can be lowered and decrease nephrotoxicity
from Amph B.
 Amphotericin B may enhance the toxicity of flucytosine by impairing its
renal excretion
Route:
CNS Pen:
Toxicity:
Spectrum:
Resistance:
uptake and conversion to 5fluorouracil and 5-FUMP
(use in combo w/other drugs)
AmpB
Flucytosine
IV
No
>
>
<
Oral
Yes
<
<
>
Distrib/Elim
Absorption:
GI: bad
CNS: bad w/IV, give
intrathecal.
Slow renal excret.
Long tissue ½ life
Oral. Goes to CNS.
Kidney excretion.
No metabolism
Renal Impaired:
no change
modify dose
Caspofungin = echinocandin
 MOA: Blocks the synthesis of Beta (1,3)-d-glucan (polysaccharide part of fungi cell wall)
 Uses: Candidiasis, invasive aspergillosis
 SE: fever, rash, nausea, vomiting and phlebitis at the injection site
AZOLES:
 MOA: Inhibit the fungal enzyme sterol 14-alpha-demethylase, a microsomal cytochrome P450 - dependent enzyme system
o Impaired biosynthesis of ergosterol for the cytoplasmic membrane
o Leads to accumulation of 14-alpha-methyl sterols and disruption of the phospholipids in the fungal membrane
o Resistance via multiple mechanisms
 Selective Toxicity: Differential requirement for ergosterol. Greater affinity for fungal rather than human cytochrome P450 enzymes
 Consequences of inhibition of human cytochrome P450 enzymes
o Interfere with biosynthesis of adrenal and gonadal steroid hormones
 Gynecomastia (abnormal development of male mammary glands), infertility and menstrual irregularities
o Potential for drug interactions: Alters the metabolism of other drugs
Imidazoles
Ketoconazole
Clotrimazole
Miconazole
Econazole
Butoconazole
Oxiconazole
Sulconazole
Triazoles
Fluconazole
Itraconazole
Voriconazole
Terconazole
With systemic administration:
•Triazoles are more slowly metabolized than imidazoles, thus longer duration of action
•Triazoles have less effect on human sterol synthesis than do imidazoles
•Triazoles are replacing use of imidazoles, especially in systemic infections
Imidazoles (Keto = prototype) = Most effective during active fungal growth
 Fewer adverse effects than Amphotericin B
 Orally available. Doesn’t penetrate the CNS. Liver metabolism (toxicity)
 Dose dependent decrease in serum testosterone, gynecomastica,
menstrual irregularities
 No longer drug of first choice in systemic fungal infections
Triazoles = Itraconazole, Fluconazole, Voriconazole
 More slowly metabolized
 Less effect on human sterol synthesis
 V: Best activity against Aspergillus, but drug interactions
 F: Penetrates CNS. Fewer drug interactions
In General:
 Imidazoles and triazoles (‘azoles’) are better tolerated than Amphotericin B and Flucytosine.
 The 'azoles' may decrease effectiveness of Amphotericin B by inhibiting ergosterol synthesis and decreasing the binding of Amphotericin B.
 The ‘azoles’ are replacing Amphotericin B and Flucytosine in many situations.
 In general, Amphotericin B and Flucytosine are used when more aggressive treatment is needed.
Superficial Infections:



AZOLES: Miconazole, Ketoconazole, Clotrimazole, (Not metronidazole d/t interactions w/EtOH)
Polyenes: Nystatin, AmpB (not absorbed from skin/mucous membranes; no AE/resistance)
Terbinafine: MOA: Inhibits squalene epoxidase, leading to accumulation of squalene which is toxic to the fungi (thus fungicidal)
o Given orally for superficial infections, also used topically. Binds to keratin and protects the skin from infection fungal toenail infections. AE rare.
Pneumocystis jiroveci lung infections: Treat with Trimethoprim & sulfamethoxazole (Bactrim) - Trimetrexate is another effective agent
 Organism does not possess a folate transporter. Very susceptible to folate metabolism inhibitors
Antifungal Drug Classes
Class
MOA
Allylamin
Inhibits squalene epoxidase (blocks ergosterol synth)
Azole
Impairs ergosterol synth
Echinocandin
Impairs B 1,3 glucan synthesis
Nucleoside analog
Impairs Pyrimidine metabolism
Polyene
Binds to ergosterol, prevents cell wall growth
Drugs
Terbafine
Ketoconazle. Fluconazole. Itraconazole. Voriconazole
Caspofungin
Flucytosine
AmpB deoxycholate. AmpB colloidal dispersion.
AmpB lipid complex. Liposomal ampB
Treatment of invasive fungal infections:
 Aspergillosis: Voriconazole, Lipid AmpB, Caspofungin



Candidiasis: Fluconazole (esophagus, blood). Caspofungin, AmpB deoxycholate (esophagus & blood, refr to Fluc)
Cryptococcosis: AmpB / lipid AmpB + flucytosine (meninges)
Febrile neutropenia: liposomal AmP, voriconazole.