Anti Fungal

Dr. dr. Nico L Lumbuun, SpFK

Clinical Pharmacologist-Faculty of Medicine
Universitas Pelita Harapan
 Learning Objectives
• To describe the principles of antifungal therapy.
• To describe the pharmacokinetics &
pharmacodynamics of antifungal therapy.
• To list the classes of antifungal therapy, topical
and systemic antifungal agents.
 MICOSIS = FUNGAL INFECTION
• SYSTEMIC:
Aspergillosis, Coccidioidomycosis, Cryptococcosis,
Histoplasmosis, Paracoccidiomycosis, Candidiasis
• SUPERFICIAL:
Dermatophytosis :
Trichophyton, Microsporum, Epidermophyton; e.g.,
Tinea capitis, tinea cruris, tinea unguium ,
(onicomikosis)
Non-Dermatophytosis :
Pythiriasis Versicolor, Piedra
 ANTIFUNGAL VS ANTIBIOTIC
• Fungal & Bacteria had different structure, especially on
it’s cell membrane  fungal has an ergosterol.
• Mammalians (human) cholesterol
• Fungal resistant to antibiotic and bacteria resistant to
antifungal

• There’s a Control mechanism between fungal & bacterial

Drugs Mechanism of Actions
1. Polyenes, azoles, allylamines target
ergosterol destroying the cell
membrane’s integrity
Azoles & allylamines inhibit ergosterol
synthesis
β-1,3-glucan synthase inhibitor, block
the production of the β-(1,3)-glucan
protein damaging the cell wall.
Every component of the cell wall and
membrane can be targeted. Drugs not
available in the market such as
Nikkomycin and Polyoxin target chitin
synthase. Mannoproteins are another
potential target.

2. Other antifungals such as flucytosine

inhibit DNA/RNA synthesis and
griseofulvin inhibit fungal cell mitosis
preventing cell proliferation and
function.
 ANTIFUNGAL
• SISTEMIC
Amphotericin B, Azole derivatives , Pyrimidines analog
(Flucytosine), Echinocandine (Kaspofungin), Terbinafine

• SUPERPHYICIAL
Griseofulvine, Azole derivatives, Tolnaftate, Nystatin
 FUNGAL INFECTIONS
Systemic
• Incidence - increasing trend
• Slow onset
• Difficult to diagnose & eradicate
• Long duration of therapy

7
 AMPHOTERISIN B
Mechanism of Action :
The polyene antifungal
bind with sterols in the
fungal cell membrane,
principally ergosterol.
This causes the cell's
contents (K+) to leak out
and the cell dies
 SPECTRUM OF AMPHOTERICIN B
• Fungistatic & fungicidal (depends on dose)

• Broad spectrum, effectively inhibits:

Histoplasma capsulatum, Cryptococcus neoformans,
Coccidioides immitis, Candida, Aspergilus spp,
Trichophyton,… etc.
Pharmacokinetic of Amphotericin B
• Absorption : Very poor bioavailability
• Distribution : widely distribution across placenta,
cerebral spinal fluid & vitreous humour fluids
• Metabolism: unclear
• Excretion: slowly and mainly by renal!!!
 INDICATION
• First line drug for life threatening fungal infect., such as :
Coccidiomycosis, Paracoccidioidomycosis, Aspergillosis,
Chromoblastomycosis, Candidosis
• Oral : oral trush  azole resistant
• topical drops: keratitis mycotic
• U/ endophtalmytis  intraorbital injection
 Adverse Reaction Amphotericin B
Renal impairment  dose
Fever, chills  antipiretic, steroid adjustment
 AMPHOTERISIN B PREPARATION
• Conventional formulation :
Amphoterisin B deoxycholate (Fungizone® )

• Lipid formula / Amfoterisin B liposomal

- Amfoterisin B lipid complex (ABLC)
- Amfoterisin B coloid dispersion (ABCD)
- Ambisome®, unilamelar vesicle: spheris
 ADRs Conventional Vs Liposome
• Nephrotoxicity : ABCD & Ambisome fewer than
amphotericin B deoxycholate

• Fever, chills reaction and hypoxemia often happen

in ABCD than amphotericin B deoxycholate
 POSOLOGI
• amphotericin B deoxycholate : lipophilic powder vial 50
mg +10 mL sterile aquades, dilute w/ dextrose 5%.

• Administration : slow IV (need a test dose), intra-thecal,

intra-orbita, topical eye drops or ointment.

• Oral solution for local fungal infections in mouth’s cavity

 FLUCYTOSINE
• Synthetic antifungal from pyrimidin fluorination
• Mechanism of action:
Inhibit protein synthesis of fungal cell due to inhibition of DNA
synthesis via inhibition of thymidylate synthetase

(*) Thymidylate synthetase

dUMP : deoxyuridine monophosphate
dTMP : deoxythymidine monophosphate
 Antifungal Spectrum
• Narrow Spectrum, fungistatic
• Effective for Cryptoccocosis, Candidosis, Chloromomycosis,
Aspergillosis
• Flucytosine + Amphotericin B  supraadditive for candidosis
& delay resistance of both drugs
Pharmacokinetics
• Absorption : complete & fast rate
• Distribution : wide to all tissue, can penetrate to CSF
• Excretion : mainly renal excretion, patients w/ renal
impairment need an adjustment dose
 Side effect
• Hematologic: neutropenia, thrombocytopenia, pancytopenia,
bone marrow depression
• Liver : elevated serum SGPT/OT
• GIT: nausea, vomiting, diarrhea, enterocolitis
• Preparation: Caps 250 mg & 500 mg
 AZOLE-derivate
• Inhibit 14α-demethylase (fungal enzime)  convert lanosterol
to ergosterol, required in cell membrane synthesis
• These drugs also block steroid synthesis in humans.
• Imidazole : Ketoconazole, Miconazole, Clotrimazole
• Triazole : Itraconazol, Fluconazol, Voriconazol
KETOCONAZOLE
• Derivative of synthetic imidazole.
• Lipophilic & water soluble in acid pH
• Broad spectrum fungal, for systemic & topical treatment
• Mostly effective to : Candida, Coccidioides immitis,
Cryptococcus neoformans, Aspergillus spp.
 Pharmacokinetics of Ketoconazole
• Absorption: vary interpersonal, impaired when taking w/ food
– Absorption decrease when acidity of stomach is decrease (pH↑),
never concomitantly use with H2 antagonist or antacid
• Distribution : tissue limited distribution, effectively eradicate
fungal infection in lungs, bones, skins & soft tissues
– Can not pass the blood brain barrier
• Metabolism : extensively metabolism in liver. Can inhibit
many drugs metabolism which its metabolize by CYP 450
• Excretion trough gall bladder to GI tract
 INDICATION
• Ultimately effective for lungs, bone & join histoplasmosis
• Itraconazole is safer than ketoconazole, so it replace of
ketoconazole uses for systemic treatment.
• Some situation still need this drug, due to low cost th/
Tab. oral 200mg ; Topical: cream, shampoo 2%
Side effect Ketoconazole
• Gastrointestinal disturbance : nausea, vomiting
• Liver function impairment
• Endocrine effect: blocks synthesis of androgen &
steroid adrenal hormone  gynecomastia,
decrease of libido, impotency, menstrual problems
 CONTRAINDICATION
• Concomitant use with :
Terfenadin, astemizole, cisapride
 Ventricular arrhythmia
 ITRACONAZOLE
• Use as oral & parenteral (IV)
• Absorption faster & more complete than
ketoconazole, even taking w/ food
• Wider spectrum of fungal infection. Side effect &
drugs interaction fewer than ketoconazole.
• Indication same as ketoconazole
• Capsule 100 mg, IV suspension & oral susp 10 mg/mL
 FLUCONAZOLE
• Available in IV & oral preparation
• Wide & high of volume distribution, including central
nervous system
• Adverse drug effect mainly GI tract disturbance (abdominal
discomfort)
• Indication: prevent of relapsing Cryptococcus & candidosis
meningitis in AIDS pts after treating w/ amfoterisin B
• Preparation : Caps 50,150 mg. Vial IV 10mg/mL
 VORICONAZOLE
• Relatively a new triazol group
• Indication: Systemic aspergillosis, candidosis which is
resistant to other -azole
• Good GI tract absorption choose orally as long as is
possible
• Metabolism : extensively in liver, if there’s a liver impairment
 need adjusting the dose.
• ADRs: photophobia, photosensitivity
 Drugs Interaction Voriconazole
• Rifampicin, Carbamazepine, Quinidine  can not take
concomitantly (increase voriconazole’s metabolism)
• Rifabutin, sulfonylurea, benzodiazepine, statin, phenytoin 
increase blood level of those drugs  toxicity

Preparation: tabs 50 mg & 200 mg, oral suspension 40 mg/mL,

Vial dry powder for IV 200 mg/vial
 CASPOFUNGIN

• a member of a newest class of antifungals, termed

the echinocandins
• Mechanism of action : inhibits enzyme (1,3)-β-D-
glucan synthase & thereby disturb the integrity of
fungal cell wall
• Indication: Invasive candidosis & refracter of
aspergillosis
• Caspofungin administered intravenously
• Adverse reaction: fever, nausea, vomit, flushing,
pruritus
Spectrum of Antifungal
 Drugs Interaction
CASPOFUNGIN

• Decrease cyclosporine & tacrolimus serum

concentration of taking concomitantly
• Carbamazepine, dexamethasone, efavirenz,
nelfinavir, phenytoin, rifampicin  reduced
caspofungin serum concentration
ANTIFUNGAL
 TERBINAFINE

• A derivative of synthetic alylamine

• Mechanism of action: impaired ergosterol
biosynthesis of fungal cell wall trough inhibition
of enzyme squalene epoxidase
• Indication : Dermatophytosis, esp. onikomikosis
• Also tinea versicolor & candidosis cutis, usually
combine azole’s group
 Adverse drug effect of
TERBINAFIN

• Usually GI tract disturbance & headache.

• Rarely: Hepatotoxic, severe neutropenia, Steven
Johnson Syndrome, toxic epidermal necrolysis

Preparation: oral tab 250 mg, cream 1%, spray 1%

 GRISEOFULVIN
• Its isolation from Penicillium griseovulvum
• Effective for dermatophytosis, as a fungicidal &
fungistatic.
• Ineffective against other fungal infections
• Mechanism of action: inhibits mitosis of the
young cell of fungal, due to inhibition of nucleic
acid synthesis & polymerization
 FARMACOLOGY OF GRISEOFULVIN

• Absorb well in GI tract, micronized preparation’s

absorbed better. Absorption increase with fatty meal.
• Metabolism : ultimately at liver
• Excretion mainly via kidney  urine
• Highly affinity at infected skin area which is high
keratinization. A new skin cell, relatively resistant to
dermatophyte’s infection.
 Side Effects & Drugs Interaction

• Headache & GI tract symptoms

• Arthralgia, Neuritis peripheral, abdominal discomfort,
flatulence, urticarial
• Griseofulvin  induce metabolism of warfarin & oral
contraception
• Barbiturates  inhibit metabolism of Griseofulvin
 Miconazole (Daktarin®)
• A Synthetic imidazole
• Fungal spectrum: dermatophytosis, candidosis,
pythiriasis versicolor.
• Mechanism of actions : not fully known, hypothesis this
drug impaired fungal wall cell permeability and nucleic
acid synthesis.
• Adverse effect: skin irritation, rash, maceration
• Cream 2%, powder 2%, diaper ointment 2.5%
(+ zinc oxide), oral gel 2%.
Clotrimazole (Canesten®)
 TOLNAFTATE
• A tiocarbamate derivative
• Effective for dermatophyte, not for candida spp.
• Distorting the hyphae and stopping mycelial
growth
• Cream, gel, aerosol, topical solution
• Hyperkeratosis lesion: tolnaftate is used
alternately with salicylic acid powder 10%
 NYSTATIN (Mycostatin®)
• Mechanism of action : same as amphotericin B, but
much toxic to mammalian  that’s why not used for
systemic treatment
• Not absorbed via GI tract, skin or vagina
• Indication: candidosis cutis and GI tract. Paronychia
and vaginitis, used topical preparation.
• Oral susp. 100.000u/mL, vag. ovule 500mg/100.000u.
• Adverse effect : nausea, vomiting, abdominal
discomfort
 Principle of choosing anti fungal
• Systemic Vs Non-Systemic
• Number or severity of lesion
• Use concomitant with corticosteroid topical, only
when there is a significant inflammation. As soon
as controlled, stopped topical steroid.
 Clinical implications
• Most critical interactions can occur in patients with
immunocompromised status
– Cancer, transplant, HIV, diabetes
– On immunosuppressant agents which are mostly CYP
3A4 substrates or inducers
– On multiple drugs
• Drug interactions can get complicated.