ANTIFUNGAL

AGENTS
1
 Fungi causing mycosis (Fungal infections = mycosis) live
as commensals or are present in the environment.
 Recently there is increase in local as well as systemic
fungal infections.
 Reason for this is opportunistic infections
 Immuno-suppression due to Cancer chemotherapy,
AIDS, Corticosteroid overuse
 Indiscriminate use of broad spectrum antibiotics
 Fungal infections - Mycoses
4

 Superficial mycoses
 Affect the skin, hair and nails
 Subcutaneous mycoses
 Affect the muscle and connective tissue immediately below the
skin
 Systemic (invasive) mycoses
 Involve the internal organs
 Primary vs opportunistic
 Allergic mycoses
 Affect lungs or sinuses
 Patients may have chronic asthma, cystic fibrosis or sinusitis
 Antifungal drugs
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1. Antifungal antibiotics
i. Amphotericin B
ii. Nystatin

2. Antimetabolite: Flucytosine

3. Azoles (imidazoles and triazoles)

4. Allylamine e.g. Terbinafine

5. Echinocandins
 Amphotericin B

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 antifungal antibiotic produced by Streptomyces nodosus
 belongs to a group of drugs known as polyene antibiotics,
so named because their structures contain a series of
conjugated double bonds.
 Binds ergosterol; sterols in fungal cell membrane
 Creates transmembrane channel and electrolyte leakage.
 Fungicide at high and static at low conc.
 Amphotericin B – Pharmacokinetics

 Absorption from the GI tract is negligible

 Oral solution sometimes used to decontaminate gut; few
side effects
 Only reliable method of administration is IV
 Uses
 severe systemic and CNS infections caused by susceptible
fungi:
 Candida species
 Histoplasma capsulatum
 Cryptococcus neoformans (combined with flucytosine)
 Aspergillus species
 Blastomyces dermatitidis
 Coccidioides immitis

 Fungal infection in patients with bone marrow transplantation

 Amphotericin B is also used in the treatment of the protozoal
infection leishmaniasis.
 Adverse effects
 Nephrotoxicity, anemia, Hepatotoxicity, Fever and chills
Adverse Drug Reactions
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

 Acute reactions- occurs with each infusion

1. Chills 5. Nausea
2. Fever 6. Vomiting
3. Aches
4. Pain
 So corticosteroids are administered along with the drug
 Kidney damage is the most serious adverse effect of amphotericin B
 Bone marrow depression
 Reversible anemia
 Nystatin

 Polyene antifungal with mechanism similar to amphotericin B

 Use

 Orally (not absorbed from the GI tract) for intestinal

candidiasis

 It is too toxic for parenteral administration and is only used

topically

 Topically for candidiasis of the oral and vaginal cavity

 FLUCYTOSINE…


 is a water-soluble pyrimidine analog related to the

chemotherapeutic agent 5-fluorouracil (5-FU)
 It is widely distributed throughout the body fluids,
including the cerebrospinal fluid.
 About 90% is excreted unchanged via the kidneys, and
the plasma half-life is 3-5 hours.
 The dosage should be reduced if renal function is
impaired.
Mechanism of action
 Flucytosine is converted to the antimetabolite 5-
fluorouracil in fungal but not human cells
 5-Fluorouracil inhibits thymidylate synthase and thus
DNA synthesis
 Mammalian cells remain unaffected except few bone
marrow cells.
FLUCYTOSINE
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Uses
 Never used alone.
 Narrow spectrum.
 Resistance develop rapidly.
 Always used in combination with
amphotericin B
 Useful for cryptococcal meningitis as it can penetrate CSF
ADR
1. Mild BM depression
2. Loss of hair

3.Dose should be decreased in the presence of renal impairment

 Azole anti-fungal drugs
 Are synthetic and broad antifungal spectrum antifungal
agents
 Drugs include:
 Imidazole (clotrimazole, econazole, fenticonazole,
ketoconazole, miconazole, tioconazole) or
 Triazole (itraconazole, voriconazole and fluconazole).
 Pharmacokinetics
 Systemic drugs are well absorbed orally
 Fluconazole is the azole antifungal that best penetrates
blood-brain barrier (BBB)
 Renal clearance
 Fluconazole
 Hepatic clearance
 Ketoconazole
 Itraconazole
 Posaconazole
 Voriconazole
Mechanism of action
inhibit cytochrome P-450s that are
involved in ergosterol synthesis in
fungi
Essential component of the fungal
cell membrane
 Amphotericin B & Azoles have antagonistic
actions
 Ketoconazole
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 Ketoconazole was the first oral azole introduced into clinical use

 It is distinguished from triazoles by its greater propensity to

inhibit mammalian cytochrome P450 enzymes; that is, it is less
selective for fungal P450 than are the newer azoles.

 As a result, systemic ketoconazole has fallen out of clinical use

 Spectrum: yeasts and molds - poor absorption limits its role

for severe infections, generally used in mucosal infections
only
 Ketoconazole..
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 Pharmacokinetics
 Variable oral absorption, dependent on pH
 T1/2 7-10 hours
 Protein binding > 99%
 Hepatic, bile and kidney elimination
 Adverse effects
 N&V, worse with higher doses (800 mg/day)
 Hepatoxicity (2-8%), increase in transaminases, hepatitis
 Dose related inhibition of CYP P450 responsible for testosterone
synthesis
 Gynecomastia, decreased libido, oligospermia
 Dose-related inhibition of CYP P450 responsible for adrenal cortisol
synthesis
 35 Ketoconazole - Drug Interactions

 Potent inhibitor of cytochrome P450 3A4

 Rifampin and phenytoin decrease ketoconazole levels
 Ketoconazole increases cyclosporin, warfarin, astemizole,
corticosteroid, and theophylline levels
 Many of these drug interactions are severe
 Drugs that increase gastric pH will decrease blood levels of
ketoconazole
 Antacids, omeprazole, H2 blockers
36 Itraconazole
 Is azole whose absorption is increased by food and by low gastric pH
 Like other lipid-soluble azoles, it interacts with hepatic microsomal enzymes,
though to a lesser degree than ketoconazole
 An important drug interaction is reduced bioavailability of itraconazole when
taken with rifamycins (rifampin, rifabutin, rifapentine)
 It does not affect mammalian steroid synthesis, and its effects on the
metabolism of other hepatically cleared medications are much less than those
of ketoconazole.
 While itraconazole displays potent antifungal activity, effectiveness can be
limited by reduced bioavailability.
 Itraconazole
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 Broadest spectrum
 Itraconazole is the azole of choice for treatment of disease due
to the dimorphic fungi (histoplasma, blastomyces, and
sporothrix).
 Itraconazole has activity against aspergillus species, but it has
been replaced by voriconazole as the azole of choice for
aspergillosis.
 Itraconazole is used extensively in the treatment of
dermatophytoses and onychomycosis
 Fluconazole
 displays a high degree of water solubility and good
cerebrospinal fluid penetration.
 Unlike ketoconazole and itraconazole, its oral
bioavailability is high.
 Drug interactions are also less common because
fluconazole has the least effect of all the azoles on hepatic
microsomal enzymes.
 Fluconazole..
 Because of fewer hepatic enzyme interactions and better gastrointestinal tolerance,
fluconazole has the widest therapeutic index of the azoles, permitting more aggressive
dosing in a variety of fungal infections.
 The drug is available in oral and intravenous formulations
 Fluconazole is the azole of choice in the treatment and secondary prophylaxis of
cryptococcal meningitis.
 Fluconazole is the agent most commonly used for the treatment of mucocutaneous
candidiasis
 Fluconazole displays no activity against Aspergillus and mucormycosis
 Voriconazole
 is well absorbed orally, with a bioavailability exceeding
90%, and it exhibits less protein binding than
itraconazole.
 Observed toxicities include rash and elevated hepatic
enzymes.
 Visual disturbances are common, occurring in up to
30% of patients receiving intravenous voriconazole, and
include blurring and changes in color vision or
brightness.
 Voriconazole is less toxic than amphotericin B and is
the treatment of choice for invasive aspergillosis and
some environmental molds
 Topical azoles
 clotrimazole and miconazole are most common
 Both are available over-the-counter and are often used
for vulvovaginal candidiasis.
 Oral clotrimazole troches are available for treatment of
oral thrush and are a pleasant-tasting alternative to
nystatin.
 In cream form, both agents are useful for dermatophytic
infections, including tinea corporis, tinea pedis, and tinea
cruris.
 Absorption is negligible, and adverse effects are rare.
 Griseofulvin
 Griseofulvin is a very insoluble fungistatic drug derived from a species of
penicillium griseofulvum
 Its only use is in the systemic treatment of dermatophytosis

 Pharmacokinetics

 Absorption enhanced by fatty meals

 best absorbed when taken with a fatty meal

 Concentrates in keratinized tissue

 Selectively localizes in the skin

 Extensive hepatic metabolism

 Mechanism of action

 it is deposited in newly forming skin where it binds to keratin,

protecting the skin from new infection

 It works by inhibiting mitosis

 Adverse effects

 Headache

 Photosensitivity

 Rash, Hepatotoxicity
 Duration of treatment depends upon tissue turn over
 3-6 wks for skin & hair
 3-6 months for nails
 Treatment should continue till whole infected tissue is
shed off.
 Allylamine antifungal drugs

 Examples

 Butenafine (topical)

 Naftifine (topical)

 Terbinafine (oral; topical)

 Terbinafine

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 Terbinafine is a synthetic allylamine that is available in an oral
formulation.
 It is used in the treatment of dermatophytoses, especially
onychomycosis
 Like griseofulvin, terbinafine is a keratophilic (Concentrates in
keratinized tissue) medication, but unlike griseofulvin, it is
fungicidal.
 Like the azole drugs, it interferes with ergosterol biosynthesis, but
rather than interacting with the P450 system, terbinafine inhibits the
fungal enzyme squalene epoxidase. This leads to the accumulation of
the sterol squalene, which is toxic to the organism.
 Terbinafine
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 One tablet given daily for 12 weeks achieves a cure rate of up to
90% for onychomycosis and is more effective than griseofulvin
or itraconazole
 Adverse effects are rare, consisting primarily of gastrointestinal
upset and headache
 Terbinafine does not seem to affect the P450 system and has
demonstrated no significant drug interactions to date
 Echinocandin antifungal drugs

 are a new class of drugs available to treat fungal infections

refractory to conventional drugs.

 Examples

 Caspofungin (prototype)

 Micafungin

 Mechanism of action

 Inhibits the synthesis of β (1,3)-D-glucan, which is an

essential component of the fungal cell wall
 Uses

 invasive Aspergillus infections in patients who are

refractory or intolerant of other therapy

 Treatment of candidemia and other Candida infections

 Esophageal candidiasis

 Adverse effects

 Hypotension and tachycardia

 Fever, chills and headache

 Rash, Anemias
Spectrum of action-summary