Antifungal Agents
Sanjaya Mani Dixit
Assistant Prof of Pharmacology
Antifungal Agents
Fluconazole
Clotrimazole
Ketoconazole
Itraconazole
Terbinafine
Tolnaftate
Amphotericin B
Nystatin
Micafungin
Caspofungin
Griseofulvin
Flucytosine
Contents
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Fungal Infections
Fungal infections in Nepal
Antifungal Drugs
Mechanisms involved
Classification of Antifungal Drugs
Individual Drugs and Classes
Fungal Infections
• Human fungal infections have increased dramatically
in incidence and severity in recent years.
• A large extent of fungal infections are iatrogenic.
• This is mainly due to:
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–
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–
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advances in surgery,
indwelling catheters and implants
cancer treatment,
increases in use of broad-spectrum antimicrobials and
the HIV epidemic.
Fungal Infections
• Major Types of Mycoses
– superficial
– cutaneous
– subcutaneous
– systemic
– Opportunistic
Fungal Infections
• Symptoms vary from cosmetic to life threatening.
• Fungal infections are usually more difficult to treat than
bacterial infections, because:
– fungal organisms grow slowly and
– fungal infections often occur in tissues that are poorly
penetrated by antimicrobial agents (e.g., devitalized or
avascular tissues).
• Therapy of fungal infections usually requires prolonged
treatment.
Burden of Serious Fungal Infections in Nepal
-2012 Study
• About 1.94% of the Nepalese population is estimated to
suffer from a serious fungal infection annually
• The most serious fungal infections occur in HIV/AIDS and
immunocompromised patients.
• Both pathogenic and allergenic fungi including Aspergillus
species are common in the air in Kathmandu valley.
• Fungal keratitis is the most prevalent fungal infection in
Nepal.
• There is also a high burden of ABPA and CPA.
Antifungal Agents
Classification of Antifungals
Based on Site of Action
Systemic antifungal agents:
Amphotericin-B,
Flucytosine,
Imidazoles –Ketaconazole
Triazoles – Fluconazole, Itraconazole
Topical antifungal agents:
Imidazole and Triazoles --Clotrimazole, Miconazole,
Polyenes --Nystatin
Tolnaftate, Naftifine
Classification of Antifungals
Based on Mechanism of Action
Alter cell membrane permeability:
Azoles
Terbinafine
Polyenes
Block nucleic acid synthesis:
Flucytosine
Disrupt microtubule function:
Griseofulvin
Nystatin
Targets of Antifungal drugs
• Despite differences in the composition of the
cell membrane and the presence of the cell wall,
fungi are metabolically similar to mammalian
cells and offer few pathogen- specific targets.
• Azole and polyene antifungal agents exert their
antifungal effects by targeting ergosterol- the
principal cell membrane sterol of many
pathogenic fungi.
Timeline of Systemic Antifungal Agents
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Introduction of Amphotericin B - deoxycholate in 1958
Standard treatment for serious fungal infections
Infusion-related adverse effects and dose-limiting nephrotoxicity
Introduction of fluconazole in 1990, excellent oral bioavailability
Fluconazole - one of the most widely prescribed antifungal agents for
mucosal and systemic yeast infections.
Timeline of Systemic Antifungal Agents
• Fluconazole --lack of activity against opportunistic molds (ie,
Aspergillus, Mucorales, and Fusarium species) and intrinsic resistance
among some Candida species.
• Itraconazole (1992) improved activity against endemic fungi and
Aspergillus species, but the oral dosing formulations were plagued by
erratic absorption (capsules) or adverse gastrointestinal (GI) effect.
• Introduction of broader-spectrum triazoles voriconazole (2002) and
posaconazole (2006) transformed the management of invasive mold
infections in severely immunocompromised patients.
• Unfortunately, the broader spectrum of activity with triazole
antifungal agents often comes at the expense of increased
pharmacokinetic variability and risk of drug interactions.
Echinocandins
• Echinocandins are semisynthetic lipopeptides that inhibit synthesis of β1,3-d-glucan in susceptible fungi, leading to damage of the fungal cell
wall.
• Because a glucan-rich cell wall is a target not found in mammalian cells,
these agents were predicted to be effective antifungal agents with very
little collateral toxicity in mammalian cells—a prediction that has been
proven true in clinical trials of patients with invasive candidiasis and
aspergillosis.
• However, echinocandins still lack activity against some common
opportunistic yeasts (Cryptococcus species) and less common molds (ie,
Fusarium, Scedosporium, and Mucorales) that often develop as
breakthrough infections in severely immuno-compromised patients.
Timeline of Systemic Antifungal Agents
The search continues
No single antifungal agent is appropriate for all patients for a
given mycosis because of :
• patient-specific comorbid conditions,
• hypersensitivities,
• risk of drug interactions,
• immunosuppression,
• site of infection, and
• risk of infection with more intrinsically antifungal-resistant
pathogens.
Azoles
• Inhibit 14α-demethylase (lanosterol demethylase), a fungal
cytochrome P450 (CYP)–dependent enzyme
• Deplete cell membrane ergosterol,
• Impair membrane fluidity, and
• Lead to accumulation of toxic 14α-methylated sterols,
• Resulting in growth arrest and
• Eventual fungal cell death.
• However, this inhibition is not entirely selective to fungi;
indeed, collateral inhibition of human CYP enzymes by azoles
is often responsible for pharmacokinetic drug-drug
interactions.
Allylamine-Terbinafine
• The allylamine, terbinafine inhibits ergosterol biosynthesis by inhibiting
squalene monoxygenase —an enzyme in fungi responsible for conversion
of squalene to squalene epoxide, a precursor to lanosterol in the
ergosterol synthesis pathway.
• Although allylamines do not seem to have the same collateral effects on
human CYP enzymes as azole antifungal agents, drugs such as rifampin
that strongly induce CYP metabolism in mammals will increase the
metabolism of terbinafine.
• Once taken orally, terbinafine concentrates in the skin and nail beds and
has relatively low bloodstream concentrations.
• Consequently, its use as a systemic antifungal agent is primarily restricted
to the treatment of onychomycosis and cutaneous fungal infections.
Amphotericin B
• The broad-spectrum polyene amphotericin B targets the
fungal cell membrane.
• Amphotericin B directly binds to ergosterol, forming
complexes that intercalate the cell membrane, thereby
resulting in pore formation and leakage of intracellular
contents.
• Amphotericin B has greater affinity for ergosterol-rich fungal
cell membranes vs cholesterol-rich mammalian cell
membranes; however, this specificity may be lost when the
drug accumulates to high concentrations in organs such as
the kidney, where the drug causes direct damage to distal
tubular membranes.
Amphotericin B
• Consequently, nephrotoxicity is a common dose-limiting
adverse effect of amphotericin B therapy.
• Amphotericin B also directly stimulates release of
proinflammatory cytokines by mononuclear phagocytic cells,
often resulting in fever, rigors, and chills during drug infusion.
• This infusion reaction can be attenuated to varying degrees by
reformulation of amphotericin B into lipid carriers.
• However, the principal advantage of lipid amphotericin B
formulations are their reduced distribution of amphotericin B
to the kidneys, which reduces but does not eliminate the
nephrotoxicity of amphotericin B.
Different Fungal infections
Sporotrichosis
Sporotrichosis
Sporothrix schenckii, found
in vegetation.
Infection commonly occurs
when the skin is broken
while handling plant
materials such as
rosebushes, or dirt.
Cryptococcosis
Cryptococcus
neoformans. It is usually
found in soil. If you
breathe it in, it infects
your lungs. The infection
may go away on its own,
remain in the lungs only,
or spread throughout
the body (disseminate).
Blastomycosis is an
infection caused by
breathing in the
Blastomyces dermatitidis
fungus. The fungus is found
in wood and soil. The
disease may affect the skin,
bones and joints, and other
areas.
Different Fungal infections
Valley fever is an
infection that occurs
when the spores of
the fungus
Coccidioides immitis
enter your body
through the lungs.
Tinea versicolor is caused by
Pityrosporum ovale, a fungus
normally found on human skin that
only causes a problem in certain
settings.
The condition is most common in
adolescent boys and young adult
men. It typically occurs in hot
climates.
Histoplasmosis is an
infection that occurs from
breathing in the spores of
the fungus Histoplasma
capsulatum.
Soil that contains bird or
bat droppings may have
larger amounts of this
fungus
AMPHOTERICIN B
Polyene anti-fungal agent
Amphotericin A and B are antifungal antibiotics
produced by Streptomyces nodosus. Amphotericin A
is not in clinical use.
Amp B is insoluble in water, but is
given IV in diff forms:
1. C-AMB
Colloidal Amp. With deoxycholate
2. AMBD
Lipid formulations for IV infusion
Amp B colloidal dispersion
3. ABLC
Amphotericin B lipid complex
AMPHOTERICIN B
M/A
• Amphotericin B is selective in its fungicidal effect.
• It binds to Ergosterol, a cell membrane sterol, found in the cell
membrane of fungi [bacteria and human –cholesterol].
• Increases the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane
• Leakage of intracellular ions and macromolecules [K+]
• Oxidative damage to fungal cells
• Fungistatic or Fungicidal depending
on the organism and drug concentration
Clinical Use
• Owing to its broad spectrum of activity and fungicidal
action, amphotericin B remains the drug of choice for
nearly all life-threatening mycotic infections.
• It is often used as the initial induction regimen for serious
fungal infections and is then replaced by one of the
newer azole drugs. Such induction therapy is especially
important for immunosuppressed patients and those with
– severe fungal pneumonia,
– cryptococcal meningitis with altered mental status, or
– sepsis syndrome due to fungal infection.
Clinical Use
• Broad spectrum activity:
• For mucormycosis, invasive aspergillosis, extracutaneous
sporotrichosis, cryptococcosis
• In blastomycosis, histoplasmosis, coccidiomycosis,
immunocompromised host or involving CNS
• Candidiasis: bones, heart, CNS, urinary, esophagus, peritoneum
& disseminated disease
• In other antimicrobial agents failure (selected cases)
• As prophylactic in AIDs, cryptococcosis
• For cutaneous candida infection (topical)
• Oral use to prevent colonization of intestinal flora by candida.
Mucormycosis is a fungal infection of the sinuses, brain, or lungs that occurs
in some people with a weakened immune system.
Adverse Effects
• Highly toxic drug (intravenously)
• Headache, fever, dyspnea, malaise tachycardia, phlebitis, gut
distress malaise (symptomatic treatment)
• Nephrotoxicity: Renal acidosis, potassium& magnesium ion
depletion
• Azotemia-80% cases [infuse 1L of N/S before drug
administration]
• Hypochromic normochromic anemia , mild leukopenia
• Anaphylactic reactions, rashes, diplopia, myalgia, convulsion,
peripheral neuritis
AMPHOTERICIN B
• Although resistance to amphotericin B among Candida strains
remains rare, there are recent reports of increasing MICs to
amphotericin B among C. krusei and C. glabrata isolates.
• Most clinicians use an MIC of >1.0 mcg/mL to indicate resistance to
amphotericin B.
• Defects in the ERG3 gene involved in erogosterol biosynthesis lead to
accumulation of other sterols in the fungal membrance.
• Consequently, polyene-resistant Candida and Cryptococcus isolates
have relatively low ergosterol content, compared with that of
polyene-susceptible isolates.
• Resistance to amphotericin B may also be mediated by increased
catalase activity, with decreasing susceptibility to oxidative damage.
Nystatin
• Polyene anti-fungal agent
• Not absorbed orally
M/A
Like Amphotericin B,
Ergosterol synthesis Inhibitor
• For superficial mycosis: skin, Oral, gut and vaginal
candidiasis.
C/I parenterally (Highly Toxic)
Flucytosine
• 5-fluorocytosine, 5-FC
• Fluorinated Pyrimidine antimetabolite
related to the anti-cancer drug
5- fluorouracil (5-FC).
M/A
• Flucytosine is taken up by fungal cells via the enzyme membrane
permease.
• It is converted intracellularly first to 5-FU and then to 5fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and RNA synthesis,
respectively.
• Human cells are unable to convert the parent drug to its active
metabolites so selective toxicity occur.
• Synergistic activity with amphotericin-B.
Flucytosine
Clinical Uses
• Narrow anti-fungal spectrum
• For Cryptococcus and C. albicans with Amphotericin-B.
S/Es
• Prolonged & high dose flucytosine cause
– reversible bone marrow depression ,
– alopecia, and
– liver dysfunction
Anorexia, Nausea, Vomitting and Diarrhoea
Skin Rashes
Has narrow therapeutic window, with an increased risk of toxicity at higher drug levels and
resistance developing rapidly at sub-therapeutic concentrations.
Flucytosine
Resistance
• Some yeast strains are intrinsically resistant to flucytosine
because of impaired cellular uptake secondary to a
mutation in cytosine permease.
• On the other hand, acquired resistance results from defects
in flucytosine metabolism through mutations in cytosine
deaminase or uracil phosphoribosyl transferase.
• The prevalence of primary resistance to flucytosine remains
low
– 1%–2% among Candida isolates
– < 2% among C. neoformans isolates
Azole Antifungal Agents
• Azoles are synthetic compounds that can be classified as either
imidazoles or triazoles derivatives.
• Ketoconazole Fluconazole
• Itraconazole Clotrimazole
• Miconazole
• Oral bioavailability variable (normal pH)
• Fluconazole: is absorbed orally > others & has highest therapeutic index
among azoles. It therefore is preferred agent for oral use. It is the azole of
choice in the treatment and secondary prophylaxis of cryptococcal meningitis.
Mechanism Of Action
• Inhibition of fungal cytochrome
P450 enzymes
• Inhibit the synthesis of
ergosterol
• Interfere with fungal cell
membrane permeability
• Selective action--The specificity of
azole drugs results from their
greater affinity for fungal than for
human cytochrome P450 enzymes.
Imidazoles exhibit a lesser degree of
specificity than the triazoles,
accounting for their higher incidence
of drug interactions and side effects.
Uses
For Superficial candida infection
• Oropharyngeal: fluconazole, ketoconazole (orally);
nystatin, clotrimazole (topically)
• Cutaneous: itraconazole, terbinafine, griseofulvin
(orally); triazoles, ciclopirox, haloprogin, naftifin, etc
(topically)
• Vulvovaginitis: fluconazole (orally); nystatin,
clotrimazole, miconazole (topically)
Adverse effects:
Relatively non-toxic
• GI upset (most common)
• Abnormalities in liver enzymes and,
• very rarely clinical hepatitis.
Pulse dosing
• Pulse or intermittent dosing with the azoles is effective in
onychomycosis as continuous dosing, because drug persists in
the nails for several months
• Treat for one week, followed by three weeks without drug
Azoles
Resistance
• Azoles exert their action by inhibiting the C14alpha
demethylation of lanosterol in fungi, which interferes
with the synthesis of ergosterol in the fungal cell
membrane.
• Azoles differ in their affinities to their target, which may
account for differences in their spectrum of activity
• In addition, variations in the structure of azoles are
thought to be responsible for the cross-resistance
patterns among Candida species.
ITRACONAZOLE
• A very important drug even to be considered
for its potential drug interactions.
• Available as a capsule and two solution
formulations, one for oral and one for I/V
administration.
ITRACONAZOLE: USES
• Azole of choice for treatment of disease due to the dimorphic
fungi• histoplasma,
• blastomyces, and
• sporothrix.
• Has activity against aspergillus species, but it has been
replaced by Voriconazole as the azole of choice for
aspergillosis.
• Used extensively in the treatment of dermatophytoses and
onychomycosis.
• Dose: 100–400 mg/d
• Voriconazole -The newest triazole available in IV and oral
formulations. Dose: 400 mg/d
ITRACONAZOLE: S/Es
• Hepatotoxicity; rarely hepatic failure and death
[Discontinue the drug and assess LFT.]
• A dose-dependent inotropic effect may precipitate CHF
in patients with impaired ventricular function.
• GI distress less common at small dose (up to 200 mg).
• OTHERS:
• Nausea, vomiting, hypokalemia, increased serumaminotransferases, rash [occasional discontinuation]
• High Doses > 300 mg BID
• Adrenal insufficiency, lower limb edema, hypertension
or rhabdomyolysis.
• Phlebitis at injection site.
Ketoconazole
• Ketoconazole was the first oral azole introduced into clinical
use.
Drug of choice in following conditions:
• Non-meningeal blastomycosis,
• Histo-blasmomycosis,
• Coccidoidomycosis &
• Chronic mucocutaneous candidiasis
• In griseofulvin resistant ring worm of skin and taenia
versicolor
• A/Es
• Menstrual irregularity, Gynecomastia
• Decreased libido and Azoospermia
• Hypertension & salt retention [Elevated mineralocorticoid]
• Teratogenicity
CLOTRIMAZOLE
• Topical Azole
• Absorption of clotrimazole is less than 0.5%
after application to the intact skin; from the
vagina, it is 3% to 10%.
• Fungicidal concentrations remain in the vagina
for as long as 3 d.
• Small amount absorbed is metabolized in the
liver and excreted in bile.
CLOTRIMAZOLE
THERAPEUTIC USES:
• Available as a 1% cream, lotion, and
solution, 1% or 2% vaginal cream or vaginal
tablets of 100, 200, or 500 mg, and 10 mg
troches.
• On the skin, applications are made BID.
CLOTRIMAZOLE
A/E:
Skin--stinging sensation, erythema, edema, vesication,
desquamation, pruritus, and urticaria.
Applied to the vagina, a mild burning sensation, and
rarely of lower abdominal cramps, a slight increase in
urinary frequency, or skin rash.
Occasionally, the sexual partner may experience penile
or urethral irritation.
By the oral route; can cause GI irritation.
In patients using troches, the incidence of this side
effect is about 5%.
Griseofulvin
• Griseofulvin is a very insoluble fungistatic drug
• Oral absorption depends on physical state of the drug, better absorption
when taken with high fat foods
• Well distributed
• Biliary excretion
M/A: Fungistatic
• Interferes with microtubule function
• Inhibits the synthesis and polymerization of nucleic acids
It is deposited in newly forming skin where it binds to keratin, protecting the
skin from new infection.
Griseofulvin
Uses
For dermatophytoses of the skin, hairs, and nails
Side Effects:
• Headache,
• Mental confusion,
• Gut distress,
• Photosensitivity and
• Changes in liver enzyme function
• Enhances coumarin metabolism
TERBINAFINE
• A synthetic allylamine.
• A systemic antifungal (Oral) for systemic
infections; however 1% cream is also available for
topical use.
• Acts the interfering the synthesis of Sterols
(LANOSTEROL) in sensitive fungi.
• Like Griseofulvin, it is keratophilic, but unlike
griseofulvin, it is fungicidal.
• Pregnancy Category: B; unsafe.
TERBINAFINE
MECHANISM:
• Interferes with synthesis of Lanosterol by binding and
inhibiting to squalene epoxidase of sensitive fungi
accumulation of squalene  death.
• Squalene is a sterol but it is toxic to fungi.
TERBINAFINE
PHARMACOKINETICS:
• Good oral absorption but extensive 1st pass
metabolism in liver bioavailability ~40%.
• ~99% drug bound to plasma protein; accumulates well
in skin, nails and fats.
• CSF concentrations are about 10 %
• Initial T1/2 of ~12 h increases significantly to almost
200-400 h at SS.
• Not recommended to patients with azotemia and
*hepatic failure  *increased concentration.
TERBINAFINE
THERAPEUTIC USES:
Nail Onchomycosis:
250-mg tablet OD, is at least as effective as 200 mg OD of itraconazole,
and slightly more effective than pulse itraconazole therapy.
Duration of treatment varies with the site being treated but typically is
3 months.
Ringworm:
Ringworm elsewhere in body responds well to 250 mg OD.
No pediatric dose is available.
Contraindicated in pregnancy; systemic therapy
onychomycosis postponed until pregnancy is complete.
for
TERBINAFINE
ADVERSE EFFECTS:
• Well tolerated
• Low incidence of GI distress, headache, or
rash.
• Rarely, hepatotoxicity, severe neutropenia,
Stevens-Johnson syndrome, or toxic epidermal
necrolysis.
Newer Antifungal Agents
Isavuconazole
• Isavuconazonium sulfate, is a water-soluble triazole prodrug that
can be administered both orally and intravenously.
• It is broken down by plasma esterases to the active component,
isavuconazole.
• Its structure confers activity against some pathogens resistant to
other azoles, including itraconazole, voriconazole, and
posaconazole.
• Isavuconazole appears to be highly active against all Candida species
including species such as C. glabrata and C. krusei, which are
inherently less susceptible to other azoles such as fluconazole.
• Isavuconazole also has an excellent activity against Cryptococcus
gattii and C. neoformans.
Lulliconazole
• Luliconazole is an imidazole antifungal agent that has been shown to
have potent activity against a variety of fungi, especially dermatophytes.
• Luliconazole is the R-enantiomer, and has more potent antifungal
activity than lanoconazole, which is a racemic mixture.
• Luliconazole, although belonging to the azole group, has strong
fungicidal activity against Trichophyton spp., similar to that of
terbinafine. This is possibly attributable to a combination of strong in
vitro antifungal activity and favorable pharmacokinetic properties in the
skin.
• Luliconazole 1% cream was approved in Japan in 2005 for the treatment
of tinea infections.
• Further studies to evaluate its efficacy in onychomycosis are underway.
Novamycin
• A potent synthetic antimicrobial peptide (AMP) - poly-Arginine
based cationic peptide.
• It acts through membrane perturbation and lysis; this mode of
action rapidly killing both non-metabolising and metabolically active
fungi.
• This mechanism of action minimises or negates the risk of acquired
drug resistance. A mechanism of action that is specific only to
fungal cells, is not toxic to human cells.
• A rapidly acting fungicidal peptide that has demonstrated
superiority over existing antifungal classes in preclinical testing (with
a placebo like safety profile) for a number of fungal infections.
• Treatment of aspergillosis, candidiasis
Novexatin
• Novexatin is a novel, potent, synthetic antimicrobial peptide (AMP) , cyclic
arginine-based heptamer.
• Novexatin is rapidly fungicidal through a membranolytic mode of action that
targets both non-metabolising and metabolically active nail fungal pathogens.
This includes both dermatophyte and non-dermatophyte fungi associated with
onychomycosis.
• Novexatin remains stable and bioavailable within the nail for more than 12
months post-application.
• Phase I and IIa clinical studies have demonstrated that NP213 is safe, welltolerated and effective in resolving toenail infections following just one month of
daily application (currently available topical treatments require up to 52 weeks of
treatment).
• It is applied topically. It is the first treatment for fungal nail infections to address
both the underlying cause by killing the fungi and to rapidly improve the nail's
appearance.
Candida vaccine-Oral
• Enolase 1 (Eno1p) of Candida albicans is an immunodominant antigen.
• To develop a novel type of oral vaccine against candidiasis,
Saccharomyces cerevisiae cells that display the Eno1p antigen on their
surfaces were generated.
• Oral delivery of the engineered S. cerevisiae cells prolonged survival
rate of mice that were subsequently challenged with C. albicans .
• Together, C. albicans and Candida glabrata are responsible for 70–80%
of Candidainfections in patients with candidiasis or candidemia.
• Pharmacotherapy of candidiasis often involves the administration of
caspofungin, micafungin, anidulafungin and amphotericin B. However,
mutants of Candida with reduced susceptibility to these drugs have
emerged (Rodloff et al. , 2011 ).
Amphotericin B -Nanoparticles
BENZOIC ACID & SALICYLIC ACID
Whitfield's ointment:
• An ointment containing benzoic and salicylic acids.
• Combines the fungistatic action of benzoate with the
keratolytic action of salicylate.
• Contains BA and SA in a ratio of 2:1 (usually 6% to 3%) and
used mainly in the treatment of tinea pedis.
• Since BA is only fungistatic, eradication of the infection
occurs only after the infected stratum corneum is shed, and
continuous medication is required for several weeks to
months, scrapping accelereted by SA.
• Also sometimes used to treat tinea capitis.
• Mild irritation may occur at the site of application.
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