ANTI FUNGAL AGENT
• Very large and diverse group of microorganisms
• Classified into yeast and molds
• Yeast is single cell organism, useful for baking and alcohol beverages
• Molds are multicellular, characterized by long, branching filaments called hyphae
• Fungi are eukaryotic, heterotrophic (not self sustaining)
organisms that live as saprobes or parasites.
• They are complex organisms in comparison to bacteria.
Thus antibacterial agents are not effective against fungi.
• Fungal infections are also called as mycoses
• They have nucleus and well defined nuclear
membrane, and chromosomes.
• They have rigid cell wall composed of chitin ( N –
• Fungal cell membrane contains ergosterol , human cell
mebmrane is composed of cholesterol.
• Yeast infections
• Candida species
• Cryptococcus neoformats
• Moulds (filamentous fungi)
• A fungal infection of animals, including humans.
• Common and a variety of environmental and physiological conditions can
contribute to the development.
• Initiation of persistent infections:• Inhalation of fungal spores
• localized colonization of the skin
• Therefore, mycoses often start in the lungs or on the skin.
Epidemology:• Skin Fungal infections- the 4th most common disease in 2010
• Affecting 984 million people.
• Individuals being treated with antibiotics are at higher risk of fungal
• Individuals with weakened immune systems are also at risk of developing
• This is the case of people with HIV/AIDS, people under steroid treatments, and people
• People with diabetes also tend to develop fungal infections.
• Very young and very old people, also, are groups at risk.
MAJOR TYPES OF MYCOSES
• Symptoms vary from cosmetic to life threatening
• Classified according to the tissue levels initially colonized.
• Limited to the outermost layers of the skin and hair.
• Tinea versicolor
• Affects the skin of young people, especially the chest, back, and upper arms and legs.
• Tinea versicolor
• Caused by a fungus that lives in the skin of some adults.
• It does not usually affect the face.
• This fungus produces spots that are either lighter than the skin or a reddish brown.
• Extend deeper into the epidermis, and also include invasive hair and
• These diseases are restricted to the keratinized layers of the skin,
hair, and nails.
• Host immune responses may be evoked resulting in pathologic
changes expressed in the deeper layers of the skin.
• The organisms that cause these diseases are called dermatophytes.
• The resulting diseases are often called ringworm (even though there
is no worm involved) or tinea.
• Caused by Microsporum, Trichophyton, and Epidermophyton fungi,
which together comprise 41 species.
• One common disease is the athlete's foot which most commonly
affects children before puberty.
MYCOSES DUE TO
SUBCUTANEOUS MYCOSES SYSTEMIC
• Involve the dermis,
• Originate primarily in
the lungs and may
muscle and fascia.
spread to many organ
• Infections are chronic
and can be initiated by
piercing trauma to the
• Organisms that cause
skin which allows the
systemic mycoses are
fungi to enter.
• These infections are
difficult to treat.
• May require surgical
interventions such as
removal of damaged
tissue or foreign objects
from a wound.)
SYSTEMIC MYCOSES DUE TO OPPORTUNISTIC
• These are infections of patients with immune deficiencies who would otherwise not
• Examples of immunocompromised conditions include AIDS, alteration of normal flora
by antibiotics, immunosuppressive therapy, and metastatic cancer
• Examples of opportunistic mycoses include
• Candidiasis (infection caused by yeast Candida, common cause of vaginal
infections in women. )
• Cryptococcosis (systemic infection caused by Cryptococcus that affect the
lungs, skin, or other body organs ,brain and meninges.)
• Aspergillosis ( infections in the ear canal, eyes, nose, sinus cavities, and
ANTI FUNGAL AGENT
BASED ON MECHANISM OF ACTION
Bind to fungal cell membrane
• Amphotercin–B, Nystatin.
Inhibition of ergosterol + lanosterol
• Terbinafine, Naftifine, Butenafine.
Inhibition of ergosterol synthesis
Inhibition of nucleic acid synthesis
Disruption of mitotic spindle and
inhibition of fungal mitosis
• Ciclopirox, Tolnaftate, Haloprogin,
Undecylenic acid, Topical azoles.
ROUTE OF ADMINISTRATION
BASED ON STRUCTURE
C. Heterocyclic benzofuran:
• Clotrimazole, Econazole,
B. Triazoles: (systemic)
• Fluconazole, Itraconazole,
2. Antimetabolite:• Flucytosine (5-FC)
5. Other topical agents
Ciclopirox olamine, Butenafine,
Polyenes (Disrupt membrane structure & function)
Flucytosine inhibits DNA synthesis
• Amphotericin B
• Obtained from Streptomyces
• Amphoteric in nature
• Polyene group- Multi lactone
ring with conjugated double
• One end – Hydroxyl group
MECHANISM OF ACTION
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
• Other end – Hydrocarbon
group-non polar (Lipophilic)
Cell contents leak out
MECHANISM OF ACTION
- Fungicidal at high & static at low
- Broadest spectrum of action
Also active against Leshmania
• Replacement of ergosterol by other
sterols in fungal plasma membrane.
• Poorly absorbed orally
• Insoluble in water so colloidal
suspension prepared with sodium
deoxycholate (1:1 complex)
• Plasma proteins bound 90%
• Metabolized in liver
• Slowly excreted in urine
DI:• Flucytosine – synergetic action inc.
• Aminoglycoside inc. renal toxicity.
– Acute reaction:
– Chills, fever, headache,
pain all over, nausea,
lasting 2-5 hrs because of
release of IL & TNF
– Long term toxicity:
Azotemia ( inability of
the kidneys to excrete
blood urea nitrogen) ,
– CNS toxicity : intrathecal
administration, headache, vomiting,
– Hepatotoxicity rarely
Disadvantages of AMB
• Useful drug in nearly all life
Acute infusion related reactions
• Rapidly progressive
Blastomycosis (Infection with
a fungus called
Hypopotassemia, anemia, hepatic
Blastomyces dermatitidis) &
(caused by inhaling spores of
the fungus Coccidioides immiti
• Cryptococcus neoformans
• Reserve drugs for resistant
( visceral leishmaniasis caused
by L. tropica)
• Topical uses: for oropharngeal
Obtained from S.Noursei
Similar to AMB
In antifungal properties
High systemic toxicity so
used locally only
Poorly absorbed from
Available as ointment,
cream , powder, tablet
(Yeast infection of the
mouth and throat )
Prevention of oral candidiasis
Can be used in oral,
Hindustan antibiotics Pimpri
More water soluble, fraction absorbed
orally but unreliable in systemic
Topical use in thrush (develops on the
mucous membranes of the mouth ),
cutaneous candidiasis, trichomonas &
monilial vaginitis, otomycosis by
Similar to nystatin, broad spectrum
Used topically 1%, 3% ointment
For Fusarium solani keratitis (ocular
(sexually transmitted disease (STD)
caused by a small organism
called Trichomonas vaginalis.)
monilial vaginitis (Vaginal Yeast
• Obtained from Penicillium
• Systemic drug for superficial
• Narrow spectrum
• Dermatophytes concentrate it
• loss of drug concentrating ability
• MECHANISM OF ACTION:
polymerized microtubules and
• Disrupts the mitotic spindles thus
arresting fungal mitosis
• Irregular absorption
• Increased by fatty food
• Gets conc in keratinized tissue
• Headache most common
• GIT disturbances
• CNS symptoms: confusion, fatigue,
• Peripheral neuritis
• Rashes, photoallergy
• Leukopenia, albuminuria (the
presence of albumin in the urine).
dermatophytosis, ineffective topically
• In athletes foot (a fungal infection
affecting mainly the skin between the
• Systemic azoles more effective and
DI :• Induces warfarin metabolisrn
• Phenobarbitone reduces the oral
metabolism of griseofulvin
• failure of therapy may occur.
• Has useful activity against
Candida and Cryptococcus.
MECHANISM OF ACTION
• It is converted to antimetabolite
5-florouracil in a fungal but not
• Inhibits thymidylate synthetase
• Thus DNA synthesis.
• Should never be used alone,
resistant may occur.
• Combination with itraconazole
fungal infection of the skin and the
• With amphotericin for treating
cryptococcal meningitis in AIDS
• Bone marrow depression.
• Nausea, vomiting ,diarrhea,
• Severe enterocolitis (inflammation
of both the small intestine and the colon.)
• Hepatic enzyme elevation.
5-flucytosine permease 5-flucytosine
Mechanism of action of Flucytosine
Orally & topically effective drug
Against candida & dermatophytes
shorter courses of therapy required
& low relapse rates
Well absorbed orally 75%
Highly keratophilic & lipophilic
High protein bound , poor BBB
Negligible effect on CYP450
MECHANISM OF ACTION:
• Acts as a noncompetitive
• an early step enzyme in
ergosterol biosynthesis by
• Accumulation of squalene
within fungal cells appears to
be responsible for the
• The mammalian enzyme is
inhibited only by higher
concentration of terbinafine.
Nausea , vomiting , Diarrhoea
Rarely hepatic dysfunction
Topical: erythema (superficial
reddening of the skin) , itching,
dryness , urticaria, rashes
• Topically as cream in tinea pedis
(Infection that usually begins
between the toes)/ cruris (fungal
infection of the groin region)
infection of the arms and legs,) and
appear mainly on the chest and
• Oral treatment reserved for
onychomycosis (fungal infection of
the nail.) , tinea capitis (a fungal
infection of the scalp and hair
• Efficacy in nail infection is ~80%.
• Less effective against cutaneous
and mucosal candidiasis.
Mechanism of action of terbinafine
• A new class of potent semisynthetic
• With large cyclic peptides linked to a
long chain fatty acid
• Have low toxicity compared to
• Active mainly against Candida and
• Strains of candida that have become
resistant to azoles are susceptible
MECHANISM OF ACTION
• Inhibits the synthesis of β-1, 3glucan
• which is a unique component of the
fungal cell wall.
• Cross linking between chitin and β1, 3-glucan gives toughness to the
fungal cell wall.
• Weakening of the cell wall leads to
osmotic susceptibility of fungal cell,
which then burst out.
USE:• In deep and invasive candidiasis.
• Esophageal candidiasis
• In invasive aspergillosis.
patients whose fever is not
(reactions are fever, chills, pruritus,
• Phlebitis of the injected vein.
hypokalemia and joint pain may
TOPICAL AGENTS USED IN DERMATOPHYTE
• An effective drug for tinea
cruris and tinea corporis
• Poor penetrability
• Resistance does not occur.
• Causes little irritation
• Penetrates superficial layers
and reaches hair roots
• Negligible Systemic absorption.
• No irritation
onychomycosis:Formulated as nail lacquer
• Vaginal candidiasis :- as vaginal
• Effective in tinea infections,
• Undecyclenic acid:
• Generally combined with
• Weaker antifungal action
used in tinea cruris, tinea
pedis and nappy rash
(inflammation of a baby's skin
caused by prolonged contact with
a damp nappy)
• Sodium thiosulfate:
• A weak fungistatic,
• Active against Malassezia
(a fungus species can cause tine
a versicolor, folliculitis)
• Effective in
• Used in combination
with salicylic acid
( benzoic acid 6% +
salicyclic acid 3 %)
• Salicyclic acid due to its
keratolytic action helps
to remove infected
tissue & promotes
penetration of benzoic
acid in fungal infected
irritation & burning
• Luminal amoebicide
Dermatophytosis , mycosis
barbae (Ringworm of the beard) ,
• Also used in vaginal creams for
monilial and trichomonas
• A benzylamine congener of
• Same mechanism of action.
Use:• Topically in dermatophytosis.
• Efficacy in tinea cruris /
corporis / pedis
• Synthetic anti fungals
• Broad spectrum
• Fungistatic / Fungicidal
• Most commonly used
• Classified as imidazoles & triazoles
• Both these groups are
• Structurally related compounds
• Have same mechanism of action
• Have similar antifungal spectrum
• Two nitrogen in structure
• Systemic :
• ketoconazole (topically also)
• Triazoles :
• Three nitrogen in structure
• Fluconazole and itraconazole -----largely replaced ketoconazole for
• Because of greater efficacy, longer t½,
as well as fewer side effects.
• Some newer triazoles have been
• Covering dermatophytes, Candida,
other fungi involved in deep mycosis
(except mucor), Nocardia and
THE MECHANISM OF
• They inhibit the fungal cytochrome
P450 enzyme ‘lanosterol 14demethylase’
• Thus impair ergosterol synthesis.
• Leading to a cascade of membrane
abnormalities in the fungus.
• The lower host toxicity :-
• Lower affinity for
• Lesser propensity to
inhibit mammalian sterol
RESISTANCE:• Mutation of the gene
• Encoding for fungal 14demethylase enzyme.
• By enhanced removal
from the fungal cell.
MICONAZOLE & CLOTRIMAZOLE
• Topical use
• First orally effective broad spectrum
• Effective against
• Cream, gel, spray, lotion, solution ,
(pedis, cruris, corporis, versicolor)
• Candida: oral pharyngeal, vaginal,
• Local irritation , itching or burning
• Miconazole shows higher incidence of
vaginal irritation & pelvic cramps
• No systemic side effects
• Deep mycosis
• Restricted use, most serious mycoses
• Monilial vaginitis
• Systemic mycosis: blastomycosis (Parasitic fungi affecting the skin or the internal
organs), histoplasmosis (infection by a fungus confined to the lungs but can be
fatal if spread throughout the body), Coccidioidomycosis (a serious fungal disease
of the lungs and other tissues)
• Less efficacious than AMB & produces slower response
• Efficacy low in immunocompromized and meningitis
• Lower toxicity than AMB higher than triazoles
• So triazoles have replaced it in systemic mycosis
• High dose used in cushings syndrome (a metabolic disorder caused by
overproduction of corticosteroid hormones)
• Topical: T.pedis, cruris, corporis, versicolor
• Inhibits CYP450 enzyme
• Nausea , vomiting , anorexia
• ↑ Sr conc of cisapride, terfenadine,
• Headache , paresthesia, alopecia
• Reduces steroid, testosterone
(enlargement of a man's breasts, usually
due to hormone imbalance),
• Oligospermia (deficiency of sperm cells
in the semen), loss of libido (loss of sex
& impotence ( sexual
dysfunction) in males.
• Menstrual irregularities & amenorrhoea
(an abnormal absence of menstruation)
• Elevation of liver enzymes
• Hypersensitivity reaction like skin
• Itraconazole or fluconazole, that have
largely replaced it for systemic use.
• Phenytoin toxicity
• Sulfonylureas: hypoglycemia
• Cyclosporine: nephrotoxicity
• Warfarin: bleeding
• Rifampicin, phenytoin ↑ metabolism of
• Should not combine with AMB
• Newer water soluble
• Oral, IV as well as topical
• Candida, cryptococcosis,
• 94% oral bioavailability
• Not affected by food or gastric pH
• Primarily excreted unchanged in urine
• Poor protein binding (10-12%)
• Widely distributed
• Crosses BBB
• T ½ -27-32hrs
• GIT upset
• Teratogenic effect
• CYP450 Enzyme inhibiting property
• No anti androgenic & other endocrine
• Effects hepatic drug metabolism to
lesser extent than Ketoconazole
• H2 blockers & PPI do not effect its
cryptococcal, coccidiodal meningitis &
other systemic fungal infections
• Candida UTI
• Meningitis preferred drug
drops for fungal keratitis
(infection of the cornea)
Broadest spectrum of activity also against aspergillus
Absorption is variable, enhanced by food & gastric acidity
High protein binding 99 %
Well distributed accumulates in vaginal mucosa, skin, nails
but CNS penetration is poor
Metabolized in liver CYP3A4
Excreted in feces
T1/2= 30- 64hr
• GI Intolerance
• Increase plasma transaminase
• Rarely Hepatotoxicity
• Oral absorption decreased by antacids, H2
blockers , and proton pump inhibitors
• Rifampicin, phenobarbitone , phenytoin
• Clarithromycin and HIV protease inhibitors
reduce the metabolism of itraconazole and
raise its blood levels.
• Potentiates effect of hypnotic drugs
• Inhibits CYP3A4 drug interaction profile
similar to ketoconazole
• For paracoccidomycosis (a fungal infection caused by the
fungus Paracoccidioides brasiliensis. )& chromoblastomycosis
• For histoplasmosis, sporotrichosis (infection caused by a fungus
called Sporothrix schenckii )& blastomycosis in AIDS patients
• Esophageal, oropharyngeal, vaginal candidiasis
• Dermatophytosis: less effective than fluconazole
• Second generation triazole
• High oral bioavailability,
• Low protein binding
• Good CSF penetration
• Metabolized by CYP2C19
vision , altered color
• Doesn’t require gastric acidity
• T1/2-6 hrs
• DOC for invasive aspergillosis
• Most useful for esophageal candidiasis
• First line for moulds like fusarium
(infestation with any of the fusaria or
• Useful in resistant candidal infections
• Rashes in 5 -6 %
• Prolongation of QT