Introduction

• Fungi are also called mycoses
• They are eukaryotic organisms & possess cell wall.
• Fungal cell wall is made up of chitin (NAG)
• Cell membrane is made up of Ergosterol.
• Fungal infections are iatrogenic/ drug induced
• Infections majorly occur in immunocompromised people receiving immunosuppressants

• Similar to animals, fungi are heterotrophs, that is, they acquire their food by absorbing _dissolved

molecules, typically by secreting

enzymes into their environment.

digestive

• The discipline of biology devoted to the study of fungi is known as mycology.

• Fungal cells contain membrane-bound nuclei with chromosomes that contain DNA with noncoding regions called introns and coding regions called exons. Fungi have membrane-bound cytoplasmic organelles such as mitochondria, sterol-containing membranes, and ribosomes of the 80S type.
• Fungi have a cell wall and vacuoles. They reproduce by both sexual and asexual means, and like basal plant groups (such as ferns and mosses) produce spores.

• A mold

or mould

is a fungus

multicellular

that grows in

filaments

form of

hyphae.

In contrast, fungi

the called adopt

that can habit are

a single-celled growth

called yeasts.

TYPES OF FUNGAL ORGANISMS

TYPES OF FUNGAL ORGANISMS

CLAS

S

MODE OF TRANSMISS IO N

SPECIES INVOVLVED DISEASE

CAUSED

MOULDS

Filamentous fungi reproduce by forming spores

Dermatophytoses/Tinea infections

Tinea barbe

T. capitis

T. corporis

T. Cruris

T. manum

T. pedis

T. unguium

Aspergillus fumigans

Infection

of Beard Scalp Body Groin Hand

Athelete

foot Nails

Pulmonary aspergillosis

DIMORPHIC FUNGI

Grow as filaments or as yeast

Histoplasma capsulatum Coccidiodes immitis Blastomyces deramtides Sporothrix sp.,

Histoplasmosis Coccidiomycosis Blastomycoses Sporotrichosis

• Cryptococcus

gattii

are

neoformans and Cryptococcus

significant

of immunocompromised people. They are the

pathogens

species

primarily responsible for cryptococcosis, a fungal disease that occurs in about one million HIV/AIDS patients, causing over 600,000 deaths annually.

• The cells of these yeast are surrounded by a rigid polysaccharide capsule, which helps to prevent them from being recognized and engulfed by white blood cells in the

human body.

genus, another group of cause oral and vaginal

• Yeasts of the Candida

opportunistic pathogens,

infections in humans, known as candidiasis.

• Candida is commonly found as a commensal yeast in

the mucous membranes of humans and other blooded animals.

warm-

• Aspergillosis is the group of diseases by Aspergillus. The most common subtype

paranasal sinus infections associated

caused among

with

aspergillosis is A. fumigatus.

• The symptoms include fever, cough, chest pain, or breathlessness, which also occur in many other

illnesses, so diagnosis can be difficult. Usually, only patients with already weakened immune systems or who suffer other lung conditions are susceptible.

DIFFERENCE BETWEEN BACTERIA AND FUNGI

• BACTERIA

• Peptidoglycan ^layer present in the ^cell

• consists of NAGA & NAMA
• Cell wall is composed of proteins

• Lipids present in membrane are cholesterol

the cell

made of

is and

FUNGI

of polysaccharides

• Consists

both simple (β – glucans 1,3

& 1,6)

and complex

polysaccharides

NAG) constituting the cell wall

(Chitin –

80%

is made of

• Cell membrane ergosterol

CLASSIFICATION OF FUNGAL INFECTIONS

FUNGAL INFECTIONS

SUPERFICIAL

INFECTIONS

On the surface of the skin

CUTANEOUS

INFECTIONS

Dermatophytes Ringworm infections

All Tinea sps Candida

sps

SUB CUTANEOUS

INFECTIONS

DEEP MYCOSAL INFECTIONS OR SYSTEMIC MYCOSAL INFECTIONS

CLASSIFICATION OF ANTIFUNGAL AGENTS

ANTIFUNGALS

ERGOSTEROL SYNTHESIS INHIBITORS

Voriconazole Itraconazole Posaconazole Fluconazole

CLASSIFICATION OF ANTIFUNGAL AGENTS

BASED ON CHEMICAL NATURE

POLYENES

AMPHOTERICIN B NYSTATIN

ECHINOCANDINS

MICAFUNGIN CASPOFUNGIN ANIDULAFUNGIN

ANTIMETABOLITES

FLUCYTSOINE

ALLYLAMINES

NAFTIFINE TERBINAFINE BUTENIFINE

AZOLES

MISCELLANEOUS

GRISEOFULIVIN BENZOIC ACID UNDECYCLINIC ACID

SODIUM

METBISULPHATE

TRIAZOLES

VORICONAZOLE ITRACONAZOLE POSACONAZOLE FLUCONAZOLE

IMIDAZOLES

SYSTEMIC KETOCONAZOLE

TOPICAL CLOTRIMAZOLE SECONAZOLE OXICONAZOLE MOCONAZOLE ECONAZOLE

CLASSIFICATION OF ANTIFUNGAL AGENTS

BASED ON SITE OF INFECTION

CUTANEOUS/TOPICAL INFECTIONS

NYSTATIN GRISEOFULVIN CLOTRIMAZOLE SECONAZOLE OXICONAZOLE MECONAZOLE BENZOIC ACID UNDECYCLINIC ACID

SODIUM METABISULPHATE

SYSTEMIC/ SUB CUTANEOUS INFECTIONS

AMPHOTERICIN B KETOCONAZOLE VORICONAZOLE ITRACONAZOLE POSACONAZOLE MICAFUNGIN CASPOFUNGIN FLUCONAZOLE

POLYENE ANTIBIOTICS - AMPHOTERICIN B

• Amphotericin B is a naturally occurring polyene antifungal produced

toxic potential,

the treatment of

by Streptomyces nodosus. In spite of its amphotericin B remains the drug of choice for several life-threatening mycoses.

• It is a macromolecule and consists of both lipophilic and hydrophilic groups i.e., it is amphiphilic in nature
• Conjugated nature is responsible for lipophilicity and OH group is responsible for hydrophilicity
• The amphiphilicity of the drug is responsible for its unique mechanism of action

PHARMACOKINETICS

• Yellowish colour powder
• Unstable in aqueous solutions
• Given through IV route in salt form along with

AMPHOTERICIN DESOXYCHOLATE

​

• Metabolised in liver

• ^t1/2

- 15 days

• It is extensively bound to plasma proteins and is distributed throughout the body.

• Inflammation favors penetration into various body fluids, but little of the drug is found in the CSF, vitreous humor, or amniotic fluid. However, amphotericin B does cross the placenta.

​

• Accumulates in renal cells causing nephrotoxicity leading to Azotemia characterized by decreased GFR, Urinary output, Cr_cl and increased Scr and BUN

MECHANISM OF ACTION

AMPHOTERICIN B

HYDROPHILIC PART

LIPOPHILIC PART

Binds with ergosterol and bilipid

layer

Forms pores in the cell membrane

Cell contents such as Na⁺ and K⁺ leak trough the spores from the cytoplasm

FUNGICIDAL ACTION

Antifungal spectrum:

It is effective against a wide range of fungi, including

• Candida albicans
• Histoplasma capsulatum
• Cryptococcus neoformans
• Coccidioides immitis
• Blastomyces dermatitidis
• Aspergillus

Amphotericin B is also

used in the treatment of the

protozoal infection leishmaniasis.

Dose

• Amphotericin B has a low therapeutic index.
• The total adult daily dose of the conventional formulation should not exceed 1.5 mg/kg/d,

whereas

lipid formulations have been given safely in doses up to

10 mg/kg/d.

Adverse effects

starting the IV administration but usually subside with repeated administration of the drug. Premedication with a corticosteroid or an antipyretic helps to prevent this problem.

Fever and chills:

​

^{These occur most} commonly 1

to 3 hours after

Renal impairment

• Patients may exhibit a decrease in glomerular filtration rate and renal tubular function.
• Serum creatinine may increase, creatinine clearance can

decrease, and potassium and magnesium are lost.

• Renal function usually returns with discontinuation of the drug, but residual damage is likely at high doses.
• To minimize nephrotoxicity, sodium loading with infusions of normal saline and the lipid-based amphotericin B products can be used.

Hypotension:

• A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation.
• Care must be exercised in patients taking digoxin and other drugs that can cause potassium fluctuations.

Thrombophlebitis:

Adding heparin to the infusion

problem.

can alleviate this

THERAPEUTIC USES

• Intestinal candidiasis
• Topical candidiasis
• Neutropenia
• Leishmaniasis – kala Azar

• Limited use in systemic because of increased toxicity

infections

AMB FORMULATIONS

CONVENTIONAL AMB

• Na⁺ salt of AMB i.e., Sodium desoxycholate AMB
• It is water soluble and stable

LIPOPHILIC AMB

• AMB formulated in which releases

periodically

liposomes

drug

• 10% AMB is unilammellar,

surrounded by

lipophilic

membrane made up of Lecithin

• Increased specificity as liposomes will be coated with Abs mediating site specific

delivery

• Increased BA nephrotoxicity

and decreased

NYSTATIN

• Posses very high systemic toxicity

​

• Not given in IV
• Used to treat topical infections

​

• Earlier it was used to treat moniliasis

It is administered as an oral agent

(“swish and

swallow” or “swish and spit”) for the treatment of --

• Oropharyngeal candidiasis (thrush)
• Intravaginally for vulvovaginal candidiasis
• Topically for cutaneous candidiasis.

ANTIMETABOLITES

FLUCYTOSINE

• FLUCYTOSINE is a cytosine moiety
• It is a pyrimidine analogue
• 6 membered ring structure

​

• Posses 2 „N‟ atoms
• Earlier used as an Anticancer agent

​

• But was proved to have potent action

Cryptococcus sp., and Candida sp.,

against

PHARMACOKINETICS

• ^t1/2

- 3 to 6 hours

• Orally well absorbed
• Distributes throughout the body and even into CSF.
• Metabolized by liver
• 5-FU is detectable in patients and is probably the

5-FC by intestinal

result of metabolism of bacteria.

• Excreted unchanged in urine

MECHANISM OF ACTION

FLUCTYOSINE INACTIVE

CYTOSINE PERMEASE

5 - FLUCYTOSINE

CYTOSINE DEAMINASE

5 - FLUROURACIL

5 - FUMP

5 - FUDP

5 - FUTP

Inhibition of protein sysnthesis

5 – FLUORO DEOXYURIDINE MONOPOSPAHTE

Inhibit thymidylate synthase

Inhibit DNA synthesis

FUNGICIDAL

FUNGICIDAL

FUNGAL CELL MEMBRANE

MECHANISM OF ACTION

present only in fungal cells and absent

• CYTOSINE PERMEASE and DEAMINASE are

in

mammalian cells

• Hence activation of 5 – FC to 5 – FU occurs only in fungal cells causing inhibition of both DNA and protein synthesis resulting in fungicidal action

Resistance:

• Resistance due to decreased levels of any of the

enzymes in the conversion of 5-FC to 5-

fluorouracil (5-FU) and beyond or from increased synthesis of cytosine can develop during therapy. This is the primary reason that 5-FC is not used

as a single antimycotic drug.

• The rate of emergence of resistant fungal cells is lower with a combination of 5-FC plus a second antifungal agent than it is with 5-FC alone.

THERAPEUTIC USES

ADRs

• Synergistic with

AMPHOTERICIN as it

in

increases permeability

to fungal cells by

formation of pores in the cell membrane.

​

• Cryptococcosis

​

• Candidiasis

colonic which Cytosine

• Bone marrow suppression
• Hepatotoxicity
• 5 FC administered in excess ^stimulate

intestinal bacteria produce

deaminase

ECHINOCANDINS

• Newer antifungal agents that inhibit the fungal cell

wall synthesis

​

• Discovered serendipitously
• During fermentation process, some metabolites were found to inhibit Candida sp., and they were named Echinocandins

• The echinocandins have potent activity Aspergillus and most Candida species, including species resistant to azoles.

against

those

• One of the first echinocandins, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis.
• Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.

so far have low oral be given intravenously

• All these preparations bioavailability, so must only.

Chemistry

Chemistry

• The present-day clinically used echinocandins are semisynthetic pneumocandins, which are chemically

cyclic

lipopeptide in nature, consisting of large

(hexa)peptoid.

• Caspofungin, micafungin, and anidulafungin are

similar

cyclic hexapeptide antibiotics linked to long N-linked acyl fatty acid chains.

modified

• The chains act as anchors on the fungal cell membrane

to help facilitate antifungal activity

MECHANISM OF ACTION

Inhibits the synthesis of β 1,3 – D- glucan

via noncompetitive inhibition of the enzyme 1,3-β

glucan synthase and are thus called "penicillin of

antifungals“ resulting in the inhibition of cell wall, leading to lysis and death.

Pharmacokinetics

• Due to the large molecular weight of echinocandins, they have poor oral bioavailability and are administered by intravenous infusion.
• In addition, their large structures limit penetration into cerebrospinal fluid, urine, and eyes. In plasma,

echinocandins have a high affinity to serum proteins.

• Echinocandins do not have primary interactions with CYP450 or P-glycoprotein pumps.

• ^{Caspofungin has triphasic} nonlinear ^{pharmacokinetics.}
• Micafungin (hepatically metabolized by arylsulfatase, catechol O-methyltransferase, and hydroxylation) and anidulafungin (degraded spontaneously in the system and excreted mostly as a metabolite in the urine) have linear elimination.

Resistance

• Echinocandin resistance is rare.
• Resistances include alterations

in the glucan

synthase and overexpression of efflux pumps.

Advantages of echinocandins:

• Broad range (especially against all Candida), thus can be given empirically in febrile neutropenia and stem cell transplant.
• Can be used in case of azole-resistant Candida or use as a second-line agent for refractory aspergillosis
• Long half-life (polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50 hours)

• ^{Not an inhibitor, inducer, or substrate} of the ^{cytochrome P450 system, or P-glycoprotein,} thus minimal drug interactions

necessary

fluconazole

based on age, effective) than

• No dose adjustment is gender,

race Better (or no less

amphotericin B and against yeast infections

• Low toxicity: only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis

Disadvantages of echinocandins:

• Embryotoxic (category C) thus should be avoided if

possible in pregnancy

• Needs dose adjustment in liver disease
• Poor ocular penetration in fungal endophthalmitis

Caspofungin

Caspofungin is a first-line option for patients with invasive candidiasis, including candidemia, and a second-

line option for invasive aspergillosis in patients who have failed or cannot tolerate amphotericin B or an azole.

Micafungin and Anidulafungin

Micafungin and anidulafungin are first-line options for

the treatment of invasive candidiasis, including candidemia.

Micafungin is also indicated for the prophylaxis of invasive Candida infections in patients who are undergoing hematopoietic stem cell transplantation.

AZOLE ANTIFUNGALS

Azole antifungals are made up of two different classes of drugs

• Imidazoles
• Triazoles.

Although these drugs have action and

similar of

their vary

mechanisms of activity,

spectra and

pharmacokinetics significantly.

therapeutic uses

• Imidazoles are given topically for cutaneous

​

infections.

​

• Triazoles are given systemically for the treatment or

prophylaxis of cutaneous and systemic fungal infections.

AZOLES

TRIAZOLES

VORICONAZOLE ITRACONAZOLE POSACONAZOLE FLUCONAZOLE

IMIDAZOLES

SYSTEMIC

KETOCONAZOLE

TOPICAL CLOTRIMAZOLE SECONAZOLE OXICONAZOLE MICONAZOLE ECONAZOLE TERCONAZOLE

AZOLE ANTIFUNGALS

• Broad spectrum of cation with minimal ADRs
• More efficacious, Fungicidal

MECHANISM OF ACTION

Lanosterol

​

Lanosterol 14 demethylase

(CYP 450 enzyme)

​

AZOLES

Ergosterol

TOPICAL AZOLES

cutaneous

• Used to treat oral, vulvovaginal,

candidiasis

​

• Used to treat T. corporis,

infections

cruris and capitis

• MICONAZOLE is more efficacious than topical azoles

other

• ^t1/2

- 1 to 6 hours

• Treatment ranges from 2 – 6 months based on the area of infection

SYSTEMIC AZOLES

KETOCONAZOLE

• Oral ketoconazole has historically been used

for the

treatment of systemic fungal infections but is rarely used

adrenal

today due to the risk for severe liver injury,

insufficiency, and adverse drug interactions.

PHARMACOKINETICS

• Orally well absorbed
• Metabolised by liver
• Well absorbed through out the body but does not enter CSF
• It is a potent CYP 450 enzyme inhibitor

PHARMACOKINETICS

• By inhibiting CYP enzymes it increases the concentration of drugs such as

• DIGOXIN
• WARFARIN
• SULFONAMIDES
• AMLODIPINE
• STATINS

• PHENYTOIN
• NIFEDIPINE
• CIMETIDINE
• PHENOBARBITONE
• CARBAMAZEPINE
• TERFINADINE – QT

interval prolongation

and tachyarrhythmias

ADRs

enzymes _useful

hair, and

• Inhibits

for sterol synthesis

• Decreased production of testosterons

leading to impotency,

loss of

oligozoospermia Gynaecomastia

• Menstrual irregularities
• Hepatotoxicity

USES

• Systemic candidiasis
• Vaginal moniliasis
• Deep mycotic infections
• Cryptococcal infections
• Coccidioiodo infections

TRIAZOLES

FLUCONAZOLE

• Most of its spectrum limited dimorphic fungi.

​

• Available in oral and IV formuations.

to yeasts

and some

PHARMACOKINETICS

• Orally well absorbed
• Excreted unchanged in urine upto 90%
• Crosses BBB
• Has increased affinity towards fungal lanostreol

Ineffective against

• Aspergillosis
• Histoplasmosis
• Blastomycoses

​

INDICATIONS

• It is used for prophylaxis against invasive fungal infections in recipients of bone marrow transplants.

• It also is the drug of choice for Cryptococcus neoformans after induction therapy with amphotericin B and flucytosine and is used for the treatment of candidemia and coccidioidomycosis.

​

• It is commonly used as a single-dose oral treatment

for vulvovaginal candidiasis

TRIAZOLES

hypokalemia,

ITRACONAZOLE

• Orally well absorbed
• IV can be given in serious infections
• Not effective against fungal meningitis
• Adverse effects include nausea, vomiting, rash hypertension, edema, and headache, hepatotoxicity.
• It has a negative inotropic effect and should be

avoided in

patients with evidence of ventricular dysfunction, such as heart

failure.

INDICATIONS

• FLUCONAZOLE resistant fungal meningitis
• Histoplasmosis
• Blastomycoses

• Sporotrichosis
• Mucormycosis

• Coccidioiodomycosis
• Paracoccidioidomycosis

ITRACONAZOLE is the drug

of choice

POSACONAZOLE

• Newer and most costliest of all the azoles
• Limited use due to increased cost
• It is available as an oral suspension, oral tablet, or IV

formulation.

• It is commonly used for the treatment and

prophylaxis

of invasive Candida and Aspergillus infections in

severely immunocompromised patients.

​

• CYP inhibitor

VORICONAZOLE

• It has replaced amphotericin B as the drug of choice for invasive aspergillosis.
• It is also approved for treatment of invasive candidiasis, as well as serious infections caused by Scedosporium and Fusarium species.
• Adverse effects are similar to those of the other azoles;

however, high trough concentrations are associated with

increased

visual and auditory hallucinations and an incidence of hepatotoxicity.

All azoles are teratogenic hence contraindicated in

pregnant and lactating women

DRUGS FOR CUTANEOUS MYCOTIC INFECTIONS

• Mold-like fungi that cause cutaneous infections are called dermatophytes or tinea.
• Common dermatomycoses, such as tinea infections that appear as rings or round red patches with clear centers, are often referred to as “ringworm.” This is a misnomer because fungi rather than worms cause the disease.
• Trichophyton, Microsporum, and

Epidermophyton.

Squalene epoxidase inhibitors

Allylamine derivatives

• Terbinafine
• Butenafine
• Naftifine

Terbinafine

• Oral terbinafine is the drug of choice for treating dermatophyte onychomycoses (fungal infections of nails, therapy requires 3 months)
• Topical terbinafine (1% cream, gel or solution) is used to treat tinea pedis, tinea corporis (ringworm), and tinea cruris (infection of the groin). Duration of treatment is usually 1 week.

Pharmacokinetics

• Terbinafine is available for oral and topical administration, although its bioavailability is only 40% due to first-pass metabolism.
• It is highly protein bound and is deposited in the

skin, nails, and adipose tissue.

• It accumulates

in breast milk and should not be

given to nursing mothers.

• A prolonged terminal half-life of 200 to 400 hours

may reflect the slow release from these tissues.

Adverse effects

effects of terbinafine

• Common adverse

gastrointestinal disturbances

include

(diarrhea,

dyspepsia, and nausea), headache, and rash.

• Taste and visual disturbances have been reported, as well as transient elevations in serum hepatic

transaminases.

Terbinafineis an inhibitor of the CYP450 2D6 isoenzyme.

GRISEOFULVIN

• Obtained from Streptomyces griseus.
• Effective against dermatophytes.

PHARMACOKINETICS

• Well absorbed orally.

• Absorption

substances.

• Accumulation

is enhanced in the presence of lipophilic

is enhanced in

tissues

made

up of

keratin such as skin, nails, and hair.

MECHANISM OF ACTION

GRISEOFULVIN

Binds to

​

Tubulins

inhibiting

​

Mitotic spindle formation

Resulting in

​

Inhibition of separation of daughter nuclei

FUNGISTATIC EFFECT

INDICATIONS

• It has been largely replaced by oral terbinafine for the treatment of onychomycosis, although it is still used for dermatophytosis of the scalp and hair.
• Griseofulvin is fungistatic and requires a long duration of treatment (for example, 6 to 12 months for onychomycosis).
• Duration of therapy is dependent on the rate of replacement of healthy skin and nails.

USES

ADRs

• Rashes
• Nausea
• Vomitings
• Diarrhoea
• Mild Hepatotoxicity

​

GRISEOFULVINs use

• T. unguium
• T. corporis
• Dermatophyte infections

is limited because of

extensive replacement by Azoles and Terbinafine

NYSTATIN

• Polyene antifungal, Posses very high systemic toxicity

​

• Not given in IV
• Used to treat topical infections

​

• Earlier it was used to treat moniliasis

It is administered as an oral agent (“swish and swallow” or “swish and spit”) for the treatment of --

• Oropharyngeal candidiasis (thrush)
• Intravaginally for vulvovaginal candidiasis
• Topically for cutaneous candidiasis.

Ciclopirox

• Ciclopirox inhibits the transport of essential elements in the fungal cell, disrupting the synthesis of DNA, RNA, and proteins.
• It is active against Trichophyton, Epidermophyton, Microsporum, Candida.
• Ciclopirox 1% shampoo is used for treatment of seborrheic dermatitis. Tinea pedis, tinea corporis, tinea cruris, cutaneous candidiasis, and tinea versicolor may be treated with the 0.77% cream, gel, or suspension.

Tolnaftate

and stunts

• Tolnaftate

distorts the hyphae

mycelial growth in susceptible fungi.

• It is active against Epidermophyton, Microsporum, and Malassezia furfur.

• Tolnaftate is

used to treat tinea pedis, tinea

cruris, and tinea corporis.

• It is available as a 1% solution, cream, and powder.

DRUG OF CHOICE FOR VARIOUS FUNGAL INFECTIONS

DRUG OF CHOICE FOR VARIOUS FUNGAL INFECTIONS