1. ANTIFUNGALs Mr. Sachin Shinde S. M. Joshi College Hadapsar, Pune
Assistant Professor
S. M. Joshi College Hadapsar, Pune

3. FUNGI
Fungi are eukaryotic cells and as such contain nuclei, mitochondria, ER, golgi, 80S ribosomes, etc., bound bya plasma membrane.
The fungal kingdom includes yeasts, molds, rusts and mushrooms. In general most fungi are beneficial and are involved in biodegradation. A few can cause opportunistic infections if they are introduced into a human through wounds or by inhalation.
The importance of fungi as pathogens is increasing due to aging population, HIV, immunosuppression in organ transplant and unknown factors.
Fungi possess a rigid cell wall containing chitin, glucans and other sugar polymers. Arrangement of the biomolecular components of the cell wall accounts for the individual identity of the organism. Although, each organism has a different biochemical composition, their gross cell wall structure is similar.
Fungal cell wall differs greatly from bacterial cell wall. Therefore, fungi are unaffected by antibacterial cell wall inhibitors such as -lactams and vancomycins.

4. Classification of Fungi
Fungi are classified as
•Yeasts - round/oval cells that divide by budding. (e.g. Candida, Cryptococcus neoformans )
•Molds - tubular structures (hyphae) that grow by longitudinal extension and branching. A mass of hyphae is called a mycelium. (Aspergillus)
Dimorphic have growth characteristics of both. At body temperature, they grow as yeast in host tissues; whereas at ambient temperature they grow as molds in saprophytes

5. Infections caused by Fungi
Fungal infections are classified depending on the degree of tissue involvement and mode of entry:
1. Superficial - localized to the skin, hair and nails.
2. Subcutaneous - infection confined to the dermis,
subcutaneous tissue, or adjacent structures.
3. Systemic - deep infections of the internal organs.
4. Opportunistic - cause infection only in the
immunocompromised (AIDS, chemotherapy, post-surgery).

6. Superficial The Dermatophytes
Superficial infections are caused by a variety of fungi, especially the dermatophytes (causing infection of the skin, hair and nails) belonging to 40 related fungi of three genera: Microsporum, Trichophyton, Epidermophyton. Dermatophytic infections known as Tinea and are named for the site of infection rather than the causative organism.
Tinea pedis
“athletes foot”
Epidermophyton spp.
Tinea capitis
Microsporum spp.
Tinea corporis
Ringworm, dermatophyte infection (zoophilic)

7. Subcutaneous Subcutaneous infections are confined to the
dermis, subcutaneous tissue, or adjacent
structures; there is no systemic spread.
They tend to be slow in onset and chronic in
duration.
These mycoses are rare in the US and are
primarily confined to tropical regions (the
Americas, South Africa, Australia).
Variety of fungi involved. Infection starts with trauma inoculation from soil or plants.
Lobomycosis

8. Discoloration of the skin caused by Histoplasma capsulatum
Systemic
Systemic mycoses are invasive infections of the internal
organs.
The organism typically gains entry via the lungs, GI tract,
or through intravenous lines.
Examples include:
•Histoplasmosis - Histoplasmosis is caused by Histoplasma, a dimorphic fungus
•Coccidiomycosis - An infection caused by the dimorphic fungus, Coccidioides immitis.
•Blastomycosis - A disease caused by the dimorphic, fungus Blastomyces dermatitidis
Discoloration of the skin caused by Histoplasma capsulatum
The lesion on the
Nose Resulted From
dissemination
From the lungs
Skin lesion following
dissemination from
the lungs

9. Skin lesions resulting from disseminated
Opportunistic
Opportunistic fungi are normally of marginal pathogenicity, but can infect the immunocompromised host.
Patients usually have some serious immune or metabolic defect, or have undergone surgery.
Examples include:
Candidiasis - an infection caused by a Candida spp.
Aspergillosis is a large spectrum of diseases caused by
members of the genus Aspergillus.
Cryptococcus is an encapsulated yeast found world-wide; it is found in pigeon droppings, eucalyptus trees, some fruits and contaminated milk.
Oral Thrush- the white material consists of budding yeast cells and pseudohyphae.
Skin lesions resulting from disseminated
C. neoformans
Fruiting body in a lung cavity

10. Classification of Antifungal Drugs
According to Mechanism of action
1. Drugs affecting synthesis / Functions of cell membrane
Synthesis (inhibit synthesis of ergosterol)
- Ketoconazole, Fluconazole, traconazole, Voviconazole, Miconazole, Turbenafine (inhibit enzyme squaline epoxide so interfere ergosterol synthesis)
ii. Function
Polyene antibiotics = Amphotericin B, Nystatin
2. Block nucleic acid synthsis
- Flucytosine
3. Distrupts microtubular function
- Griseofulvin
4. Reduction of fungal cell wall viability
- Pradimicin, Nikkomycin
5. Fungal protein synthesis inhibitor
-Jordanians

11. B. According to route of administration :
Topical
Nystatin, Clotrimazole, Econazole, Amphotericin-B
Oral
Miconazole, Ketoconazole, Fluconazole, Itraconazole, Flucytosine, Grisofulvin, Terbenafine
3. Intravenous
Amphotericin, Miconazole, Fluconazole, Flucytosine

12. C. According to Therapeutic action :
Superficial
Dermatophytes (ringworms)
Griseofulvin, Terbanafine, Ketoconazole, Nystatin
ii. Candidacies
Fluconazole, Miconazole
Systemic
Ketoconazole
Histoplassm, Blastomycosis
ii. Ketoconazole
- cocciciodomy, para
iii. Amphotericin B cocdiodo
- Cryptococcus, Candidacies, zygomycosis
iv. Fluconazole
- candidiasis
v. Flucytosine
- candidiasis, Cryptococcus

13. D. According to Chemical /structure :

14. Antibiotic Antifungal Drugs
Polyenes: Amphotericin B, Nystatin

15. Amphotericin B
Produced by Streptomyces nodosus. Amphoteric polyene macrolide.
Chemistry
-Amphotericin B is a polyene antibiotic (polyene: containing many double bonds)

17. Pharmacological Effect: broad-spectrum
Mechanism of action
-Binding to ergosterol present in the membranes of fungal cells 
Formation of “pores” in the membrane
Leaking of small molecules (mainly K+) from the cells
-The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
Pharmacological Effect: broad-spectrum
Mechanism: binds to ergosterol in fungi (cholesterol in humans and bacteria) to form pores

18. Pharmacokinetics: Adverse Effects:
Poorly absorbed from the gastrointestinal tract.
More than 90% bound by serum proteins.
Metabolized in liver, excreted slowly in the urine.
Adverse Effects:
Infusion-Related Toxicity: fever, chills, muscle spasms, vomiting, headache, hypotension.
Slower Toxicity:
Renal toxicity
K+↓, Mg2+↓
Anemia: due to erythropoietin ↓
Abnormalities of liver function
Neurologic sequelae (Neurological symptoms like convulsions, seizures)

19. Pharmacokinetics
-f(oral): < 1% (too irritant to be given IM) (f=Bioavailibility) -Distribution in all body tissues, except CNS and eye (concentrations in CSF are <10% than in plasma; however therapeutic concentrations in CNS can usually be achieved with parenteral administration) -Biotransformation: > 95% -Renal excretion: < 5% -Half life: » 14 days Drug formulations and administration -Formulations: a) complex with deoxycholate b) liposomal complex (adverse effects seem diminished) -Administration: IV infusion, intrathecal, topical, oral (to treat intestinal mycoses)

20. Adverse effects (the therapeutic index of the drug is very narrow)
-Headache, arthralgias, nausea and vomiting fever with chills, hyperpnea (increased rate of respiration), shock-like features like tachycardia and hypotension
-Malaise (Muscle pain), weight loss
-Nephrotoxicity (azotemia , decreased GFR, renal tubular acidosis, renal wasting of K+ and Mg++,). It is common (up to 80% of patients) and may be severe
-Normocytic anemia, likely due to decreased production of erythropoietin (frequent)
-Thrombophlebitis
-Delirium, seizures (after intrathecal injection)

21. used for deep and superficial infections
Therapeutic uses:
used for deep and superficial infections
Amphotericin is the drug of choice for:
-Disseminated histoplasmosis
-Disseminated and meningeal coccidioidomycosis
-Disseminated and meningeal cryptococcosis
-Invasive aspergillosis
-Deep candidiasis
-Mucormycosis
Amphotericin is an alternative drug for:
-Blastomycosis (fungal infection of humans and other animals, notably dogs and occasionally cats)
-Paracoccidioidomycosis
-Extracutaneous sporotrichosis
[Amphotericin is preferred when these mycoses are rapidly progressive, occur in immunocompromised host or involve the CNS]

22. Azoles Synthetic compounds.
Classification: according to the number of nitrogen atoms in the five-membered azole ring
Imidazoles: Ketoconazole, Miconazole, Econazole, Clotrimazole, Bifonazole
Triazoles: Itraconazole, Fluconazol, Vorionazole → systemic treatment

24. Mechanism of Action
Reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes.
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.

25. Ketoconazole The first oral azole introduced into clinical use.
Less selective for fungal P450
Inhibition of human P450 interferes with biosynthesis of adrenal and gonadal steroid hormones;
Alter the metabolism of other drugs.
Best absorbed at a low gastric pH.

27. Miconazole, Econazole, Clotrimazole
Bioavailability is low by taking orally.
Used topically.
Bifonazole
Double inhibition, antifungal action is more powerful.
Itraconazole
Its absorption is increased by food and by low gastric pH.
Treatment of dermatophytoses and onychomycosis .
The only agent with significant activity against aspergillus species.

28. Fluconazole Vorionazole
Water solubility and good cerebrospinal fluid penetration.
The widest therapeutic index of the azoles (broad spectrum).
Treatment and secondary prophylaxis of cryptococcal meningitis .
Vorionazole
Available in an intreavenous and an oral formulation.
Metabolism is predominantly hepatic, but the propensity for inhibition of mammalian P450 appears to be low.
Similar to itraconazole in this spectrum of action, having good activity against candida species.
More effective than itraconazole.

29. PHARMACOLOGY OF ANTIFUNGAL AZOLES
Chemistry
-Imidazole derivatives: ketoconazole, miconazole, econazole, clotrimazole
-Triazole derivatives: itraconazole, fluconazole.
Mechanism of action
-Inhibition of sterol 14-alpha-demethylase, a cytochrome P450-dependent enzyme (relative selectivity occurs because the affinity for mammalian P450 isozymes is less than that for the fungal isozyme) 
blockade of the synthesis of ergosterol in fungal cell membranes
-The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.

30. Pharmacologic properties of five systemic azole drugs

31. Pharmacokinetics and administration
-F(oral): itraconazole » 55%, fluconazole >90%.
(acidity favors oral absorption of ketoconazole)
-Distribution in all body tissues. Penetration into CNS is generally negligible, but good for fluconazole.
-Renal excretion: fluconazole » 75%, others < 1%
-Half-lives (hrs): ketoconazole » 8, itraconazole » 35
-Administration: oral, IV, topical
Adverse effects
-Anorexia (lack or loss of appetite for food, thereby loss of weight), nausea and vomiting (they are dose-dependent and patients receiving high doses may require antiemetics)
-Gynecomastia, decreased libido, impotence, menstrual irregularities (with ketoconazole, due to blockade of adrenal steroid synthesis)
-Hepatitis (is rare, but can be fatal)
-Hypokalemia, hypertension (itraconazole)
-Azoles are potent teratogenic drugs in animals

32. Therapeutic uses
Azoles are first choice drugs for:
-Blastomycosis (ketoconazole)
-Paracoccidioidomycosis (ketoconazole)
-Chronic pulmonary histoplasmosis
-Meningeal coccidioidomycosis (fluconazole)
-Meningeal cryptococcosis (fluconazole)
-Cutaneous and deep candidiasis
Azoles are alternative drug for:
-Invasive aspergillosis
-Sporotrichosis
Topical azoles are used for:
-Dermatophytoses (not of hair and nails)
-Tinea versicolor
-Mucocutaneous candidiasis
Contraindications
-Systemic azoles are contraindicated in pregnancy (potential teratogenic effects and endocrine toxicity for the fetus)

33. β-Glucan Synthetase inhibitor (Echinocandins)
Newest class of antifungal agents
Intravenous
inhibiting the synthesis of (1–3)-glucan
Well tolerated
Caspofungin
Micafungin
Anidulafungin

34. Pharmacokinetics and administration
-f(oral): » 50% (micronization of the drug and a high-fat food favor oral absorption)
-Distribution is mainly in keratinized tissues where the drug is tightly bound and where it can be detected 4-8 hours after oral administration. Concentration in other tissues and body fluids is negligible.
-Elimination: mainly in the feces.
-Half-life (hrs): » 24 hours
-Administration: oral
Adverse effects
(incidence is quite low)
-Xerostomia, nausea and vomiting, diarrhea
-Headache (up to 15%), fatigue, blurred vision, vertigo, increased effects of alcohol
-Hepatotoxicity (rare)
-Leukopenia, neutropenia
-Allergic reactions (urticaria, skin rashes, serum sickness, angioedema)
-Teratogenic effects in several animal species
Therapeutic uses
-Mycotic disease of the skin, hair and nails (long treatments are needed)

35. TOPICAL ANTIFUNGAL DRUGS
Nystatin
-A polyene antibiotic useful only for local candidiasis.
-Administration: cutaneous, vaginal, oral.
Haloprogin
-The drug is fungicidal to various species of dermatophytes and candida.
-Principal use: in tinea pedis (cure rate » 80% )
Tolnaftate
-The drug is effective against most dermatophytes and Malassezia furfur but not against Candida
-In tinea pedis the cure rate is » 80%
Antifungal azoles
-Azoles are reported to cure dermatophyte infections in % of cases
-The cure rate of mucocutaneous candidiasis is > 80% and that of tinea versicolor > 90%.
-Administration: cutaneous, vaginal.
-Cutaneous application rarely causes erythema, edema, vescication, desquamation and urticaria
-Vaginal application may cause mild burning sensation and abdominal pain.

37. Allylamine Include Naftifine and Terbinafine.
non-competitive and reversible inhibitor of Squalene epoxidase.
Terbinafine is synthetic, oral formulation.
Fungicidal
Treatment of dermatophytoses, especially onychomycosis, more effective than griseofulvin or itraconazole.

39. Griseofulvin Derived from a species of penicillium. Fungistatic drug.
Non-polyenes:
Griseofulvin
Derived from a species
of penicillium.
Fungistatic drug.
Insoluble.
Administered in a microcrystalline form only using in the systemic treatment of dermatophytosis .
Deposited in newly forming skin where it binds to keratin, protecting the skin from new infection.

40. PHARMACOLOGY OF GRISEOFULVIN
Chemistry
-Griseofulvin is a benzofuran derivative
-The drug is practically insoluble in water
Mechanism of action
-An active transport accumulates the drug in sensitive fungal cells where 
griseofulvin causes disruption of the mitotic spindle by interacting with polymerized mycrotubules
-The ultimate effect is fungistatic
Antifungal spectrum and resistance
-Antifungal spectrum includes only Dermatophytes
(Microsporum, Epidermophyton, Trichophyton)
-The drug is ineffective against other fungi producing superficial lesions (like Candida and Malassezia furfur) and those producing deep mycoses.
-Resistance is uncommon. It seems to be due to a decrease of the energy-dependent transport mechanism.

41. Pyrimidine derivatives
Flucytosine （5-FC）is a water-soluble pyrimidine analog.
Its spectrum of action is much narrower than that of amphotericin B.
Poorly protein-bound and penetrates well into all body fluid aompartments, including the cerebrospinal fluid.
Flucytosine
Fluorouracil

42. Synergy with amphotericin B.
Mechanism
5-FC (taken up by fungal cells via the enzyme cytosine permease) → 5-FU → F-dUMP and FUTP → inhibit DNA and RNA synthesis, respectively.
Synergy with amphotericin B.
Spectrum of action: Cryptococcus neoformans, some candida species, and the dematiaceous molds that cause chromoblastomycosis.

44. Adverse effects: result from metabolism to fluorouracil (5-FU)
Not used as a single agent because of its demonstrated synergy with other agents and to avoid the development of secondary resistance.
Adverse effects: result from metabolism to fluorouracil (5-FU)
Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia

45. PHARMACOLOGY OF FLUCYTOSINE
Chemistry : Flucytosine is a fluorinated pyrimidine
Mechanism of action
-The drug is accumulated in fungal cells by the action of a membrane permease and is converted by a cytosine deaminase to 5-fluorouracil (selectivity occurs because mammalian cells do not accumulate and do not deaminate flucytosine) 
5-fluorouracil is metabolized to 5-fluorouridylic acid which can be
a) incorporated into the RNA (this leads to a misreading of the fungal genetic code)
b) further metabolized to 5-deoxyfluorouridylic acid, a potent inhibitor of thymidylate synthase (this leads to a blockade of fungal DNA synthesis)
-The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.

46. Pharmacokinetics and administration
-F(oral): > 80%
-Distribution in all body tissues, including CNS and the eye.
-Volume of distribution: » 42 L
-Renal excretion: » 99%
-Half-life: » 4 hours (in renal failure, half-life may be as long as 200 hours)
-Administration: oral, IV

47. Adverse effects Therapeutic uses Contraindications
(toxicity is generally not pronounced)
-Anorexia (Weight loss), nausea and vomiting, diarrhea
-Severe ulcerative enterocolitis (rare)
-Skin rashes
-Headache, dizziness, confusion
-Reversible bone marrow depression (8-13%)(leukopenia, thrombocytopenia)
-Liver dysfunction (5-10%)
-Alopecia, peripheral neuritis (rare)
[toxicity may be due to the conversion of flucytosine to 5-fluorouracil by the intestinal flora of the host]
Therapeutic uses
-Deep candida infections, cryptococcal meningitidis (always in combination with amphotericin B)
-Chromomycosis (effectiveness is limited)
Contraindications
-Pregnancy ( 5-fluorouracil is teratogenic (harmfull to the foetus))

48. Targets of antifungal drugs

49. Thankyou