This document discusses various types of fungi that cause infections and the antifungal drugs used to treat them. It covers superficial and deep fungal infections, outlines the mechanisms of several commonly used antifungal classes including azoles, polyenes, and echinocandins. It summarizes the pharmacokinetics, uses, and adverse effects of many individual antifungal drugs. New approaches to antifungal treatment and drug development are also briefly mentioned.

1. By:
Meenu Saharan
Ph.D scholar (Pharmacology)
SMS Medical College, Jaipur
Under Guidance of:
Dr. Lokendra Sharma
Professor Pharmacology
SMS Medical College, Jaipur

2. Yeasts Yeast like Fungi
Molds Dimorphic
C.Neoformans
(Meningitis)
C.Albicans
P.orbiculare
Dermatophytes
A.fumigatus
H.capsulatum,
Sporothrix sp.,
Blastomyces
dermatids

3. Fungal infection-Mycoses
Fungal infection occurs due to
More difficult to treat than bacterial infections
Fungal infections usually requires prolonged treatment.

4. Superficial fungal infections: involve
-Cutaneous surfaces (skin, nails, and hair): caused by
Dermatophytes
- Mucous membrane surfaces (oropharynx &vagina):caused
by Candida
Deep Infections: caused by dimorphic fungi
Occurs in immunocompromised pts
Involve internal organs such as :lung(pneumonia)
,heart(endocarditis) , brain (meningitis)

6. Drugs for systemic fungal infections
Polyene antibiotics
-Amphotericin B
Pyrimidine antimetabolites
-Flucytosine
Antifungal azoles
-Ketoconazole
-Fluconazole
-Itraconazole
Echinocandins
Caspofungin, Micafungin, & Anidulafungin
Cont……

7. Oral systemic antifungal drugs for mucocutaneous
infections
-Griseofulvin
-Terbinafine
Topical Antifungal
-Nystatin
-Azoles: Clotrimazole, Miconazole, Ketoconazole ,
Butaconazole, Oxiconazole, Sulconazole, Econazole etc.
Other Topical Antifungal Drugs:Tolnaftate, Ciclopirox,
Clioquinol, Banzoic acid, Sodium thiosulfate, Undecylenic
acid

9. Amphotericin B is a Amphoteric polyene macrolide
Source: Streptomyces nodosus
Insoluble in water: for I.V.infusion complexing with bile
salts(deoxycholate)
Fungizone: AMB(50mg)+Deoxycholate (41 mg)+Small
amount of Phoshate buffer
Fungicidal or Fungistatic depending on the organism and on
drug concentration

10. Bind to ergosterol present
in membranes of fungal cells

Formation of “pores” in the
membrane

Leaking of small molecules
(mainly K+) from the cells

11. Resistance occurs due to:
1.By impairing drug binding to ergosterol
2. By decreasing the membrane conc. of ergosterol
3. By modifying the sterol target molecule.
Intrinsic AMB resistance- C.lusitaniae, P. boydii

12. Oral Absorption: not absorbed
Half-life :15 days
Metabolism:60% in liver
Excertion: urine, bile
In I.V. infusion wide distribution
Lesser CSF penetration

13. 1.Oral Administration: Intestinal Moniliasis (50—100mg)
2.Topical Administration: Oral, vaginal,& cutaneous
candidiasis , otomycosis, myotic corneal ulcer, keratitis
3Intravenous Administration:For systemic fungal infection
by slow infusion(0.5-1mg/kg) to a total dose (1-2g).
To prevent relapse of Cryptococcosis, Histoplasmosis in
AIDs patients.
4.Intrathecal Administration:For fungal meningitis
5. Bladder irrigation:For Candida cystitis.

14. Infusion related toxicity: Fever ,vomiting
Chills , Headache, Muscle spasm ,Hypotension
Reduced by:1.Pretreatment with oral acetaminophen or i.v.
hydrocortisone(0.7mg)
2. If reactions lasts for 2-5 hrs. If severe increase the dose.
Cumulative Toxicity:Nephrotoxicity(dose related), can be
reduced by infusion of normal saline before AMB
Anaemia: Due to decrease erytheopoietin production.
Seizures

15. 1.Amphotericin B colloidal dispersion(ABCD): for
invasive aspergillosis.
2.ABISOME:Neutropenia (3mg/kg), Mycoses(3-
5mg/kg), Visceral Leishmaniasis(3-4mg/kg daily)
3.ABLC:For mycoses except cryptococcal meningitis
(5mg/kg)

16. Selectivity of 5-FU:
Host cells having low
levels of cytosine
deaminase except bone
marrow
Resistance:Due to loss of
permease
-Decreased activity of
cytosine deaminase

17. Pharmacokinetics:
Absorption : from GIT
Distribution: widely
distributed (volume of
distribution approximate the
total body water)
P.Protein bound: Less
Halfe-life:3-6 hrs
Excretion : Urine
CSF concentrated
Penetrate aqueous humor
Toxicity: in AIDS pts. With
renal insufficiency
USES: not used as single agent
1.Due to synergistic action with
other agents
2. Due to development of
resistance.
1.Cryptococcal meningitis in
AIDs pts: Given with
Amphotericin –B
In Non-AIDS pts. Begin with
C-AMB+FC & then change to
Fluconazole.
2.Chromoblastomycosis: used
with Itraconazole.

18. ADRS: Occur due to
conversion of 5- FC into
Fluorouracil
1.Dose dependent: Bone
marrow suppression, GIT
disturbances
2.Liver Dysfunction: mild &
reversible
Narrow Therapeutic
Window, Increased toxicity
at higher dose & resistance
at subtherapeutic dose

19. IMIDAZOLE:
Ketoconazole:oally/Topical
Clotrimazole, Miconazole:
Topical
Econazole
Oxiconazole
Sulconazole
Butoconazole
TRIAZOLE: for systemic use
Fluconazole
Itraconazole
Posaconazole(experimntal
drug)
Terconazole

20. Resistance: occur due to
prolonged therapy
Resistance in C.albicans: due to
mutation in ERG11 gene coding
for 14alpha sterol demthylase.
Cross resistance confered to all
azoles
Fluconazole resistance in
C.albicans & C. glabrata due to
increased efflux by ABC &
trasporters

21. Pharmacokinetics:
Absorption : From GIT, acidic
content
CSF penetration poor
Metabolism: Liver
Excretion: Bile
Half –Life: 8-10 hrs
Therapeutic concentration in
skin & vaginal fluid
USES: replaced by
Itraconazole
1. Silent non CNS
blastomycosis
2. Coccidioidomycosis
3. Oropharyngeal candidiasis
4. Cushing Syndrome

22. ADRs:
Most common: Nausea,
vomiting
Loss of apetite,
Headache, Rashes &
Hair loss
Supression of Estradiol
synthesis
Decrease androgen
production
Elevation of serum
transaminase

23. Fluconazole Itraconazole Voriconazole Posaconazole
Absorption From GIT Tolerated
below200mg/d
Complete
from GIT
Well absorbed
Fatty meal
Acidic
Gastric pH
Not required Required Not Required Not Required
BA Not altered
by food &
acidity
50-60% when
taken with
food
96% Not altered by
food & acidity
P. Protein
Binding
11-12% 99% 50% 98%
Distribution Rapid in
breast milk,
sputum,
saliva
Wider except
CSF
Wider Rapid body
distribution
Half- life 27-37 hrs so
once daily
dosing
30-35 hrs 6 hrs non
linear
metabolism
24 hrs
Metabolism Liver Liver( CYP3A4) Liver
(CYP2C19)
Liver
Cont…….

24. Fluconazole Itraconazole Voriconazole Posaconazole
Excretion 80% urine, 10%
faeces
Bile 2% free drug
in urine
Liver
Preparation Oral/I.V. Capsule, 2
solution
forms
Oral/i,.v Liquid oral
Uses: 1.Candidiasis
2.Candidiasis in
allogeneic B.
marrow
transplant
3.Cryptococosis
4. Fungal
Keratits
1.Indolent
non-
meningeal
infection
2. Invasive
Aspergillosis
3.I.V. for
febrile
neutropenia
4.Onychomy
cosis
5.
Histoplasmo
sis
1.Aspergillosis
2. Esophageal
candidiasis
3. Febrile
neutropenia
1.Mucormyco
sis
2.Candida &
Aspergillosis
Cont……

25. Fluconazole Itraconazole Voriconazole Posaconazole
ADRS Nausea,
Vomiting
Alopecia
No antiandrogenic
effects
Hepatotoxicity
Inotropic
effect
Rashes
GIT distress
Hepatotoxicity
QTc
prolongation
Visual
changes
Headache, GIT
distress
Interactio
ns
Less H2 blockers
Cisapride,
Terfenadine
Clarithromyci
n
Rifampicin
Voriconazole
Grape fruit
juice
Increase
Tacrolimus &
cyclosporin
levels

26.  Large cyclic peptide
 Only in I.V. forms
 Water soluble
 Highly Protein bound
 Half- life 9-11 hrs
 Excretion :kidney & GIT
 Dose Adjustment: Hepatic failure
Caspofungin
Micafungin
Anidulafungin

27. Selectivity: Host cell
does not require
Beta- Glucan

28. 1. Mucocutaneous candida infection
2.Invasive Aspergillosis
3.Prophylaxis of candida infection in bone marrow
transplant ( Micafungin)
ADRs:
Elevate liver enzyme
Histamine release (amidulafin)

29.  Fugistatic, Insoluble
 Source: P.Griseofulvin
 Absorption from GIT irregular
 Given in micro-crystalline oral dose
 Absorption more with fatty meal
 Deposited in newly formed skin
 Duration of treatment depends on : site of infection, thickness
of infected area
 Plasma half life 24 hrs

31.  USES:
1. Dermatophytosis: orally
Duration of Treatment: on site of infection
Body skin-3wks, Palms, soles- 4-6 wks, Finger
nails-4-6 mths, Toe nail-8-12 mths
2. Athletes' foot
ADRS:Commonest : Headache & GIT disturbance
Rashes, Photpallergy
Drug interactions:Disulfiram like reactions,
Reduce efficacy of OCPs, induce warfarin metabolism

32. New allylamine
Fungicidal
Preparation: oral/topical
Oral absorption: 50-70%
Highly lipophilic & keratophilic
Half-life: 15 days
Dose adjustment: Renal& Heaptic

34.  Uses:
1. Onychomycosis of toenail/fingernail
2. Ringworm, Athlete foot
Unlabelled Use: cutaneous candidiasis
Pityriasis versicolor
 ADRs:
GIT Distress
Hepatic dysfunction
Urticaria
Dryness

35.  TOPICALANTIFUNGAL:
Nystatin: for corticosteroids aerosols cause oral
candidiasis.
Allylamines: Naftifine, Butenafine, Naftifine
Topical Azoles:
Clotrimazole Miconazole
Butaconazole Oxiconazole
Uses:Tinea infection
Tolnaftate: for T. cruris, T. coporis
Ciclopirox: For onychomycosis of fingernail/toenail
Clioquinol: Dermatophytosis

36.  New Traizole:
Efinaconazole
Albaconazole
Ravuconazole
 New Imidazole:
Luliconazole
Under Trials:
AMB cochleates
Nanoparticle formulations of AMB
Nanoparticle
Formulations of itraconazole

37. 1.Reactive Oxygen Species (ROS):AMB is able to induce
oxidative and nitrosative bursts in Candida,Cryptococcus,
and Trichosporon, enhancing its fungicidal effect
2.Inhibition of Heat Shock Protein 90 : Related to fungal
pathogenicity, phase transition in dimorphic fungi and
antifungal drug resistance.
3. Inhibition of Calcineurin Signaling: Triphenylethylenes,
novel class of antifungal drugs that act on calcium
homeostasis in C. neoformans via direct inhibition of the
calcineurin activator calmodulin.

38. For invasive candidiasis two promising vaccines in the
clinical trial phase.
The first, containing the rAls3p-N antigen, prevents fungal
adhesion and invasion in immunized hosts. Protection
mediated by T cells via neutrophil recruitment
Second:virosome-based vaccine containing a Sap2 antigen.
Given intra-muscularly or intra-vaginally induces systemic and
100% mucosal protective immunity

39. THANK
YOU