This document discusses antifungal drugs and fungal infections. It begins by classifying fungi as either yeasts or molds and describes some common pathogenic fungi in each group. Superficial and deep fungal infections are described. The mechanisms of action and classifications of major antifungal drug classes are discussed, including those that target the fungal cell wall, cell membrane, nucleic acid synthesis, and mitosis. Key drugs from each class like amphotericin B, azoles, and flucytosine are described in detail regarding their mechanisms, spectra of activity, pharmacokinetics, uses, and adverse effects. Resistance development and newer formulations are also mentioned.

1. ANTIFUNGAL
1

2.  Fungi
are eukaryotes
VIJAy
 Fungal
infections Mycoses
 Less
frequent than bacterial & Virus but
common.
 Anyone
can succumb to fungal infection but
more at risk in older people, diabetics, pregnant
women and burn wound.
2

3. FUNGI MAY BE CLASSIFIED AS YEAST OR MOULDS.
Yeast like pathogenic
 Histoplasmosis

Coccidioidomycosis
Blastomycosis
 Cryptococcosis
 Candida

Mould group of pathogenic
 Aspergillosis
 Dermatophytes
 Mucormicosis

Candida Spp. and Pneumocyst carinii are not pathogenic

pathogenic in immuno compromised patients
OPPORTUNISTIC INFECTION.
3

4. Oropharyngeal
 Vaginal candidiasis
 Sporotrichosis (Granulomatus of skin & Lymph abscess)
 Pityrosporum orbiculare - hyperpigmetnation

4

5. 
Fungal infections classified as Superficial & Deep
mycosis (Systemic)

Superficial affecting skin, hair, nails, mucous
membranes.

Most common: Dermatophytoses
Encouraged by hot (Hygiene)and humid environment
 Dermatophytoses classified according to body site
• Tinea barbae
• Tenia capitis(Scalp)
• Tinea corporis(Body)
• Tinea manuum(Hand)
• Tinea pedis(Foot)
• Tinea unguium(Nails)

5

6. 
Systemic fungal infections: Affect deeper tissues
and organs.

Systemic candidiasis (RTI)

Meningitis, endocarditis

Rhinocerebral mucormycosis (Thrombosis)

Pulmonary aspergillosis

Blastomycosis (lesion of skin)

Histoplasmosis (cough , fever, multiple pneumonic
infiltrates)

Coccidioidomycosis

Pneumocystis carinii pneumonia
6

7. 
Fungal cell structure and function is essential for
understanding the pharmacology of antifungal agents.

Four targets in fungal pathogens:

Fungal Cell Wall

Fungal Cell Membrane

DNA/RNA Synthesis

Inhibition of fungal mitosis
7

8. Fungal Cell Wall contain β- 1,3-D-glucan
 Depletion of glucan  Leads to death

Capsofungin
8

9. Altering membrane permeability
AMPHOTERICIN-B
Leading to cell death.
9

10. MEMBRANE SYNTHESIS

Ergosterol is the predominant sterol in many pathogenic
fungi.
Squalene
Terbinafine
squalene 2,3 epoxide
Lanosterol
Azoles
14-demethylase
Ergosterol
10

11. 
Inhibits DNA synthesis by blocking the functions of
a key enzyme in DNA replication- thymidylate
synthetase.

Fungal cell mitosis by disrupting mitotic spindle
formation-a critical step in cellular division.
11

12. 12

13. CLASSIFICATION BASED ON MECHANISM OF ACTION
Inhibitor of cell wall
synthesis:

Caspofungin
Drugs altering membrane
synthesis
 Inhibition of ergosterol
Drugs altering membrane
permeability
Trimidazoles
 Fluconazle,
 Itraconazole,
 Voriconazole
Imidazoles
 Ketoconazole,
 Miconazole,
 Clotrimazole.
Amphotericin-B,
 Nystatin,
 Hamycin

Inhibit nucleic acid
Synthesis

5 Flucytosine
Disruption of mitotic
spindle

Griseofulvin

Inhibition of ergosterol+
lanosterol

Terbinafine
13

14. Drugs altering membrane permeability

Amphotericin-B
Nystatin
Hamycin
Amphotercin:

First drug introduced in 1950s

Obtained from Strepomyces nodosus

Systemic Antifungal drug

Polyene group- Multi lactone ring with conjugated double
bond .

One end – Hydroxyl group (OH)–polar (Hydrophilc)

Other end – Hydrocarbon group-non polar (Lipophilic)
14

15. 
MOA:
Lipophilc end
Hydrophilc end
Creates ion channel
15
Leading to cell death.

16. PK:

Poor absorbed from GIT- effective against intestinal fungal
infection

For systemic - IV slow infusion

Peak antifungal activity at pH 6.0-7.5.

High con- Fungicidal, low- fungi static

90% plasma protein binding

T1/2- 15days ( binds with sterol)

It is insoluble in water  colloidal suspension with sodium
16
desoxycholate(1:1)

17. Antifungal spectrum & uses:

After advent of azoles groups, the use of AMB declined.

Still it is DOC for

Treatment of Invasive aspergillosis in immune
compromised patients

Mucormycosis

Rapidly progressing histoplasmosis, blastomycosis,
meningeal cocciodomycosis(intrathecal)
Topical use:- 3% cream for oropharngeal candidiasis,
 Reserve drug for resistant case of KALA AZAR. Leishmania
. Splenic enlargement

17

18. Dose: 0.5 mg/kg/day
 Adverse events:


Acute reaction (infusion related events, chills, fever,
headache, nausea, vomiting)

Long term toxicity: nephrotoxicity(>4g), anemia (D. Ery)

azotemia, hypokalemia

CNS toxicity : intrathecal administration-seizures,
headache, vomiting, nerve palsies


Hepatotoxicity rarely
DI:Flucytosine –synergetic action inc. permeability FC
 Aminoglycoside inc. renal toxicity.

18

19. 
3 new formulations available

AMB Lipid complex (ABLC): 35% AMB incorporated in
ribbon like particles of dimyristoyl phospholipids

AMB colloidal dispersion (ABCD): Disc shaped particles
containing 50% each of AMB & cholesteryl ester in
aqueos dispersion

Liposomal AMB (Small Unilamellar Vesicles) : 10% AMB
incorporated in SUV made up of lecithin
19

20.  Special
features of these formulations:

Milder acute reaction

Dec. infusion associated side effects

Can be used in intolerance to conventional
preparations

Lower nephrotoxicity & anemia

Deliver AMB to reticular endothlial cell of liver
spleen so useful in leshmania & immuno
compromised
20

21. 
Nystatin:

Similar to AMB in antifungal properties

high systemic toxicity so used locally only
Poorly absorbed from mucus membrane
 Available as ointment, cream, powder, tablet


Uses:5 lac U in intestinal moniliasis TDS
 1 lac U in vaginitis (1mg=2000U)
 Can be used in oral, cutaneous, conjunctival candidiasis
 Adverse events: Gastrointestinal disturbances with oral
tablets

21

22. 
Drugs altering membrane synthesis
Azoles: 1970


Broad spectrum

Fungistatic / Fungicidal

Most commonly used


Synthetic anti fungals
Classified as imidazoles & triazoles
Imidazoles: Two nitrogen in structure
Topical: Econazole, Miconazole, Clotrimazole
 Systemic : ketoconazole


Newer : Butaconazole, Oxiconazole, Sulconazole
22

23. 
Triazoles : Three nitrogen in structure 1980



Fluconazole, itraconazole, voriconazole, Terconazole
Topical for superficial infections
Both these groups are

Structurally related compounds

Have same mechanism of action

Have similar antifungal spectrum
23

24. Acetyl CoA
Squalene
Allylamine
Drugs (Terbinafine)
Squalene
monooxygenase
Squalene-2,3 oxide
Lanosterol
Azoles
14-α-demethylase
(ergosterol)

25. 
Miconazole & clotrimazole:
Topical use
 Cream, gel, spray, lotion ,solution , pessary




Dermatophyte infections ( pedis, cruris, corporis, versicolor)
Candida: oral pharyngeal, vaginal, cutaneous
Adverse events:

Local irritation , itching or burning

Miconazole shows higher incidence of vaginal irritation & pelvic
cramps

No systemic side effects
25

26. Ketoconazole:
First orally effective broad spectrum antifungal
 Effective against

Dermatophytosis
 Deep mycosis
 Candidiasis


Pharmacokinetics:
 Effective orally
 Requires acidic environment for absorption
 High protein binding
 Readily distributed, not to BBB
 Metabolized in liver, excreted in bile t1/2 = 8-10 hrs
26

27. 
Dose : 200 mg OD or BD

Adverse events:

Nausea , vomiting , anorexia

Headache , paresthesia, alopecia

Reduces steroid, testosterone & estrogen synthesis

Thus can cause gynaecomastia,

oligospermia, loss of libido & impotence in males.

Menstrual irregularities & amenorrhoea in females

Elevation of liver enzymes

Hypersensitivity reaction like skin rashes
27

28. 
Drug interactions: Inhibits CYP450 enzyme

H2 receptor blockers

↑ Sr conc of cisapride, terfenadine, astemizole, quinidine

Phenytoin toxicity

Sulfonylureas: hypoglycemia

Cyclosporine: nephrotoxicity

Warfarin: bleeding

Rifampicin, phenytoin ↑ metabolism of ketoconazole

Should not combine with AMB
28

29. 
Use: Restricted use, most serious mycoses

Dermatophytosis: conc in stratum corneum

Monilial vaginitis : 5-7 days

Systemic mycosis: blastomycosis, histoplasmosis,
Coccidioidomycosis

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

Topical: T.pedis, cruris, corporis, versicolor
29

30. RESISTANCE
May develop by altered
demethylase or
by enhanced removal from
the fungal cell.

30

31. Fluconazole:

Newer water soluble triazole

Oral, IV as well as topical

Broad spectrum antifungal activity

Candida, cryptococcosis, coccidioidomycosis

Dermatophytosis

Blastomycosis

Histoplasmosis

Sporotrichosis
31

32. 
Pharmacokinetics:

94% oral bioavailability

Not affected by food or gastric pH

Primarily excreted unchanged in urine t1/2 = 25 -30 hrs

Poor protein binding (10-12%)

Widely distributed crosses BBB


T ½ -27-32hrs
Adverse events:

GIT upset

Headache, alopecia, skin rashes, hepatic necrosis

Teratogenic effect

CYP450 Enzyme inhibiting property less

No anti androgenic & other endocrine effects
32

33. 
Drug Interactions:

Effects hepatic drug metabolism to lesser extent than
Ketoconazole


H2 blockers & PPI do not effect its absorption
Uses:

Candida:



150 mg oral dose  cure vaginal candidiasis with few relapse
Oral candidiasis  2 weeks treatment required
Tinea infections & cutaneous candidiasis:

150 mg weekly  4 weeks, tinea unguim  12 months
33

34. 
Disseminated candidiasis, cryptococcal, coccidiodal
meningitis & other systemic fungal infections:

200-400 mg / day 4- 12 weeks or longer

3 days oral  Candida UTI (100-800mg OD)

Meningitis preferred drug

Eye drops for fungal keratitis
34

35. Itraconazole:



Broadest spectrum of activity also against aspergillus
Fungistatic
Pharmacokinetics:

50-60% bioavailability, 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
35

36. 
Adverse events:


Dizziness, pruritis , headache, hypokalemia, hypotension

Increase plasma transaminase


GI Intolerance
Rarely Hepatotoxicity
Drug interactions:

Oral absorption decreased by antacids, H2 blockers

Rifampicin, phenytoin induce metabolism

Potentiates effect of hypnotic drugs

Inhibits CYP3A4 drug interaction profile similar to ketoconazole
36

37. 
Uses:

DOC for paracoccidomycosis & chromoblastomycosis

DOC for histoplasmosis & blastomycosis in AIDS patients

Esophageal, oropharyngeal vaginal candidiasis


Dermatophytosis: less effective than fluconazole


Not superior to fluconazole : 200 mg OD X 3 days
100- 200 mg OD X 15 days
Onychomycosis : 200 mg / day for 3 months

Intermittent pulse regime 200 BD once weekly for 3 months equally
effective

Aspergillosis: 200 mg OD/ BD with meals for 3 months or more
37

38. Voriconazole:


High oral bioavailability, low protein binding

Good CSF penetration

Metabolized by CYP2C19

Doesn’t require gastric acidity for absorption


II generation triazole
T1/2-6 hrs
Uses:

DOC for invasive aspergillosis

Most useful for esophageal candidiasis

First line for moulds like fusarium

Useful in resistant candidal infections
38

39. Dose : 200 mg BD
 Adverse events:


Transient visual changes like blurred vision , altered color
perception & photophobia

Rashes in 5 -6 %

Elevated hepatic enzymes

Prolongation of QT
39

40. Cell wall synthesis inhibitor: Capsofungin

Introduced in 2000s.

Echinocandins

MOA: Inhibits- β-(1,3)-D-glucan

T½-9-11hrs.

P.B- albumin 97%

Excreted through urine(41%) and feces (35%)

Dose: IV infusion (intial 70mg slowly then 50mg/day)
40
»Contd.,

41. 
Active against wide variety of fungi.

Effective treatment for Aspergillus infection and
Candidiasis (Esophageal, intra abdominal
peritontis).

ADR: Sensation of warmth,
flushing,
rashes.

DI:- Cyclosporine hepatotoxicity.
41

42. 5 Flucytosine


Prodrug, pyrimidine analogue, anti metabolite
Mechanism of action
Converted to 5 FU by FUNGAL CYTOSINE DEAMINASE
 5FU  5FUTP RNA DEFECTIVE
 5FU 5dUMP Inhibit Thymidylate synthesis

,
Human cells cant convert it to 5FU
 Adverse events:


Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely
hepatitis

43. 5-flucytosine permease 5-flucytosine
(outside)
(inside)
Cytosine
deaminase
5-fluorouracil
5dUMP
(inhibits
thymidylate
synthase)
RNA
Phosphoribosyl
transferase
5-FUMP

44. 
Uses: in combination with AMB in cryptococcal meningitis

,

Advantages of combination:
Entry of 5 FC
 Reduced toxicity
 Rapid culture conversion
 Reduced duration of therapy & resistance


45. SYSTEMIC ALLY FOR TOPICAL INFECTIONS

Terbinafine:
Orally & topically effective drug against candida &
dermatophytes
 Fungicidal : shorter courses of therapy required & low
relapse rates

Mechanism of action:
 Inhibition of Lanosterol + Ergosterol production
 Pharmacokinetics:






Well absorbed orally 75%
Highly keratophilic & lipophilic
High protein bound , poor BBB permeability
Metabolized in liver excreted in urine & feces t1/2- 15
days
Negligible effect on CYP450

46. Adverse events:
 Nausea , vomiting , Diarrhoea
 Taste disturbances
 Rarely hepatic dysfunction
 Topical: erythema , itching , dryness , urticaria,
rashes
Uses:
 Dermatophytosis: topically/ orally 2- 6 weeks
 Onychomycosis: first line drug 3- 12 months
 Candidiasis: less effective 2- 4 weeks therapy
may be used as alternative 250 mg OD

47. Griseofulvin :

Systemic administration for topical infections

Fatty meal inc. BV

T1/2- 24hrs


Obtained from Pencillium griseofulvum


Fungistatic
Drug binds to keratin in stratum corneum of the skin
Mechanism of action:-
Interact with polymerised microtubles causing
disruptions of mitotic spindle and arrest mitosis
metaphase
47

48. 
Uses:-

Dematophytosis caused by Microsporum

Trichophyton, Epidermatophyton

Duration of therapy depend open the body area

TINEA CORPORIS – 2-4 WEEKS



TINEA CAPITIS -4-6WEEKS
TINEA PEDIS – 4-8 WEEKS
Dose- 500-1000mg/day/in 2doses
48

49. OTHER DRUGS
 Ciclopirox
olamine - may block amino acid
transport - penetrates well - useful for Candida
and dermatophytes
 Haloprogin
- useful for dermatophytes and
Candida, may cause burning
 Tolnaftate
- useful for dermatophytes - inhibits
synthesis of macromolecules
 Undecylenic
 KI
acid - dermatophytes
- taken orally for cutaneous sporotrichosis may cause a rash and irritation of salivary and
lacrimal glands

50. Disease
1st choice drugs
2nd choice drugs
Candiasis
oral/vaginal/cutaneous
disseminated
FLU/NYS/CLO
AMB/VOR
ITR
FLU
Cryptococcosis
AMB+/- 5-FC
FLU
Histoplasmosis
ITR/AMB
FLU
Coccidioidomycosis
AMB/FLU
ITR/KTZ
Blastomycosis
ITR/AMB
KTZ/FLU
Sporotrichosis
AMB
ITR
Paracoccidioidomycosis
ITR
AMB
Aspergillosis
AMB/VORI
ITR
Mucormycosis
AMB
-
Chromomycosis
ITR
VIJAY
KTZ/5-FC
50

51. Topical
Ketoconazole
Miconazole
Clotrimazole
Terbinafine
Nystatin
VIJAy
Systemic
administration
Griseofulvin
Ketoconazole
Fluconazole
Itraconazole
Terbinafine
51

52. SPECTRUM OF ACTION
AMB
5FC
KTZ
FLU
ITR
Aspergillus
--
--
--
Y
Blastomycosis
--
Y
Y
Y
cryptococcus
Y
--
Y
Y
Coccidiodo
--
Y
Y
Y
candida
Y
Y
Y
Y
Histoplasma
--
Y
Y
Y
Mucor
--
--
--
--
Sporotrichosis
--
--
Y
Y
chromoblast
dermatophyte
52
Fusarium

53. TOPICAL AZOLES
 Clotrimazole
 Terconazole
 Miconazole
 Sulconazole
 Econazole
 Tioconazole
 Oxiconazole
 Butoconazole
 Sertaconazole

54. 
Nystatin:
Candidiasis only

Griseofulvin: Dermatophytosis only

Terbinafine : Dermatophytosis & candidiasis

Caspofungin: Aspergillosis & candidiasis
54

55. Some important characteristics:

Broad spectrum: AMB, KTZ, FLU, ITR

Resistance: 5 FC

Nephrotoxic/ Anemia: AMB

LEUCOPENIA: 5 FC

GIT upset: All

Over all toxicity: highest for AMB lowest for fluconazole,
itraconazole
55

56. 
Grisofulvin K M C
VIJAy
For SYSTEMIC
F I T Nystatin
For Topical
56

57. TH
VIJAy
57