Fungi Classification; Antifungal Drugs

1. Dr. Vikram Sharma, MD
MAMC

2. Eukaryote

4. 1. Yeasts – Crypyptococcus neoformans
2. Yeast –like fungi- Candida albicans
3. Moulds – Dermatophytes
(Trichophyton, Epidermophyton, Microsporum)
4. Dimorphic fungi- (Filament - 25◦; Soil / Yeast - 37◦; Host)
Blastomyces dermatitidis, Histoplasma
capsulatum, Coccidioides immitis, Sporothrix
Pathogenic Fungi Classification

6. Fungal infections (Mycoses)
SUPERFICIAL - Black Piedra
CUTANEOUS - Tinea
SUBCUTANEOUS - Sporotrix
SYSTEMIC-
Blastomycosis, Histoplasmosis, Coccidioidomycosis,
Cryptococcosis
OPPORTUNISTIC –
Mucormycosis, Aspergillosis,
Candidiasis

7. Classification based on MOA
1. Acting on fungal cell wall :
Echinocandins
2. Acting on fungal cell membrane : Polyenes,
Azoles & Allylamine
3. Inhibition of nucleic acid synthesis: 5-Flucytosine.

8. 4. Acting on mitotic spindle: Griseofulvin
5. Topical: Cicloprix, Tolnaftate,
Haloprogin,Butenafine, Undecylenic acid, Topical
Azoles, Clotrimazole, Nystatin

9. DRUGS
i)Polyenes: Amphotericin, Nystatin, Natamycin
ii)Azoles:
A) Imidazoles - Ketoconazole, Butaxonazole,
Clotrimazole, Econazole, Miconazole
Oxiconazole, Sulconazole
B) Triazoles – Fluconazole Itraconazole Tioconazole

10. DRUGS
iii) Allyamines: Terbinafine, Naftifine, Butenafine
(iv) Echinocandins: Caspofungin, Micafungin,
Anidulafungin

11. Mechanism of Action

12. Echinocandins

13. Polyenes

14. Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
Cell contents leak out
Cell death

15. Squalene
Ergosterol
14--demethylase
Squalene Epoxidase
Lanosterol
Fungal cell membrane
Azoles & Allylamines
Allylamines
Azoles

16. 5-Flucytosine

17. Griseofulvin
Binds to polymerised microtubules
Disrupt Mitotic Spindles
Inhibit Mitosis

19. ECHINOCANDINS

20. Echinocandins
 Spectrum: Candida (Broad -spectrum activity against all
Candida species); Aspergillus
(NOT active againt Cryptococcus)
 High PPB
 Metabolites are eliminated by kidneys & GIT
 Available only as i/v formulations
 Adv.- Relatively low toxicity among the safest

21. Caspofungin
o FDA approved in 2001
o Dose – Single loading dose 70mg followed by
daily dose of 50mg iv over 1 hr
o Use -
 Invasive forms of candidiasis
 Invasive aspergillosis

22. Micafungin
FDA approved in 2005
 Candida esophagitis (150 mg/day)
 Candidemia (100mg/day)
 Prophylaxis of fungal infections in those
receiving stem cell transplant (50mg/day)
 D/I: Micafungin -↑ the levels of
nifedipine,cyclosporine and sirolimus

23. Anidulafungin
FDA approved in 2006
 Candida esophagitis (100mg 1st day followed by 50mg/day)
 Candidemia (200mg 1st day followed by 100mg/day)

24. Adverse Effects
 Flushing , phlebitis (Anidulafungin)
 Increase in liver enz, GI disturbances
(Caspofungin)

25. Lactone ring
Lipophilic part
 Amphotericin B:
 Streptomyces Nodosus
 Amphoteric
Hydrophilic part

26. Mechanism Of Resistance
 Replacement of ergosterol by other
sterols in fungal plasma membrane.

27. Pharmacokinetics
 Poorly absorbed orally
 Insoluble in water so colloidal
suspension prepared with sodium
deoxycholate(1:1 complex)
 t ½ = 15 days

28. Lipid formulations of AMB
Amphotericin B Lipid Complex(ABLC)
(ABLC; Abelcet®)
Amphotericin B Colloidal Dispersion(ABCD)
® ®)
Liposomal Amphotericin B
(L-AMB; Ambisome®)

29. part l
r ipi DMPC, PG
J Liposome Res 1993; 3:
451
AMB Lipid
complex
(ABLC)

30. AMB
Colloidal
Dispersion
(ABCD)

31. Hospital Practice 1992; 30: 53
Liposomal AMB
(Small unilamellar vesicles)

32. Antifungal spectrum
- Aspergillus
Broadest
spectrum
- Blastomyces
- Candida albicans
- Cryptococcus neoformans
- Coccidioides immitis
- Histoplasma capsulatum
- Mucor

33.  Systemic mycotic infections
• Invasive aspergillosis
• Rapidly progressive Blastomycosis &
Coccidiomycosis
• Mucormycosis
• Disseminated rapidly progressing
Histoplasmosis
• Cryptococcus neoformans (intra-
thecal)
Uses

34. Liposomes in the therapy of infectious
diseases and cancer 1989: 105
Antiprotozoal spectrum
• Mucocutaneous Leishmania
• Naegleria fowleri

35. Liposomes in the therapy of infectious
diseases and cancer 1989: 105
Release from
macrophage
Macrophage
Endocytosis
Liposome Lysosome
Fusion
Liposome
degradation
Endocytic
vesicle
Release in blood
compartment
Reserve drugs
for resistant
kala azar

36. Adverse events (Amphoterrible !!!)
o Acute reaction (infusion related)
o Long term toxicity
 Nephrotoxicity (Renal Tubular
necrosis, ↓ K+/Mg2+,Azotaemia; Irreversible)
 CNS toxicity (Arachanoiditis, Seizures)
 Anaemia (Hypochromic Microcytic)
o Hepatotoxicity (Jaundice,rarely)

37. Measures to Avoid Nephrotoxicity
 Prior hydration with 1L N.S.
 Avoid Concomitant Diuretics
 Liposomal AMB

38. Topical Uses
 Intestinal Monoliasis (Orally)
 Vaginitis
 Otomycosis (3 % drops)
 Mycotic infections of the bladder (bladder irrigation)
 Mycotic corneal ulcers & keratitis

39. Nystatin
 S. noursei
 Toxic; Locally
Uses:
 Intestinal moniliasis
 Vaginitis
 Prevention of oral candidiasis
 Oral, cutaneous, conjunctival candidiasis

40. Hamycin
 S. Pimprina
Topical use
 Thrush, cutaneous candidiasis,
trichomonas & monilial vaginitis,
otomycosis by aspergillus

41. Natamycin
Broad spectrum
Used topically
Fusarium solani keratitis, Trichomonas
& Monilial vaginitis

42. AZOLES

43. Azoles
 Synthetic (Imidazoles; Triazoles)
 Broad spectrum
 Fungistatic or fungicidal depending on conc.
of drug
 Also block fungal respiratory chain?

44. Imidazoles:
 Two nitrogen in structure
 Topical: Econazole, Miconazole,
Clotrimazole, Butaconazole, Oxiconazole,
Sulconazole
 Systemic: Ketoconazole

45. Triazoles
o Three nitrogen in structure
o Topical: Terconazole
o Systemic: Fluconazole, Itraconazole, Voriconazole

46. SYSTEMIC TOPICAL
 Ketoconazole
 Fluconazole
 Itraconazole
 Voriconazole
 Clotrimazole
 Miconazole
 Econazole
 Oxiconazole
 Sertaconazole
 Terconazole
 Sulconazole
 Tioconazole
 Butaconazole

47. Imidazoles

48. Miconazole & Clotrimazole
 Topical use:
 Miconazole - 2% ; Clotrimazole - 1%
 Uses:
 Dermatophyte infections
 Candida: oral pharyngeal, vaginal,
cutaneous
 Adverse events:
 Local irritation

49.  First orally effective broad spectrum antifungal
 Acidic environment favours absorption
Antacids, H2 blocker ↓ absorption
 CSF penetration is less Ineffective for fungal
meningitis
 Elimination thru Bile Ineffective for fungal
cystitis
Ketoconazole

50. Ketoconazole and Steroid hormone
synthesis
o Inhibit cholesterol side-chain cleavage
enzyme
 17α-hydroxylase - which converts cholesterol
to pregnenolone
 17,20-lyase ,which convert pregnenolone into
androgens
 11β-hydoxylase, which converts 11- deoxycortisol
to cortisol.

51. Ketoconazole
 ADRs:
 ↓ Steroid, Testosterone & Estrogen synthesis
o Males: Gynaecomastia, oligospermia ,
loss of libido & impotence
o Females: Menstrual irregularities
& amenorrhoea

52. Drug Interactions

53. Dangerous interaction with
terfenadine, astemizole and
cisapridePolymorphic ventricular
tachycardia (Torsades De Pointes)
Drug Interactions

54. Uses
Monilial vaginitis
Systemic mycosis
Topical: T.pedis/cruris/corporis/
versicolor

55. Non-antifungal Uses of Ketoconazole
 Prostate cancer
 Precocious puberty
 Cushing syndrome
 Hirsuitism

56. Triazoles

57. Fluconazole
 Broad spectrum:
 Candida, Cryptococcosis,
Coccidiodomycosis
 Dermatophytosis
 Blastomycosis
 Histoplasmosis
 Sporotrichosis
 Oral; IV;Topical
 Not effective against Aspergillosis & Mucormycosis

58. Pharmacokinetic Advantages of Fluconazole
 Notaffected by food or gastric pH
 Crosses BBB → Fungal meningitis
 Least effect on heaptic microsomal enzyme
Fewer D/I
 Noanti-androgenic & other endocrine effects

59. Uses of Fluconazole
 Candida:
 Vaginal candidiasis (150 mg oral dose)
 Oral candidiasis (2 weeks treatment required)
 Tinea infections & Cutaneous candidiasis:
o 150 mg weekly for 4 weeks
o Tinea unguim : 12 months[
 Systemic fungal infections
 Meningitis: preferred drug
 Fungal keratitis (eye drops)

60. Itraconazole
Broad spectrum of activity
including Aspergillus.
Does not inhibit steroid hormone
synthesis and no serious
hepatoxicity.

61. Pharmacokinetics of Itraconazole
 Absorption enhanced by food & gastric acidity
(D/I: Oral absorption ↓ by Antacids, H2 blockers)
 Accumulates in vaginal mucosa, skin, nails
 CNS penetration is poor

62. Uses of Itraconazole
 (DOC)Paracoccidomycosis,Chromoblastomycosis,
Histoplasmosis & Blastomycosis.
 Candidiasis - Oesophageal, Oropharyngeal, Vaginal
 Dermatophytosis
 Onychomycosis
 Aspergillosis

63. Adverse events of Itraconazole
 Hypokalaemia
 Increase plasma transaminase
 Hypertension, Edema
 Headache, nausea, epigastric distress

65. Voriconazole
o High Oral Bioavailability
o Good CSF penetration
o Doesn’trequire gastric acidity for absorption
o Extensive Hepatic Metabolism (2C19)
o Enzyme Inhibitor

66. Uses of Voriconazole
 DOC for Invasive Aspergillosis
 Most useful for Esophageal Candidiasis
 First line for moulds like Fusarium
 Resistant Candida infections

67. ADRs of Voriconazole
 Transient visual changes like blurred vision ,
altered color perception & photophobia
 QT Prolongation
 Rashes (5-6%)

68. Posaconazole
 Broadest spectrum azole
 Liquid oral formulation
 Fatty meal ↑ absorption
 Dose : 800 mg/day
 Potent Inhibitor of CYP3A4

69. Uses of Posaconazole
Prophylaxis of invasive candidiasis
Salvage therapy for invasive
aspergillosis
Mucormycosis & Zygomycosis
(only activeazole !!!)

70. Ravuconazole
Phase II clinical trial
Spectrum: Candida, Aspergillus,
Dermatophytes
Oral

71. Water
solubility
Absorption Halflife (hr) Elimination ROA
Ketoconazole low variable 7-10 Hepatic Oral
Itraconazole low variable 24-42 Hepatic Oral/IV
Fluconazole high high 22-31 Renal Oral/IV
Voriconazole high high 6 Hepatic Oral/IV
Posaconazole low high 25 Hepatic Oral

72. Allyamines

73. Terbinafine
 Orally & topically effective
 Fungicidal
 Pharmacokinetics:
 Well absorbed orally
 Highly keratophilic & lipophilic (very slow release
of drug from skin, nails & adipose tissue)
 Poor BBB permeability
 t1/2 - 15 days

74. Terbinafine
 Adverse events:
 Taste disturbances
 Rarely hepatic dysfunction (symptomatic
hepatobiliary dysfunction)
 Uses:
 Dermatophytosis
 Onychomycosis
 Candidiasis

75. 5-Flucytosine
 Narrow spectrum
 Prodrug; pyrimidine analog
 Adverse events: (Fluotoxin)
 Bone marrow toxicity, alopecia, reversible
hepatomegaly
 Uses: In combination with AMB for cryptococcal
meningitis

76. Advantages of
combination:
 Entry of 5 FC
 Reduced toxicity
 Rapid culture
conversion
 Reduced duration of
therapy
 Decreased
resistance

77. Griseofulvin
 Penicillium griseofulvum
 Fungistatic
 Systemic drug for superficial fungal
infections (topically binds to newly synthesized keratin in stratum
corneum of skin, hair & nails)
 Active against dermatophytes
(Dermatophytes concentrate it actively hence selective toxicity)

78. Pharmacokinetics
o Increased absorption by fatty food &
Micronisation
o Accumulates in keratinized tissue
o t1/2 - 24 hrs
o CytP450 INDUCER !!!

79.  Adverse events:
 Headache most common
 CNS symptoms: confusion, fatigue, vertigo
 Peripheral neuritis
 Photoallergy
 Transient leukopenia, albuminuria
Griseofulvin

80.  Uses:
o Systemically only for dermatophytosis, ineffective
topically.
o Duration of treatment depends on site, thickness
of keratin & turnover of keratin.
o Treatment must be continued till infected
tissue is completely replaced by normal
skin,hair, nail.
o Dose: 125-250 mg QID

81. Duration of treatment
•
•
•
•
Body skin -- 3 weeks
Palm, soles -- 4-6 weeks
Finger nails -- 4-6months
Toe nails -- 8-12 months

82.  Interactions:
 Warfarin, OCP Failure
 Phenobarbitone
 Disulfiram-like reaction
Griseofulvin

83. Topical Agents
for Dermatophytes

84.  Ciclopirox olamine:
 Tinea infections, pitryasis versicolor
, dermal candidiasis, vaginal
candidiasis
 Penetrates superficial layers
 Tolnaftate:
 Tinea infections
 Not effective in hyperkeratinized lesions
 Salicylic acid aids its effect by keratolysis

85.  Undecylenic acid: 5% (Tineafax)
 Generally combined with zinc (20%)
 Used in Tinea cruris & nappy rash
 Sodium thiosulfate: (Karpin lotion)
 Reducing agent known as hypo
 Effective in Pitryasis versicolor only 20%
solution for 3-4 weeks

86.  Benzoic acid:
 Used in combination with salicylic acid
 Whitfields ointment: (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 lesion
 Adverse events: irritation & burning
sensation
(Ring cutter ointment)

87.  Haloprogin
 Dermatophytosis (Mainly T. pedis)
 Quinidiochlor
 Luminal amoebicide
 Weak antifungal & antibacterial
 External application: dermatophytosis, mycosis
barbae, pitryasis versicolor

88.  Selenium sulfide: T. versicolor
 Potassium iodide

89. THANK YOU
ALL
vikramsharma161@gmail.com
8826012309
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