Description on types of fungal organisms with differences between bacteria and fungi. A note on useful and harmful fungi. Brief insight on Antifungal classification, mechanism of actions and pharmacological profile with drug of choices for various fungal infections.
2. CONTENTS
■ Introduction
■ Types of fungal organisms
■ Difference between bacteria and fungi
■ Classification of fungal infections
■ Classification of antifungal agents
■ Pharmacology of antifungal agents
■ Drug of choice for various fungal infections
3. 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.
■ In 1950s the incidence of fungal infections were
predominant
■ Fungal infections are iatrogenic/ drug induced
■ Infections majorly occur in immunocompramised
people receiving immunosuppressants
4. TYPES OF FUNGAL ORGANISMS
CLASS MODE OF
TRANSMISSION
SPECIES INVOVLVED DISEASE CAUSED
YEASTS Budding Cryptococcus neoformans Meningitis
YEAST LIKE
FUNGI
Partly grows like
yeast and partly as
filaments (hyphae)
Candida albicans Oral thrush
Vaginal thrush
Systemic Candidiasis
Pityrosporom orbiculare Pityriasis versicolor
Tinea versicolor
MOULDS Filamentous fungi
reproduce by
forming spores
Dermatophytes
(pathogenic moulds)
Trichophyton sp.,
Microsporum sp.,
Epidermophyton sp.,
Skin/ nail infections
5. TYPES OF FUNGAL ORGANISMS
CLASS MODE OF
TRANSMISSION
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
6. USEFUL & HARMFUL FUNGI
ORGANISM USES
Saccharomyces cerviciae Manufacturer of beverages and bread
Majorly used in fermentation processes
Penicllium notatum
Penicillium crysogenum
Produce PENICILLIN
Streptomyces griseofulvin Griseofulvin
HARMS
Claviceps purpurea Produces mycotoxins causing food poisoning
Aspergillus Produces Alfatoxin that is carcinogenic
7. DIFFERENCE BETWEEN BACTERIA AND FUNGI
BACTERIA
• Peptidoglycan layer is
present in the cell and
consists of NAGA & NAMA
• Cell wall is composed of
proteins
• Lipids present in the cell
wall are made of cholesterol
FUNGI
• Consists of polysaccharides
both simple (β – glucans 1,3
& 1,6) and complex
polysaccharides (Chitin –
NAG) constituting 80% of
the cell wall
• Cell wall is made of
ergosterol
8. 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
10. CLASSIFICATION OF ANTIFUNGAL AGENTS
BASED ON CHEMICAL NATURE
POLYENES
AMPHOTERICIN B
NYSTATIN
ECHINOCANDINS
MICAFUNGIN
CASPOFUNGIN
ANIDULAFUNGIN
ANTIMETABOLITES
FLUCYSOINE
ALLYLAMINES
NAFTIFINE
TERBINAFINE
BUTENIFINE
MISCELLANEOUS
AZOLES
GRISEOFULIVIN
BENZOIC ACID
UNDECYCLINIC
ACID
SODIUM
METBISULPHATE
TRIAZOLES
VORICONAZOLE
ITRACONAZOLE
POSACONAZOLE
FLUCONAZOLE
IMIDZOLES
SYSTEMIC
KETOCONAZOLE
TOPICAL
CLOTRIMAZOLE
SECONAZOLE
OXICONAZOLE
MOCONAZOLE
ECONAZOLE
11. CLASSIFICATION OF ANTIFUNGAL AGENTS
BASED ON SITE OF INFECTION
CUTANEOUS/TOPICAL
INFECTIONS
SYSTEMIC/ SUB CUTANEOUS
INFECTIONS
NYSTATIN
GRISEOFULVIN
CLOTRIMAZOLE
SECONAZOLE
OXICONAZOLE
MECONAZOLE
BENZOIC ACID
UNDECYCLINIC ACID
SODIUM METABISULPHATE
AMPHOTERICIN B
KETOCONAZOLE
VORICONAZOLE
ITRACONAZOLE
POSACONAZOLE
MICAFUNGIN
CASPOFUNGIN
FLUCONAZOLE
12. POLYENE ANTIBIOTICS
AMPHOTERICIN B
■ 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
13. PHARMACOKINETICS
■ Yellowish colour powder
■ Unstable in aqueous solutions
■ Given through IV route in salt form
■ AMPHOTERICIN DESOXYCHOLATE
Metabolised in liver
t1/2 - 15 days
Accumulates in renal cells causing
nephrotoxicity leading to Azotemia
characterized by decreased GFR, Urinary
output, Crcl and increased Scr and BUN
14. 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
15. ADRS
■ Nephrotoxicity
■ Nausea
■ Vomitings
■ Diarrhoea
■ Bone marrow
depression
THERAPEUTIC USES
■ Intestinal candidiasis
■ Topical candidiasis
■ Febrile neutropenia
■ Leishmaniasis – kala
Azar
Limited use in systemic infections because of
increased toxicity
16. AMB FORMULATIONS
CONVENTIONAL AMB
■ Na+ salt of AMB i.e., Sodium
desoxycholate AMB
■ It is water soluble and
stable
LIPOHILIC AMB
■ AMB formulated in liposomes
which releases drug
periodically
■ 10% AMB is surrounded by
unilammellar, lipophilic
membrane made up of Lecithin
■ Increased specificity as
liposomes will be coated with
Abs mediating site specific
delivery
■ Increased BA and decreased
nephrotoxicity
17. NYSTATIN
■ Posses very high systemic toxicity
■ Not given in IV
■ Used to treat topical infections
■ Earlier it was used to treat moniliasis
18. 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 against
Aspergillus sp., and Candida sp.,
19. PHARMACOKINETICS
■ t1/2 - 3 to 6 hours
■ Orally well absorbed
■ Metabolized by liver
■ Excreted unchanged in urine
21. MECHANISM OF ACTION
■ CYTOSINE DEAMINASE is present only in
fungal cells and absent 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
22. ADRS
■ Bone marrow
suppression
■ Hepatotoxicity
■ 5 FC administered in
excess stimulate
intestinal colonic
bacteria which
produce Cytosine
deaminase
THERAPEUTIC USES
■ Invasive aspergillosis
■ Candidiasis
■ Synergistic with
AMPHOTERICIN as it
increases permeability
in to fungal cells by
formation of pores in
the cell membrane
23. 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
24. CASPOFUNGIN
■ First discovered Echinocandin
■ It is a large molecular weight lipopeptide
■ It is Amphiphilic in nature
MECHANISM OF ACTION
Inhibit the synthesis of β 1,3 – glucan synthase
resulting in the inhibition of cell wall
26. MICAFUNGIN
■ Approved by FDA
INDICATIONS
Immunocompramised patients who have
undergone organ transplantation and on
immunosuppressant therapy
Used in the prophylaxis of candida infections in
persons undergoing hematopoietic stem cell
transplantation
27. AZOLE ANTIFUNGALS
■ Broad spectrum of cation with minimal ADRs
■ More efficacious
MECHANISM OF ACTION
Squalene
Lanosterol 14 demethylase
AZOLES
Ergosterol
28. TOPICAL AZOLES
■ Used to treat oral, vaginal, cutaneous
candidiasis
■ MICONAZOLE is more efficacious than other
topical azoles
■ t1/2 - 1 to 6 hours
■ Used to treat T. corporis and T. capitis
infections
■ Treatment ranges from 2 – 6 months based on
the area of infection
29. SYSTEMIC AZOLES
KETOCONAZOLE
■ Used to treat various systemic fungal infections
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
30. By inhibiting CYP enzymes it increases the
concentration of drugs such as
DIGOXIN
WARFARIN
SULFONAMIDES
DHF DERIVATIVES
AMLODIPINE
STATINS
PHARMACOKINETICS
PHENYTOIN
NIFEDIPINE
CIMETIDINE
PHENOBARBITONE
CARBAMAZEPINE
TERFINADINE – QT
interval prolongation
and tachyarrhythmias
31. ADRS
■ Inhibits enzymes useful
for sterol synthesis
■ Decreased production of
testosterons leading to
impotency, loss of hair,
oligozoospermia and
Gynaecomastia
■ Menstrual irregularities
■ Mild hepatotoxicity
■ Increased transaminases
THERAPEUTIC USES
■ Systemic candidiasis
■ Vaginal moniliasis
■ Deep mycotic infections
■ Cryptococcal infections
■ Coccidioiodo infections
35. ■ FLUCONAZOLE resistant fungal meningitis
■ Histoplasmosis
■ Blastomycoses
■ Sporotrichosis
■ Mucormycosis
■ Coccidioiodomycosis
■ Paracoccidioidomycosis
INDICATIONS
ITRACONAZOLE is the drug of
choice
36. VORICONAZOLE
■ Used to treat
aspergillosis during
catheterization
POSACONAZOLE
■ Newer and most
costliest of all the
azoles
■ Limited use due to
increased cost
All azoles are teratogenic hence contraindicated in
pregnant and lactating women
37. ALLYLAMINES
TERBINAFINE
MECHANISM OF ACTION
■ These agents are non competitive inhibitors of
squalene epoxidase
Squalene
Ergosterol
Squalene is increasingly toxic to fungal cells leading to
fungicidal action
Squalene epoxidase
ALLYLAMINES
38. MISCELLANOEUS
GRISEOFULVIN
■ Obtained from Streptomyces griseus
■ Effective against dermatophytes
PHARMACOKINETICS
■ Well absorbed orally
■ Absorption is enhanced in the presence of lipophilic
substances
■ Accumulation is enhanced in tissues made up of
keratin such as skin, nails, and hair
■ Can prevent further spread but cannot treat already
infected keratinocytes
39. PHARMACOKINETICS
■ Orally well absorbed
■ Oral dosage form have increased bioavailability
■ Has increased affinity towards keratin, hence
used in topical fungal infections
INDICATIONS
■ Onychomycosis
■ Used as 1% cream in topical infections
■ Highly effective when compared to
GRISEOFULVIN
40. MECHANISM OF ACTION
GRISEOFULVIN
Binds to
Tubulins
inhibiting
Mitotic spindle formation
Resulting in
Inhibition of separation of daughter nuclei
FUNGISTATIC EFFECT
41. ADRS
■ Rashes
■ Nausea
■ Vomitings
■ Diarrhoea
■ Mild Hepatotoxicity
THERAPEUTIC USES
■ T. unguium
■ T. corporis
■ Dermatophyte infections
GRISEOFULVINs use is limited because of
extensive replacement by Azoles and Terbinafine
42. DRUG OF CHOICE FOR VARIOUS
FUNGAL INFECTIONS
FUNGUS DISEASE FIRST DOC SECOND DOC
Cryptococcus neoformans Meningitis AMPHOTERICIN B
±
5-FLUCYTOSINE
FLUCONAZOLE
Candida albicans
Candidiasis (oral, vaginal, or
cutaneous)
FLUCYTOSINE
NYSTATIN
CLOTRIMAZOLE
ITRACONAZOLE
Deep mycosal/ disseminated AMPHOTERICIN B
VORICONAZOLE
FLUCONAZOLE
Pityrosporom orbiculare Pityriasis versicolor/ Tinea
versicolor
TREBINAFINE FLUCONAZOLE
Histoplasma capsulatum Histoplasmosis ITRACONAZOLE
AMPHOTERICIN B
FLUCONAZOLE
Coccidiodes immitis Coccidiomycosis AMPHOTERICIN B
FLUCONAZOLE
ITRACONAZOLE
KETOCONAZOLE
Blastomyces dermatides Blaatomycosis ITRACONAZOLE
AMPHOTERICIN B
KETOCONAZOLE
FLUCONAZOLE
Sporothrix sp., Sporotrichosis AMPHOTERICIN B ITRACONAZOLE
43. DRUG OF CHOICE FOR VARIOUS
FUNGAL INFECTIONS
FUNGUS DISEASE FIRST DOC SECOND DOC
Aspergillus fumigatus Pulmonary aspergillosis
Asperglioma
Asthma associated with
aspergillosis
Sinusitis
Respiratory infections
AMPHOTERICIN B
VORICONAZOLE
ITRACONAZOLE
Paracoccidioides braziliensis Paracoccidioidomycosis ITRACONAZOLE AMPHOTERICIN B