Antifungal agents

Yeasts
• Fungi may be classified as

Moulds

• Yeasts: Blastomyces, candida, histoplasma, coccidioides,

cryptococcus.

• Moulds: Aspergillus spp. Dermatophytes, mucor

Superficial mycosis

• Clinically classified as:

Deep (systemic) mycosis

 Polyenes (Disrupt membrane structure & function)

Azoles inhibit

Flucytosine inhibits DNA synthesis

Caspofungin inhibits
cell wall synthesis
 Classification based on mechanism of
action
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotercin–B,
Nystatin.
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine,
Naftifine, Butenafine.
4. Inhibition of ergosterol synthesis: Azoles
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis:
Griseofulvin.
7. Miscellaneous:
• Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles.
 Classification based on structure
• ANTIBIOTICS
Polyene: Amphotericin, nystatin, hamycin
Hetrocyclic benzofuran: griseofulvin

• ANTIMETABOLITE : Flucytosine

• AZOLES

Imidazoles: Ketoconazole, clotrimazole, oxiconazole,

miconazole,

Triazoles: Fluconazole, itraconazole, voriconazole,

 Classification based on structure

• ALLYLAMINES
– Terbinafine, butenafine

• ECHINOCANDINS
– Caspofungin, anidulafungin, micafungin

• OTHER TOPICAL AGENTS

– Tolnaftate, Undecyclinic acid, benzoic acid
 Polyene antibiotics
• Amphotericin B:
– Obtained from Streptomyces Nodosus
– Amphoteric in nature
Hydrophilic part

Lactone ring

Lipophilic part
Mechanism of action
 Mechanism of action
Amphotericin B

Binds ergosterol in fungal cell membrane

Form pores in cell membrane

Cell contents leak out

Cell death
 Antifungal spectrum
- Aspergillus
- Blastomyces dermatitidis
Broadest spectrum
- Candida albicans of action
- Cryptococcus neoformans
- Coccidioides immitis Fungicidal at high &
static at low conc.
- Histoplasma capsulatum
- Mucor spp.
Also active against Leshmania
 Mechanism of resistance

• Resistance:
– Replacement of ergosterol by other sterols in
fungal plasma membrane.
– Resistance is not a problem clinically.
 Pharmacokinetics
• Poorly absorbed orally
• Insoluble in water so colloidal
suspension prepared with sodium
deoxycholate(1:1 complex)
• 90% bound to plasma proteins
• Metabolized in liver slowly
excreted in urine
• t ½ = 15 days
 Administration & dose
• Systemic mycosis: IV
– Available as 50mg vial – suspended in 10 ml water
and then diluted with 500 ml glucose
– 0.5mg/kg to 1 mg/kg
– Total dose- 3-4 gm over 2-3 months
• Intestinal Monoliasis: 50-100 mg QID Orally
• Vaginitis: topical
• Otomycosis: 3 % drops
• Intrathecal: 0.5 mg BD in fungal meningitis
 Uses
• Useful drug in nearly all life threatening mycotic
infections
• Treatment of invasive aspergillosis
• Rapidly progressive Blastomycosis &
Coccidiomycosis
• Cryptococcus neoformans
• Mucormycosis.
• Disseminated rapidly progressing Histoplasmosis
• Reserve drugs for resistant kala azar
• Topical uses:
• Adverse events:
– Acute reaction:
– Chills, fever, headache, pain all over,
nausea, vomiting, dyspnoea lasting 2-5 hrs
because of release of IL & TNF
– can be treated with hydrocortisone
0.6mg/kg
– Long term toxicity:
– Nephrotoxicity: Azotemia,
Hypokalemia, acidosis, ↓ GFR
– anemia
– CNS toxicity : intrathecal administration,
headache, vomiting, nerve palsies
– Hepatotoxicity rarely
 Nystatin
 Obtained from S.Noursei
 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
 Prevention of oral candidiasis
 Can be used in oral, cutaneous, conjunctival candidiasis
 Adverse events:
 Gastointestinal disturbances with oral tablets
 Griseofulvin
• One of early antibiotics from penicillium
griseofulvum
• Fungistatic, systemic drug for superficial
fungal infections
• Active against most dermatophytes
• Dermatophytes concentrate it actively hence
selective toxicity
• Resistance: loss of concentrating ability
• Mechanism of action:
– Griseofulvin interacts with
polymerized microtubules and
disrupts the mitotic spindles thus
arresting fungal mitosis
• Pharmacokinetics:
– Oral administration, irregular
absorption, increased by fatty food
and microfine particles
– Gets conc in keratinized tissue
– Metabolized in liver, excreted in
urine,t1/2=24 hrs
• Adverse events:
– Headache most common
– GIT disturbances
– CNS symptoms: confusion, fatigue, vertigo
– Peripheral neuritis
– Rashes, photoallergy
– Transient leukopenia, albuminuria
• Uses:
– Systemically only for dermatophytosis, ineffective
topically
• Systemic azoles more effective and preferred
• Duration of treatment depends on site,
thickness of keratin and turnover of keratin.
• Treatment must be continued till infected
tissue is completely replaced by normal
skin,hair, nail.
• Dose: 125-250 mg QID
 Duration of treatment
• Body skin = 3 weeks
• Palm, soles = 4- 6 weeks
• Finger nails = 4- 6months
• Toe nails = 8 – 12 months
• Griseofulvin should be reserved for nail hair or
larger body surface involvement
• Interactions:
– Warfarin , OCP
– Phenobarbitone, Disulfiram like reaction
 5 flucytosine
– Prodrug, pyrimidine analog, antimetabolite
– Converted to 5 FU
– Human cells cant convert it to 5FU
– Adverse events:
• Bone marrow toxicity , GIT , Alopecia, skin rashes,
itching , rarely hepatitis
– Uses: in combination with AMB in cryptococcal
meningitis
– Narrow spectrum of action
Advantages of combination:
–Entry of 5 FC
–Reduced toxicity
–Rapid culture conversion
–Reduced duration of therapy
–Decreased resistance
• Differences between AMB & 5 FC
• AMB = Active drug, broad spectrum, antibiotic,
fungicidal
• Not absorbed, high protein binding, no BBB,
metabolized in liver, highly efficacious,
IV,Intrathecal,topical
• Azoles:
– Synthetic antifungals
– Broad spectrum
– Fungistatic or fungicidal depending on conc of
drug
– Most commonly used
– Classified as imidazoles & triazoles
• Imidazoles: Two nitrogen in structure
– Topical: econazole, miconazole, clotrimazole
– Systemic : ketoconazole
– Newer : butaconazole, oxiconazole, sulconazole
• Triazoles : Three nitrogen in structure
– Fluconazole, itraconazole, voriconazole
– Terconazole: Topical for superficial infections
• Both these groups are
– Structurally related compounds
– Have same mechanism of action
– Have similar antifungal spectrum
 Mechanism of action:
Terbinafine
Squalene
Ѳ
squalene 2,3 epoxide

Lanosterol

Ѳ Azoles
14 α demethylase

Ergosterol
 Miconazole & clotrimazole
• Topical use:
– Miconazole 2 % and clotrimazole 1 % applied BD for
2 weeks in pityriasis versicolor, 4 weeks in cruris,
capitis and corporis
• Uses:
– Dermatophyte infections
– Candida: oral pharyngeal, vaginal, cutaneous
• Adverse events:
– Local irritation , itching or burning
– Miconazole shows higher incidence of vaginal irritation &
pelvic cramps
 Ketoconazole
– First orally effective broad spectrum antifungal
– Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
 Pharmacokinetics
• Effective orally
• acidic environment
favours absorption
• High protein binding
• Readily distributed, not to
BBB
• Metabolized in liver,
excreted in bile
• t1/2 = 8- 10 hrs
• Dose : 200 mg OD or BD
 Adverse events
• Nausea , vomiting , anorexia
• Headache , paresthesia, alopecia
• ↓ steroid, testosterone & estrogen synthesis
– Gynaecomastia, oligospermia , loss of libido &
impotence in males
– Menstrual irregularities & amenorrhoea in
females
• Elevation of liver enzymes
• Hypersensitivity reaction - skin rashes, itching
Drug Interactions
 Uses
• Dermatophytosis: conc in stratum corneum
• Monilial vaginitis : 5-7 days
• Systemic mycosis: blastomycosis,
histoplasmosis, coccidiodomycosis
– Less efficacy than AMB & slower response
– ↓Efficacy in immunocompromized and meningitis
– Lower toxicity than AMB higher than triazoles
• High dose used in cushings syndrome
• Topical: T.pedis, cruris, corporis, versicolor
 Fluconazole
• Newer water soluble triazole
– Oral, IV as well as topical
– Broad spectrum antifungal activity
• Candida, cryptococcosis, coccidiodomycosis
• Dermatophytosis
• Blastomycosis
• Histoplasmosis
• Sporotrichosis
• Not effective against aspergillosis & mucormycosis
 Pharmacokinetics

94% oral bioavailability

Not affected by food or gastric pH
Primarily excreted unchanged in urine t1/2 =
25 -30 hrs
Poor protein binding
Widely distributed crosses BBB
 Adverse events
 GIT upset
 Headache, alopecia, skin rashes, hepatic necrosis
 Teratogenic effect
 CYP450 Enzyme inhibiting property less Interactions:
 Effects hepatic drug metabolism to lesser extent than
Ketoconazole
 H2 blockers & PPI do not effect its absorption
 No anti androgenic & other endocrine effects
 Uses
Candida:
 150 mg oral dose can cure vaginal candidiasis with
few relapse
 Oral candidiasis- 2 weeks treatment required
Tinea infections & cutaneous candidiasis: 150 mg
weekly for 4 weeks, tinea unguim : 12 months
systemic fungal infections: Disseminated
candidiasis, cryptococcal, coccidiodal meningitis
200-400 mg / day 4- 12 weeks or longer
Meningitis: preferred drug
Eye drops for fungal keratitis
 Itraconazole

Broadest spectrum of activity also against

aspergillus
Fungistatic but effective in
immunocompromised
Does not inhibit steroid hormone synthesis
and no serious hepatoxicity
 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
 Uses
 DOC for paracoccidomycosis & chromoblastomycosis
 DOC for histoplasmosis & blastomycosis
 Esophageal, oropharyngeal vaginal candidiasis
 Not superior to fluconazole : 200 mg OD X 3 days
 Dermatophytosis: less effective than fluconazole
 100- 200 mg OD X 15 days
 Onychomycosis : 200 mg / day for 3 months
 Intermittent pulse regime 200 BD once a week / month for 3
months equally effective
 Aspergillosis: 200 mg OD/ BD with meals for 3 months
or more
 Adverse events

• GI Intolerance
• Dizziness, pruritis , headache , hypokalemia
• Increase plasma transaminase
• Rarely hepatotoxicity
• Drug interactions:
– Oral absorption ↓by antacids, H2 blockers
– Rifampicin, phenytoin induce metabolism
– Inhibits CYP3A4 drug interaction profile similar to
ketoconazole
 Triazoles

Itraconazole Fluconazole
- Varied absorption. - Completely absorbed and
Metabolized by cyt P450 better tolerated, Renal
excretion
- less endocrine effects but - Less endocrine effects
occur at high doses
- Penetrates well into CSF
- Less penetration in CSF
- Many drug interactions - Drug Interactions
(due to inhibition of CYT
P450/ 3A4)
 Voriconazole
II generation triazole
High oral bioavailability, low protein binding
Good CSF penetration
Metabolized by CYP2C19
Doesn’t require gastric acidity for absorption
T1/2= 6 hrs
 Uses:
 DOC for invasive aspergillosis
 Most useful for esophageal candidiasis
 First line for moulds like fusarium
 Useful in resistant candida infections
 Dose and Adverse effects

• 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
 Terbinafine
Orally & topically effective drug against
candida & dermatophytes
Fungicidal : shorter courses of therapy
required & low relapse rates
 Mechanism of action:
 Pharmacokinetics:
 Well absorbed orally 75%
 Highly keratophilic & lipophilic
 High protein bound , poor BBB permeability
 t1/2- 15 days
 Negligible effect on CYP450
 Adverse events and uses
 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
 Caspofungin acetate

Semisynthetic antifungal
MOA: Inhibits B (1,3) D glucan an essential
component of fungal cell wall
Uses: Treatment of invasive aspergillosis &
candidiasis (esophageal, intraperitoneal)
Dose: IV 70 mg slowly then 50 mg daily infusion
Adverse events:
 Flushing rashes , nausea, vomiting, phlebitis
Systemic Topical
administration
Griseofulvin Ketoconazole
Ketoconazole Miconazole
Fluconazole Clotrimazole
Itraconazole Terbinafine
Terbinafine Nystatin
 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 Fusarium
 Spectrum of action

• Nystatin: Candidiasis only

• Griseofulvin: Dermatophytosis only
• Terbinafine : Dermatophytosis & candidiasis
• Caspofungin: Aspergillosis & candidiasis
 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