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Anti-fungal drugs

Fungal Infection in Humans (Mycosis)


Major Types of Mycoses
superficial
cutaneous
subcutaneous
systemic
opportunistic

Symptoms vary from cosmetic


to life threatening

Fungal infections
Superficial mycoses hair, skin, mucous membranes eg
dermatophytosis (ringworm), candida (thrush, intertrigo)
and malassezia furfur (pityriasis versicolor)

Subcutaneous mycoses dermis, subcut and adjacent


bones eg mycetoma, chromoblastomycosis, sporotrichosis

Systemic mycoses
1. Inhalation =>pulmonary infection=>disseminated (eg
histoplasmosis, coccidioidomycosis, blastomycosis)
2. Opportunist aspergillus, candida, crytococcus. Patients
compromised by disease, drugs

Fungal infections

Incidence ; increasing trend


Slow onset
Difficult to diagnose & eradicate
Long duration of therapy

Background
3 main groups:
Moulds reproduce by spores, which may produce
mycotoxins

Yeasts grow by budding, ferment sugars


Dimorphic fungi capable of changing growth

Facts on Fungi
Fungal cell membranes have a unique sterol,
ergosterol, which replaces cholesterol found in
mammalian cell membranes
Tubule proteinproduction of a different type in
microtubules
formed during nuclear division.

Chitin biosynthesis occurs in fungi.


Most fungi have very small nuclei, with little
repetitive DNA.

Mitosis is generally accomplished without


dissolution of the nuclear envelope.

Fungal cell

Background - fungi
May be:
= pathogenic in all exposed patients (eg
histoplasma capsulatum, coccidioides immitis)

= opportunists (eg candida, aspergillus)


= or cause illness via mycotoxins or allergic
reaction after inhalation of spores

Fungal infections
Risks:

= Exposure (living conditions, occupation and leisure


activities), animal contact, warm climates,
geography
= AIDS
= Immunosupression (transplant)

= Broad spectrum antibiotics

FUNGAL INFECTIONS
SYSTEMIC
HISTOPLASMOSIS
ASPERGILLOSIS
CRYPTOCOCCOSIS
BLASTOMYCOSIS
MUCORMYCOSIS
CANDIDIASIS

LOCAL
DERMATOPHYTOSIS
SPOROTRICHIOSIS
ZYGOMYCOSIS
CHROMOMYCOSIS
RHINOSPOIDIOSIS

Common fungal infections


Pityriasis versicolor
Candidiasis : intertrigo,
paronychia , stomatitis,
vulvovaginitis
Tinea: corpis, cruris,
barbae, capitis, pedis,
manum, unguium

Histoplasmosis
coccidoiomycosis
blastomycosis
cryptococcosis
aspergillosis
mucormicosis
mycetoma

Classification in GeneMedRx
Antifungals
Polyenes

Imidazoles

nystatin

amphotericin
B

Triazole

-3-glucan
Allylamines synthase
inhibitors

miconazole

fluconazole

clotrimazole

itraconazole terbinafine

ketoconazole

naftifine

voriconazole butenafine

posaconazole

Other

caspofungin

griseofulvin

micafungin

flucytosine

anidulafungin

tolnaftate

ANTIFUNGAL AGENTS
How do they work?
Polyenes, triazoles, and
imidazoles target ergosterol
destroying the cell
membranes integrity.
Allylamines inhibit
ergosterol synthesis.

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

-3-glucan synthase
inhibitor block the
production of the -(1,3)glucan protein damaging
the cell wall.

ANTIFUNGAL AGENTS
How do they work?
Every component of the cell
wall and membrane can be
targeted. Drugs not available
in the market such as
Nikkomycin and Polyoxin
target chitin synthase.
Mannoproteins are another
potential target.

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Other antifungals such as


flucytosine inhibit DNA/RNA
synthesis and griseofulvin
inhibit fungal cell mitosis
preventing cell proliferation
and function.

Ergosterol synthesis pathway &


site of action of antifungal drugs
Squalene
]
] squalene epoxidase === inhibit (Terbinafine, Butenafine,Tolnaftate)
]
Squalene 2, 3-epoxide
]
]
Lanosterol
]
] ===Azoles
]
4, 14 dimethylzymosterol
[
[________________>Zymosterol--------------ERGOSTEROL

Why is this important?

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

36% of drugs are


metabolized by
CYP 3A4 and
antifungals are
largely 3A4
inhibitors
Antifungals can
effect up to 60%
of all drugs due
to inhibition of
3A4, 2C9, 2C19,
1A2.

ANTIFUNGAL AGENTS
SYSTEMIC ANTIFUNGALS
TOPICAL ANTIFUNGALS

Systemic antifungals
1.
2.
3.
4.
5.

PATKI

GRISEOFULVIN
AMPHOTERICIN- B
FLUCYTOSINE
IMIDAZOLES
TRIAZOLES

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GRISEOFULVIN
A heterocyclic benzofuran antibiotic
Most commonly used for fungal infections of skin
caused by dermatophytes

It is derived from the mold Penicillium griseofulvum


MOA==Fungistatic drug interfere with mitosis to form
multinucleated, stunted, & curled hyphae (hence called
the curling factor)

Indications
Tinea capitis
Tinea pedis & tinea manuum(optional)
Tinea corporis that is either
Widespread, or
Has underlying predisposing factor like DM, HIV,
Immunosuppresive therapy
Is not responding to topical antifungals

Tinea unguium: however newer oral antifungals


like Terbinafine & Itraconazole are preferred b/c
of higher efficacy in nail infections

GRISEOFLFULVIN
DOSE
250mg twice a day (micronized) or
375mg once a day (ultramicronized) for an
ordinary adult
10mg/kg/day (micronized) for children

PREGNANCYCategory C

Duration of Griseofulvin therapy


in Dermatophytosis

Body skin
Hair
Palms & soles
Finger nails
Toe nails

4 weeks
4-6 weeks
6-8 weeks
6-12 months
12-18 months

Adverse Effects

Systemic
Headache (commonest)
GIT disturbances
Transient leukopenia
Peripheral neuritis
Albuminuria (without renal damage)

Cutaneous
Fixed drug eruptions, photoallergic dermatitis, & lichenoid
drug eruption
Precipitation of acute intermittent porphyria or lupus
erythematosus

KEY POINTS
Duration of treatment depends upon the site of
infection, thickness of SC, its turnover rate, &
immunological status
Since it is fungistatic drug, fungus persists in
already infected keratin till it is shed off

Ineffective against pityrosporum, candidal, molds,


& deep mycotic infections

KEY POINTS
Griseofulvin can cause alcohol intolerance

Reduces efficacy of oral contraceptive pills


Absorption of griseofulvin depends upon the
particle size & presence of fat in the food.
Phenobarbitone reduces the absorption.

FLUCONAZOLE
Broad-spectrum triazole antifungal;
It is also somewhat effective against some Grampositive & anaerobic bacteria
MOA==Fungicidal drug, inhibits fungal ergosterol
synthesis by blocking fungal enzyme lanosterol
14-demethylase.
Mechanism of antibacterial action remains
unexplained

FLUCONAZOLE
Cryptococcal meningitis & coccidioidal meningitis
Disseminated candidiasis
Candidiasis including oropharyngeal, vaginal, &
mucocutaneous (except C. krusei)
Histoplasmosis, paracoccidiodomycosis, &
sporotrichosis
Pityrosporum ovale infections
Fungal keratitis
Dermatophyte infections of the skin, hair, & nail

Doses & Duration


Dermatophyte &
cutaneous candidiasis

150mg/wk for 4-6 week

Vaginal candidiasis &


candidial balanoposthitis

150mg single dose or


repeat for 3 weeks in
cases off recurrences or
uncorrectable
predisposing factor

Pityriasis versicolor

400 mg stat (repeat after


2 weeks)

Doses & Duration


Cryptococcosis

400mg OD for 8-10


weeks in non-AIDS pts.
In AIDS patients, 200mg
OD (suppressive dose)
after i.v. amphotericin B
+ flucytosine (5-FC)

Onychomycosis

150 mg/wk till cure


(not more than 1 year)

FLUCONAZOLE
Systemic: Well tolerated; side effects may
occur like nausea, vomiting, abdominal pain,
headache, thrombocytopenia, & raised
creatinine levels.
Cutaneous: Maculopapular rash (rare)

Pregnancy=== Category C

KEY POINTS
Of the orally administered fluconazole 94% is
absorbed;

Oral bioavailability is not affected by food or gastric pH;


80% of drug is excreted unchanged in urine.
Longer half life (25-30h) permits its single dose &
once weekly regimen

Penetration in brain & CSF is good, hence used for


cryptococcal meningitis

KEY POINTS
Unlike ketoconazole, it does not inhibit steroid
synthesis & hence is not antiandrogenic
(no gynecomastia)
Plasma levels of drug is reduced by rifampicin
& enhanced by zidovudine
Fluconazole potentiates hypoglycemic effects
of tolbutamide & glipizide.
Can cause elevation of hepatic transaminases
in HIV pts (due to high doses for prolong period)

ITRACONAZOLE
Broad-spectrum antifungal with fungistatic
action that also includes Aspergillus & Mucor
MOA=== Inhibits fungal ergosterol synthesis
like other azoles

ITRACONAZOLE
Subcutaneous mycoses like eumycetoma &
chromoblastomycosis (DOC)
Systemic mycoses not associated with
meningitis like blastomycosis &
paracoccidiomycosis (DOC)
Aspergillosis & mucormycosis (partially
effective & 2nd DOC)

ITRACONAZOLE
Pityrosporum ovale infections

Dermatophyte infections of the skin, hair,


and nail
Candidiasis

Dose== 200mg OD / BD , 3-5mg/kg OD

Doses & Duration in superficial fungal


infections
Dermatophytosis

5mg/kg/day x 2-4 week


100mg daily for 4 weeks
tinea pedis/manuum

Vaginal candidiasis
Oral candidiasis
Pityriasis versicolor

600mg single dose


100mg daily for 15 days
1000 mg stat

Doses & Duration


Finger nail
onychomycosis

200 mg BD for 7
consecutive days/per
month x 2 months

Toe nail onychomycosis

200 mg BD for 7
consecutive days/per
month x 3 months

Seborrhec dermatitis
(experimental
indication)

200 mg daily for 7 days

ADVERSE EFFECTS
Systemic: More side effects as compared to fluconazole,
nausea, dizziness, headache, abdominal pain, constipation,
hypokalemia, & impotence.
Cutaneous: skin rash & cutaneous vasculitis

Pregnancy=== Category C

Drug Interactions
Phenytoin , rifampicin, H2 blockers decrease plasma
concentration of drug.

Increases concentration of cyclosporine & warfarin.


Itraconazole & statins can lead to rhabdomyolysis.
Itraconazole and terfenadine, astemizole, cisapride can cause
ventricular tachycardia.
Itraconazole & nifedipine: peripheral edema.

KEY POINTS

Oral absorption is enhanced by food or gastric pH.


Penetration of drug in brain & CSF is poor.
Half-life = 24-42 hrs
Unlike ketoconazole, it does not inhibit steroid
synthesis & hence does not have antiandrogenic
effects like gynecomastia, loss of libido or
oligospermia.
Drug may persist in stratum corneum for 3-4 weeks
after discontinuation justifying pulse therapy of
itraconazole.

KETOCONAZOLE
First oral broad-spectrum antifungal with mechanism of
action similar to that of other azoles.

Dose== 200mg OD/ BD , 3-6mg/kg OD


Conaz 200mg tab, NIZRAL 2% cream, NIZRAL 2% shampoo

Drug Interactions
H2 blockers, proton pump inhibitors, & antacids decrease oral
absorption.

Phenytoin & rifampicin drecrease plasma concentration of


ketoconazole.
Ketoconazole increases concentration of cyclosporine &
warfarin, sulfonyureas.

ADVERSE EFFECTS
Systemic

Cutaneous

Nausea & vomiting (most common)


Rash
Anorexia
Alopecia
Headache
Paresthesia
Antiandrogenic effects
(loss
of libido, gynecomastia, hair loss,
oligospermia)

KEY POINTS

Oral absorption is enhanced by gastric acid.


Penetration in brain & CSF is poor.
Half-life = 7-10 hrs
Ketoconazole is not a preferred drug for fungal
infections b/c of its antiandrogenic effects &
potential drug interactions.
But still can be used for candidial, dermatophyte,
& pityrosporum infections for short period of
time.

TERBINAFINE
Oral & topical broad-spectrum allylamine
antifungal.
MOA=== Inhibits the squalene epoxidase, leading
to accumulation of intrcellular squalene &
deficient ergosterol synthesis with subseqent
fungal cell death.
Drug reaches the body surface through diffusion
from dermal vasculature and via sebum to the
hair follicle.

TERBINAFINE
Widespread dermatophytosis (as an effective
alternative to griseofulvin).
Candidiasis (less effective than other alternative
anticandidial drugs like fluconazole).
Adult 250mg OD ,
Children <20kg : 62.5 mg/day in divided doses, QID
Children >20kg : 125 mg/day in divided doses, QID
Pregnancy== Category B

Doses & Duration


Dermatophytosis

250mg daily for 2-4 weeks=tinea


corporis/tinea cruris
250mg daily for 4-6 wks=tinea pedis
250mg daily for 4-6 wks=tinea
capitis

Cutaneous candidiasis
250 mg once daily for 2-4 weeks
(not routinely
recommended)

Doses & Duration


Finger nail
onychomycosis

200mg OD for 6 weeks-3 month


200mg BD for 7 consecutive days/per
month x 2 months

Toe nail
onychomycosis

200mg OD for 6 weeks-3 month


200mg BD for 7 consecutive days/per
month x 3 months

ADVERSE EFFECTS
Systemic
Mild gastrointestinal
distrabances
Dreanged hepatic & renal
function

Cutaneous

Skin rash
Autoimmune hepatitis
Precipitation of lupus
erythematosus
Acute exanthematous
pustulosis & dyschromatosis
are also reported

KEY POINTS
70-80% oral absorption, not significantly affected by presence
of food.
Being liphophilic, it accumulates in keratinous tissues & is
present in the tissues long after it is withdrawn. This is the
basis of terbinafine pulse therapy.
Less effective against candida & pityrosporum infections
particularly when used topically.

Rifampicin increases elimination of terbinafine.

AMPHOTERICIN B (AMB)
Broad-spectrum polyene macrolide antibiotic is the most
potent antifungal agent for systemic mycosis.
Fungicidal drug at higher concentrations & static at lower
levels.
MOA=== High affinity for fungal ergosterol, forms
micropore in fungal cell membrane through which ions,
amino acids, & other water soluble substances move out.
Markedly increases cell permeability.
Cholestrol, present in host cell membranes, closely resembles
fungal ergosterol & thus explains the high toxicity of AMB in
humans.

AMPHOTERICIN B (AMB)
Disseminated candidiasis, cryptococcosis, &
coccidioidomycosis (in combination with 5-FC)

Histoplasmosis (in combination with itraconazole or ketoconazole)


Aspergillosis & mucor mycosis (DOC)
Disseminated sporotrichosis
Chromoblastomycosis
Paracoccidioidomycosis (2nd DOC)
Leishmaniasis (reserve drug)

AMPHOTERICIN B (AMB)
0.4 -0.6 mg/kg OD for 6-12 weeks
(available in powdered form to be dissolved in 5% dextrose)

Pregnancy== Category B

Liposomal AMB
New lipid formulations (DOSE: 3-5mg/kg/day)
AMB is incorporated into lipid formulations to reduce toxicity
& enhance efficacy. This allows higher dose to be used
without increasing the toxicity.
Much more expensive than ordinary AMB.

Currently three such formulations are avilable:


AmBisome incorporates AMB with liposomes
Abelact - ribbons of lipids interspersed with AMB
Amphocil AMB colloidal suspension

ADVERSE EFFECTS
Systemic

Cutaneous

Nephrotixicity -most serious

Hypersensitivity

(dose>5mg/day may produce


irreversible renal damage)

Nausea & vomiting


Fever & chills
Hypokalemia
Thrombophlebitis
Thrombocytopenia
Anaphylaaxis

KEY POINTS
AMB is not absorbed enterally; hence can be given orally for
intestinal candidiasis.
Drug concentration achieved in infected skin is very low, &
hence ineffective against superficial fungal infections.
Penetration in brain & CSF is poor (but extremely effective in
fungal meningitis when combined with 5-FC)
Drug should be preferably given through CVP line due to risk
of thrombophlebitis.

KEY POINTS
Antihistamines & IV Hydrocortisone 100mg is routinely given prior
to the administration of AMB to avoid hypersensitivity reactions.
IV or oral K+ supplementation is necessary with monitoring of
serum potasium levels.
Daily monitoring of BUN & Crt is mandatory.
Start with test dose of 1mg on day 1. If there is no hypersensitivity,
increase to 0.5mg/kg/day. If no other side effects, the dose can be
steadily increased (except in candidiasis) to reach a maximum of
1mg/kg/day
For serious infections, one can dispense with the test dose & start
with higher dose.

FLUCYTOSINE (5-FC)
Pyrimidine antimetabolite, narrow-spectrum fungistatic

MOA=== It is taken up by fungal cells and converted into


5-fluorouricil & then 5-fluorodeoxyuridylic acid, which is an
inhibitor of thymidylate synthesis.
Spectrum
Cryptococcus neoformans, strains causing
chromoblastomycosis, a few species of Candida & Aspergillus.

FLUCYTOSINE (5-FC)
Indications
Chromoblastomycosis
Meningeal & nonmeningeal cryptococcosis and disseminated
candidiasis (synergistic action with AMB)

Dose
100-150 mg/kg/day in four divided doses orally

Pregnancy== Category B

FLUCYTOSINE (5-FC)
Adverse Effects
Mylosuppression
GI disturbances
Mild & reversible liver dysfunction

KEY POINTS
Since this is a narrow-spectrum fungistatic, it is mainly used as
an adjuvant drug & not used as a sole therapy.
CSF penetration is excellent, hence it is combined with AMB in
fungal meningitis.
Mammalian bone marrow cell have the capacity to convert 5FC to 5-FU, and this explains marrow toxicity with flucytosine.
Concurrent use of other mylosuppressive drugs should be
avoided.

TOPICAL ANTIFUNGAL
AZOLES - CLOTRIMAZOLE,ECONAZOLE,
MICONAZOLE,TERCONAZOLE
.BUTOCONAZOLE
CICLOPIROX OLAMINE
HALOPROGIN,BENZOIC+SALICYLIC,
TOLNAFTATE,TERBINAFINE, NYSTATIN
UNDECYLENIC ACID,

PATKI

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CLOTRIMAZOLE

fungicidal,1% cream,lotion,vaginal cream


100 mg -vaginal tab-o.d-7 days
cure for dermatophytes ,vulvovaginitis,
cut.candidiasis-80% success
ADRs-erythema,pruritis,burning sensations

PATKI

63

Local antifungals
MICONAZOLE
Cream,powder,lotion
,100mg Pessaries,
Teniasis,vulvovaginitis,-80%
Success.
Terconazole Butoconazole-

CICLOPIROX OLAMINE,
HALOPROGIN ,
TOLNAFTATETRICHOPHYTONS AND
MICROSPORUM.
TERBINAFINE CREAM

NYSTATIN

similar to amphotericin B
used topically and for GI use
used against candida and dermatophytes
(Epidermophyton, Trichophyton, Microsporum).

Useful Only For Candidiasis- cutanious, Oral Or


Vaginal
100,000 Units/Gm Cream,powder.
Vaginal Tab-twice A Day-2weeks

ADRs- RARE
PATKI

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OLDER LOCAL ANTIFUNGALS


BENZOIC ACID 6% &SALICYLIC ACID 3%WHITFIELD OINTMENT-TINEA PEDIS.
KERTOLYTIC TOO,

POTASSIUM IODIDE-1 GM/ML-CUTANIOUS


SPOROTRICHIOSIS
GENTIAN VOILET, IODINE, SULPHUR
PATKI

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Alternatives
Research conducted in 1996 indicated that the following
substances or essential oils had anti-fungal properties:[12]
Allicin - created from crushing garlic
Tea tree oil - ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol
type")
Citronella oil - obtained from the leaves and stems of
different species of Cymbopogon (Lemon grass)
Iodine - Lugol's iodine
olive leaf
orange oil
palmarosa oil

Alternatives

patchouli
lemon myrtle
Neem Seed Oil
Coconut Oil - medium
chain triglycerides in the oil have
antifungal activities
Zinc - in dietary supplements or natural
food sources, including pumpkin
seeds and chick peas

Alternatives
Selenium - in dietary supplements or natural food
sources, particularly Brazil nuts
Horopito (Pseudowintera colorata) leaf - contains
the anti-fungal compound polygodial[5]
Israeli researchers at Tel Aviv University's
Department of Plant Sciences published a study in
2009 indicating that carnivorous plants like the
Venus flytrap contain compounds that may be
useful in providing a new class of anti-fungal drugs
for use in humans, for fungal infections that are
resistant to current anti-fungal drugs

ANY QUESTION ??

Thank you