ANTI-fungal

Fungal Infection in humans(Mycosis)

FACTS ON FUNGI
1.

ERGOSTEROL-w/c replaces cholesterol found in

mammalian cell membranes.

Major Types
1.

Fungal cell membranes have a unique sterol-

Superficial
2.

TUBULE PROTEINSproduction of different

type in microtubules formed during nuclear
division.

5. Oppurtunistic
(symptoms vary from cosmetic to life threatening)

3.
4.

CHITIN biosynthesis occurs in fungi.

Most fungi have very small nuclei, w/ little

Fungal Infections

5.

2.
3.
4.

1.

Cutaneous
Subcutaneos
Systemic

Superficial Mycoses
a. Hair
b. Skin
c. Mucous membranes
d. Dermatophytosis(ringworm)
e. Candida (thrush, intertrigo)
f. Malassezia furfur (pityriasis vesicolor)

2.

Subcutaneous Mycoses
a. Dermis
b. Subcutaneous & adjacent bones
c. Mycetoma
d. Chromoblastomycosis
e. Sporotrichosis

3.

Systemic Mycoses
a.

Inhalation

A. Pulmonary Infection

B. Disseminated (histioplasmosis
C. Coccidioidomycosis
D. Blastomycosis)

b. Oppurtunist
A.

Aspergillus

B. Candida

C. Cryptococcus

D. Patients compromised by disease, drugs.

FUNGAL INFECTIONS
1.
2.
3.
4.

Incidence; increasing trends

Slow onset

Difficult to diagnose and eradicate

Long duration of therapy

BACKGROUND
3 main groups;
1.

Moulds
Reproduce by spores
Which may produce mycotoxins

2.

Yeast
Grow by budding
Ferment sugars

3.

Dimorphic fungi
Capable of changing growth

repetitive DNA.

Mitosis generally accomplished without dissolution

of the nuclear envelope.

BACKGROUND-Fungi
Maybe :
1. Pathogenic in all exposed patients2. Histoplasma capsulatum, Coccidioides immitis.
3. Opputunist-(candida, aspergillus)
4. Or cause illness via mycotoxins or allergic reaction
ia mycotoxins or allergic reaction after inhalation of
spores.
Risk:
1. Exposure (living conditions. Occupations and
leisure activities)
2. Animal contacts, warm climates, geography.
3. AIDS
4. Immunosuppression(transplant)
5. Broad spectrum antibiotics
FUNGAL Infections
SYSTEMIC
1. Histoplasmosis
2. Aspergilossis
3. Cryptococcosis
4. Blastomycosis
5. Mucormycosis
6. Candidiasis
LOCAL
1. Dermatophytes
2. Sporotrichiosis
3. ZYgomycosis
4. Chromomycosis
5. Rhinospoidiosis
COMMON FUNGAL INFECTION
a. Pityriasis Vesicolor
b. Candidiasis:intertrigo, paronchyma,stomatitis ,
vulvaginitis
c. Tinea;corpis, cruris,barbae, capitis, pedis, manum,
ungulum.
d. Histoplasmosis
e. Coccidioimycosis
f. Blastomycosis

g.
h.
i.

Aspegillosis
Mucormycoses
Mycetoma

4.
5.

Anti-fungals
Polyenes

Imidazoles

Triazoles

Nystatin

Miconazole

Fluconazol
e

Amphoteri
cin B

Clotrimazole

Itraconazol
e

Ketoconaxole

Variconazo
le

Anti-Fungal

Naftiline
Terbinafine

Caspofungin
Micafungin

synthase

Others

inhibitors

butenafine

Griseolfolvin
Flucytosine
Tolnaftate.

How do they work?

1. Polyenes, Imidazoles. Triazoles
target ERGOSTEROL destroying the
cell membranes integrity.
2. Allylamines-inhibit ERGOSTEROL
synthesis
3. B-3 glucan synthase inhibitorsblock the production of the B-(1-3)
glucan protein damaging the cell wall.
4. Nikkomycin & Polyoxin-target chitin
synthase
Flucytosine-inhibit DNA/RNA synthesis

5.
6. Griseofulvin-inhbit fungal cell mitosis preventing
cell proliferation and function.

7. 36% of the drugs are metabolized by 3A4

inhibitors

8. Antifungal can effect u to 60% OF ALL DRUGS

DUE TO INHIBITION OF 3A4, 2C9,2C19,1A2.

AGENTS
SYSTEMIC ANTIFUNGALS
1.
2.
3.

Griseofulvin

Amphotericin-B
Flucytosine

Heterocyclic benzofuran antibiotic

Used for skin caused by dermatophytes
Derived fr. Penicillium griseofulvin
FUNGISTATIC drug that interfere with

mitosis to form multinucleated, stunted &

curled hyphae(CURLING FACTOR)
INDICATIONS
a. Tinea Capitis(scalp/hair)
b. Tinea pedis(soles) & tinea manuum(palms)
c. Tinea corporis(body)c(predisposed to-DM, HIV
immunosuppressed therapy)
d. Tinea unguium(nails)newer antifungals

retodrine

B-3 glucan

Triazoles

1. GRISEOFULVIN

Classification of GeneMedRx-

Allylamines

Imidazoles

terbinafine & itraconazole.

Dose
250mg 2x a day(micronized)
375mg OD (ultramicronized) for an ordinary adult.
10mg/kg/day(micronized) for children
Pregnancycategory C(Animal reproduction studies have shown
an adverse effect on the fetus and there are no adequate and wellcontrolled studies in humans, but potential benefits may warrant
use of the drug in pregnant women despite potential risks.)
Duration of therapy in dermatophytes

1. Body Skin-4 weeks

2. Hair---------4-6 weeks
3. Palms & soles6-8 weeks
4. Finger nails------6-12 months
5. Toe nails----------12-18 months
Adverse Effects
SYSTEMATIC
1.
2.
3.
4.
5.

Headache(COMMON)
GIT disturbances
Transient leukopenia
Peripheral Neuritis
Albuminuria(w/o renal damage)

CUTANEOUS
1.
2.
3.
4.
5.

Fixed drug eruptions

Photoallergic dermatitis
Lichenoid drug eruption
Precipitation of acute intermittent porphyria
Lupus erythematosus

KEYPOINTS
Duration of treatment depends upon:
a. site of infection
b. Thickness of SC
c. Turnover rate
d. Immunological status

It is FUNGISTATIC drug, fungus persist in

already infected keratin till it is shed off.

Ineffective against:
a. Pityrosporum
b. Candida
c. Molds
d. Deep mycotic infections
Can cause alcoholic intolerance
Reduces efficacy of oral contraceptive pill

Absorption depends upon the particle size &

Phenobarbitone reduces the absorption.

suppressive dose after i.v

amphotericin b+ flucytosine
Onychomycosis
Keypoints

presence of fat in the food

2. FLUCONAZOLE

Broad spectrum Triazole antifungal

Effective against some Gram positive and
anaerobic bacteria.
FUNGICIDAL

Inhibit fungal ergosterol synthesis by blocking

fungal enzyme lanosterol 14-demethylase
INDICATIONS
a. Cryptococcal meningitis
b. Coccidioidal meningitis
c. Disseminated candidiasis
d. Oropharyngeal
e. Vaginal
f. Mucocutaneous(except C.krusei)
g. Histoplasmosis
h. Paracoccidioidomycosis
i. Sporotrichosis
j. Pityrosporum ovale infections
k. Fungal keratitis
l. Dermatophyte infections of the skin,hair &
nails.
SYSTEMIC : well tolerated side effects
a. Nausea/vomiting
b. Abdominal pain
c. Headache
d. Thrombocytopenia
e. Raised creatinine levels

Fluconazole is 94% absorbed orally

Oral bioavailability is not affected by food or
gastric pH
80% is excreted unchanged in urine
Longer half life(25-30h) permits single doses
and once weekly regimen
Can penetrate in brain and CSF , hence used

for CRYPTOCOCCAL MENINGITIS.

It does not inhibit steroid synthesis snd is not
antiandrogenic(no gynecomastia)

RIFAMPICIN=reduces plasma levels

ZIDOVUDINE= enhance plasma levels

Fluconazole potentiates hypoglycemic effects of

Tolbutamide & glipizide

Cause eleveation of hepatic transaminases in
HIV pt.(due to prolong)

CUTANEOUS: Maculopapular rash

Pregnancy category C
DOSES and DURATION

150mg/wk till cure

3.

ITRACONAZOLE
Broad spectrum antifungal with fungistatic
action that includes
a. Aspergillus
b. Mucor
MOAinhibits fungal ergosterol synthesis like other azoles
DOC for subcutaneous mycoses like:
a. Eumycetoma
b. Chromoblastomycosis
DOC for systemic mycoses not associated with memningitis
like:
a. Blastomycosis
b. Paracoccidiomycosis
Partially effective and 2nd DOC for:
a. Aspergillosis
b. Mucormycosis

Dermatophyte & cutaneous

candidiasis

150mg/wk for 4-6 weeks

Pityrosporum ovale infections

Dermatophyte infections of the skin, hair nails and
Candidiasi

Vaginal candidiasis &

candidal balanoposthitis

150mg single dose or repeat

for 3 weeks in cases of
recurrences

Doses=200mg/OD?BID, 3-5mg/kg OD

Pityriasis vesicolor

400mg stat(repeat after 2

weeks)

Cryptococcosis

400mg od for 8-10 weeks in

non aids pt.
In aids pt, 200mg od

Dermatophytosis

5mg/kg/day for 2-4 weeks

100mg daily for 4 weeks Tinea
pedis,manuum

Vaginal Candidiasis

600mg single dose

Oral Candidiasis

100mg daily for 15 days

Pityriasis versicolor

1000mg stat

Finger nail
onychomycosis

200mg BID for 7 consecutive

days/per month for 2 days

Toe nail onychomycosis

200mg BID for 7 days/month for 3

months

Seborrhec dermatitis

200mg daily for 7 days

ADVERSE EFFECTS
SYSTEMIC:
a. Nausea
b. Dizziness
c. Headache
d. Abdominal pain
e. Constipation
f. Hypokalemia
g. Impotence
CUTANEOUS
a. Skin rash
b. Cutaneous vasculitis
c. Pregnancy category C.
DRUG INTERACTION
Decreases plasma concentration of drugs
a. Phenytoin
b. Rifampicin
c. H2 blockers
Increases concentration of :
a. Cyclosporine
b. Warfarin
Leads to rhabdomyolysis
a. Itraconazole
b. Statins
Causes ventricular Tachycardia
a. Itraconazole
b. Terfenadine
c. Astemizole
d. Cisapride
Causes peripheral edema
a. Itraconazole
b. Nifedipine
Key Points

Oral absorption is enhanced by food or gastric

pH
Poor penetration of drug in brain and CSF
Half life =24-42 hours
It does not inhibit steroid synthesis and
Does not have antiandrogenic effects like
gynecomastia, loss of libido or oligospermia.

4.

Persist in stratum corneum for 3-4 weeks after

discontinuation justifying pulse therapy of
itraconazole.

KETOCONAZOLE
First oral broad spectrum antifungal
Similar to azole-MOA

DOSE= 200 mg OD/BID, 3-6 mg/kg OD

Conaz 200mgtab
Nizral 2% cream
Nizral 2% shampoo
Drug Interactions
Decrease Oral absorption
a. H2 blockers
b. Proton Pump inhibitors
c. Antacids
Decreases Plasma Concentrations of ketoconazole
a. Phenytoin
b. Rifampicin
Increases concentration of:
a. Cyclosporine
b. Warfarin
c. Sulfonylureas
Adverse effects

SYSTEMIC
a. Nausea & vomiting(most common)
b. Anorexia
c. Headache
d. Paresthesia
e. Antiandrgenic effects(loss of libido, gynecomastia,
hair loss, oligospermia)
CUTANEOUS
a. Rash
b. Alopecia
Keypoints

5.

Oral absorption is enhanced by gastric acid

Poor penetration in brain & CSF
Half life =7-10 hrs
Ketoconazole is not preffered drug for fungal
infections b/c of its antiandrogenic effects &
potential drug interactions.
Still can be used for short period of time
a. Candidial
b. Dermatophyte
c. Pityrosporum infections

TERBINAFINE

Oral & tropical broad spectrum allylamine

antifungal
MOA=inhibits the squalene epoxidase, leading
to accumulation of intracellular squalene and
deficient ergosterol synthesis w/ subsequent
fungal cell death.
Drug reaches the body through:
a. Diffusion fr. Dermal vasculature
b. Sebum to the hair follicle
Dermatophytosis (as an effective alternative to
griseofulvin
Candidiasis(less effective than other
alternative anticandidial drugs like
fluconazole.

DOSE
Adult-250mg OD
Children <20kg:62.5mg/day in divided doses, QID
Children >20kg :125mg/day in divided doses QID
Pregnancy category B

6.

Dermatophytosis

250mg daily 2-4 weeks=tinea

Corporis/tinea cruris
250mg daily for 4-6 weeks=tinea pedis
250mg daily for 4-6 weeks=tinea
capitis.

Cutaneous
candidiasis

350mg once daily for 2-4 weeks

Finger nails
onychomycosis

200mg OD for 6 weeks -3months

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

Toe nails
onychomycosis

20mg OD for 6 weeks-3 month

200mg BID for 7 consecutive days per
month X 3 months

ADVERSE EFFECTS
SYSTEMIC
a. Mild GI disturbances
b. Dreanged heaptic & renal function
CUTANEOUS
a. Skin rash
b. Autoimmune hepatitis
c. Precipitation of lupus erythematous
d. Acute exanthematous pustulosis & dyschromatosis

KEYPOINTS
70-80% oral absorption, not significantly
affected by presence of food

AMPHOTERICIN B (AMB)
Broad spectrum polyene macrolide antibiotic
Most potent antifungal agent for systemic
mycosis.
Fungicidal drug at higher concentrations
Static at lower levels

MOA

DOSES and DURATION

Being LIPHOPHILIC, it accumulates in

keratinous tissues and is present in the tissues
long after it is withdrawnthis is the basis of
terbinafine pulse therapy
Less effective against Candida & pityrosporum
infections particularly used topically
RIFAMPICIN increases elimination of
terbinafine

High affinity for fungal ergosterol, forms

micropore in fungal cell membrane through w/c
ions amino acids and other water soluble
substances move out.
Markedly increases cell permeability
Cholesterol, present in host cell membranes,
closely resembles fungal ergosterol and thus
explains the high toxicity of AMB in humans.

In combination with 5-FC

a. Disseminated candidiasis
b. CRyptooccosis
c. Coccidioidomycosis
In combination with itraconazole/ketoconazole
a. Histoplasmosis
DOC for :
a.

Aspergillosis

b. Mucor mycosis
c. Disseminated sporotrichosis
d. Chromoblastomycosis
2nd DOC for :
a. Paracoccidioidimycosis
Leishmaniasis-reserved drug.
Doses
0.4-0.6mg/kg OD for 6-12 weeks(available in powdered form
to be dissolved in 5% dextrose)
Pregnancy category B
LIPOSOMAL AMB
Dose=3-5mg/kg/day
AMB is incorporated into lipid formulations to reduce
toxicity and enhance efficacy.
This allows higher dose to be used w/o increasing the
toxicity.

Currently 3 such formulations:

a. AMBISOME- incorporates AMB w/ liposome
b. ABELACT- ribbons of lipids interspersed w/ AMB
c. AMPHOCIL- AMB colloidal suspension
ADVERSE EFFECTS
SYSTEMIC
a. Nephrotoxicity-most serious
b. Dose of 5mg/day may produce irreversible renal
damage
c. Nausea & vomiting
d. Fever & chills
e. Hypokalemia
f. Thrombocytopenia
g. Anaphylaxis
CUTANEOUS
a. Hyprsensitivity
KEYPOINTS
AMB is not absorbed enterally, it can be given
orally for intestinal candidiasis
Drug concentration achieved in infected skin is
very low, then ineffective against superficial
fungal infections
Penetration in brain & CSF is poor but
effective against fungal meningitis when
combined with 5-FC
Drug should be preferably given through CVP
line due to risk of thrombophlebitis.
Antihistamines & IV hydrocortisone 100mg
given prior to the admin of AMB to avoid
hypersensitivity rxns.
IV/ORAL K+ supplementation is necessary w/
monitoring of serum potassium levels.
Daily monitoring of BUN and CRT is
mandatory
The dose can be increased except in candidiasis
FLUCYTOSINE (5-FC)
Pyrimidine antimetabolite
Narrow spectrum fungistatic
MOA
Taken up by fungal cells and converted into 5-fluorouracil &
then 5 fluorodeoxyuridylic acidw/c is an inhibitor of
thymidylate synthesis
SPECTRUM
Cryptococcus neoformans-strains causing
chromoblastomycosisa few species of candida
and aspergillus.
INDICATIONS
a. Chromoblastomycosis

b.

Meningeal & nonmeningeal cryptococcosis and

disseminated candidiasis(synergistic action w/
AMB)

Dose
100-150mg/kg/day in 4 divided doses orally
Pregnancy category B
ADVERSE EFFECTS
a. Myelosuppression
b. GI disturbances
c. Mild and reversible liver dysfunction
Key POINTS
Mainly used as adjuvant drug and not as a sole
therapy
Excellent CSF penetration hence it is combined
w/ AMB in fungal meningitis
Mammalian bone marrow cell have the
capacity to convert 5-Fc to 5 F-FU and this
explains marrow toxicity w/ flucytosine
Avoid use of other drug that cause
myelosuppression
TOPICAL ANTIFUNGAL
AZOLES
a. Clotrimazole
b. Econazole
c. Miconazole
d. Terconazole
e. Butoconazole
f. Ciclopirox olamine
g. Haloprogin
h. Benzoic+ salicylic
i. Tolnaftate
j. Terbinafine
k. Nystatin
l. Undecylenic acid
CLOTRIMAZOLE
Fungicidal, 1% cream lotion, vaginal cream
100mg-vaginal tab-o d-7dyas
Cure for dermatophytes, vulvovaginitis
Cut.candidiasis-80% success
ADRs-eryhthema, pruritis, burning sensations
LOCAL ANTIGUNGALS
MICONAZOLE-cream, powder,lotion, 100mg pessaries
Teniasis vulvovaginitis-80% success
Terconazole Butoconazole
NYSTATIN
Similar to amphotericin B
Used topically and for GI use

Used topicaly and for Gi use

Used for candida and dermatophytes
a. Epidermophyton
b. Trichophyton
c. Microsporum
Useful only for candidiasis-cutaenous, oral or
vaginal
100,000 units /Gm cream powder.

OLDER LOCAL ANTIFUNGALS

benzoic acid 6% & salicylic acid 3% whitefield
ointment-tinea pedis,kertolytic too.
Potassium iodine-1GM/ML cutaneous
sporotriosis
Gentian violet, iodine, sulphur