ANTIFUNGAL AGENTS(SYSTEMIC)

Fungal infection Drugs used commonly

Candidiasis Fluconazole(most effective against this)

Itraconazole
Voriconazole
Ketoconazole
Amphotericin B
TERBINAFINE IS FUNGISTATIC for C. albicans.
Dermatophytosis Azoles, triazoles, terbinafine,
Griseofulvin

P. versicolor Ketoconazole
Fluconazole
Itraconazole

sporotrichosis Itraconazole (DOC) = 100-200 mg/day x 3-6 mon. 200mg BD for

osteoaarticular forms x 12 mon. SSKI is ineffective in osteoarticular
forms.
Fluconazole (400 mg x 6 mon) --- not so effective and should be given
to those who cannot tolerate itraconazole
Amphotericin B(1mg/kg/day) for pulmonary forms. Switch to
itraconazole once the crisis is over.

Chromoblastomycosis Itraconazole = 200-400 mg x 12 mon. Can be combined with

(no ideal antifungal) flucytosine in difficult cases.
Terbinafine = 500 mg x 12 mon
Flucytosine combined with Amp B or thiabendazole (alone flucytosine
is not so effective.

zygomycosis Itraconazole = 200-400 mg/day

Ketoconazole = same
Fluconazole = 200 mg/day.

lobomycosis surgery

phaeohyphomycosis Surgery
Amphotericin B in cases not amenable to surgery
Itraconazole is also effective in some
(The condition is known to recur after drugs are stopped therefore
treatment for several months is needed.

histoplasmosis Itraconazole for less severe cases and maintenance therapy

Amphotericin B for serious life threatening infection.

Blastomycosis Same as above

Cocciodomycosis Same. Fluconazole is also effective

Paracoccidiodomycosis Itraconazole is the DOC

Ketoconazole is as effective
If oral agents cannot be taken, iv fluconazole is given.
In refractory cases, Amphotericin B is administered.
Mucormycosis Correct metabolic and immunologic defects
Amphotericin is the only DOC.
cryptococcosis Initial intensive treatment with Amphotericin B and Flucytosine
followed by maintenance with fluconazole.

GRISEOFULVIN:
FUNGISTATIC
Nature of drug --------- It is an antifungal antibiotic derived from a number of Penicillium species.

Important feature -------- It was the first oral drug for the treatment of dermatophytosis.

MOA: It binds to microtubular proteins and inhibits fungal cell mitosis. It also acts as an inhibitor of nucleic acid synthesis.

ITS USE IS RESTRICTED TO DERMATOPHYTES.

Resistance is uncommon.

Pharmacokinetics:
 Absorption is increased with a fatty meal
 It reaches stratum corneum 4-8 hours after oral administration and then the levels fall so that by 48-72 hours it is no longer
detected.
 Metabolized by the liver and excreted in 9-12 hours.

Adverse effects ---------

 headache and GI side effects are most common,
 rashes ------- morbilliform, urticaria, angioedema, erythema multiforme, FDE, SJS, TEN, exfoliative dermatitis have been
reported.
 detoriate liver function in patients with preexisting liver disease.
 Photosensitivity has been reported ----------- mechanism -------- photoallergic.
 It can precipitate an attack of acute intermittent porphyria. Diminished alcohol intolerance has been reported in patients
taking Griseofulvin.
 Drug induced LE

Dose:
1. tinea capitis --------- 10 mg/kg/day-8 weeks. It is increased to 20 mg/kg/day for T.tonsurans.
2. tinea cruris and barbae ----------- 500 mg daily for 1 month.
3. tinea pedis -------- 500 mg daily for 3 months
4. tinea mannum ------- 750 mg daily for 6 weeks to 3 months
5. tinea ungium ----- higher doses for 6-12 months. 500-1000 mg.

Drug interactions --------------

1. it stimulates the metabolism of warfarin --------- reduces the anticoagulant effect.
2. OCP failure has been reported.
3. absorption is reduced with phenobarbitone. This can be countered by taking the drug with fatty meal.

FLUCONAZOLE:
Nature of drug ------- triazole
MOA: It is a potent inhibitor of ergosterol biosynthesis by inhibiting the Cyt P450 enzyme ----- lanosterol 14a demethylase. Depletion
of ergosterol and accumulation of methylated sterols leads to alterations of membrane structure and function.

Resistant candida species -------- C. krusie and C. tropicalis.

Pharmacokinetics:
 rapid and complete oral absorption
 first pass metabolism is negligible
 it has very low protein binding --------- therefore there is a high level of unbound drug in the serum which is widely
distributed in the tissue including CNS. Levels of the drug in most tissues and fluids usually exceed 50% of the simultaneous
blood concentration.
 it is not extensively metabolized with about 80% drug being eliminated unchanged
 the serum half life is 30 hours but this is prolonged in renal failure.

Mode of administration -------- oral administration is preferred for high rate of absorption . if the patient is unable to take the drug by
mouth -------- IV is used at a maximum rate of 200 mg/hr.

Dose:
1. dermatophytic infection and cutaneous candidiasis -------- 150 mg weekly for 4-6 weeks
2. Vaginal candidiasis -------- 150 mg SD
3. oropharyngeal candidasis ----- 200 mg on day 1 followed by 100 mg daily for 2 weeks. For children --- 3mg/kg
4. Esophageal candidiasis ---- 200 mg on day 1 followed by 100 mg daily for at least 3 weeks. Treatment should be continued
for at least 2 weeks following resolution of symptoms. For children --- 3 mg/kg
5. cryptococcosis or deep forms of candidosis --- the dose is 6 mg/kg/day. At least 6-8 weeks treatment is needed in HIV
negative persons. Because of rapid clearance in children, the drug should be administered at 12 hour intervals for life
threatening infections.
6. long term maintenance treatment with fluconazole to prevent relapse in AIDS patients with cryptococcosis should be
administered at a dosage of 200 mg/day
7. To reduce the risk of invasive candidosis in neutropenic HSCT patients, prophylactic treatment with fluconazole should be
given at a dosage of 400 mg/day.
8. for onychomycosis ------- 150-300 mg weekly or 200-400 mg on alternate days.

S/E:
1. GI side effects --------- most common
2. transient elevation of liver enzymes are quite common in AIDS patients. The drug should be discontinued if tests suggest
persistent hepatic dysfunction. There have been reports of serious hepatic reactions with fluconazole ---- hepatitis,
 cholestatitis and fulminating hepatic failure: occasionally fatal hepatic reactions has occurred in patients of AIDS and
malignancies.
3. fatal exfoliative skin rashes have been reported in patients of AIDS or cancer. It is advisable to discontinue fluconazole in
superficial fungal infection if any rash occurs. In cases of deep fungal infection who develops rashes --------- should be
monitered and the drug discontinued if the lesions progress despite fluconazole (remember, rashes are a feature in deep
fungal infections).

Drug interactions:
1. Absorption of fluconazole is not reduced by drugs that alter the gastric pH.
2. drugs whose levels are raised if co administered with fluconazole -----
 Cisapride
 Terfinadine
 Glipizide
 Tolbutamide

3. fluconazole levels are reduced by ----------

 Rifampicin
 Phenytoin

ITRACONAZOLE:
Nature of drug: Triazole. Highly lipophilic and keratophilic. It has higher specificity for fungal cyt P450 unlike ketoconazole
MOA: like Fluconazole. Another postulated mechanism is inhibition of cyclic oxidase and peroxidase enzyme ---- there is resulting
increased peroxide generation --------- this contributes to degradation at the subcellular levels.

Pharmacokinetics:
1. its absorption is not complete (about 55%) but is improved if the drug is given with food. Serum concentrations are
markedly reduced when the gastric acid production is impaired.
2. As with ketoconazole there is a disproportionate increase in blood levels with increasing dosage.
3. It is better distributed than fluconazole but does not reach CNS
4. The half life is 15-24 hours.
5. The main active metabolite is hydroxyitraconazole. Its plasma levels are more than the parent drug
6. There are 3 main routes of delivery of itraconazole to the statum corneum ------- through the sweat, sebum and
incorporation into basal cells. Sites rich in sebaceous glands show 5-10 times higher concentration than those of plasma.
Measurable drug levels in the stratum corneum are detectable even 3-4 weeks after discontinuation of the drug.
7. Nail kinetics shows that it penetrates the nail readily via the nail matrix and bed. It persists in toenails for 6 months after a 3
month course
8. It is extensively metabolized by human cyt P450 enzyme. The metabolites are excreted in the bile and urine.

Dose:
1. vaginal candidiasis --- 200 mg --- 2 doses at 6-8 hour interval
2. pit versicolor ----- 200 mg daily for 7 days or 1000 mg stat.
3. oropharyngeal candidiasis -----
• 100 mg daily for 2 weeks in immunocompetant.
• 200-400 mg daily for 2 weeks in immunocompromized.
4. dermatophytosis ---- 100 mg daily
• T. corporis and T. cruris = 2 weeks
• T.pedis = 4 weeks
5. tinea ungium ---- pulse therapy : 2 pulses for fingernails and 3 pulses for toenails. Continous treatment with 200 mg for 3
months can also be given.
6. For deep fungal infections ---- aspergillosis, blastomycosis and histoplasmosis --- 200-400 mg daily. IV dose is 200 mg BD
doe 4 doses then 200 mg OD for 2 weeks. Each has to be infused over 1 hour.
7. It is used at a dose of 200 mg BD for long term maintenance of AIDS patient with histoplasmosis to prevent relapse.

Drug interactions:
1. like fluconazole
2. it causes rhabdomyolysis if given with hipolipidemic agents.
3. H2 blockers reduce the absorption of these drugs.

ADR : GI side effects, rashes, headache, dizziness, liver failure.

TERFINAFINE:
Nature of drug: Allylamine. Greatly lipophilic and keratophilic. It is mostly effective against dermatophytes but is less effective
against candida.
MOA: It inhibits squalene epoxidase leading to accumulation of intracellular squalene and deficiency of ergosterol thus resulting in
fungal cell death.
Pharmacokinetics ---
 Well absorbed orally. Food does not interfere
 It reaches stratum corneum by diffusion and via sebum . drugs persist even after 2 years of discontinuation
 It is metabolized in the liver by cyt P450 --- different isoenzyme.
 The metabolites are excreted in urine.
Dose:
 Tinea corporis/cruris --- 250 mg OD for 2-4 weeks
 Tinea pedis --- 250 mg for 4-6 weeks
 Onychomycosis --- 250 mg OD for 6 weeks to 3 months
 Cutaneous candidiasis --- 250 mg OD for 2-4 weeks

Drug is not recommended with ---------

  MAO inhibitors
 Beta blockers
 SSRI
 Simvastatin
 Lovastatin
ADR:
1. GI --- commonest ---- taste disturbance, diarrhea, abdominal pain
2. allergic skin rashes
3. rare cases of liver failure. It is not recommended in patients with chronic or active liver disease.
4. it is also contraindicated in pregnancy and lactation.

Drug interactions --------

1. Cimetidine decreases its elimination
2. rifampicin increases its elimination