Anti Fungal Agents

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. Azoles, triazoles, terbinafine, Griseofulvin

Dermatophytosis

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 (no ideal antifungal)

Itraconazole = 200-400 mg x 12 mon. Can be combined with 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. Correct metabolic and immunologic defects Amphotericin is the only DOC. Initial intensive treatment with Amphotericin B and Flucytosine followed by maintenance with fluconazole.

Mucormycosis cryptococcosis

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,

 

detoriate liver function in patients with preexisting liver disease.

  Dose: 1. 2. 3. 4.

5.

rashes ------- morbilliform, urticaria, angioedema, erythema multiforme, FDE, SJS, TEN, exfoliative dermatitis have been reported. 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 tinea tinea tinea tinea

capitis --------- 10 mg/kg/day-8 weeks. It is increased to 20 mg/kg/day for T.tonsurans. cruris and barbae ----------- 500 mg daily for 1 month. pedis -------- 500 mg daily for 3 months mannum ------- 750 mg daily for 6 weeks to 3 months

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. 2.

3. 4. 5. 6.

7. S/E:

dermatophytic infection and cutaneous candidiasis -------- 150 mg weekly for 4-6 weeks Vaginal candidiasis -------- 150 mg SD oropharyngeal candidasis ----- 200 mg on day 1 followed by 100 mg daily for 2 weeks. For children --- 3mg/kg 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 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. long term maintenance treatment with fluconazole to prevent relapse in AIDS patients with cryptococcosis should be administered at a dosage of 200 mg/day

8.

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. for onychomycosis ------- 150-300 mg weekly or 200-400 mg on alternate days.

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,

3.

cholestatitis and fulminating hepatic failure: occasionally fatal hepatic reactions has occurred in patients of AIDS and malignancies. 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. 3. 4. 5. 6.

As with ketoconazole there is a disproportionate increase in blood levels with increasing dosage.

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. 2. 3.

4.

5. 6. 7.

It is better distributed than fluconazole but does not reach CNS The half life is 15-24 hours. The main active metabolite is hydroxyitraconazole. Its plasma levels are more than the parent drug 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.

vaginal candidiasis --- 200 mg --- 2 doses at 6-8 hour interval pit versicolor ----- 200 mg daily for 7 days or 1000 mg stat. oropharyngeal candidiasis ----• 100 mg daily for 2 weeks in immunocompetant. • 200-400 mg daily for 2 weeks in immunocompromized. dermatophytosis ---- 100 mg daily • T. corporis and T. cruris = 2 weeks • T.pedis = 4 weeks 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. 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. 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 ---------

     ADR:

MAO inhibitors Beta blockers SSRI Simvastatin Lovastatin 1. 2. 3. 4.

GI --- commonest ---- taste disturbance, diarrhea, abdominal pain allergic skin rashes rare cases of liver failure. It is not recommended in patients with chronic or active liver disease. it is also contraindicated in pregnancy and lactation.

Drug interactions -------1. Cimetidine decreases its elimination 2. rifampicin increases its elimination