Antifungal Agents

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 Fungal infections are termed mycoses Can be divided into: Superficial mycoses
Affect the skin, hair and nails

Subcutaneous mycoses (topical)

Affect the muscle and connective tissue below the skin

Systemic (invasive) mycoses

Involve the internal organs

Allergic mycoses
Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis or sinusitis
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Introduction
Fungal infections are usually more difficult to treat than

bacterial infections, because.

Fungal organisms grow slowly and,

Fungal infections often occur in tissues that are poorly

penetrated by antimicrobial agents.

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Systemic Antifungal Drugs

Amphotericin B
Amphotericin B is a polyene antifungal drug produced by

the actinomycete Streptomycin nodosus

Consists of a large ring structure with both hydrophilic

and lipophilic regions (Amphoteric).

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Mechanism of Action
Amphotericin B and other polyene macrolide antibiotics bind to

the fungal cell membrane sterol moiety, primarily ergosterol

Form pores or channels that increase the permeability of the membrane Leakage of a variety of small molecules.

Its Amphipathic characteristic facilitates pore formation.

It avidly with lipids (ergosterol) along the double bond-rich side Associates with water molecules along the hydroxyl-rich side

The lipophilic portions surround the outside of the pore and the hydrophilic regions line the inside.

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 Amphotericin has a lesser affinity for the mammalian cell

membrane component cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.
The predominant sterol of bacteria, like in human cells, is

cholesterol hence amphotericin B is selective in its fungicidal effect.

Poorly absorbed from GIT.

Oral amphotericn B effective only on fungi with in the GIT tract and not be used for treatment of systemic infection .

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The IM administration is painful

Is given iv in the treatment of systemic infections

The original preparation of amphotericin B for intravenous use is a deoxycholate dispersion in dextrose. This micellar suspension is associated with serious toxic side effects, in particular renal damage

the toxic side effects were partially ameliorated when a lipid

carrier was used.
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Three lipid-associated formulations have been used: 1) Liposomal : drug is encapsulated in phospholipid-containing liposomes 2) Colloidal dispersion: drug is packaged into small lipid disks containing cholesterol sulphate 3) Lipid complex: drug is complexed with phospholipids to produce ribbon-like structures
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Lipid Amphotericin B Formulations Abelcet ABLC Amphotec ABCD Ambisome L-AMB

Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (m): 1.6-11
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Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (m): 0.120.14

Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (m) : 0.08
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DMPC-Dimyristoyl phospitidylcholine HSPC-Hydrogenated soy phosphatidylcholine DMPG- Dimyristoyl phospitidylcglycerol DSPG-Distearoyl phosphitidylcholine

Antifungal Activity
Has the broadest spectrum of antifungal and is fungicidal action

including;

Sporotrichum schenkii and Cryptococcus neoforman, Histoplasma capsulatum, Blastomycosis Coccidioides immitis,

Aspergillus fumigatus.
Candida albicans respond to higher concentrations
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Therapeutic use
The use of amphotericin B has diminished due to reduced

toxicity profile and ease of administration of newer drugs, the

azoles
But amphotericin B remains the drug of choice for initiation of

treatment in nearly all life-threatening mycotic infections.

Once a clinical response has been elicited maintenance therapy is continued with an azole.

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 For the AIDS patient with moderate to severe cryptococcal

meningitis,

Amphotericin B appears to be superior to fluconazole for initial treatment;

Once infection is controlled, fluconazole in a daily oral dose is superior to and more convenient than weekly intravenous amphotericin B in the prevention of clinical relapses.

For the AIDS patient with disseminated histoplasmosis,

But once infection is controlled, daily oral itraconazole is preferred

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 Amphotericin B remains the drug of choice in the treatment of

invasive aspergillosis.

An opportunistic infection by a fungus of the genus Aspergillus;

Characterized by inflammation and lesions of the ear and

respiratory organs

The patient should be hospitalized For systemic infections

Its toxicity could be reduced by using smaller doses of the drug

in combination with other systemic antifungal agents

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Adverse Effects
Infusion-Related Adverse Effects

IV infusion may cause phlebitis, fever, chills, muscle

spasms, vomiting, headache, and hypotension.

Possibly mediated by interlukines or prostaglandins.

Test dose of 1mg infused over 30-60 minutes is given to

reduce the risk of serious events anaphylaxis

Premedication with antipyretics, antihistamines, meperidine,

or corticosteroids can be helpful.

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 Nephrotoxicity is the most common and the most serious long-

term toxicity of amphotericin B.

It reduces glomerular and renal tubular blood flow through

a vasoconstrictive effect on afferent renal arterioles,

Which can lead to destruction of renal tubular cells and disruption of the tubular basement membrane.

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 Renal tubular acidosis and renal wasting of K+ and Mg2+ also

may be seen during and for several weeks after therapy.

May necessitates replacement of the minerals.

Nephrotoxicity is increased by concurrent therapy with other

nephrotoxic agents, such as aminoglycosides or cyclosporine.

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 Keeping patients well hydrated may reduce nephrotoxicity; Saline infusions prior to amphotericin B dosing have been

advocated, and
Concomitant diuretic therapy should be avoided.
Prolonging the infusion rate may decrease toxicity infuse

over 4-6 hrs for first dose and if tolerated reduce infusion to over 2 hrs.
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Contraindications, Precautions, and Interactions

Amphotericin B is contraindicated in patients with a history of

allergy to the drug and during lactation.

It is used in caution in patients with renal dysfunction, electrolyte imbalances, and in combination with antineoplastic

drugs (because it can cause severe bone marrow suppression).

is used during pregnancy only when the situation is life

threatening.
When given with the corticosteroids, severe hypokalemia may

occur.
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 There may be an increased risk of digitalis toxicity if digoxin is

administered concurrently with amphotericin B.

Administration with nephrotoxic drugs (eg, aminoglycosides or

cyclosporine) may increase the risk of nephrotoxicity in patients

Amphotericin B decreases the effects of miconazole.

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Flucytosine
Flucytosine (5-fluorocytosine) is a fluorinated pyrimidine

related to fluorouracil. Mechanism of Action and Resistance

Flucytosine is taken up by fungal cells via the enzyme

cytosine permease and 5-FC is converted to 5-fluorouracil

inside the cell by the fungal enzyme cytosine deaminase

Fluorouracil is metabolized first to 5-fluorouracil-ribose

monophosphate (5-FUMP) by the enzyme uracil

phosphoribosyl transferase.
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 5-FUMP is then;

Either incorporated into RNA in place of uracil (may inhibit

protein synthesis) or

Metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (5-FdUMP),

A potent inhibitor of thymidylate synthetase (interfere with fungal DNA synthesis).

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 The selective action of flucytosine is due to ;

The lack or low levels of cytosine deaminase in mammalian

cells.

Mechanism of resistance can be;

Loss of the permease,

Decreased activity of the enzyme uracil phosphoribosyl transferase or cytosine deaminase

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Antifungal Activity and Clinical Uses

Spectrum of activity is restricted to Cryptococcus neoformans

and some candida species

The Clinical use at present is confined to combination therapy,

either with amphotericin B for cryptococcal. meningitis or with

itraconazole for chromoblastomycosis (A fungal infection

characterized by itchy warty nodules on the skin).
When it is used as monotherapy, resistance and clinical failure

are common.

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Adverse Effects
Fluorouracil is responsible for the ADRs of flucytosine. Bone marrow toxicity with anemia, leukopenia, and

thrombocytopenia are the most common adverse effects.

Other ADRs such as skin rash, epigastric distress, diarrhea,

and liver enzyme elevations can occur.

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The Azoles
Are broad spectrum antifungal Concentration-independent fungistatic agents Drugs include

Triazoles :

Clotrimazole, Miconazole, Ketoconazole, Econazole, Butoconazole, Oxiconazole, Sertaconazole, and Sulconazole

Imidazoles:

Fluconazole, Itraconazole, Voriconazole, and Terconazole

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Mechanism of Action
All azoles exert antifungal activity by binding to cytochrome

P450 enzyme (14-a-sterol demethylase)

W/h is responsible for the demethylation of lanosterol to

ergosterol.

Impair the biosynthesis of ergosterol for the cytoplasmic membrane. Result in damaged, leaky cell membranes.

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Resistance
The primary mechanism of resistance in C. albicans is

accumulation of mutations in ERG11, the gene coding for the 14-a-sterol demethylase.
Increased production of 14-a-sterol demethylase and Increased azole efflux are other potential cause

Cross resistance is conferred to all azoles.

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Mechanisms of antifungal resistance

Target enzyme modification

Ergosterol biosynthetic

pathway Efflux pumps Drug import

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Fluconazole
Fluconazole is very effective and commonly used in the treatment

of infections with most Candida spp.

AIDS patients with esophageal candidiasis usually respond to fluconazole.

Thrush in the end-stage AIDS patient, often refractory to

Nystatin, Clotrimazole, and ketoconazole, can usually be suppressed with oral fluconazole.

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 Fluconazole is the azole of choice in the treatment and

secondary prophylaxis of cryptococcal meningitis.

It is a good alternative to amphotericin B in the initial

treatment of mild cryptococcal meningitis and superior to

amphotericin B in the long-term prevention of relapsing meningitis.

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 Prophylactic use of fluconazole in end-stage AIDS patients can

reduce the incidence of:

Cryptococcal meningitis, Esophageal candidiasis, and

Superficial fungal infections.

It has a plasma t of 31hrs and given once daily It penetrates readily into the CSF Almost 80% of the drug is eliminated in urine unchanged

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Adverse Effects
Fluconazole is well tolerated. Nausea, vomiting, abdominal pain, diarrhea, and skin rash

have been reported in few patients.

Asymptomatic liver enzyme elevation have been reported.
Alopecia has been reported as a common adverse event in

patients receiving prolonged high-dose therapy.

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Drugs interaction
Fluconazole is an inhibitor of CYP3A4 and CYP2C9.

Significantly increases plasma concentrations of cisapride,

cyclosporine, phenytoin, sulfonylureas (glipizide, tolbutamide, others), tacrolimus, theophylline, telithromycin, and warfarin.

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Biopharmaceutical Characteristics of the Triazole Antifungals

Fluconazole
Spectrum vs. Candida and

Itraconazole
Similar Candida coverage as fluconazole, + Aspergillus

Voriconazole
Broad, includes most Candida spp.,

Aspergillus

C. albicans, C. tropicalis +/C. glabrata No Aspergillus

Tablet (>90%) Available, no solubilizer

Aspergillus, Fusarium sp. Not Zygomycoses

Tablet (>90%) Available, cyclodextrin

Oral formulation (% bioavailibility) Intravenous formulation

Capsule (6-25%) Solution (20-60%) Available, cyclodextrin

Clearance
Serum half life (hr) CSF penetration CYP 3A4 inhibition Adverse effects
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Renal (80%)
24 Excellent Weak N&V, hepatic

Hepatic 3A4
24-30 Poor Strong N&V, diarrhea (solution), hepatic, CHF

Hepatic 2C19, 3A4

6-24 Excellent Moderate-Strong N&V, visual disturbances, hepatic, rash

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Ketoconazole
Systemic use of ketoconazole has diminished;

It has been replaced by itraconazole for the treatment of all mycoses except when the lower cost of ketoconazole

outweighs the advantage of itraconazole.

But it remains useful in the treatment of cutaneous and

mucous membrane dermatophyte and yeast infections.

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 Ketoconazole has activity against some Gram-positive bacteria

and some antiprotozoal activity against Leishmania spp.

Itraconazole lacks ketoconazole's corticosteroid suppression,

while retaining most of ketoconazole's pharmacological properties and expanding the antifungal spectrum.

IN large doses, Ketoconazole inhibit several biosynthetic steps in the synthesis of adrenal and gonadal steroids. Thus reduce the plasma conc. Of cortisol and testosterone

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 Several factors affect the time taken for peak serum

concentrations (2-4hrs) :
1) disintegration/dissolution rate (favoured by acidic pH?) 2) Gastric emptying rate 3) Intestinal metabolism (CYP 3A4 in intestinal wall) 4) Rate of absorption from the intestine 5) First Pass effect (metabolism in liver) 6) Clearance rate. Food delays absorption, but does not decrease peak serum concentrations significantly.
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Ketoconazole - Drug Interactions

Potent inhibitor of cytochrome P450 3A4

Rifampin and phenytoin decrease ketoconazole levels

Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophylline levels

Many of these drug interactions are severe

Drugs that increase gastric pH will decrease blood levels of

ketoconazole

Antacids, omeprazole, H2 blockers

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Ketoconazole - Adverse effects

Adverse effects

N&V, worse with higher doses (800 mg/day)

Hepatoxicity (2-8%), increase in transaminases, hepatitis Dose related inhibition of CYP P450 responsible for

testosterone synthesis

Gynecomastia, oligosperma, decreased libido

Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

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Griseofulvin
Griseofulvin is fungistatic in vitro for various species of the

dermatophytes.
It is not effective against candida albicans. Is mild cytotoxic and damage the microtubular protien, thus

inhibits fungal mitosis.

Acts mainly on the growing fungal cells Exhibit greater affinity for the diseased than the normal skin
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 It is not effective topically is administered orally

But has poor gastrointestinal absorption .

Can be improved by microcrystalline processing of the drug

and by taking the drug with fatty meals

The drug binds to keratin precursor cells and newly

synthesized keratin in the stratum corneum of the skin, hair, and nails, stopping the progression of dermatophyte infection
.
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 Indications

Tinea capitis; clinical cure occurs within 4-6wks of therapy

Tinea pedis, Tinea cruris, Tinea barbae the treatment is

continued for 4-8wks

Onychomycosis: treatment for fingernail infection takes 4-

6months while infection of the toenail is treated for 6-12 months. Since chronic fungal infections tend to cause

hyperkeratosis, concomitant topical keratolytic therapy with

salicylic acid is beneficial
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Adverse effect
Headache, skin rashes and urticaria, dry mouth, an altered

sensation of taste, and gastrointestinal disturbances.

There have been a few reports of hepatotoxicity

Drug interaction
Griseofulvin increases warfarin metabolism, and Griseofulvin metabolism is increased by phenobarbital. Griseofulvin has been largely replaced by newer antifungal

medications such as itraconazole and terbinafine.

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Topical Antifungal
Nystatin
Nystatin is a polyene macrolide much like amphotericin B.
It has similar mechanism of action with amphotericin B. Nystatin is active against most candida species.

Is most commonly used for suppression of local candidal

infections.

Some common indications include oropharyngeal thrush, vaginal candidiasis

Nail involvement due to candida does not respond to it

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 It is too toxic for parenteral administration and is only used

topically.
Produce nephrotoxicity

It is not absorbed to a significant degree from skin, mucous

membranes, or the gastrointestinal tract.

oral administration may cause N,V,AND D

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Topical Azoles
Often used in vulvovaginal candidiasis and oral thrush.
Several other azoles are available for topical use. Clotrimazole Fungicidal concentrations remain in the vagina for as long as 3

days after application of the drug.

Clotrimazole is available as a 1% cream, lotion, and solution 1% or 2% vaginal cream or vaginal tablets of 100, 200, or 500

mg.
On the skin, applications are made twice a day
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 For the vagina, the standard regimens are one 100-mg tablet

once a day at bedtime for 7 days, one 200-mg tablet daily for 3 days, one 500-mg tablet inserted only once, or 5 g of cream once a day for 3 days (2% cream) or 7 days (1% cream).
Clotrimazole has been reported to cure dermatophyte

infections, cutaneous candidiasis, vulvovaginal candidiasis,

Recurrences are common after all regimens.
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Other topical azoles include

miconazole, ketoconazole, tolnaftate, terbinafine

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