Antifungal Chemotherapy

• Fungal infections are termed mycoses and can be divided into:

(1) Superficial infections: affecting skin, nails, scalp or mucous membranes

(2) Systemic infections: affecting deeper tissues and organs.

• Superficial fungal infections can be classified into the dermatomycoses and candidiasis.

• Dermatomycoses are infections of the skin, hair and nails, caused by dermatophytes. The commonest are due to Tinea organisms which cause various forms of “ringworm”.

• In superficial candidiasis, the yeast-like organism infects the mucous membranes of the mouth (thrush), the vagina (vaginal thrush).

• systemic diseases (infections) include: systemic candidiasis, cryptoccocal meningitis or endocarditis, pulmonary aspergillosis.

Antifungal Chemotherapy

Antifungal AntibioticsAmphotericine B & Nystatin

• Mechanism of action:

Binds to ergosterol in fungal cell membranes, causing its damage and increases their permeability

Yeast cell cytoplasm

Cell membrane

Resistance occurs when ergosterol binding is impaired

Amphotericine B• Amphotericin B remains the antifungal agent with the

broadest spectrum of action.

• Candida albicans and Cryptococcus neoformans

• Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis

• Aspergillus fumigatus, mucormycosis.

Amphotericine B• amphotericin B remains a useful agent for nearly all life-

threatening mycotic infections.

• Amphotericin B is often used as the initial induction regimen to rapidly reduce fungal burden.

• Immunosuppressed patients with :1. Severe fungal pneumonia, 2. severe cryptococcal meningitis, 3. disseminated histoplasmosis.

Therapeutic use of mphotericinBMycotic corneal ulcers and keratitis can be cured with topical

drops as well as by direct subconjunctival injection.

Fungal arthritis has been treated with adjunctive local injection directly into the joint.

Candiduria responds to bladder irrigation with amphotericin B, and this route has been shown to produce no significant systemic toxicity.

Adverse Effects• Fever, chills, muscle spasms, vomiting, headache, and hypotension.Premedication with antipyretics, antihistamines or corticosteroids can

be helpful.

• Many clinicians administer a test dose of 1 mg intravenously to gauge the severity of the reaction.

• Main toxicity of Amphotericin is renal. (Azotemia) 80% of patients get reduction in kidney function which generally

recovers after treatment.

Nystatin• Topical agent

• Creams, ointments, suppositories and others

• oropharyngeal thrush,

• vaginal candidiasis,

• and intertriginous candidal infections.

Antimetabolite Drugs• Flucytosine is 5-flourocytosine. It is converted to the

antimetabolite 5-FU selectively within the fungus by the microbial cytosine deaminase.

• Its subsequently converted to FdUMP which antagonises thymidylate synthase.

• DNA synthesis is impaired as the ultimate result of this latter reaction.

• The selective action of flucytosine is due to the lack or low levels of cytosine deaminase in mammalian cells, which prevents metabolism to fluorouracil.

Antimetabolite Drugs• Flucytosine is absorbed orallyand used predominantly in

combination with amphotericin B or azols. (resistance if used alone ).

• Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis.

• It has the usual side effects associated with antimetabolites, ie bone marrow suppression.

Azole Antifungal Agents

• The azole antifungal agents can be divided into two broad classes : the Imidazoles and the Triazoles.

• They are used topically and systemically. (The systemic triazoles are metabolized more slowly and have less effect on human sterol synthesis than do the imidazoles).

• The Imidazoles and Triazoles inhibit fungal sterol 14-a-demethylase, a microsomal cytochrome P450-dependent enzyme system.

• In this way, they impair the biosynthesis of the ergosterol required for the fungal cytoplasmic membrane which leads to cessation of growth.

Azole Antifungal Agents

The Azole FamilyAzole Family

Imidazoles Triazoles

Ketoconazole

Miconazole

Clotrimazole

Fluconazole

Itraconazole

Voriconazole

Azole resistance has emerged gradually during prolonged azole therapy, mutations in ERG11, the gene coding for the 14--sterol demethylase. Cross resistance is conferred to all azoles.

Azoles 1. minor gastrointestinal upset.

2. abnormalities in liver enzymes and, very rarely, clinical hepatitis.

3. drug interactions because they affect the mammalian cytochrome P450 system

Systemic Azoles• Ketoconazole, Itraconozole, Voriconazole and Fluconazole

are used systemically.

• Ketoconazole was the first azole that could be given orally to treat systemic fungal infections.

• It is well absorbed from the GI tract, distributes widely but doesn’t enter the CNS.

• Ketoconazole sometimes is used to inhibit excessive production of glucocorticoids in patients with Cushing's syndrome.

ketoconazole• Main hazard with ketoconazole is liver toxicity, which is

rare but can be fatal.

• Other problems include GI disturbances and inhibition of adrenocortical steroid and testosterone synthesis.

Itraconazole• Itraconazole (administered orally) has fewer side effects,

more potent, and has a wider spectrum of activity than ketoconazole.

• Thus, Itraconazole has largely replaced Ketoconazole in the treatment of most mycoses.

• Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi Histoplasma, Blastomyces.

• Itraconazole has activity against Aspergillus sp, but it has been replaced by voriconazole as the azole of choice for aspergillosis.

• Itraconazole is used extensively in the treatment of dermatophytoses and onychomycosis.

OTHER DRUG CONCENTRATION INCREASED ITRACONAZOLE CONCENTRATION DECREASEDAlfentanil Drugs that decrease gastric acidityAlprazolam H2-receptor blockersAmprenavir Proton pump blockersAtorvastatin Simultaneous antacids (includes didanosine buffer)Buspirone CarbamazepineBusulfan IsoniazidCerivastatin NevirapineCisapride PhenobarbitalCyclophosphamide PhenytoinCyclosporine Rifampin, rifabutinDelavirdine St. John's wortDiazepam ITRACONAZOLE CONCENTRATION INCREASED Digoxin AmprenavirDocetaxel Grapefruit juiceFelodipine IndinavirHaloperidol LopinavirIndinavir RitonavirLoratidineLovastatinMethylprednisoloneMidazolamNisoldipinePhenytoinPimozideQuinidineRitonavirSaquinavirSildenafilSimvastatinSirolimusSulfonylureas (glyburide, others)TacrolimusTerfenadine TriazolamTrimetrexateVerapamilVinca alkaloids (vincristine, vinblastine)Warfarin

Fluconazole clinical uses

• oropharyngeal candidiasis. Esophageal candidiasis

• Fluconazole has been recommended as continuation therapy in non-AIDS patients with cryptococcal meningitis who have responded to an initial course of amphetracine B and for patients with pulmonary cryptococcosis.

• Fluconazole can be given orally or intravenously. It reaches high concentrations in the CNS and ocular fluids and is the agent of choice for most types of fungal meningitis. (Much less morbidity than with intrathecal amphotericin B).

Voriconazole• Voriconazole is the newest triazole. (modified fluconazole)

• Voriconazole a broad spectrum antifungal agent

• Generally used to treat serious, invasive fungal infections.examples: Invasive aspergillosis, Candidemia

It is available in intravenous and oral formulations.

• Unique side effects associated with voriconazole is transient visual disturbances.

Echinocandins• The echinocandins (caspofungin, micafungin, and

anidulafungin) are a new class of antifungal agents.

• Act as concentration-dependent, noncompetitive inhibitors of (1,3)-D-glucan synthase, an essential component of the cell wall of susceptible filamentous fungi that is absent in mammalian cells.

• Echinocandins are available only as parenteral formulations

• adverse effects of echinocandins include histamine release resulting in rash, facial swelling, and itchiness.

Caspofungin clinical uses• currently licensed for disseminated and mucocutaneous

candida infections.

• as well as for empiric antifungal therapy during febrile neutropenia.

• licensed for use in invasive aspergillosis only as salvage therapy in patients who have failed to respond to amphotericin B.

Topical Azoles• Clotrimazole, Econazole, and Miconazole are

used topically.

• Effective for tinea corporis, tinea pedis, tinea cruris, tinea versicolor, and cutaneous candidiasis. They should be applied twice a day for 3 to 6 weeks.

• Miconazole is a potent inhibitor of Warfarin metabolism and has resulted in bleeding in Warfarin-treated patient even when Miconazole applied topically

Topical Azoles• Oral clotrimazole troches are available for treatment of oral

thrush and are a pleasant-tasting alternative to nystatin.

• Three vaginal formulations—clotrimazole tablets, miconazole suppositories, and terconazole cream—come in both low- and high-dose preparations.

• Adverse local reactions to the imidazoles may include stinging, pruritus, erythema, and local irritation

Griseofulvin• It inhibits fungal mitosis by inhibiting mitotic spindle formation

• Its only use is in the systemic treatment of dermatophytosis.

• it is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection.

• Adverse Effects -- Headache is the most common side effect.

• Adverse effects include an allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital.

• Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine.

Griseofulvin1. infections of the hair (tinea capitis) 2. "ringworm" of the skin; 3. tinea cruris and tinea corporis 4. tinea of the hands5. Griseofulvin also is highly effective in "athlete's foot" or

epidermophytosis involving the skin and nails,

Treatment must be continued until infected tissue is replaced by normal hair, skin, or nails, which requires 1 month for scalp and hair ringworm, 6 to 9 months for fingernails, and at least a year for toenails.

Terbinafine• A synthetic allylamine that is available in an oral formulation.

• It is used in the treatment of dermatophytoses, especially onychomycosis.

• Terbinafine is a keratophilic medication, but unlike griseofulvin, it is fungicidal.

• Like the azole drugs, it interferes with ergosterol biosynthesis, but inhibits the fungal enzyme squalene epoxidase.

• this leads to the accumulation of the sterol squalene, which is toxic to the organism.

Terbinafine• topical uses1% cream or spray is applied twice daily and is effective in tinea

corporis, tinea cruris, and tinea pedis.