USMLE1 Antifungal Drugs

Antifungal Agents

General information:

Mycosis (plural: mycoses): an inflammatory condition caused by a fungus

Dermatophytes: are a common label for a group of three types of fungus that commonly causes skin/nail/hair diseases. These are: Microsporum,  Epidermophyton and Trichophyton.

Classification: mycoses are classified according to the tissue levels initially colonized:

·         Superficial fungal infections

·         Deep seated or disseminated fungal infections

Superficial fungal infections involve:

·         Cutaneous surfaces : such as the skin, nails, and hair.

·         Mucous membrane surfaces : such as the oropharynx and vagina.

·         Deepseated or disseminated fungal infections caused by

·         Dimorphic fungi (fungi which can exist as mold/hyphal or as yeast.

Example include: Coccidioides, Paracoccidioides , Candida)

Yeasts Cryptococcus neoforman various Candida spp.

Clinical fungal infections are generally divided into four types:

1. superficial, including tinea versicolor, piedra, and tinea nigra

2.cutaneous, including onychomycosis, tinea capitis, tinea corporis, tinea barbae, tinea pedis, and candidiasis of skin, mucosa, and nails

3. subcutaneous, including mycetoma, sporotrichosis and

4. systemic, including blastomycosis and cryptococcosis.

·         Superficial fungal infections are defined as infections in which a pathogen is restricted to the stratum corneum, with little or no tissue reaction.

·         Superficial and cutaneous infections are both sometimes regarded as superficial.

Types of Dermatophyte Infections:

·         Tinea Infections , AKA-Ringworm

·         Athlete's foot or tinea pedis:  affects the webs between the toes

·         Jock itch or tinea cruris : groin to the perianal skin and gluteal cleft

·         Tinea corpora : Ringworm of the body

·         Tinea capitis :  Scalp ringworm

·         Onychomycosis ( tinea unguium) :  Ringworm of the nail

·         Tinea barbae :  is a superficial dermatophyte infection that is limited to the bearded areas of the face and neck and occurs almost exclusively in older adolescent and adult males

Tinea versicolor AKA Pityriasis versicolor and Tinea flava

·          is a condition characterized by a rash on the trunk and proximal extremities.

·         Recent research has shown that the majority of pityriasis versicolor is caused by Malassezia globosa, although M. furfur is responsible for a small number of cases.

·          These yeasts are normally found on the human skin and only become troublesome under certain circumstances, such as a warm and humid environment.

Symptoms:  include:

·         Generally oval or irregularly-shaped spots (0.6 to 2.5 cm), often merging together to form a larger patch

·         Occasional fine scaling of the skin producing a very superficial ash-like scale

·         Sometimes itching in the affected areas

·         These spots commonly affect the back, underarm, upper arm, chest, lower legs, and neck. Occasionally in the face.

·         In people with dark skin, hypopigmentation  are common, while in those with lighter skin color  hyperpigmentation. These discolorations have led to the term "sun fungus“

Antifungal agents:

The antifungal drugs presently available fall into several categories:

·         systemic drugs (oral or parenteral) for systemic infections, topical drugs for mucocutaneous infections.

Systemic agents:

Polyenes: Amphotericin B

Flucytosine

The newer azoles, including

         Ketoconazole

         Fluconazole

         Itraconazole

         Voriconazole

         Capsofungin-à inhibits synthesis of beta-D- glucon in fungal CW.

Topical :

POLYENES : Nystatin

Miconazole

Clotrimazole

Terbinafine

ketokonazole

Polyenes:

·         Amphotericin B (Amp B)

·         Nystatin: (too toxic for Systemic use) is used topically for Localized Infections (Eg;Candidiasis)

Mechanisms:

·         Amphoteric compounds with both polar and non polar structural components interact with ergosterol in fungal membranes to form Artificial “pores”, which disrupt membrane permeability.

·         Resistant Fungal strains appear to have low ergosterol content in their cell membranes.

Clinical Uses:

·         Amphotericin B has a wide Fungicidal spectrum and remains the DOC for severe infections caused by……

·         Aspergillus

·         Candida

·         Cryptococcus

·         Histoplasma

·         Mucor and Sporothrix.

Amp B is Synergistic with Flucytocine in Candidiasis and Cryptococcoses.

Infusion Related:

·         Fever, Chills (premedication with steroid or antipyretic helps prevent this S/E)

·         Muscle Rigor

·         Hypotension (Histamine release) occur during IV infusion (a test dose is advisable)

This S/E can be alleviated partly by pretreatment with NSAIDs, Antihistamines, Meperidine and Adrenal steroids.

Dose Dependent:

·         Nephrotoxicity includes decreased  GFR, tubular acidosis, decreased K+ and Mg2+.

Nephrotoxicity is potentiated if given with aminoglycosides, cyclosporine, pentamidine

·         Anaemia through decreased Erythropoietin

·         Neurologic effect : intrathecal administration

·         Thrombophlebitis       

Flucytosine(5-FC):

·         Activated by Fungal cytosine deaminase toà5-Fluorouracil(5-FU), which after triphosphorylation is incorporated into Fungal RNA to disrupt NA and protein synthesis.

·         5-FU also forms 5-Fluorodeoxyuridine monophosphate (5-Fd-UMP),which inhibits Thymidylate synthaseàwhich decreases thymineàinhibits DNA synthesisà death of fungal cells

Resistance emerges rapidly if Flucytosine is used alone.

Used in Combination with Amphotericin B in Severe Candidal and Cryptococcal infections

Enters CSF

5-Fluorouracil (5-FU)is used as an Anti neoplastic(Anti cancer) drug.

Adverse Effects: Flucytosine and 5-FU

·         Bone marrow suppression: pancytopenia

·         Hepatic dysfunction

·         GI distress

·         Alopecia.

Azoles-

·         Ketoconazole

·         Fluconazole

·         Itraconazole

·         Voriconazole

·         Clotrimazole

Mechanism of action:

·         Azoles are fungicidal and interfere with the synthesis of ergosterol by inhibiting the P450 dependent 14 alpha methylation of its precursor molecule, Lanosterol.

Resistance occurs via decreased intracellular accumulation of Azoles.

Clinical Uses:

Ketoconazole:

·         Co-DOC for Paracoccidioides and back up for Blastomyces and Histoplasma.

·         Oral use in Mucocutaneous candidiasis or dermatophytoses.

Itraconazole:

·         DOC in Blastomycoses and Sporotrichoses

·         back up drug for several other mycoses and Candidiasis

Fluconazole:

• DOC for Esophageal and Invasive Candidiasis and Coccidioidomycosis.
• Prophylaxis and suppression in Cryptococcal Meningitis.

Voriconazole: Newest Triazole (azole)

·         Well absorbed orally

·         Low propensity for inhibition of CyP450

·         Excellent for candida specis, more effective in Rx of invasive aspergillosis

Clotrimazole and Miconazole:

·         Used topically for Candida and Dermatophytic infections.

Biodisposition of  Azoles:

·         Effective orally

·         Absorption of Ketoconazole is decreased by Antacids.

·         Absorption of Itraconazole is increased by Food.

·         Itraconazole requires an acidic gastric environment for absorption; any drug reducing gastric acid production (H2 blockers, proton pump inhibitors) or neutralizing gastric acid (antacids) will significantly reduce itraconazole absorption.

·         Only Fluconazole penetrates into the CSF and can be used in Meningeal Infection.

·         Ketoconazole and Itraconazole  are eliminated  by Liver

·         Fluconazole eliminated by kidney

Adverse Effects:

·         Decreased synthesis of steroids, including cortisol and androgens--àdecreased libido, gynecomastia, menstrual irregularities.

·         Rash

·         Fluid retention--àincreased BP

·         Abnormal LFTs and hepatotoxicity

·         Inhibition of Hepatic P450s---àdecrease metabolism of cyclosporine, vincristine , phenytoin,  warfarin etc.

·         Disulfiram like reactions with Ethanol

·         Transient visual disturbance (Voriconazole)

Other antifungal drugs:

Griseofulvin:

·         Active only against Dermatophytes  by disrupting Microtubule structure.

·         It accumulates in the infected, keratin-containing tissues, making them unsuitable for the growth of the fungi.

·         Active only against Dermatophytes (fungi that cause superficial skin inf) :  Trichophyton, Microsproum, Epidermophyton

·         Absorption is promoted if ingested with a high fat diet

·         Distributes mainly to infected keratinized tissue where it becomes bound.

Adverse Effects:

·         Headache, nausea

·         Peripheral neuritis

·         hepatotoxicity

·         Potentiates Ethanol toxicity

·         Avoid with History of Porphyria

·         Teratogenic

·         Induces CyP450 (Azoles inhibit cyP450)

Terbinafine:

·         Active only against Dermatophytes by inhibiting Squalene epoxidase , inhibits ergosterol synthesis

·         Possibly superior to Griseofulvin in Onychomycoses (fungal infection of the nail)

Adverse Effects:

·         GI distress

·         Rash

·         Headache

·         Alters LFTs----possible Hepatotoxicity.

Rx: Topical antifungal medications:

• 2.5% selenium sulfide: applied to dry skin and washed off after 10 minutes, repeated daily for 2 weeks.
• Ketoconazole
• Clotrimazole, miconazole or terbinafine are less widely recommended