Antifungal Drugs

• Fungi are eukaryotic organisms with cell walls containing chitin, and their cell membranes include ergosterol.
• Fungal infections are termed mycoses.

Types of Fungal Infections

• Mucocutaneous infections affect skin, hair, and nails (dermatophytes) or moist skin and mucous membranes (yeasts).
• Systemic mycoses are fungal infections affecting internal organs, often in immunocompromised patients.

Classification of Antifungal Drugs

• Antifungals are grouped based on their mechanism of action.
• Polyenes like amphotericin B bind to ergosterol, disrupting the fungal membrane.
• Azoles inhibit ergosterol synthesis in the fungal cell's endoplasmic reticulum.
• Flucytosine converts to 5-fluorouracil, inhibiting DNA synthesis within the fungal cell.

Drugs for Subcutaneous and Systemic Mycotic Infections

Amphotericin B

• Amphotericin B is a polyene antifungal derived from Streptomyces nodosus, used for life-threatening mycoses.
• It binds to ergosterol, forming pores in the fungal cell membrane, leading to leakage and cell death.
• Exhibits both fungicidal and fungistatic properties against a wide range of fungi and is also used in treating leishmaniasis.
• Resistance develops via reduced ergosterol content in the fungal membrane.
• Administered via slow IV infusion due to its insolubility in water, requiring co-formulation.
• Exhibits extensive plasma protein binding, broad distribution, and primary excretion in urine.
• Adverse effects may include fever, chills, renal impairment, hypotension, hypokalemia, and thrombophlebitis.

Antimetabolite Antifungals

• Flucytosine (5-FC) is a synthetic pyrimidine antimetabolite, often combined with other antifungals.
• Enters fungal cells via cytosine-specific permease, converting to compounds like 5-fluorouracil (5-FU) that disrupt nucleic acid and protein synthesis.
• Fungistatic and effective with itraconazole for chromoblastomycosis, or with amphotericin B for systemic mycoses and meningitis caused by C. neoformans and C. albicans.
• Resistance is linked to decreased enzyme levels in the conversion of flucytosine to active metabolites.
• Combining with another antifungal agent lowers the emergence of resistant fungal cells, emphasizing that it is not employed as a standalone antifungal drug.
• Well-absorbed orally and widely distributed with good CSF penetration.
• Both the parent drug and its metabolites are excreted through glomerular filtration, necessitating dose adjustments in individuals with impaired renal function.
• Adverse effects include reversible neutropenia, thrombocytopenia, bone marrow depression, hepatic dysfunction, nausea, vomiting, and diarrhea.

Azole Antifungals

• Azoles include imidazoles (typically topical) and triazoles (systemic).
• Triazoles: fluconazole, itraconazole, posaconazole, voriconazole, and isavuconazole.
• Mechanism of action: Fungistatic agents inhibiting 14-α-demethylase, disrupting ergosterol biosynthesis and compromising fungal membrane structure/function.
• Resistance can occur through mutations in the 14-α-demethylase gene, efflux pumps, or reduced ergosterol.
• Azoles are teratogenic and that they should be avoided in pregnancy.

Fluconazole

• Fluconazole is a triazole antifungal with activity against yeasts and certain dimorphic fungi.
• Ineffective against aspergillosis or mucormycosis but highly effective against C. neoformans and specific Candida species.
• Used in bone marrow transplant recipients for fungal infection prevention.
• The preferred treatment for C. neoformans after initial therapy with amphotericin B and flucytosine.
• Also used for candidemia, coccidioidomycosis, and mucocutaneous candidiasis.
• For vulvovaginal candidiasis, it is commonly administered as a single oral dose.
• Available in oral and IV formulations, well-absorbed, widely distributed, and primarily excreted in urine.
• Doses must be reduced in patients with renal dysfunction.
• Adverse effects include nausea, vomiting, headache, and skin rashes.

Itraconazole

• Itraconazole is a synthetic triazole with a broad antifungal spectrum.
• Preferred treatment for blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis.
• The capsule is best taken with food and an acidic beverage for enhanced absorption, while the solution is more effective on an empty stomach.
• Distributes well in tissues including bone and adipose tissues.
• Extensively metabolized by the liver.
• Both the drug and its inactive metabolites are excreted in urine and feces.
• Itraconazole is a potent inhibitor of CYP3A4 and coadministration of other agents metabolized by CYP3A4 should be avoided, if possible.
• Adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, hypertension, edema, and headache.
• Liver toxicity is a concern, particularly with other hepatotoxic drugs.
• Exhibits a negative inotropic effect, making it unsuitable for patients with ventricular dysfunction or heart failure.

Posaconazole

• Posaconazole is a synthetic triazole similar to itraconazole, available in oral suspension, tablet, and IV forms.
• Used for treating and preventing invasive Candida and Aspergillus infections.
• Effective against infections caused by Scedosporium and Mucorales.
• Has low oral bioavailability and requires administration with food.
• Not metabolized by CYP450 but is eliminated via glucuronidation.
• Drugs that increase gastric pH may decrease the absorption of oral posaconazole and should be avoided.
• Concomitant use of posaconazole with various agents is contraindicated due to posaconazole's potent inhibition of CYP450 3A4.

Voriconazole

• Voriconazole is a synthetic triazole related to fluconazole, available in IV and oral forms.
• Has replaced amphotericin B as the preferred treatment for invasive aspergillosis.
• Approved for invasive candidiasis and serious infections caused by Scedosporium and Fusarium species.
• Exhibits high oral bioavailability, effective tissue penetration, and extensive metabolism by CYP2C19, CYP2C9, and CYP3A4 isoenzymes.
• High concentrations may cause visual and auditory hallucinations, increased risk of hepatotoxicity and hypokalemia, and reversible visual impairment upon discontinuation.
• Contraindicated with many drugs that are inducers of CYP450.

Isavuconazole

• Isavuconazole is a broad-spectrum antifungal agent available in intravenous and oral forms, supplied as the prodrug isavuconazonium.
• Effective against invasive aspergillosis and invasive mucormycosis, similar to voriconazole.
• Exhibits high bioavailability orally and distributes well into tissues.
• Metabolism involves CYP3A4, CYP3A5, and uridine-diphosphate-glucuronosyltransferases.
• Coadministration with potent CYP3A4 inhibitors and inducers is contraindicated due to drug interactions.
• Inhibits the CYP3A4 isoenzyme, leading to increased concentrations of drugs that are substrates of CYP3A4.
• Common side effects include nausea, vomiting, diarrhea, and hypokalemia.

Echinocandins

• Echinocandins (caspofungin, micafungin, and anidulafungin) disrupt fungal cell wall synthesis by inhibiting β(1,3)-d-glucan synthesis.
• Administered intravenously once daily.
• Effective against Aspergillus and various Candida species, including azole-resistant strains.
• Micafungin stands out for not requiring a loading dose.
• Adverse effects include fever, rash, nausea, and phlebitis.
• Slow IV infusion is recommended to prevent histamine-like reactions.
• Caspofungin is a first-line treatment for invasive candidiasis and a second-line option for invasive aspergillosis.
• Dosing adjustments are necessary for moderate hepatic dysfunction.
• Concurrent use with cyclosporine is discouraged due to a high risk of elevated hepatic transaminases.
• Micafungin and anidulafungin are recommended as first-line treatments for invasive candidiasis.
• Micafungin also serves for prophylaxis against invasive Candida infections.
• Notably, both drugs are not substrates for CYP450 enzymes and do not pose any associated drug interactions.

Drugs for Cutaneous Mycotic Infections

• Cutaneous infections, caused by mold-like fungi, are known as dermatophytes or tinea.
• Classified by the affected site and commonly referred to as "ringworm".
• Primary fungi: Trichophyton, Microsporum, and Epidermophyton.
• Skin infections can also be caused by yeasts like Malassezia and Candida.

Squalene Epoxidase Inhibitors

• These agents inhibit squalene epoxidase, blocking ergosterol biosynthesis.
• Accumulation of toxic amounts of squalene results in increased membrane permeability and death of the fungal cell.
• Oral terbinafine is preferred for dermatophyte onychomycoses, also applicable for tinea capitis.
• Topical terbinafine treats tinea pedis, tinea corporis, tinea cruris, and tinea versicolor.
• Effective against Trichophyton and Malassezia. While it may potentially work against Candida, Epidermophyton, and Scopulariopsis.
• 40% bioavailability orally due to first-pass metabolism.
• Highly protein-bound and accumulates in the skin, nails, and adipose tissue, leading to a prolonged half-life of 200 to 400 hours.
• Metabolized by various CYP450 isoenzymes.
• Excreted through urine.
• Should be avoided in patients with significant renal or hepatic impairment.
• Inhibits CYP2D6 isoenzyme, posing a risk of adverse effects when used concurrently with CYP2D6 substrates.
• Oral formulation adverse effects include diarrhea, dyspepsia, nausea, headache, and rash. Taste and visual disturbances may also occur, along with elevated levels of serum hepatic transaminases.
• Topical formulations are generally well tolerated.
• Naftifine: Effective against Trichophyton, Microsporum, and Epidermophyton, used topically for tinea infections.
• Butenafine: Effective against Trichophyton rubrum, Epidermophyton, and Malassezia, used topically for tinea infections.

Griseofulvin

• Griseofulvin disrupts the mitotic spindle and inhibits fungal mitosis, effective for dermatophytosis of the scalp and hair.
• Largely replaced by oral terbinafine for onychomycosis treatment.
• Fungistatic, requiring prolonged treatment.
• Absorbed well with high-fat meals, concentrating in skin, hair, nails, and adipose tissue.
• Induces hepatic CYP450 activity, impacting drug metabolism.
• Contraindicated in pregnancy and porphyria patients.

Nystatin

• Nystatin is a polyene antifungal similar to amphotericin B.
• Used for treating cutaneous and oral Candida infections.
• Not administered parenterally due to minimal absorption and potential systemic toxicity.
• Given orally, intravaginally, or topically.

Imidazoles

• Imidazoles include butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, sulconazole, terconazole, and tioconazole.
• These topical agents have broad activity against Epidermophyton, Microsporum, Trichophyton, Candida, and Malassezia.
• Used for treating tinea infections, oropharyngeal, and vulvovaginal candidiasis.
• Topical use may lead to contact dermatitis, vulvar irritation, and edema.
• Clotrimazole and miconazole are available in troche and buccal tablet forms for treating thrush.
• Topical ketoconazole is effective against tinea versicolor and seborrheic dermatitis.

Efinaconazole

• Efinaconazole is a topical triazole antifungal agent designed for treating toenail onychomycosis.

Ciclopirox

• Ciclopirox, a pyridine antimycotic, disrupts the synthesis of DNA, RNA, and proteins by inhibiting the transport of essential elements.
• Exhibits activity against various fungi.
• Comes in multiple formulations, such as shampoo for seborrheic dermatitis, and cream, gel, or suspension for conditions like tinea pedis, tinea corporis, tinea cruris, cutaneous candidiasis, and tinea versicolor.
• Onychomycosis can be addressed with the nail lacquer formulation of ciclopirox.

Tavaborole

• Tavaborole is a topical solution used to treat toenail onychomycosis by inhibiting an aminoacyl-transfer ribonucleic acid synthetase.

Tolnaftate

• Tolnaftate, a topical thiocarbamate, disrupts hyphae and inhibits mycelial growth in susceptible fungi.
• Specifically targets Epidermophyton, Microsporum, and Malassezia furfur, and is not effective against Candida.