Antifungal Medications Quiz

Antifungal Drugs

• Antifungal drugs are used to treat infections caused by fungi.
• Increased use of broad-spectrum antimicrobial therapy in critically ill patients, along with advances in surgery, cancer treatment, and solid organ/bone marrow transplantation, have led to an increase in fungal infections.
• Fungal infections can manifest as skin rashes, skin lesions, nail bed infections, and oral thrush.

Classification of Antifungals

• Systemic drugs: Used for systemic infections (oral or parenteral).
• Oral systemic drugs: Used for mucocutaneous infections (affecting mucosal surfaces, skin, and nails).
• Topical drugs: Used for mucocutaneous infections.

Antifungal Drugs Classification Chart

• Antibiotics: Flucytosine
• Antimetabolites: Flucytosine, Heterocyclic benzofuran (e.g., Griseofulvin)
• Azoles: Imidazoles (e.g., Clotrimazole, Miconazole, Ketoconazole, Oxiconazole) and Triazoles (e.g., Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole, Oteseconazole)
• Allylamine: Terbinafine
• Polyenes: Amphotericin B, Nystatin, Hamycin
• Echinocandins: Caspofungin, Micafungin, Anidulafungin
• Topical Agents: Tolnaftate, Undecylenic acid, Benzoic acid, Ciclopirox olamine, Butenafine, Quiniodochlor, Sod. thiosulfate

Mechanism of Action of Amphotericin B

• Amphotericin B binds to ergosterol in fungal cell membranes.
• It forms pores in the membrane, leading to leakage of electrolytes and small molecules.
• This disruption leads to cell death.

Amphotericin B: Properties and Spectrum

• Amphotericin B is the only effective antifungal drug for systemic use, but it's highly toxic.
• Newer agents offer more targeted therapy, with less toxicity.
• The spectrum of activity is wide, encompassing Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, and strains of Aspergillus. It is also used for leishmaniasis (protozoan infection).
• Resistance is infrequent but may be associated with a decreased ergosterol content in the fungal membrane. Some organisms, including those causing chromoblastomycosis, Aspergillus terreus, Candida lusitaniae, Scedosporium spp., and some Fusarium spp. are usually resistant.

Amphotericin B: Pharmacokinetics

• Amphotericin B is administered by slow intravenous infusion.
• It's insoluble in water and requires co-formulation with sodium deoxycholate or artificial lipids (liposomes).
• Liposomal preparations have a reduced toxicity profile, particularly concerning renal toxicity and infusion toxicity, but at a higher cost.
• The drug and its metabolites are present in low concentrations in the urine for an extended period. Some are also eliminated via the bile.

Amphotericin B: Dosage Adjustment

• Dosage is not adjusted for hepatic dysfunction.
• If renal dysfunction occurs, the daily dose is lessened by 50%.

Amphotericin B: Adverse Effects

• Amphotericin B has a narrow therapeutic index.
• The traditional formulation dose should not exceed 1.5 mg/kg/day. Lipid formulations allow for a higher dose (up to 10 mg/kg/day)
• Immediate toxicities (fever, chills, muscle spasms, vomiting, headache, phlebitis) often occur 1-3 hours post-administration. Preventative premedication with corticosteroids, heparin, and antipyretics can help.
• Cumulative toxicity can lead to renal impairment, exacerbation by other drugs, and a need for adequate hydration.
• Hypotension, anemia, seizures, and arachnoiditis are also possible side effects.

Flucytosine: Characteristics and Mechanism of Action

• Flucytosine is a pyrimidine analog related to 5-fluorouracil.
• Discovered in 1957 as an antineoplastic agent.
• It works by being converted into a toxic metabolite that interferes with fungal DNA and RNA synthesis.
• It has synergy with amphotericin B.
• The spectrum of activity is limited to C. neoformans, some Candida species, and dematiaceous molds.
• The drug is not used alone but as part of a combination therapy.

Flucytosine: Pharmacokinetics and Adverse Effects

• Well absorbed orally (over 90%) with peak concentrations within 1-2 hours.
• Poorly protein-bound.
• Penetrates well into body fluids, including the cerebrospinal fluid (CSF).
• Half-life is about 3-4 hours
• Toxicity is often a result of metabolism to a toxic compound, fluorouracil
• Common adverse effects include bone marrow toxicity (anemia, leukopenia, thrombocytopenia), liver enzyme abnormalities, and toxic enterocolitis.
• Toxic levels can increase rapidly with renal dysfunction, often needing to be managed in AIDS patients with renal issues.

Azoles Characteristics

• Azoles are divided into Imidazoles and Triazoles.
• They are notable for their broad spectrum of activity, while also exhibiting varying degrees of selectivity.
• Usually, Imidazoles are used topically for cutaneous infections, whilst Triazoles are used systemically for cutaneous and systemic infections.
• The mechanism of action involves the reduction of ergosterol synthesis through the inhibition of cytochrome P450 enzymes.
• A higher affinity for fungal cytochrome P450 enzymes compared to human enzymes explains their selective toxicity.

Azoles: Spectrum, Effects, and Practical Uses

• Azoles are generally fungistatic against Candida species.
• They're effective against various infections, including dermatophytes, Aspergillus infections, blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis.
• Side effects are usually minor gastrointestinal upset; liver enzyme abnormalities; and ketoconazole-associated, drug-induced infertility or gynecomastia are possible.
• Azole use during pregnancy should be avoided.
• The drugs may interact with other medications, mainly because they affect human cytochrome P450 enzymes.

Azoles: Pharmacokinetics

• Water solubility, absorption, CSF-serum concentration ratios, half-lives, and routes of elimination vary between the different azole drugs.
• The elimination often takes place via hepatic metabolism, but fluconazole is primarily excreted unchanged from the kidneys.

Echinocandins Summary

• Echinocandins are the first systemic, selective antifungal that destroys fungal cell walls.
• They work by inhibiting the synthesis of β(1-3)-glucan.
• Semisynthetic derivatives (e.g., Caspofungin, Micafungin, Anidulafungin) are available for intravenous (IV) administration, with dosages generally adjusted only for moderate hepatic dysfunction rather than renal issues.
• Adverse effects are typically mild, but can include fever, rash, nausea, and phlebitis.
• They're primarily used to treat candidiasis and invasive aspergillosis.

Griseofulvin

• A very insoluble, fungistatic drug derived from a species of Penicillium.
• The drug inhibits keratin production.
• Primarily used for systemic treatment of dermatophytosis and administered at a dosage of 1 g daily.
• Absorption is best when ingested with fatty foods.

Terbinafine

• A topical allylamine
• Used in the treatment of dermatophytoses, especially onychomycosis.
• It's administered orally at 250 mg/day for 12 weeks
• Oral administration has approximately a 90% cure rate for onychomycosis
• Effective compared to Griseofulvin and Itraconazole.
• Adverse effects are mainly gastrointestinal disturbance and headache,
• It doesn't appear to inhibit the P450 system significantly.

Topical Antifungal Therapy

• Nystatin is a polyene macrolide, too toxic for IV administration so it is topical.
• It is not absorbed significantly and has minimal toxicity.
• Commonly used for suppressing local Candidal infections, such as oral thrush, vaginal candidiasis and intertriginous candidal infections (areas where skin surfaces rub).
• Available as creams, ointments, suppositories, and other forms for application to skin and mucous membranes, is used for treatment of infections such as seborrheic dermatitis, tinea capitis, and pityriasis versicolor
• Clotrimazole and miconazole both are OTC and used frequently for vulvovaginal candidiasis, oral thrush as well as vaginal candidiasis.

Antifungal Drugs in Pregnancy

• The risk categories of different antifungal drugs during pregnancy vary.
• Some, such as amphotericin B and nystatin, are in Category B or A, indicating relative safety.