How Do Systemic Antifungals Work?

Systemic antifungal drugs are used to treat systemic mycoses which are fungal infections affecting internal organs. The infection-causing fungi enter the body via the lungs, through the gut, paranasal sinuses, or the skin and can spread through the bloodstream to multiple organs including the skin, often causing multiple-organ failure and eventually resulting in the death of the patient. Systemic antifungals are either fungicidal (kill the fungus) or fungistatic (inhibit fungal growth).

Drugs for systemic antifungal treatment include:

• Polyene macrolides (e.g., amphotericin B and its lipid formulations)
• Various azole derivatives (fluconazole, isavuconazole, and itraconazole)
• Echinocandins (anidulafungin, caspofungin, and micafungin)
• Allylamines (e.g., terbinafine)
• Griseofulvin
• Flucytosine

Polyene macrolides such as amphotericin B and nystatin are important antifungal agents that have a fast fungicidal effect, broad spectrum of activity, and very low tendency of resistance development among fungal pathogens. Amphotericin B works by binding with ergosterol, a component that maintains the integrity of the fungal cell wall and forms pores in the wall. This causes leakage of cellular ions which leads to fungal death. Amphotericin B is an effective but relatively toxic drug and has long been the mainstay of antifungal therapy for invasive and serious mycoses.

The azole antifungals work primarily by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is necessary for the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi. Disruptions in the biosynthesis of ergosterol cause significant damage to the cell membrane by increasing its permeability, resulting in cell lysis and death. Despite this mechanism of action, the triazoles are generally considered fungistatic against Candida species. Voriconazole demonstrates fungicidal activity against Aspergillus species.

Echinocandins work by inhibiting a glucosyltransferase enzyme (1→3)-β-D-glucan synthase, which is essential for the generation of (1→3)-β-D-glucan, an essential component that maintains the integrity of the fungal cell wall. The inability of the organism to synthesize (1→3)-β-D-glucan leads to osmotic instability and cell death. The spectrum of activity of echinocandins is limited to pathogens that rely on these glucan polymers. Echinocandins exhibit fungistatic activity against Aspergillus species, whereas they exhibit fungicidal activity against Candida species.

Allylamines work by inhibiting ergosterol synthesis by inhibiting the enzyme squalene epoxidase which catalyzes the conversion of squalene to lanosterol and further converts lanosterol to ergosterol, a major component in the fungal cell wall. The inhibition of this enzyme causes squalene, a substance toxic to fungal cells, to accumulate intracellularly and leads to rapid cell death. The absence of ergosterol causes damage to the cell membrane, increases permeability, and leads to cell death.

Griseofulvin is considered to be fungistatic, even though the exact mechanism of action against dermatophytes is not clear. It is thought to inhibit fungal cell mitosis and nuclear acid synthesis. It also binds to and interferes with the function of spindle and cytoplasmic microtubules by binding to alpha and beta tubulin.

The exact mechanism of action of flucytosine is unknown. It has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits the synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.

Systemic antifungals are available in various forms such as intravenous agents, oral tablets, oral suspensions, cream, gel, foam, and shampoo. They are used to treat several fungal infections, including:

• Aspergillosis (mold [type of a fungus] infection usually affects the lungs)
• Histoplasmosis (a type of lung infection caused by inhaling Histoplasma capsulatum fungal spores)
• Gastrointestinal candidiasis (fungal infection caused by Candida fungi)
• Systemic candidiasis (Candida infection spread throughout the body)
• Blastomycosis (fungal infection caused by inhaling fungus Blastomyces dermatitidis)
• Cryptococcal meningitis (a type of meningitis caused by a fungus Cryptococcus neoformans)
• Coccidioidomycosis (a pulmonary disease caused by the spores of fungus Coccidioides immitis)
• Fungal endocarditis (inflammation of the inner lining of heart chambers and valves)
• Mucormycosis, invasive (life-threatening fungal infection caused by Mucorales fungi)
• Paracoccidioidomycosis (fungal infection of the skin, mucous membrane, lymph nodes, and organs caused by fungus Paracoccidioides brasiliensis)
• Prophylaxis for invasive fungal infections
• Ringworm (a highly contagious fungal infection of the skin or scalp)
• Pityriasis versicolor (a common fungal infection that causes small, discolored patches of skin)
• Atopic dermatitis
• Folliculitis
• Seborrheic dermatitis
• Psoriasis

Side effects of systemic antifungals may include:

• Alopecia (loss of hair)
• Chapped lips
• Skin toxicity
  • Photosensitivity (inflammation of the skin when exposed to ultraviolet rays)
  • Rash
• Photophobia (sensitivity to bright light)
• Periostitis (inflammation of the layer present around the bone)
• Gastrointestinal symptoms
• Nail changes or loss
• Refractory fungal infection (fungal infections that are resistant to treatment)
• Nausea and vomiting
• Diarrhea
• Headache
• Hypokalemia (low potassium levels in the blood)
• Peripheral edema
• Severe itching
• Depression
• Dark-colored urine

Serious side effects of systemic antifungals may include:

• Photopsia (appearance of flashes of light)
• Neurologic toxicity 
  • Confusion
  • Agitation
  • Auditory hallucinations
  • Visual hallucinations
  • Myoclonic movements (sudden involuntary movements such as jerks)
• Cardiac toxicity
  • QT prolongation (the heart takes longer to recharge between beats which may lead to tachycardia)
  • Cardiac arrest
  • Torsades de pointes (life-threatening abnormal heartbeats in the lower chambers of the heart)
  • Sudden death
• Nephrotoxicity
• Hepatotoxicity
  • Elevation of liver enzymes
  • Hepatitis (inflammation of the liver)
  • Cholestasis (reduced bile flow from the liver because of liver infection, gallstones, or cancer)
  • Hepatic failure
• Severe allergic reactions
  • Fever
  • Swollen lymph nodes
  • Rash
  • Swelling of face, throat, or tongue
  • Breathing difficulties
  • Dizziness

Rare but serious side effects of systemic antifungals may include:

• Peripheral demyelinating neuropathy (swelling and irritation of peripheral nervous system that causes loss of sensation and reflexes and slows nerve conduction)
• Toxic epidermal necrolysis (a life-threatening skin condition characterized by widespread redness and death of skin tissue)
• Stevens-Johnson syndrome (severe skin reaction where the skin and mucous membranes are damaged)
• Skin cancer
  • Squamous cell carcinoma
  • Melanoma

The information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of systemic antifungals include:

• Amphotericin B cholesteryl sulfate (Amphotec)
• Amphotericin B deoxycholate (Amphotericin B [conventional])
• Amphotericin B liposomal (AmBisome)
• Amphotericin B phospholipid complex (Abelcet)
• Anidulafungin (Eraxis)
• Caspofungin (Cancidas)
• Fluconazole (Diflucan)
• Flucytosine (5-FC, 5-fluorocytosine, Ancobon)
• Griseofulvin (Grifulvin V, Gris-PEG)
• Ibrexafungerp (Brexafemme)
• Isavuconazonium sulfate (Cresemba, Isavuconazole)
• Itraconazole (Onmel, Sporanox, Tolsura)
• Ketoconazole (Nizoral)
• Micafungin (Mycamine)
• Nystatin (Mycostatin, Nilstat, Nyamyc, Nystat Rx, Nystatin Systemic, Nystex)
• Posaconazole (Noxafil)
• Terbinafine (Lamisil)
• Voriconazole (Vfend)