Fungi are unicellular or multi-cellular eukaryotic organisms that exist in all environments worldwide. From fungi visible to the naked eye, such as mushrooms, to microscopic yeasts and molds, they exist in a multitude of forms. While most fungi do not play a significant role in human disease, there are several hundred fungi that do, resulting in fungal infection or disease. Fungal infections (mycoses) range from common benign infections like 'jock itch,' to serious, life-threatening infections such as cryptococcal meningitis. The term 'antifungals' encompasses all chemical compounds, pharmacologic agents and natural products that are used to treat mycoses.
Clinically, fungal infections are best categorized first according to the site and extent of the infection, then the route of acquisition and finally the virulence of the causative organism. These classifications are essential when determining the most effective treatment regimen for a particular mycosis. Mycoses are first classified as local (superficial, cutaneous, subcutaneous) or systemic (deep, blood borne). The acquisition of the fungal infection is either an exogenous (airborne/inhalation, cutaneous exposure, percutaneous inoculation) or endogenous process (normal flora or reactivated infection). The virulence of the organism classifies as either a primary infection (disease arising in a healthy host), or opportunistic infection (disease arising in human hosts that have a compromised immune system, or other defenses).
Antifungal drugs represent a pharmacologically diverse group of drugs that are crucial components in the modern medical management of mycoses. While antimycotic pharmacology has advanced significantly, particularly in the last three decades, common invasive fungal infections still carry a high mortality rate: Candida albicans (~20 to 40% mortality), Aspergillus fumigatus (~50 to 90%), Cryptococcus neoformans (~20 to 70%). Amphotericin B deoxycholate, a polyene was the first antimycotic agent introduced in 1958 to treat systemic mycoses. While this drug is an effective agent, the demand for other efficacious topical, oral, and intravenous was apparent. Griseofulvin was introduced in 1959, representing a second class of antifungals. The next significant introduction would not take place until 1971 when the antimetabolite drug flucytosine entered the market. Azoles first became available in 1973 with the arrival of clotrimazole; with additional azoles that have been rolled out over the past five decades: miconazole (1979), ketoconazole (1981), fluconazole (1990), itraconazole (1992), voriconazole (2002), posaconazole (2006), and most recently isavuconazonium (2015) . Terbinafine, an allylamine antifungal was FDA approved in 1996 but is indicated in the treatment of local, non-systemic fungal infections. The next breakthrough in systemic therapy would have a basis in amphotericin B lipid formulations, which have more favorable side effect profiles. Following lipid formulations of azoles, a new class of antifungal agents which are highly effective in treating some systemic mycoses, are the recently developed echinocandins class. While the echinocandins demonstrate less renal toxicity than amphotericin B, they cause significant hepatotoxicity and are more expensive than azoles; this effectively relegates this class to being second or third line agents . Mechanistically, antifungal agents are diverse, yet due to the alarming and rapid increase in drug-resistant systemic fungal infections, new agents are necessary more than ever. This review article will focus on the currently available antifungal agents.
Antifungal Drug Classification and Common Specific Drugs:
Amphotericin B deoxycholate (AMB-d) is FDA indicated for treating life-threatening or potentially life-threatening fungal infections: aspergillosis, cryptococcosis, blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, and mucormycosis. AMB is also approved for treating the parasitic diseases American mucocutaneous leishmaniasis. AMB-d has off-label for use for esophageal candidiasis (both HIV infected and non-HIV infected adults and adolescents; HIV-exposed and or infected infants and children), fluconazole-refractory oropharyngeal candidiasis, candidal endophthalmitis, candidal urinary tract infections, visceral leishmaniasis, and ophthalmic aspergillosis.
Liposomal amphotericin B (L-AMB) has been approved to treat systemic aspergillosis, candidiasis, and cryptococcosis in patients with renal function impairment, and patients refractory to AMB-d therapy. Additionally, L-AMB is used in empiric antifungal therapy in febrile neutropenic patients, and HIV infected patients with cryptococcal meningitis. Visceral leishmaniasis is a parasitic infection also treated with this agent. L-AMB has extensive off-label usage for patients infected or exposed to HIV which includes candidiasis, coccidioidomycosis, cryptococcosis, and histoplasmosis.
Amphotericin B lipid complex (ABLC), like L-AMB, is indicated in the treatment of invasive mycoses in patients unable to tolerate AMB-d. Off-label use of ABLC is indicated in HIV infected patients with coccidioidomycosis, cryptococcal meningitis, and histoplasmosis; empiric therapy for candidiasis and neutropenic fever; and in the treatment of the parasitic infection visceral leishmaniasis.
Nystatin has approval as an oral "swish-and-swallow" suspension for the treatment of cutaneous, mucocutaneous, and oral Candida infections. Topically, nystatin is approved for treating mucocutaneous and cutaneous infections with Candida (most commonly C. albicans).
Ketoconazole, when applied topically, has been approved for treating tinea corporis, tinea cruris, tinea pedis, tinea versicolor, cutaneous candidiasis, and seborrheic dermatitis. Off-label, topical ketoconazole is used to treat several oral candidal pathologies including chronic mucocutaneous candidiasis and oral thrush. Ketoconazole is also a systemic agent, which has approval for treating blastomycosis, coccidioidomycosis, chromomycosis, histoplasmosis, and paracoccidioidomycosis. Off label oral ketoconazole treatment is used to treat Cushing syndrome and prostate cancer.
Topical miconazole is approved to treat cutaneous and mucocutaneous mycoses, particularly vulvovaginal candidiasis. Oral formulations of miconazole are indicated for oropharyngeal candidiasis.
In topical forms, clotrimazole is approved to treat tinea corporis, tinea pedis, tinea versicolor, cutaneous candidiasis, and vaginal yeast infections. Indications for the use of oral miconazole is the treatment of oropharyngeal candidiasis.
Itraconazole is given orally and is approved to treat: aspergillosis (pulmonary and extrapulmonary), blastomycosis (pulmonary and extrapulmonary), and histoplasmosis (systemic/disseminated not involving the CNS, cavitary pulmonary histoplasmosis) in both immunocompromised and immunocompetent patients. This drug is also approved to treat oropharyngeal candidiasis, esophageal candidiasis, and onychomycosis (toenail or fingernail) in immune-competent patients.
Fluconazole is indicated in the treatment of esophageal, oropharyngeal, peritoneal, urinary tract and vaginal candidiasis — additionally, fluconazole treats systemic fungal infections including candidemia, candida pneumonia, and cryptococcal meningitis. Fluconazole is used as a first line agent in prophylaxis for mycosis in allogeneic hematopoietic stem cell transplant patients. Off-label, fluconazole has a variety of applications including blastomycosis, empiric antifungal therapy in non-neutropenic ICU patients, candida prophylaxis (ICU with a high risk of invasive Candida spp., transplant patients), and tinea.
Voriconazole has approval for the following indications: invasive aspergillosis, candidemia in non-neutropenic patients, esophageal candidiasis, and disseminated candidiasis. This drug also treats life-threatening mycoses from fungi like Fusarium spp. Off-label uses for voriconazole are mostly aimed at prophylactic and suppression therapy of fungal infections, including but not limited to aspergillosis, candidiasis, coccidioidomycosis, hematopoietic stem cell transplant patients with or without graft versus host disease, acute myelogenous leukemia, empiric therapy in neutropenic fever, and myelodysplastic syndrome.
Isavuconazole is approved to treat invasive aspergillosis and invasive mucormycosis in adult populations.
Posaconazole has approval for prophylaxis of both invasive aspergillosis and invasive candidiasis. Additionally, posaconazole is used to treat oropharyngeal candidiasis, typically in patient populations refractory to treatment with fluconazole and itraconazole.
Terbinafine has approvals as both a topical and systemic agent. Topical terbinafine is approved to treat tinea (pedis, cruris, and corporis). When administered orally, this drug is indicated in the systemic treatment of onychomycosis (tinea unguium) and tinea capitis. Common off-label use of oral formulations includes the treatment of tinea (cruris, corporis, penis, and manuum) as well as lymphocutaneous and cutaneous sporotrichosis.
The echinocandin anidulafungin is only given intravenously and has approval for the treatment of Candida infections (esophageal candidiasis, candidemia, Candida peritonitis, and intrabdominal abscesses when Candida is grown in culture or the suspected organism).
Caspofungin is only approved and administered intravenously. This agent is approved for the treatment of invasive aspergillosis in patient populations refractory to amphotericin B and itraconazole. Caspofungin has also received approval in the treatment of Candida infections (candidemia, esophageal, intra-abdominal abscess, peritonitis, and empiric therapy in neutropenic patients). Off-label this agent is utilized as an adjunct in other severe Candida infections not listed above.
Micafungin is also only approved for intravenous administration in the treatment of esophageal candidiasis, prophylaxis of Candida infections, candidemia, Candida peritonitis, Candida abscesses, and disseminated candidiasis.
Griseofulvin is only approved as a systemic agent and is indicated for the treatment of dermatophytoses of the skin, hair, and nails which is severe or refractory to topical therapy. Specifically, this drug treats tinea (corporis, pedis, cruris, barbae, capitis, and unguium).
Flucytosine has attained approval as an adjunct antifungal agent in the treatment of systemic Candida or Cryptococcus infections. Off-label, flucytosine is utilized in treating pediatric endocarditis caused by Aspergillus spp.
Ciclopirox is authorized in the treatment of tinea corporis, tinea pedis, tinea cruris, tinea unguium (onychomycosis), tinea (pityriasis) versicolor, and the Candida infection moniliasis.
Iodoquinol is a topical agent that is approved in the treatment of tinea capitis, tinea cruris, tinea corporis, tinea pedis, moniliasis, and candidal intertrigo.
Clioquinol is approved as a combined agent (clioquinol-hydrocortisone) in the United States: This agent is approved to treat the same spectrum of dermatoses as iodoquinol: tinea capitis, tinea cruris, tinea corporis, tinea pedis, moniliasis, and candidal intertrigo.
Potassium iodide, formulated as a saturated solution of potassium iodide (SSKI) has no official anti-fungal approvals; but is used in the off-label treatment of both cutaneous and lymphocutaneous sporotrichosis.
Zinc pyrithione is not officially approved for anti-fungal purposes but is utilized as primary or adjunct therapy in the treatment of mycoses leading to hyperkeratotic skin conditions. A common off-label use is in the treatment of tinea (pityriasis) versicolor.
Polyene antifungals bind ergosterol, a steroid-alcohol unique to Fungi. The polyene-ergosterol complex creates pores in the fungal cell membrane, ultimately leading to electrolyte leakage, cell lysis, and cell death.
Azole antifungal compounds are non-competitive inhibitors of the fungal enzyme lanosterol 14-alpha-demethylase; which is a rate-limiting enzyme in the fungal biosynthetic pathway of ergosterol. This action destabilizes the fungal cell membrane, causing cell content leakage, lysis, and eventual death.
Allylamines inhibit the rate-limiting enzyme squalene epoxidase, responsible for synthesizing precursors to ergosterol. This type of drug is another antifungal compound whose mechanism of action is the loss of cell membrane integrity.
Echinocandins inhibit the fungal beta-(1,3)-D-glucan synthase, which is the enzyme responsible for synthesizing beta-(1,3)-D-glucan, a key component of fungal cell walls. Losing this cell wall component leads to osmotic instability and cell death.
Griseofulvin is a mitotic inhibitor, which binds to polymerized fungal microtubules, thereby inhibiting the de-polymerization and leading to the failure of the fungal cell replication.
Flucytosine is an antimetabolite compound absorbed into fungal cells via cytosine permease. Within the fungal cell, flucytosine gets converted to 5-fluorouracil, which interferes with fungal RNA biosynthesis.
Ciclopirox has a poorly understood mechanism of action but is believed to interfere with the structural integrity of the fungal cell membrane.
Quinoline derivative antifungal compounds, also have a poorly understood mechanism of action.
Potassium Iodide exerts its effects directly on Sporothrix spp., yet the exact mechanism of action has not been proven. Leading theories suggest that human polymorphonuclear cells, convert potassium iodide to iodine via the action of myeloperoxidase. Iodine inhibits fungal germination and reduces structural integrity through the in intracytosolic destruction of structural components.
Zinc Pyrithione has a poorly understood antifungal mechanism of action; but leading theories suggest this agent modifies fungal cellular membrane transport, leading to decreased levels of key metabolic substrates, inhibiting protein synthesis and limiting ATP production. These metabolic changes are likely due to an increase in intracellular copper, and iron-sulfur clusters which lead to protein damage.
Amphotericin B has several formulations, including amphotericin B deoxycholate (d-AMB, or AMB-d), liposomal amphotericin B (L-AMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD; not available in the United States); all approved indications are intravenous administration. Off-label administration of AMB-d is also given intraventricularly and as an irrigation solution.
Nystatin, the other polyene drug, is only approved for topical and oral "swish-and-swallow' applications. Nystatin is available as a powder, cream, and oral solution.
The available preparations of systemic azole antifungals include tablets, capsules, oral solutions, and IV solutions. Azole drugs for local or topical use include powders, creams, ointments, gels, shampoos, and lozenges.
Terbinafine from the allylamine class of antifungals can be administered topically or orally, which is dependent on the fungal infection being local or systemic, respectively.
Caspofungin, anidulafungin, and micafungin the three main drugs in the echinocandin class are all given intravenously, as a reconstituted solution.
Griseofulvin is only given orally, as a tablet or suspension, which should be taken with a fatty meal to aid with absorption.
To treat mycoses, flucytosine, also commonly known as 5-fluorocytosine is almost always administered intravenously as combination therapy with amphotericin B.
Ciclopirox is approved for topical use only, not for intracavitary or ophthalmic application. For these purposes, it is available as a compounded gel, cream, lacquer, shampoo, and suspension.
The quinolines iodoquinol and clioquinol only have approval for topical administration. Iodoquinol is dispensed as a gel, typically combined with another drug, such as hydrocortisone in a compounded cream.
Potassium Iodide is most commonly administered topically as a saturated solution of potassium iodide (SSKI)
Zinc Pyrithione, a compound used to treat topical fungal infections, is administered topically as a shampoo, a solid soap-like bar, or as a non-shampoo liquid.
The systemic polyene antifungal amphotericin B (formulated as AMB-d, L-AMB, ABLC, and ABCD), has potentially severe adverse reactions. AMB-d therapy carries the risk of hypotension, chills, headache, hypokalemia, hypomagnesemia, anemia, renal insufficiency, renal function abnormalities, injection site pain, nausea, vomiting, rigors, and fever. L-AMB therapy has decreased the incidence of renal function abnormalities when compared to AMB-d, yet it still carries a risk of nephrotoxicity. The most common adverse events caused by L-AMB therapy include hypertension, hypotension, tachycardia, localized phlebitis, chills, headache, skin rash, electrolyte abnormalities (hypokalemia, hypomagnesemia, hyponatremia, hyponatremia), hyperglycemia, abnormal liver function tests. ABLC also carries a risk of nephrotoxicity leading to increased serum creatinine, fever related to infusion, rigors, and chills; but these risks are less than treatment regimens including AMB-d.
Nystatin is approved only for topical and oral "swish-and-swallow" applications because of severe systemic side effects. Adverse events related to topical nystatin include mild contact dermatitis, with the most severe side effect being Stevens-Johnson syndrome. Oral "swish-and-swallow" nystatin carries a lower risk of hypersensitivity reactions than topical formulations; there are also reports of diarrhea, nausea, vomiting, and abdominal pain.
Azoles, while typically well tolerated, frequently cause nausea, vomiting, diarrhea, and abdominal pain. Hepatotoxicity (elevated liver functions tests, hepatitis, cholestasis, and or fulminant liver failure) is a common adverse reaction associated with all azoles. Each of the azole drugs has unique adverse events as well:
Terbinafine, an allylamine, most commonly results in central nervous system side effects, with a headache being the most frequently reported symptom. Other manifestations of adverse events include, but are not limited to skin rashes, diarrhea, dyspepsia, and upper respiratory inflammation or infection.
Echinocandins, like many other antifungal drugs, can result in hepatotoxicity.
Griseofulvin has numerous potential adverse events, with the most commonly reported adverse events being skin rash and urticaria. More severe complications can occur and include an erythema multiforme-like drug reaction, skin photosensitivity, leukopenia (rare), granulocytopenia, and hepatotoxicity.
Flucytosine has adverse reactions linked to all body systems, but is most commonly associated with the following: cardiovascular (cardiotoxicity, chest pain), central and peripheral nervous systems (confusion, headache hallucination, parkinsonian-like syndrome, peripheral neuropathy), dermatologic (pruritis, urticaria, rash), gastrointestinal (abdominal pain, nausea, vomiting, GI hemorrhage), hematologic (agranulocytosis, aplastic anemia, pancytopenia, eosinophilia), hepatic (acute hepatic injury / insufficiency / necrosis), and renal (acute kidney injury, renal failure).
Ciclopirox does not have any major reported serious adverse reactions, but common benign reactions include skin irritation/burning, contact dermatitis, and pruritis.
Quinolines (clioquinol and iodoquinol) most commonly have associations with dry skin, contact dermatitis, allergic reaction, rapid hair growth in areas the agent is applied, and folliculitis.
Potassium Iodide (as saturated solution of potassium iodide) has several reported severe adverse reactions, which include arrhythmias, GI bleeding, angioedema, parotitis, thyroid adenoma, and goiter. More common and less serious reactions include a possible metallic taste, urticaria, acne, cutaneous hemorrhage, numbness, and paresthesias.
Zinc Pyrithione has no reported serious adverse reactions and most commonly correlates with mild skin irritation.
All formulations of amphotericin B (AMB-d, L-AMB, ABLC, ABCD) are contraindicated in patients with a known or likely hypersensitivity to amphotericin B or any components of the L-AMB, ABLC or ABCD formulations.
Nystatin is contraindicated in patients with a hypersensitivity to the drug or any additional components in a combination formulation.
All azoles should be avoided in patients with hypersensitivities to azole drugs or components and used with caution in patients with renal impairment/failure and or hepatic impairment/failure.
Terbinafine should be utilized with caution or avoided in patients with hypersensitivity reactions, depression, gastrointestinal issues, liver failure, and immune suppression secondary to hematologic effects.
All of the Echinocandins are contraindicated in patients with hypersensitivities to any of the echinocandin drugs, or components. Caspofungin should be used with caution in hepatic impairment.
Treatment with griseofulvin should include considerations for potential adverse events in susceptible patients, and those with existing disease states; particularly patients with a hypersensitivity to griseofulvin, a hypersensitivity to penicillins (there is a possible cross-reaction between penicillins and griseofulvin), hepatic failure, patients with known porphyrias, and patients that are pregnant or nursing.
Flucytosine carries a black box warning, warning that this agent should be used with extreme caution in renal impairment and that hematologic, hepatic and renal function should be closely monitored. This agent is contraindicated in patients with hypersensitivities to this drug/components, first trimester pregnancies, and women that are breastfeeding. Caution is advisable with this agent in patients with renal impairment, hepatic impairment, bone marrow depression, and pregnant patients in their second or third trimester.
The quinolines iodoquinol and clioquinol are contraindicated in patients with hypersensitivities to the drugs or their components.
Antifungals which are utilized only as topical agents including ciclopirox, potassium iodide, and zinc pyrithione should be avoided in patients with hypersensitivities to these agents.
Polyenes have no supporting evidence or indication at this time to support the utilization of therapeutic drug level monitoring (TDM) in patients treated with AMB-d, L-AMB, and ABLC. All patients receiving any formulations of amphotericin B should have BUN and creatinine assessed at baseline then frequently after; additionally, CBC, electrolytes, and LFTs should be monitored. Nystatin does not have supporting evidence for TDM or routine laboratory monitoring.
Azole antifungals that are generally indicated for therapeutic drug level monitoring (TDM) all come from the triazole sub-class: itraconazole, voriconazole, posaconazole. Laboratory monitoring is indicated in the use of fluconazole, isavuconazonium sulfate, and ketoconazole; there is no current monitoring indication for clotrimazole or miconazole.
Terbinafine has no supporting evidence to suggest that TDM is necessary for its utilization in prophylaxis, treatment, or toxicity. Monitoring creatinine and LFTs is, however, an indication at baseline. Immunodeficient patients receiving terbinafine for greater than 6 weeks should have a CBC checked.
Griseofulvin does not currently have supporting evidence for TDM; but laboratory monitoring includes BUN, creatinine, CBC, and LFTs.
Patients on echinocandin therapy should be regularly monitored for hepatotoxicity via hepatic aminotransferases (AST, ALT), with the additional consideration of alkaline phosphatase. There is currently no supporting evidence for TDM. Micafungin regimens should include BUN and creatinine in routine laboratory monitoring.
Patients receiving flucytosine containing combination therapy require TDM. Patients should have serum concentration measured 2 to 4 hours after each dose; the trough concentration should be between 20 to 40 mcg/L (some sources state 50 to 100mcg/mL). Toxic levels occur when serum drug concentrations exceed 100mcg/mL. Other indications for TDM in flucytosine therapy include when a drug with a known drug interaction is started or stopped, when compliance for oral therapy is uncertain, or when manifestations of toxicity occur.
Pragmatic management of mycoses is dependent on the healthcare team characterizing the fungal infection as discussed in the introduction, then selecting the most effective antifungal treatment regimen; this requires a multidisciplinary understanding of public health/epidemiology, medical microbiology/mycology, pharmacy, and healthcare infrastructure which dictates the application of the first three. There is currently a diverse and effective arsenal of antifungal agents. Still, the alarming global rise in drug-resistant fungi warrants judicious antifungal prescribing by clinicians, combinatorial strategies, utilization of antifungal adjuvants, and continued antifungal drug discovery/development.
Judicious prescribing begins with the healthcare team selecting the proper regimen based on culture and sensitivity data, patient history, and socioeconomic factors. Providers should work closely with pharmacists, and when appropriate public health officials to provide therapy that appropriately treats infections. The ultimate goal is to provide antifungal therapy without unnecessarily creating drug-resistant organisms, limiting adverse events, and reducing drug-drug interactions. Antifungal stewardship is essential if the effectiveness of current antifungal agents is to be preserved . [Level V]
Combination therapy comprises treatment regimens that include multiple antifungals from different classes, and antifungal agents combined with non-antifungal agents. Non-antifungal drug targets include heat shock proteins, calcineurin, lysine acetyltransferase, lysine deacetylase, protein kinase C, and fungal sphingolipids . [Level V]
Antifungal adjuvants have the potential to enhance and or extend the efficacy of existing antifungal regimens and limit resistance. Some of these encouraging adjuvants could eventually be the standard of care in antifungal-adjuvant combination therapy. The potential adjuvants include drugs with widely variable mechanisms of action like cyclosporin A, deferasirox, FK506, tamoxifen, and sertraline . [Level IV]
Antifungal drug discovery has been bolstered by the Orphan Drug Act (1983) and more recently the Generating Antibiotic Incentives Now (GAIN) Act (2012). These policies incentivize pharmaceutical companies and researchers to pursue new leads and add to the existing collection of antifungals. The increasing prevalence of drug-resistant fungal diseases presents a unique challenge to antifungal drug discovery, yet there are several promising new drug/class pipelines, theoretical fungal vaccines, and the opportunity to generate compounds to inhibit resistance. [Level V]
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